From a158babe2f6acbbf1176d6513e503f5a9d79f620 Mon Sep 17 00:00:00 2001 From: yuehuiqi Date: Sat, 8 Aug 2026 23:54:51 +0800 Subject: [PATCH] =?UTF-8?q?[new=20agent]=20MediGraph=20Agent=EF=BC=9A?= =?UTF-8?q?=E5=8C=BB=E7=96=97=E6=95=B0=E6=8D=AE=E2=80=94=E7=9F=A5=E8=AF=86?= =?UTF-8?q?=E2=80=94=E6=B4=9E=E5=AF=9F=E6=99=BA=E8=83=BD=E4=BD=93?= MIME-Version: 1.0 Content-Type: text/plain; charset=UTF-8 Content-Transfer-Encoding: 8bit 归档队伍 MaineCoon 的参赛作品至 通用智能体/其他/MediGraphAgent/。 基于 Nexent、DataMate、MCP 与 A2A，把非结构化医疗文本做到可溯源知识图谱 与图谱驱动的 BI 洞察，形成数据→知识→洞察闭环。 包含四个智能体，由同一套 MCP 服务（17 个工具）驱动： - 医疗数据处理智能体：编排算子完成清洗/抽取/建图，可调度 DataMate 流水线 - 医疗知识图谱生成与问答智能体：构建可溯源图谱并做 GraphRAG 问答 - 图谱驱动分析与 BI 智能体：SQL 统计与 GRAPH 关联分析自动路由，产出图表 - 闭环协作总控智能体：统一调度上述三者，支持 A2A 子智能体转交 目录内容： agent.json 平台导入入口，即闭环协作总控智能体 智能体源文件/ 4 个可导入 Nexent 的 AgentConfig mcp服务/ MCP 服务源码、知识库、配置与容器化部署文件 skills/ Nexent 技能包（zip + 源码 + 打包脚本） datamate算子包/ DataMate 平台可上传的 5 个算子（zip + 源码） README.md 运行环境依赖、启动命令与四个智能体的使用示例 随包提供知识库文件（演示知识图谱、分析数据库、词典抽取器、实体链接知识库）， 导入后无需额外下载即可运行。自训练神经抽取权重约 1.4 GB 未随包提供， 抽取级联会自动回退词典或 LLM 路径，不影响核心功能。 包内最大文件 5.56 MB，不依赖 Git LFS。 --- .../MediGraphAgent/README.md" | 270 +++++ .../MediGraphAgent/agent.json" | 41 + .../chunker.zip" | Bin 0 -> 3094 bytes .../medical_ner.zip" | Bin 0 -> 5632 bytes .../medical_re.zip" | Bin 0 -> 6284 bytes .../text_clean.zip" | Bin 0 -> 3538 bytes .../triple_validator.zip" | Bin 0 -> 3482 bytes .../\346\272\220\347\240\201/build_zip.py" | 46 + .../chunker/README.md" | 11 + .../chunker/__init__.py" | 7 + .../chunker/metadata.yml" | 43 + .../chunker/process.py" | 94 ++ .../chunker/requirements.txt" | 1 + .../medical_ner/README.md" | 23 + .../medical_ner/__init__.py" | 7 + .../medical_ner/metadata.yml" | 68 ++ .../medical_ner/process.py" | 160 +++ .../medical_ner/requirements.txt" | 1 + .../medical_re/README.md" | 16 + .../medical_re/__init__.py" | 7 + .../medical_re/metadata.yml" | 68 ++ .../medical_re/process.py" | 236 ++++ .../medical_re/requirements.txt" | 1 + .../text_clean/README.md" | 12 + .../text_clean/__init__.py" | 7 + .../text_clean/metadata.yml" | 30 + .../text_clean/process.py" | 137 +++ .../text_clean/requirements.txt" | 1 + .../triple_validator/README.md" | 21 + .../triple_validator/__init__.py" | 7 + .../triple_validator/metadata.yml" | 36 + .../triple_validator/process.py" | 96 ++ .../triple_validator/requirements.txt" | 1 + .../.dockerignore" | 34 + .../mcp\346\234\215\345\212\241/.env.example" | 81 ++ .../mcp\346\234\215\345\212\241/Dockerfile" | 31 + .../mcp\346\234\215\345\212\241/compose.yaml" | 72 ++ .../config/__init__.py" | 0 .../config/settings.py" | 187 +++ .../data/corpus/cmeie_000.txt" | 1 + .../data/corpus/cmeie_001.txt" | 1 + .../data/corpus/cmeie_002.txt" | 1 + .../data/corpus/cmeie_003.txt" | 1 + .../data/corpus/cmeie_004.txt" | 1 + .../data/corpus/cmeie_005.txt" | 1 + .../data/corpus/cmeie_006.txt" | 1 + .../data/corpus/cmeie_007.txt" | 1 + .../data/corpus/cmeie_008.txt" | 1 + .../data/corpus/cmeie_009.txt" | 1 + 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+ .../02_hypertension.txt" | 1 + .../cardiometabolic_20260701/03_diabetes.txt" | 1 + .../cardiometabolic_20260701/README.md" | 14 + ...0\346\210\220\346\240\267\344\276\213.txt" | 15 + ...0\346\210\220\346\240\267\344\276\213.txt" | 15 + ...0\346\210\220\346\240\267\344\276\213.txt" | 15 + ...0\346\210\220\346\240\267\344\276\213.txt" | 14 + .../data/models/README.md" | 25 + .../data/models/entity_linker.json" | 1 + .../data/models/fast_extractor.json.gz" | Bin 0 -> 2405131 bytes .../data/models/temperature_calibration.json" | 8 + .../integration/__init__.py" | 0 .../integration/a2a/README.md" | 28 + .../integration/a2a/__init__.py" | 0 .../integration/a2a/a2a_server.py" | 152 +++ .../mcp_server/server.py" | 1020 +++++++++++++++++ .../medigraph/__init__.py" | 0 .../medigraph/agents/__init__.py" | 0 .../medigraph/agents/dag_executor.py" | 438 +++++++ .../medigraph/agents/dataproc_agent.py" | 230 ++++ .../medigraph/agents/kg_agent.py" | 127 ++ .../medigraph/agents/plan_validator.py" | 209 ++++ .../medigraph/agents/qa_agent.py" | 382 ++++++ .../medigraph/analysis/__init__.py" | 0 .../medigraph/analysis/analysis_agent.py" | 394 +++++++ .../medigraph/analysis/assets/echarts.min.js" | 45 + .../medigraph/analysis/graph_algorithms.py" | 148 +++ .../medigraph/analysis/graph_profile.py" | 66 ++ .../medigraph/analysis/nl2sql.py" | 520 +++++++++ .../medigraph/analysis/numerals.py" | 184 +++ .../medigraph/analysis/pg_relational.py" | 256 +++++ .../medigraph/analysis/relational.py" | 266 +++++ .../medigraph/analysis/schema_linking.py" | 164 +++ .../medigraph/analysis/sql_guard.py" | 105 ++ .../medigraph/analysis/viz.py" | 254 ++++ .../medigraph/extraction/__init__.py" | 17 + .../medigraph/extraction/calibration.py" | 210 ++++ .../medigraph/extraction/cascade.py" | 110 ++ .../medigraph/extraction/entity_linker.py" | 179 +++ .../medigraph/extraction/fast_path.py" | 424 +++++++ .../medigraph/extraction/neural_gplinker.py" | 269 +++++ .../medigraph/graph/__init__.py" | 0 .../medigraph/graph/base.py" | 55 + .../medigraph/graph/local_store.py" | 505 ++++++++ .../medigraph/graph/neo4j_store.py" | 111 ++ .../medigraph/graph/pg_vector_store.py" | 160 +++ .../medigraph/graph/vector_store.py" | 63 + .../medigraph/llm/__init__.py" | 0 .../medigraph/llm/client.py" | 292 +++++ .../medigraph/operators/__init__.py" | 0 .../medigraph/operators/base.py" | 111 ++ .../medigraph/operators/chunker.py" | 86 ++ .../medigraph/operators/data_quality.py" | 84 ++ .../medigraph/operators/document_loader.py" | 150 +++ .../medigraph/operators/entity_linker.py" | 45 + .../medigraph/operators/medical_ner.py" | 214 ++++ .../medigraph/operators/medical_re.py" | 210 ++++ .../medigraph/operators/pii_redact.py" | 61 + .../medigraph/operators/text_clean.py" | 140 +++ .../medigraph/operators/triple_validator.py" | 191 +++ .../medigraph/schema/__init__.py" | 0 .../medigraph/schema/cmeie_schema.py" | 121 ++ .../medigraph/schema/normalize.py" | 110 ++ .../medigraph/schema/ontology.py" | 132 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++ 190 files changed, 15679 insertions(+) create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/README.md" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/agent.json" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/chunker.zip" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/medical_ner.zip" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/medical_re.zip" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/text_clean.zip" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/triple_validator.zip" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/build_zip.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/chunker/README.md" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/chunker/__init__.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/chunker/metadata.yml" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/chunker/process.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/chunker/requirements.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_ner/README.md" create mode 100644 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"\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_re/requirements.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/text_clean/README.md" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/text_clean/__init__.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/text_clean/metadata.yml" create mode 100644 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"\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/Dockerfile" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/compose.yaml" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/config/__init__.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/config/settings.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_000.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_001.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_002.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_003.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_004.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_005.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_006.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_007.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_008.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_009.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_010.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_011.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_012.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_013.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_014.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_015.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_016.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_017.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_018.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_019.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_020.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_021.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_022.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_023.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_024.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_025.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_026.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_027.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_028.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_029.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_030.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_031.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_032.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_033.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_034.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_035.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_036.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_037.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_038.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_039.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_1.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_10.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_11.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_12.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_13.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_14.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_15.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_2.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_3.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_4.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_5.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_6.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_7.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_8.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_9.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/pathology_\345\204\277\347\247\221\345\233\264\344\272\247\346\234\237\347\227\205\347\220\206\345\255\246_cleaned.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/pathology_\345\205\215\347\226\253\347\227\205\347\220\206\345\255\246_cleaned.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/pathology_\345\212\250\350\204\211\347\262\245\346\240\267\347\241\254\345\214\226\344\270\216\350\241\200\346\240\223\345\275\242\346\210\220_cleaned.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/pathology_\346\204\237\346\237\223_cleaned.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/pathology_\346\263\225\345\214\273\347\227\205\347\220\206\345\255\246_cleaned.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/cardiometabolic_20260701/01_heart_failure.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/cardiometabolic_20260701/02_hypertension.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/cardiometabolic_20260701/03_diabetes.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/cardiometabolic_20260701/README.md" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/outpatient_batch_demo/\351\227\250\350\257\212\347\227\205\345\216\206_01_2\345\236\213\347\263\226\345\260\277\347\227\205_\345\220\210\346\210\220\346\240\267\344\276\213.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/outpatient_batch_demo/\351\227\250\350\257\212\347\227\205\345\216\206_02_\346\205\242\351\230\273\350\202\272_\345\220\210\346\210\220\346\240\267\344\276\213.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/outpatient_batch_demo/\351\227\250\350\257\212\347\227\205\345\216\206_03_\350\204\202\350\202\252\350\202\235_\345\220\210\346\210\220\346\240\267\344\276\213.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/outpatient_record_demo/\351\227\250\350\257\212\347\227\205\345\216\206_\351\253\230\350\241\200\345\216\213_\345\220\210\346\210\220\346\240\267\344\276\213.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/models/README.md" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/models/entity_linker.json" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/models/fast_extractor.json.gz" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/models/temperature_calibration.json" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/integration/__init__.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/integration/a2a/README.md" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/integration/a2a/__init__.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/integration/a2a/a2a_server.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/mcp_server/server.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/__init__.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/__init__.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/dag_executor.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/dataproc_agent.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/kg_agent.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/plan_validator.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/qa_agent.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/__init__.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/analysis_agent.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/assets/echarts.min.js" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/graph_algorithms.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/graph_profile.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/nl2sql.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/numerals.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/pg_relational.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/relational.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/schema_linking.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/sql_guard.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/viz.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/__init__.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/calibration.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/cascade.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/entity_linker.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/fast_path.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/neural_gplinker.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/__init__.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/base.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/local_store.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/neo4j_store.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/pg_vector_store.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/vector_store.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/llm/__init__.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/llm/client.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/__init__.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/base.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/chunker.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/data_quality.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/document_loader.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/entity_linker.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/medical_ner.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/medical_re.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/pii_redact.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/text_clean.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/triple_validator.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/schema/__init__.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/schema/cmeie_schema.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/schema/normalize.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/schema/ontology.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/schema/relation_mapping.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/utils/__init__.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/utils/console.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/utils/io.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/outputs/analytics.db" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/outputs/graph.json" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/requirements-docker.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/requirements.txt" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/check_demo_services.ps1" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/docker_down.ps1" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/docker_up.ps1" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/download_encoder.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/start_a2a.ps1" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/start_finetuned_model.ps1" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/start_mcp.ps1" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/stop_demo_services.ps1" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/skills/build_skill_zip.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/skills/medical-kg-report.zip" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/skills/medical-kg-report\346\272\220\347\240\201/SKILL.md" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/skills/medical-kg-report\346\272\220\347\240\201/scripts/extract_triples.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/skills/medical-kg-report\346\272\220\347\240\201/scripts/render_report.py" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/\346\231\272\350\203\275\344\275\223\346\272\220\346\226\207\344\273\266/README.md" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/\346\231\272\350\203\275\344\275\223\346\272\220\346\226\207\344\273\266/analysis_supervisor.json" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/\346\231\272\350\203\275\344\275\223\346\272\220\346\226\207\344\273\266/collaboration_supervisor.json" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/\346\231\272\350\203\275\344\275\223\346\272\220\346\226\207\344\273\266/dataproc_agent.json" create mode 100644 "\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/\346\231\272\350\203\275\344\275\223\346\272\220\346\226\207\344\273\266/kg_qa_agent.json" diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/README.md" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/README.md" new file mode 100644 index 0000000..f38e8bc --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/README.md" @@ -0,0 +1,270 @@ +# MediGraph Agent：医疗数据—知识—洞察智能体 + +> 队伍：**MaineCoon** ｜ 第八届 CCF 开源创新大赛 · ModelEngine 开源项目贡献赛 +> +> 基于 Nexent、DataMate、MCP 与 A2A，把非结构化医疗文本一路做到可溯源知识图谱与 +> 图谱驱动的 BI 洞察。四个智能体分工协作，全部工具由同一个 MCP 服务提供。 + +## 一、这是什么 + +医疗领域的数据分析常常卡在两头：原始病历是非结构化文本，直接喂给大模型问答无法溯源； +而做成知识图谱后，又难以支撑"哪个科室接诊最多"这类统计型分析。 + +MediGraph Agent 把这条链路打通成一个闭环： + +``` +非结构化医疗文本 + ↓ DataMate 五算子流水线 / MCP 算子（清洗 → 切块 → NER → RE → 三元组校验） +结构化三元组（逐条带置信度与来源） + ↓ 实体链接 + 本体校验 + 逐边溯源 +可溯源医疗知识图谱 + ↓ GraphRAG 问答（证据不足时安全拒答） ↓ 图谱感知 NL2SQL / 图算法 +可引用的医学问答 统计洞察 + 可视化图表 +``` + +### 四个智能体 + +| 智能体 | 配置文件 | 职责 | 使用工具 | +|---|---|---|---:| +| 医疗数据处理智能体 | `dataproc_agent.json` | 理解自然语言数据处理需求，编排算子完成清洗/抽取/建图，可调度 DataMate 五算子流水线 | 10 | +| 医疗知识图谱生成与问答智能体 | `kg_qa_agent.json` | 构建可溯源图谱并做 GraphRAG 问答，证据不足时拒答 | 7 | +| 图谱驱动分析与 BI 智能体 | `analysis_supervisor.json` | 复用图谱，自动在 SQL 统计与 GRAPH 关联分析间路由，产出图表与洞察 | 2 | +| **闭环协作总控智能体** | `collaboration_supervisor.json` | 统一调度上述三者，可通过 MCP 直接执行，也可把请求转交 A2A 子智能体 | 编排 | + +只想跑单项能力就导入前三个之一；想看完整的数据→知识→洞察闭环，导入**协作总控智能体**。 + +> 按本仓库的目录规范，根目录的 `agent.json` 就是协作总控智能体的配置，直接在 +> Nexent 的「智能体开发 → 导入」里上传它即可；另外三个在 `智能体源文件/` 下按需导入。 +> 四者共用同一个 MCP 服务，导入前先按下方「三、快速开始」把服务跑起来。 + +### 核心特性 + +- **置信度路由抽取级联**：神经 GPLinker 为主力，毫秒级本地词典基线兜底，低置信难例再路由 LLM， + 三条路径共用同一套输出契约，缺 GPU 时自动降级而不是报错。 +- **逐边溯源**：每条三元组都带 `confidence` 与 `source`，问答给出的每个结论都能追回原文。 +- **安全拒答**：检索不到证据或证据置信度低于阈值时明确拒答，不顺着问题编造医学结论。 +- **图谱感知 Schema-Linking**：借图谱实体类型消歧，让"脂肪肝"匹配到 `disease` 字段而不是科室或药品字段。 +- **SQL 双层护栏**：AST 白名单 + SQLite authorizer，生成的 SQL 只读、限时、限行数。 + +## 二、目录结构 + +```text +MediGraphAgent/ +├── README.md 本文档 +├── agent.json ← 平台导入入口：闭环协作总控智能体 +│ （与 智能体源文件/collaboration_supervisor.json 相同） +├── 智能体源文件/ ← 导入 Nexent 的四个智能体配置 +│ ├── dataproc_agent.json +│ ├── kg_qa_agent.json +│ ├── analysis_supervisor.json +│ ├── collaboration_supervisor.json +│ └── README.md 各智能体的提示词与工具清单说明 +├── mcp服务/ ← 上述智能体依赖的 MCP 服务（17 个工具） +│ ├── mcp_server/ MCP 服务入口 +│ ├── medigraph/ 算子、抽取级联、图谱、分析等核心实现 +│ ├── config/ 配置解析 +│ ├── integration/a2a/ A2A 服务（协作总控智能体用） +│ ├── data/ +│ │ ├── models/ 【知识库】词典抽取器、实体链接库、标定参数 +│ │ │ （词典抽取器以 .json.gz 交付，代码直接读取，无需解压） +│ │ ├── corpus/ 示例医疗文档（60 篇） +│ │ └── demo_cases/ 端到端演示语料 +│ ├── outputs/ +│ │ ├── graph.json 【知识库】演示医疗知识图谱（7,467 实体 / 26,784 关系） +│ │ └── analytics.db 【知识库】分析用关系库（600 就诊 / 887 处方 / 885 检验） +│ ├── scripts/ 启动与部署脚本 +│ ├── requirements.txt Python 依赖 +│ ├── .env.example 配置模板（复制为 .env 后填写） +│ ├── compose.yaml / Dockerfile 容器化一键部署 +├── skills/ ← Nexent 技能包 +│ ├── medical-kg-report.zip 直接上传到 Nexent 的技能包 +│ ├── medical-kg-report源码/ 技能源码（可修改后重新打包） +│ └── build_skill_zip.py 重新打包脚本 +└── datamate算子包/ ← DataMate 平台可上传的五个算子 + ├── text_clean.zip chunker.zip medical_ner.zip + ├── medical_re.zip triple_validator.zip + └── 源码/ 算子源码与打包脚本 +``` + +## 三、运行环境依赖 + +| 项 | 要求 | 说明 | +|---|---|---| +| Nexent 平台 | 已安装并可访问 | 参考 [Nexent 安装指导](https://modelengine-group.github.io/nexent/zh/quick-start/installation.html) | +| Python | 3.10 – 3.12 | MCP 服务运行环境 | +| 大语言模型 | OpenAI 兼容 API | SiliconFlow / DashScope / DeepSeek / 本地 vLLM 均可 | +| DataMate | 可选 | 仅在使用 `plan_datamate_pipeline`、`run_datamate_pipeline` 时需要 | +| GPU | 可选 | 无 GPU 时抽取自动回退词典/LLM 路径，功能不受影响 | +| Docker | 可选 | 用容器方式启动 MCP/A2A 时需要 | + +**关于抽取模型的两点说明**： + +1. 主力的自训练 GPLinker 神经权重约 1.4 GB，超出本仓库合理体积，未随包提供。 + **不影响开箱运行**——抽取级联会自动使用随包的词典快速路径或 LLM 路径。 + 如需神经权重，见本文末尾"完整项目"一节。 +2. 词典快速路径的产物以 **`data/models/fast_extractor.json.gz`**（2.3 MiB）交付， + 因为解压后的 23 MiB 超过本仓库单文件 10 MiB 的上限。**加载时自动读取压缩包， + 无需手工解压**；若同目录存在未压缩的 `fast_extractor.json` 则优先使用它。 + +## 四、快速开始 + +### 步骤 1：启动 MCP 服务 + +```powershell +cd mcp服务 +python -m venv .venv +.\.venv\Scripts\Activate.ps1 # Linux/macOS: source .venv/bin/activate +python -m pip install -r requirements.txt + +copy .env.example .env # Linux/macOS: cp .env.example .env +# 编辑 .env，至少填写一个模型的 API Key，例如： +# LLM_PROVIDER=siliconflow +# SILICONFLOW_API_KEY=sk-你的key + +python mcp_server/server.py # 默认监听 127.0.0.1:8011 +``` + +看到服务启动后，MCP 地址为 `http://127.0.0.1:8011/sse`。 + +若 Nexent 跑在 Docker 里，容器内应使用 `http://host.docker.internal:8011/sse` +（四个智能体配置里已经预填这个地址）。 + +**容器方式**（可选，同时拉起 MCP 与 A2A）： + +```powershell +docker compose up -d --build +``` + +### 步骤 2：启动 A2A 服务（仅协作总控智能体需要） + +```powershell +python integration/a2a/a2a_server.py # 默认监听 127.0.0.1:8100 +``` + +Agent Card 地址：`http://127.0.0.1:8100/.well-known/agent.json` + +### 步骤 3：在 Nexent 中上传技能 + +智能体配置页 → 技能 → 构建技能 → 上传 `skills/medical-kg-report.zip`。 + +### 步骤 4：导入智能体 + +智能体配置页 → 导入 → 选择 `智能体源文件/` 下的 JSON 文件 → 选择大语言模型 → +安装 MCP 工具（填入步骤 1 的 MCP 地址）→ 完成安装 → 发布。 + +建议导入顺序：先导入三个专才智能体，再导入协作总控智能体。 + +> 详细的平台操作图示见仓库根目录的 [操作指导.md](../../../操作指导.md)。 + +### 步骤 5（可选）：上传 DataMate 算子 + +在 DataMate 算子市场上传 `datamate算子包/` 下的五个 zip， +之后数据处理智能体即可通过 `run_datamate_pipeline` 调度真实的 DataMate 流水线。 + +## 五、使用示例 + +导入后可直接在 Nexent 对话框里试这些问题。 + +### 示例 1 · 数据处理智能体：从文本到图谱 + +``` +请把下面这段病历清洗、切块，抽取医疗实体和关系，并校验三元组： + +患者男性，65岁，因反复胸闷 3 个月入院。既往高血压病史 10 年， +长期口服苯磺酸氨氯地平。心电图示 ST 段压低，诊断为冠心病， +予阿司匹林肠溶片抗血小板治疗。 +``` + +智能体会依次调用 `text_clean → chunker → medical_ner → medical_re → triple_validator`， +返回结构化三元组与各步骤的中间产物。 + +### 示例 2 · 知识图谱问答智能体：可溯源问答 + +``` +基于 graph.json 回答：高血压可能并发哪些疾病？ +请列出证据三元组、置信度和来源，不要补充图谱之外的医学结论。 +``` + +返回结论 + 每条结论对应的三元组证据链。 + +**安全拒答验证**——问一个图谱里不存在的实体： + +``` +幻想性紫罗兰综合征有哪些典型症状？ +``` + +智能体会明确回答图谱中没有该实体、证据为 0，拒绝作答，而不是顺着编造。 + +### 示例 3 · 分析 BI 智能体：统计与可视化 + +``` +就诊人次最多的十种疾病是什么？用柱状图展示 +``` + +自动路由到 SQL 路径，返回实际执行的 SQL、结果表和柱状图 HTML。换一个图关联型问题： + +``` +脂肪肝的并发症在知识图谱里是怎么连接的？画成关系图 +``` + +自动路由到 GRAPH 路径，返回关系网络图与证据三元组。 + +### 示例 4 · 协作总控智能体：完整闭环 + +``` +请完成一次完整的医疗数据闭环：把 data/demo_cases/ 下的文档处理成知识图谱， +就图谱内容做一次可溯源问答，再基于图谱做一次统计分析并出图。 +``` + +总控智能体会依次调度数据处理、图谱问答与分析三个环节。 + +## 六、MCP 工具清单（17 个） + +| 分类 | 工具 | 说明 | +|---|---|---| +| 数据接入 | `load_documents` | 多格式文档读取 | +| | `profile_data_quality` | 数据质量检查 | +| | `redact_medical_pii` | 医疗 PII 脱敏 | +| 算子 | `text_clean` | 文本清洗规范化 | +| | `chunker` | 语义感知切块 | +| | `medical_ner` | 医疗实体识别 | +| | `medical_re` | 医疗关系抽取 | +| | `triple_validator` | 三元组 schema/冲突校验 | +| | `link_medical_entities` | 实体链接与规范 ID | +| 图谱 | `build_medical_kg` | 端到端建图 | +| | `medical_kg_qa` | GraphRAG 可溯源问答 | +| | `inspect_medical_kg` | 图谱统计与审计 | +| 分析 | `analyze_medical_data` | SQL/GRAPH 双路由分析与出图 | +| | `inspect_analysis_assets` | 分析资产审计 | +| 平台 | `plan_datamate_pipeline` | 规划 DataMate 流水线 | +| | `run_datamate_pipeline` | 执行 DataMate 流水线 | +| 审计 | `inspect_extraction_models` | 抽取级联与模型路由审计 | + +## 七、常见问题 + +**MCP 工具在 Nexent 里显示不可用** +检查 MCP 服务是否已启动、地址是否可达。Nexent 在 Docker 中运行时， +`127.0.0.1` 指向的是容器自身，必须用 `host.docker.internal`。 + +**抽取结果为空或报模型缺失** +说明既没有神经权重也没有配置 LLM。确认 `.env` 里至少填了一个可用的 API Key； +或确认 `data/models/fast_extractor.json` 存在（词典路径可完全离线工作）。 + +**问答一直拒答** +这是安全策略生效：图谱中没有相关证据。先用 `build_medical_kg` 建图， +或在问答时指定随包的演示图谱 `graph.json`。 + +**DataMate 相关工具报错** +这两个工具需要可访问的 DataMate 服务。不使用 DataMate 时， +数据处理智能体可以直接用 MCP 算子完成同样的流水线。 + +## 八、完整项目 + +本目录是为社区复现整理的**运行包**，包含四个智能体、MCP 服务、技能包、算子包与知识库。 +完整工程（神经抽取训练代码与权重、昇腾 NPU Ascend C 融合算子、0.8B LoRA 编排模型、 +315 项自动化测试、全部评测脚本与技术报告）见参赛仓库。 + +许可：源代码 MIT。随包的知识图谱与分析数据库为项目自产或合成数据； +第三方医疗数据集不随本包重新授权。 + +> 医疗声明：本项目为比赛与研究原型，不提供诊断、处方或医学建议。 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/agent.json" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/agent.json" new file mode 100644 index 0000000..8af3dec --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/agent.json" @@ -0,0 +1,41 @@ +{ + "agent_id": 1, + "agent_info": { + "1": { + "agent_id": 1, + "tenant_id": "__TENANT_ID__", + "name": "medigraph_collaboration_supervisor", + "display_name": "MediGraph医疗数据闭环协作总控智能体", + "description": "统一调度医疗数据处理、neural GPLinker 医疗知识图谱问答和图谱驱动BI分析能力；可通过MCP工具直接执行，也可把问答/分析请求转交A2A协作子智能体。", + "business_description": "Nexent 总控编排 DataMate 五算子流水线、医疗知识图谱生成问答、NL2SQL/GRAPH 分析与 A2A 子智能体协作，形成数据→知识→洞察闭环。", + "author": "MediGraph", + "max_steps": 8, + "provide_run_summary": false, + "duty_prompt": "你是MediGraph医疗数据闭环协作总控智能体。你不直接执行底层 MCP 工具，而是依次委派给三个专业子智能体。收到“处理 data/corpus 并建图、分析高血压并发症、最后出BI图”的完整闭环请求时，严格执行四次委派：1）调用 medical_dataproc_agent，一次性完成 data/corpus 两个文件的 DataMate 五算子处理并等待完成，要求返回 task_id、status、成功率；2）调用 medical_kg_qa_agent，用 source_path='data/corpus'、max_docs=1、max_chunks=1 构建仅用于展示抽取结果的 nexent_demo_graph.json，要求返回实体数、三元组数和图谱路径；3）再次调用 medical_kg_qa_agent，只能基于医疗主图 graph.json 回答“高血压有哪些并发症”，要求返回三元组、confidence 和 source；4）调用 medical_analysis_supervisor，也只能基于医疗主图 graph.json 生成高血压并发症关系图 task3_closed_loop.html，要求返回路由、数据行、报告路径和文字洞察。四个子任务均返回后，统一汇总数据处理、知识图谱、可溯源问答和BI结果。", + "constraint_prompt": "只能调用已配置的专业子智能体，不得自己使用底层 MCP 工具、Python 文件系统或 A2A 助手代替它们。调用每个子智能体时只能传入 task 这一个字符串参数；source_path、max_docs、max_chunks、graph_json_path、输出文件名等要求必须写进 task 字符串，禁止作为额外关键字参数传入。nexent_demo_graph.json 只属于第二步展示建图，绝对不能用于第三步高血压问答或第四步BI；第三、四步的 graph_name 必须是 graph.json。第三步返回后，无论问答结论是充分、证据有限还是拒答，下一步都必须调用 medical_analysis_supervisor 生成 BI，禁止提前调用 final_answer。每个子任务只委派一次，不重复、不轮询、不虚构。必须等待一次子智能体返回后再调用下一个，四个子任务全部真实返回后才能调用 final_answer。最终答案只能引用子智能体真实返回的 task_id、状态、图谱统计、三元组、confidence、source 和报告路径。", + "few_shots_prompt": "完整闭环必须使用下面的调用形态；子智能体返回类型是字符串，严禁按字典索引或元组解包：\ndataproc_report = medical_dataproc_agent(task='在DataMate处理data/corpus的两个文件并等待完成；返回真实JSON')\nkg_build_report = medical_kg_qa_agent(task='从data/corpus抽一个文档块构建nexent_demo_graph.json；返回真实JSON；该演示图不用于后续问答')\nkg_qa_report = medical_kg_qa_agent(task='必须基于医疗主图graph.json查询高血压并发症并列证据；禁止使用nexent_demo_graph.json；返回真实JSON')\nbi_report = medical_analysis_supervisor(task='必须基于医疗主图graph.json生成高血压并发症关系图task3_closed_loop.html并给出文字结论；返回真实JSON')\nfinal_answer('数据处理：\\n' + dataproc_report + '\\n\\n建图：\\n' + kg_build_report + '\\n\\n高血压并发症：\\n' + kg_qa_report + '\\n\\nBI分析：\\n' + bi_report)\n", + "enabled": true, + "tools": [], + "managed_agents": [], + "model_id": 5, + "model_name": "deepseek-ai/DeepSeek-V4-Pro", + "business_logic_model_id": 5, + "business_logic_model_name": "deepseek-ai/DeepSeek-V4-Pro", + "skill_names": [], + "prompt_template_id": 0, + "prompt_template_name": "system_default", + "verification_config": { + "enabled": true, + "step_verification_enabled": true, + "final_verification_enabled": true, + "llm_verification_enabled": false + } + } + }, + "mcp_info": [ + {"mcp_server_name": 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z=8OfOTfk5oMH1OtIT`a(cCzH8U1RnFo&V6iFX$>YT#=ruKeZ$rnIb=P%lt9sjQMZ_ zwk&i}VYYa@)A9D&AbO~s!ufeBcd)wSno~8OalTMCufl25mPD<=t~zh+_|sni1M_CW zFFi+;FLAl;kmjEQ9|kNm9OB!b&yU1ZhSB}v z7@5W~W9v3~IU2WQXhG8=03S!RzpIaC@}im#8*{KqPeUL!dfDJ)P^iMqS{b{b@m*V;z_fKv23ztdj!v8km@34QW f%~t(yUEz8RjDO!?piO={008y3ivj!#32Z*l literal 0 HcmV?d00001 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/build_zip.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/build_zip.py" new file mode 100644 index 0000000..c74811a --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/build_zip.py" @@ -0,0 +1,46 @@ +"""Package each DataMate operator folder into a correctly named .zip. + +DataMate requires the zip file name (without extension) to equal the package +directory name referenced in __init__.py's module_path. This script zips the +*contents* of each operator folder (files at the archive root, no parent dir) +into datamate_ops/dist/.zip. + +Usage: + python datamate_ops/build_zip.py +""" +from __future__ import annotations + +import zipfile +from pathlib import Path + +OPS_DIR = Path(__file__).resolve().parent +DIST = OPS_DIR / "dist" +OPERATORS = ["text_clean", "chunker", "medical_ner", "medical_re", "triple_validator"] +INCLUDE = {"__init__.py", "metadata.yml", "process.py", "requirements.txt", "README.md"} + + +def build(name: str) -> Path: + src = OPS_DIR / name + if not src.exists(): + raise FileNotFoundError(src) + DIST.mkdir(exist_ok=True) + zip_path = DIST / f"{name}.zip" + with zipfile.ZipFile(zip_path, "w", zipfile.ZIP_DEFLATED) as zf: + for f in sorted(src.iterdir()): + if f.is_file() and f.name in INCLUDE: + zf.write(f, arcname=f.name) # at archive root + return zip_path + + +def main() -> None: + for name in OPERATORS: + try: + p = build(name) + print(f" packaged {name} -> {p}") + except FileNotFoundError as exc: + print(f" skip {name}: {exc}") + print(f"\nDone. Upload the zips in {DIST} to the DataMate operator marketplace.") + + +if __name__ == "__main__": + main() diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/chunker/README.md" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/chunker/README.md" new file mode 100644 index 0000000..ef8d920 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/chunker/README.md" @@ -0,0 +1,11 @@ +# 医疗文本切块算子 (MedicalChunker) + +按标题、段落和字符上限切分医疗文本。采用可串联 Mapper 设计：chunks 会作为流水线内部字段传给 NER/RE；若本算子是最后一步，则导出 `{"chunks":[...]}` JSON。 + +- `maxChars`：单块字符上限，默认 1200 +- `overlap`：硬切分重叠字符，默认 80 +- `maxChunks`：传给下游的最大块数，默认 8；0 表示不限制 + +推荐流水线： + +`text_clean → chunker → medical_ner → medical_re → triple_validator` diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/chunker/__init__.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/chunker/__init__.py" new file mode 100644 index 0000000..3f5f553 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/chunker/__init__.py" @@ -0,0 +1,7 @@ +# -*- coding: utf-8 -*- +from datamate.core.base_op import OPERATORS + +OPERATORS.register_module( + module_name="MedicalChunker", + module_path="ops.user.chunker.process", +) diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/chunker/metadata.yml" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/chunker/metadata.yml" new file mode 100644 index 0000000..b60fbf4 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/chunker/metadata.yml" @@ -0,0 +1,43 @@ +name: '医疗文本切块' +description: '按Markdown/中文标题、段落和字符上限将长医疗文本切成语义连贯的文本块；块列表可继续传给医学实体与关系抽取算子。' +language: 'python' +vendor: 'custom' +raw_id: 'MedicalChunker' +version: '1.0.0' +modal: 'text' +inputs: 'text' +outputs: 'text' +types: + - 'cleaning' + - 'consolidate' +release: + - '1.0.0：首次发布；支持五算子流水线内部 chunks 透传' +metrics: + - name: '内存使用' + metric: '< 64 MB' + - name: '处理延时' + metric: '亚毫秒~毫秒级（CPU规则）' +runtime: + memory: 67108864 + cpu: 0.05 + gpu: 0 + npu: 0 +settings: + maxChars: + name: '单块最大字符数' + description: '每个文本块的目标字符上限' + type: 'input' + defaultVal: '1200' + required: false + overlap: + name: '硬切分重叠字符数' + description: '超长单段硬切分时相邻块的重叠字符数' + type: 'input' + defaultVal: '80' + required: false + maxChunks: + name: '最大处理块数' + description: '限制传给下游LLM算子的块数，0表示不限制' + type: 'input' + defaultVal: '8' + required: false diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/chunker/process.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/chunker/process.py" new file mode 100644 index 0000000..d97b160 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/chunker/process.py" @@ -0,0 +1,94 @@ +# -*- coding: utf-8 -*- +"""DataMate operator: heading-aware medical text chunking. + +DataMate's Slicer writes independent files but does not feed each slice into +later operators in the same cleaning task. This operator therefore uses Mapper +semantics: it stores chunks in an internal sample field consumed by MedicalNER +and MedicalRE, while exposing a JSON ``{"chunks": [...]}`` text result when used +as the final operator. +""" +from __future__ import annotations + +import json +import re +from typing import Any, Dict + +from datamate.core.base_op import Mapper + +_HEADING_RE = re.compile(r"^(#{1,6}\s+.+|第[一二三四五六七八九十百千\d]+[章节篇卷].*)$") + + +class MedicalChunker(Mapper): + def __init__(self, *args, **kwargs): + super().__init__(*args, **kwargs) + self.max_chars = int(kwargs.get("maxChars", 1200)) + self.overlap = int(kwargs.get("overlap", 80)) + self.max_chunks = int(kwargs.get("maxChunks", 8)) + if self.max_chars < 100: + raise ValueError("maxChars must be at least 100") + if self.overlap < 0 or self.overlap >= self.max_chars: + raise ValueError("overlap must satisfy 0 <= overlap < maxChars") + if self.max_chunks < 0: + raise ValueError("maxChunks must be >= 0") + + def _split_long(self, text: str) -> list[str]: + paragraphs = re.split(r"\n\s*\n", text) + out: list[str] = [] + current = "" + for paragraph in paragraphs: + paragraph = paragraph.strip() + if not paragraph: + continue + if len(current) + len(paragraph) + 2 <= self.max_chars: + current = f"{current}\n\n{paragraph}" if current else paragraph + continue + if current: + out.append(current) + current = "" + if len(paragraph) <= self.max_chars: + current = paragraph + continue + step = self.max_chars - self.overlap + out.extend(paragraph[i:i + self.max_chars] for i in range(0, len(paragraph), step)) + if current: + out.append(current) + return out + + def _chunk(self, text: str) -> list[str]: + sections: list[str] = [] + buffer: list[str] = [] + for line in text.split("\n"): + if _HEADING_RE.match(line.strip()) and buffer: + sections.append("\n".join(buffer)) + buffer = [line] + else: + buffer.append(line) + if buffer: + sections.append("\n".join(buffer)) + + chunks: list[str] = [] + for section in sections: + section = section.strip() + if not section: + continue + if len(section) <= self.max_chars: + chunks.append(section) + else: + chunks.extend(self._split_long(section)) + if self.max_chunks: + chunks = chunks[:self.max_chunks] + return chunks + + def execute(self, sample: Dict[str, Any]) -> Dict[str, Any]: + self.read_file_first(sample) + text = str(sample.get(self.text_key, "") or "").strip() + if not text: + sample["_medical_source_text"] = "" + sample["_medical_chunks"] = [] + sample[self.text_key] = "" + return sample + chunks = self._chunk(text) + sample["_medical_source_text"] = text + sample["_medical_chunks"] = chunks + sample[self.text_key] = json.dumps({"chunks": chunks}, ensure_ascii=False, indent=2) + return sample diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/chunker/requirements.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/chunker/requirements.txt" new file mode 100644 index 0000000..8367e7d --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/chunker/requirements.txt" @@ -0,0 +1 @@ +# No third-party dependencies; pure standard library. diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_ner/README.md" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_ner/README.md" new file mode 100644 index 0000000..4d4fad6 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_ner/README.md" @@ -0,0 +1,23 @@ +# 医学实体识别算子 (MedicalNER) + +基于 LLM 的医疗实体抽取 DataMate 算子。读取文件文本，调用 OpenAI 兼容 API（硅基流动 / 百炼 / 本地 vLLM）抽取医学实体，把结果以 JSON 写回。 + +## 输入 / 输出 +- 输入：文本文件（`sample['text']`）。 +- 输出：`{"entities": [{"name", "type", "confidence"}]}` 的 JSON 文本。 + +## 实体类型 +Disease(疾病)/Symptom(症状)/Drug(药物)/Examination(检查)/Procedure(手术)/Body(身体部位)/Department(科室)/Tumor(肿瘤)/Biomarker(标志物)/Gene(基因)/Morphology(形态学特征)。 + +## 参数（在 DataMate 界面配置） +| 参数 | 说明 | +| --- | --- | +| apiBase | OpenAI 兼容 API 地址，如 `https://api.siliconflow.cn/v1` | +| apiKey | 访问密钥（必填） | +| model | 模型名，如 `Qwen/Qwen3.6-35B-A3B` | +| temperature | 抽取建议 0.0-0.3 | +| maxChars | 单次最大字符数 | +| maxChunks | 上游存在切块时最多处理的块数，0 表示不限制 | + +## 打包上传 +压缩包名必须为 `medical_ner.zip`（与注册路径包名一致）。有上游 `chunker` 时会逐块抽取并合并去重。可用 `datamate_ops/build_zip.py` 一键打包。 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_ner/__init__.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_ner/__init__.py" new file mode 100644 index 0000000..4549582 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_ner/__init__.py" @@ -0,0 +1,7 @@ +# -*- coding: utf-8 -*- +from datamate.core.base_op import OPERATORS + +OPERATORS.register_module( + module_name='MedicalNER', + module_path="ops.user.medical_ner.process", +) diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_ner/metadata.yml" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_ner/metadata.yml" new file mode 100644 index 0000000..6aa48f0 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_ner/metadata.yml" @@ -0,0 +1,68 @@ +name: '医学实体识别' +description: 'DataMate 轻量自包含版医学实体识别：基于 OpenAI 兼容 LLM 抽取疾病、症状、药物、检查、标志物、基因等实体，并输出版本与 DataMate_LLM 路由。神经 GPLinker 主力路径由 Nexent/MCP 提供。' +language: 'python' +vendor: 'custom' +raw_id: 'MedicalNER' +version: '2.0.0' +modal: 'text' +inputs: 'text' +outputs: 'text' +types: + - 'annotation' +release: + - '2.0.0：同步 MediGraph 2.0；输出 operator_version/backend/routing，明确与 Nexent/MCP neural GPLinker 主力路径的分工' + - '1.1.0：支持上游医疗文本切块，逐块抽取并合并去重' + - '1.0.1：为下游关系抽取保留原始文本；API 异常不再静默产空结果' + - '首次发布' + - '支持 OpenAI 兼容 API（硅基流动/百炼/本地vLLM），本体约束抽取' +metrics: + - name: '内存使用' + metric: '< 128 MB' + - name: '单块处理延时' + metric: '约 1-3 s/块（取决于API）' + - name: '网页端路线' + metric: 'DataMate_LLM；神经 L1 指标由 Nexent MCP inspect_extraction_models 展示' +runtime: + memory: 134217728 + cpu: 0.2 + gpu: 0 + npu: 0 +settings: + apiBase: + name: 'API Base URL' + description: 'OpenAI 兼容的 API 地址，例如 https://api.siliconflow.cn/v1' + type: 'input' + defaultVal: 'https://api.siliconflow.cn/v1' + required: true + apiKey: + name: 'API Key' + description: 'LLM 服务访问密钥' + type: 'input' + defaultVal: '' + required: true + model: + name: '模型名称' + description: '调用的模型名，如 Qwen/Qwen3.6-35B-A3B、qwen-plus' + type: 'input' + defaultVal: 'Qwen/Qwen3.6-35B-A3B' + required: false + temperature: + name: '生成温度' + description: '越低越稳定，抽取任务建议 0.0-0.3' + type: 'slider' + defaultVal: 0.2 + min: 0 + max: 2 + step: 0.1 + maxChars: + name: '单次最大字符数' + description: '超长文本截断长度' + type: 'input' + defaultVal: '4000' + required: false + maxChunks: + name: '最大处理块数' + description: '存在上游切块结果时最多调用多少个文本块，0表示不限制' + type: 'input' + defaultVal: '8' + required: false diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_ner/process.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_ner/process.py" new file mode 100644 index 0000000..1dbd080 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_ner/process.py" @@ -0,0 +1,160 @@ +# -*- coding: utf-8 -*- +"""DataMate operator: medical named-entity recognition (LLM-backed). + +Self-contained (no external project deps) so it can be zipped and uploaded to the +DataMate operator marketplace. Calls an OpenAI-compatible API (SiliconFlow / +DashScope / local vLLM) using apiBase/apiKey/model provided via the operator's +UI settings. Reads sample['text'], writes the extracted entities (JSON) back into +sample['text'] so the exported file contains the structured result. + +Note: the heavy neural GPLinker L1 used by the Nexent/MCP path lives in the host +MediGraph project. This DataMate package intentionally stays lightweight for the +operator marketplace and reports its own route as ``DataMate_LLM``. +""" +import json +import re +from typing import Any, Dict + +try: + from loguru import logger +except ImportError: # pragma: no cover + import logging + logger = logging.getLogger(__name__) + +from datamate.core.base_op import Mapper + +ENTITY_TYPES = { + "Disease": "疾病", "Symptom": "症状", "Drug": "药物", "Examination": "检查", + "Procedure": "手术", "Body": "身体部位", "Department": "科室", + "Tumor": "肿瘤", "Biomarker": "标志物", "Gene": "基因", "Morphology": "形态学特征", +} +OPERATOR_VERSION = "datamate-medical-ner-2.0.0" + +_SYSTEM = "你是严谨的医学信息抽取引擎，只输出 JSON，不要任何解释。" +_PROMPT = """从下面的医学文本中抽取医学实体。实体类型只能取：{types}。 +要求：只抽取明确出现的、有医学含义的实体；type 用英文 key；confidence 为 0~1。 +不要把文档结构当实体（忽略 "Definition / general"、"Laboratory"、"Radiology images"、 +"Gross description"、"Treatment" 等页面小节标题/导航）。 +输出 JSON：{{"entities":[{{"name":"...","type":"...","confidence":0.0}}]}} + +文本： +\"\"\" +{text} +\"\"\" +""" + + +class MedicalNER(Mapper): + def __init__(self, *args, **kwargs): + super().__init__(*args, **kwargs) + self.api_base = kwargs.get("apiBase", "https://api.siliconflow.cn/v1").strip() + self.api_key = kwargs.get("apiKey", "").strip() + self.model = kwargs.get("model", "Qwen/Qwen3.6-35B-A3B").strip() + self.temperature = float(kwargs.get("temperature", 0.2)) + self.max_chars = int(kwargs.get("maxChars", 4000)) + self.max_chunks = int(kwargs.get("maxChunks", 8)) + # Content-rich clinical records make the model emit a long entity list; + # 120s was not enough for real 265-character outpatient records. + self.timeout = float(kwargs.get("timeout", 240)) + if self.max_chars < 100: + raise ValueError("maxChars must be at least 100") + if self.max_chunks < 0: + raise ValueError("maxChunks must be >= 0") + if self.timeout <= 0: + raise ValueError("timeout must be positive") + + def _call_llm(self, prompt: str) -> str: + from openai import OpenAI + + client = OpenAI(api_key=self.api_key or "EMPTY", base_url=self.api_base, timeout=self.timeout) + resp = client.chat.completions.create( + model=self.model, + messages=[{"role": "system", "content": _SYSTEM}, {"role": "user", "content": prompt}], + temperature=self.temperature, + ) + return resp.choices[0].message.content or "" + + @staticmethod + def _extract_json(text: str) -> Any: + if not text: + return None + fence = re.search(r"```(?:json)?\s*(.+?)```", text, flags=re.DOTALL) + if fence: + text = fence.group(1) + text = text.strip() + try: + return json.loads(text) + except json.JSONDecodeError: + start, end = text.find("{"), text.rfind("}") + if start != -1 and end > start: + try: + return json.loads(text[start : end + 1]) + except json.JSONDecodeError: + return None + return None + + def execute(self, sample: Dict[str, Any]) -> Dict[str, Any]: + self.read_file_first(sample) + text = str(sample.get(self.text_key, "") or "").strip() + if not text: + return sample + + chunks = sample.get("_medical_chunks") + chunks = [str(chunk).strip() for chunk in chunks] if isinstance(chunks, list) else [] + parsed_input = self._extract_json(text) + if not chunks and isinstance(parsed_input, dict) and isinstance(parsed_input.get("chunks"), list): + chunks = [str(chunk).strip() for chunk in parsed_input["chunks"]] + source_text = str(sample.get("_medical_source_text", "") or "").strip() + if not source_text: + source_text = "\n\n".join(chunks) if chunks else text + if not chunks: + chunks = [source_text] + chunks = [chunk for chunk in chunks if chunk] + if self.max_chunks: + chunks = chunks[:self.max_chunks] + + # Keep the raw/cleaned document available to downstream MedicalRE. + sample["_medical_source_text"] = source_text + entities = [] + seen = set() + for index, chunk in enumerate(chunks): + prompt = _PROMPT.format(types="/".join(ENTITY_TYPES), text=chunk[:self.max_chars]) + try: + data = self._extract_json(self._call_llm(prompt)) or {} + except Exception as e: # noqa: BLE001 + logger.error(f"MedicalNER LLM call failed on chunk {index + 1}/{len(chunks)}: {e}") + raise + for ent in data.get("entities", []) if isinstance(data, dict) else []: + if not isinstance(ent, dict): + continue + name = str(ent.get("name", "")).strip() + etype = str(ent.get("type", "")).strip() + if not name or etype not in ENTITY_TYPES: + continue + key = (etype, name.lower()) + if key in seen: + continue + seen.add(key) + entities.append({ + "name": name, + "type": etype, + "confidence": ent.get("confidence", 0.8), + }) + logger.info(f"MedicalNER: {len(entities)} unique entities from {len(chunks)} chunk(s)") + sample[self.text_key] = json.dumps( + { + "entities": entities, + "operator_version": OPERATOR_VERSION, + "backend": "llm_schema", + "routing": { + "level": "DataMate_LLM", + "llm_called": True, + "model": self.model, + "chunks": len(chunks), + }, + "note": "Nexent/MCP path uses neural GPLinker when available; DataMate package is lightweight LLM-backed.", + }, + ensure_ascii=False, + indent=2, + ) + return sample diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_ner/requirements.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_ner/requirements.txt" new file mode 100644 index 0000000..cb05923 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_ner/requirements.txt" @@ -0,0 +1 @@ +openai>=1.30.0 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_re/README.md" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_re/README.md" new file mode 100644 index 0000000..022ea10 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_re/README.md" @@ -0,0 +1,16 @@ +# 医学关系抽取算子 (MedicalRE) + +基于 LLM 的关系三元组抽取 DataMate 算子。读取医疗文本，抽取受本体约束的关系三元组，输出 JSON。 + +## 输入 / 输出 +- 输入：医疗文本（`sample['text']`）。 +- 输出：`{"triples": [{"head","head_type","relation","tail","tail_type","confidence"}]}`。 + +## 关系类型 +has_symptom(有症状)/recommend_drug(推荐药物)/need_examination(需做检查)/complication(并发)/contraindication(禁忌)/treated_in_department(就诊于)/positive_marker(阳性标志物)/negative_marker(阴性标志物)/associated_gene(关联基因)/has_morphology(形态学表现)/located_in(位于)/subtype_of(亚型)/treated_by_procedure(手术或操作治疗)/adverse_reaction(药物不良反应)。 + +## 参数 +同 MedicalNER：apiBase / apiKey / model / temperature / maxChars / maxChunks。 + +## 打包上传 +压缩包名必须为 `medical_re.zip`。建议在 DataMate 流水线里接在 `medical_ner` 之后；有上游 `chunker` 时会逐块抽取并合并去重。 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_re/__init__.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_re/__init__.py" new file mode 100644 index 0000000..f58085f --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_re/__init__.py" @@ -0,0 +1,7 @@ +# -*- coding: utf-8 -*- +from datamate.core.base_op import OPERATORS + +OPERATORS.register_module( + module_name='MedicalRE', + module_path="ops.user.medical_re.process", +) diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_re/metadata.yml" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_re/metadata.yml" new file mode 100644 index 0000000..1665d65 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_re/metadata.yml" @@ -0,0 +1,68 @@ +name: '医学关系抽取' +description: 'DataMate 轻量自包含版医学关系抽取：基于 OpenAI 兼容 LLM 抽取本体约束三元组，并输出版本与 DataMate_LLM 路由。神经 GPLinker+CMeIE 映射主力路径由 Nexent/MCP 提供。' +language: 'python' +vendor: 'custom' +raw_id: 'MedicalRE' +version: '2.0.0' +modal: 'text' +inputs: 'text' +outputs: 'text' +types: + - 'annotation' +release: + - '2.0.0：同步 MediGraph 2.0；输出 operator_version/backend/routing，明确与 Nexent/MCP neural GPLinker+CMeIE映射路径的分工' + - '1.1.0：按上游文本块逐块抽取关系，候选实体按块过滤并合并去重' + - '1.0.1：同时使用原文与上游候选实体，修复串联后丢失原文的问题' + - '首次发布' + - '本体关系约束 + OpenAI 兼容 API' +metrics: + - name: '内存使用' + metric: '< 128 MB' + - name: '单块处理延时' + metric: '约 1-3 s/块（取决于API）' + - name: '网页端路线' + metric: 'DataMate_LLM；神经 L1 指标由 Nexent MCP inspect_extraction_models 展示' +runtime: + memory: 134217728 + cpu: 0.2 + gpu: 0 + npu: 0 +settings: + apiBase: + name: 'API Base URL' + description: 'OpenAI 兼容的 API 地址，例如 https://api.siliconflow.cn/v1' + type: 'input' + defaultVal: 'https://api.siliconflow.cn/v1' + required: true + apiKey: + name: 'API Key' + description: 'LLM 服务访问密钥' + type: 'input' + defaultVal: '' + required: true + model: + name: '模型名称' + description: '调用的模型名，如 Qwen/Qwen3.6-35B-A3B、qwen-plus' + type: 'input' + defaultVal: 'Qwen/Qwen3.6-35B-A3B' + required: false + temperature: + name: '生成温度' + description: '抽取建议 0.0-0.3' + type: 'slider' + defaultVal: 0.2 + min: 0 + max: 2 + step: 0.1 + maxChars: + name: '单次最大字符数' + description: '超长文本截断长度' + type: 'input' + defaultVal: '4000' + required: false + maxChunks: + name: '最大处理块数' + description: '存在上游切块结果时最多调用多少个文本块，0表示不限制' + type: 'input' + defaultVal: '8' + required: false diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_re/process.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_re/process.py" new file mode 100644 index 0000000..0f824c4 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_re/process.py" @@ -0,0 +1,236 @@ +# -*- coding: utf-8 -*- +"""DataMate operator: medical relation extraction (LLM-backed, self-contained). + +Reads sample['text']. The text may be raw medical text, OR the JSON output of the +MedicalNER operator ({"entities":[...]}) plus original text -- this operator +extracts ontology-constrained relation triples and writes them back as JSON +{"triples":[...]}. + +The host Nexent/MCP path can use the shipped neural GPLinker checkpoint. This +DataMate marketplace operator remains small and self-contained, so it exposes a +clear ``DataMate_LLM`` route in its output. +""" +import json +import re +from typing import Any, Dict + +try: + from loguru import logger +except ImportError: # pragma: no cover + import logging + logger = logging.getLogger(__name__) + +from datamate.core.base_op import Mapper + +RELATION_TYPES = { + "has_symptom": "有症状", "recommend_drug": "推荐药物", "need_examination": "需做检查", + "complication": "并发", "contraindication": "禁忌", "treated_in_department": "就诊于", + "positive_marker": "阳性标志物", "negative_marker": "阴性标志物", "associated_gene": "关联基因", + "has_morphology": "形态学表现", "located_in": "位于", "subtype_of": "亚型", + "treated_by_procedure": "手术/操作治疗", "adverse_reaction": "药物不良反应", +} +OPERATOR_VERSION = "datamate-medical-re-2.0.0" + +_SYSTEM = "你是严谨的医学关系抽取引擎，只输出 JSON，不要任何解释。" +_LESION = {"Disease", "Tumor"} +RELATION_CONSTRAINTS = { + "has_symptom": (_LESION, {"Symptom"}), + "recommend_drug": (_LESION, {"Drug"}), + "need_examination": (_LESION, {"Examination"}), + "complication": (_LESION, _LESION), + "contraindication": ({"Drug"}, _LESION | {"Symptom"}), + "treated_in_department": (_LESION, {"Department"}), + "positive_marker": (_LESION, {"Biomarker"}), + "negative_marker": (_LESION, {"Biomarker"}), + "associated_gene": (_LESION, {"Gene"}), + "has_morphology": (_LESION, {"Morphology"}), + "located_in": (_LESION | {"Symptom"}, {"Body"}), + "subtype_of": (_LESION, _LESION), + "treated_by_procedure": (_LESION, {"Procedure"}), + "adverse_reaction": ({"Drug"}, {"Symptom", "Disease"}), +} + +_FEWSHOT = """示例1： +文本："2型糖尿病患者常有多饮，治疗首选二甲双胍，建议检查糖化血红蛋白。" +输出：{"triples":[ +{"head":"2型糖尿病","head_type":"Disease","relation":"has_symptom","tail":"多饮","tail_type":"Symptom","confidence":0.95}, +{"head":"2型糖尿病","head_type":"Disease","relation":"recommend_drug","tail":"二甲双胍","tail_type":"Drug","confidence":0.94}, +{"head":"2型糖尿病","head_type":"Disease","relation":"need_examination","tail":"糖化血红蛋白","tail_type":"Examination","confidence":0.9}]} + +示例2： +文本："嗜铬细胞瘤多位于肾上腺髓质，CgA 常呈阳性，与 RET 基因突变相关。" +输出：{"triples":[ +{"head":"嗜铬细胞瘤","head_type":"Tumor","relation":"located_in","tail":"肾上腺髓质","tail_type":"Body","confidence":0.9}, +{"head":"嗜铬细胞瘤","head_type":"Tumor","relation":"positive_marker","tail":"CgA","tail_type":"Biomarker","confidence":0.92}, +{"head":"嗜铬细胞瘤","head_type":"Tumor","relation":"associated_gene","tail":"RET","tail_type":"Gene","confidence":0.9}]} +""" + + +def _ontology_block() -> str: + lines = [] + for relation, display in RELATION_TYPES.items(): + head_types, tail_types = RELATION_CONSTRAINTS[relation] + lines.append( + f"- {relation} ({display}): {'/'.join(sorted(head_types))} -> " + f"{'/'.join(sorted(tail_types))}" + ) + return "\n".join(lines) + + +_PROMPT = """从医学文本中抽取实体间关系三元组。 + +允许的 relation 与方向约束： +{ontology} + +{fewshot} +要求： +1. 只抽取文本明确支持的关系。 +2. head/tail 优先使用候选实体中的原文名称和类型。 +3. 严格遵守上面的关系方向与两端类型约束，不要颠倒 head/tail。 +4. 不要仅凭候选实体名称臆造关系。 +5. 给出 head/head_type/relation/tail/tail_type/confidence(0~1)。 +输出 JSON：{{"triples":[{{"head":"","head_type":"","relation":"","tail":"","tail_type":"","confidence":0.0}}]}} + +医学原文： +\"\"\" +{text} +\"\"\" + +候选实体 JSON： +{entities} +""" + + +class MedicalRE(Mapper): + def __init__(self, *args, **kwargs): + super().__init__(*args, **kwargs) + self.api_base = kwargs.get("apiBase", "https://api.siliconflow.cn/v1").strip() + self.api_key = kwargs.get("apiKey", "").strip() + self.model = kwargs.get("model", "Qwen/Qwen3.6-35B-A3B").strip() + self.temperature = float(kwargs.get("temperature", 0.2)) + self.max_chars = int(kwargs.get("maxChars", 4000)) + self.max_chunks = int(kwargs.get("maxChunks", 8)) + # Relation extraction emits one JSON object per triple, so a content-rich + # clinical record can keep the model generating well past two minutes. + # 120s timed out on real 265-character outpatient records. + self.timeout = float(kwargs.get("timeout", 240)) + if self.max_chars < 100: + raise ValueError("maxChars must be at least 100") + if self.max_chunks < 0: + raise ValueError("maxChunks must be >= 0") + if self.timeout <= 0: + raise ValueError("timeout must be positive") + + def _call_llm(self, prompt: str) -> str: + from openai import OpenAI + + client = OpenAI(api_key=self.api_key or "EMPTY", base_url=self.api_base, timeout=self.timeout) + resp = client.chat.completions.create( + model=self.model, + messages=[{"role": "system", "content": _SYSTEM}, {"role": "user", "content": prompt}], + temperature=self.temperature, + ) + return resp.choices[0].message.content or "" + + @staticmethod + def _extract_json(text: str) -> Any: + if not text: + return None + fence = re.search(r"```(?:json)?\s*(.+?)```", text, flags=re.DOTALL) + if fence: + text = fence.group(1) + text = text.strip() + try: + return json.loads(text) + except json.JSONDecodeError: + start, end = text.find("{"), text.rfind("}") + if start != -1 and end > start: + try: + return json.loads(text[start : end + 1]) + except json.JSONDecodeError: + return None + return None + + def execute(self, sample: Dict[str, Any]) -> Dict[str, Any]: + self.read_file_first(sample) + text = (sample.get(self.text_key, "") or "").strip() + if not text: + return sample + + source_text = str(sample.get("_medical_source_text", "") or "").strip() + entity_payload: Any = {} + parsed_input = self._extract_json(text) + if isinstance(parsed_input, dict) and isinstance(parsed_input.get("entities"), list): + entity_payload = parsed_input + if not source_text: + # MedicalRE also supports standalone use, where its input is raw text. + source_text = text + + chunks = sample.get("_medical_chunks") + chunks = [str(chunk).strip() for chunk in chunks] if isinstance(chunks, list) else [] + if not chunks: + chunks = [source_text] + chunks = [chunk for chunk in chunks if chunk] + if self.max_chunks: + chunks = chunks[:self.max_chunks] + + candidate_entities = entity_payload.get("entities", []) if isinstance(entity_payload, dict) else [] + triples = [] + seen = set() + for index, chunk in enumerate(chunks): + lowered = chunk.lower() + chunk_entities = [ + entity for entity in candidate_entities + if isinstance(entity, dict) + and str(entity.get("name", "")).strip() + and str(entity.get("name", "")).strip().lower() in lowered + ] + prompt = _PROMPT.format( + ontology=_ontology_block(), + fewshot=_FEWSHOT, + text=chunk[:self.max_chars], + entities=json.dumps({"entities": chunk_entities}, ensure_ascii=False), + ) + try: + data = self._extract_json(self._call_llm(prompt)) or {} + except Exception as e: # noqa: BLE001 + logger.error(f"MedicalRE LLM call failed on chunk {index + 1}/{len(chunks)}: {e}") + raise + for triple in data.get("triples", []) if isinstance(data, dict) else []: + if not isinstance(triple, dict): + continue + relation = str(triple.get("relation", "")).strip() + head = str(triple.get("head", "")).strip() + tail = str(triple.get("tail", "")).strip() + if relation not in RELATION_TYPES or not head or not tail: + continue + key = (head.lower(), relation, tail.lower()) + if key in seen: + continue + seen.add(key) + triples.append({ + "head": head, + "head_type": str(triple.get("head_type", "")).strip(), + "relation": relation, + "tail": tail, + "tail_type": str(triple.get("tail_type", "")).strip(), + "confidence": triple.get("confidence", 0.7), + }) + logger.info(f"MedicalRE: {len(triples)} unique triples from {len(chunks)} chunk(s)") + sample[self.text_key] = json.dumps( + { + "triples": triples, + "operator_version": OPERATOR_VERSION, + "backend": "llm_schema", + "routing": { + "level": "DataMate_LLM", + "llm_called": True, + "model": self.model, + "chunks": len(chunks), + }, + "note": "Nexent/MCP path uses neural GPLinker when available; DataMate package is lightweight LLM-backed.", + }, + ensure_ascii=False, + indent=2, + ) + return sample diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_re/requirements.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_re/requirements.txt" new file mode 100644 index 0000000..cb05923 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/medical_re/requirements.txt" @@ -0,0 +1 @@ +openai>=1.30.0 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/text_clean/README.md" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/text_clean/README.md" new file mode 100644 index 0000000..81d0b32 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/text_clean/README.md" @@ -0,0 +1,12 @@ +# 医疗文本清洗算子 (TextClean) + +纯规则 DataMate 算子，对医疗/病理文本执行网页噪声、页眉页脚、链接图片、LaTeX 和短碎片清洗。 + +- 输入：文本文件或上游 `text` +- 输出：清洗后的 `text` +- 参数：`minLineLength`，默认 8 +- 特点：无外部 API、低延时、可作为五算子流水线第一步 + +推荐流水线： + +`text_clean → chunker → medical_ner → medical_re → triple_validator` diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/text_clean/__init__.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/text_clean/__init__.py" new file mode 100644 index 0000000..07165fb --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/text_clean/__init__.py" @@ -0,0 +1,7 @@ +# -*- coding: utf-8 -*- +from datamate.core.base_op import OPERATORS + +OPERATORS.register_module( + module_name="TextClean", + module_path="ops.user.text_clean.process", +) diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/text_clean/metadata.yml" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/text_clean/metadata.yml" new file mode 100644 index 0000000..17a4f75 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/text_clean/metadata.yml" @@ -0,0 +1,30 @@ +name: '医疗文本清洗' +description: '清洗医疗/病理原始文本：去除网页噪声、页眉页脚、Markdown链接与图片、LaTeX残留和无意义短碎片，同时保护标题结构。' +language: 'python' +vendor: 'custom' +raw_id: 'TextClean' +version: '1.0.0' +modal: 'text' +inputs: 'text' +outputs: 'text' +types: + - 'cleaning' +release: + - '1.0.0：首次发布；与 medigraph/operators/text_clean.py 规则保持一致' +metrics: + - name: '内存使用' + metric: '< 64 MB' + - name: '处理延时' + metric: '亚毫秒~毫秒级（CPU规则）' +runtime: + memory: 67108864 + cpu: 0.05 + gpu: 0 + npu: 0 +settings: + minLineLength: + name: '最短保留行长度' + description: '短于该长度且不是标题、列表或完整句子的文本行将被移除' + type: 'input' + defaultVal: '8' + required: false diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/text_clean/process.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/text_clean/process.py" new file mode 100644 index 0000000..bc6bd46 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/text_clean/process.py" @@ -0,0 +1,137 @@ +# -*- coding: utf-8 -*- +"""DataMate operator: rule-based medical text cleaning. + +This is the self-contained DataMate mirror of +``medigraph/operators/text_clean.py``. It reads the source file when used as the +first operator and keeps the cleaned text in ``sample['text']`` for downstream +chunking and extraction operators. +""" +from __future__ import annotations + +import re +from typing import Any, Dict + +from datamate.core.base_op import Mapper + + +class TextClean(Mapper): + _ZH_HEADING_RE = re.compile( + r"^(?:第[一二三四五六七八九十百千\d]+[章节篇卷]|[一二三四五六七八九十百千]+[、])" + ) + + HEADER_FOOTER_PATTERNS = [ + r"Page\s+\d+\s+of\s+\d+", + r"第\s*\d+\s*页\s*[，,/]\s*共\s*\d+\s*页", + r"©\s*\d{4}.*?(?:All rights reserved|版权所有)", + r"Downloaded from.*?(?:\n|$)", + ] + WEB_NOISE_PATTERNS = [ + r"Home\s*[>»›]\s*.*?[>»›]", + r"Click here to.*?(?:\n|$)", + r"Show Image", + r"Read more\.{0,3}", + r"Related (?:articles?|topics?|links?).*?(?:\n|$)", + r"Share (?:on|this|via).*?(?:\n|$)", + r"Advertisement", + r"cookie(?:s)?\s*(?:policy|notice)", + ] + METADATA_FOOTNOTE_PATTERNS = [ + r"^数据来源[：:].+$", + r"^参考(?:文献|书目|资料)[：:].+$", + r"^来源[：:].+$", + r"^出版社[：:].+$", + ] + + def __init__(self, *args, **kwargs): + super().__init__(*args, **kwargs) + self.min_line_length = max(0, int(kwargs.get("minLineLength", 8))) + + @staticmethod + def _remove_line_patterns(text: str, patterns: list[str]) -> str: + out = [] + for line in text.split("\n"): + if line.lstrip().startswith("#"): + out.append(line) + continue + for pattern in patterns: + line = re.sub(pattern, "", line, flags=re.IGNORECASE) + out.append(line) + return "\n".join(out) + + @classmethod + def _remove_metadata_footnotes(cls, text: str) -> str: + out = [] + for line in text.split("\n"): + stripped = line.strip() + if any(re.match(pattern, stripped, flags=re.IGNORECASE) + for pattern in cls.METADATA_FOOTNOTE_PATTERNS): + continue + out.append(line) + return "\n".join(out) + + @staticmethod + def _clean_links(text: str) -> str: + text = re.sub(r"!\[([^\]]*)\]\([^)]*\)", "", text) + text = re.sub(r"\[([^\]]+)\]\([^)]+\)", r"\1", text) + text = re.sub(r"https?://\S+", "", text) + return re.sub( + r"^(?![ \t]*#)[^\n]*\.(?:jpg|png|jpeg|gif|tif)\)?\s*$", + "", + text, + flags=re.MULTILINE | re.IGNORECASE, + ) + + @staticmethod + def _clean_latex(text: str) -> str: + def simplify(match: re.Match) -> str: + inner = match.group(1).strip() + inner = re.sub(r"\\(?:mathrm|text|mathbf|textbf)\{([^}]+)\}", r"\1", inner) + inner = re.sub(r"[\^_]\{([^}]+)\}", r"\1", inner) + inner = re.sub(r"\\[a-zA-Z]+", "", inner) + return inner.strip("{}").strip() + + text = re.sub(r"\$\$[\s\S]*?\$\$", "", text) + text = re.sub(r"\$([^$\n]+)\$", simplify, text) + return text.replace("$", "") + + def _remove_short_fragments(self, text: str) -> str: + out = [] + for line in text.split("\n"): + stripped = line.strip() + if not stripped: + out.append(line) + continue + if stripped.startswith(("#", "|", "【")) or self._ZH_HEADING_RE.match(stripped): + out.append(line) + continue + if stripped.startswith(("-", "*", "•")) and len(stripped) > 5: + out.append(line) + continue + if re.match(r"^\d+[\.、）)]\s", stripped): + out.append(line) + continue + if len(stripped) < self.min_line_length and not stripped.endswith(("。", ".", "：", ":")): + continue + out.append(line) + return "\n".join(out) + + @staticmethod + def _normalize_whitespace(text: str) -> str: + text = re.sub(r"[ \t]+$", "", text, flags=re.MULTILINE) + text = re.sub(r"\n{3,}", "\n\n", text) + return text.strip("\n") + "\n" if text.strip() else "" + + def execute(self, sample: Dict[str, Any]) -> Dict[str, Any]: + self.read_file_first(sample) + text = str(sample.get(self.text_key, "") or "") + if not text.strip(): + sample[self.text_key] = "" + return sample + text = self._remove_line_patterns(text, self.HEADER_FOOTER_PATTERNS) + text = self._remove_line_patterns(text, self.WEB_NOISE_PATTERNS) + text = self._remove_metadata_footnotes(text) + text = self._clean_links(text) + text = self._clean_latex(text) + text = self._remove_short_fragments(text) + sample[self.text_key] = self._normalize_whitespace(text).strip() + return sample diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/text_clean/requirements.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/text_clean/requirements.txt" new file mode 100644 index 0000000..8367e7d --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/text_clean/requirements.txt" @@ -0,0 +1 @@ +# No third-party dependencies; pure standard library. diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/triple_validator/README.md" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/triple_validator/README.md" new file mode 100644 index 0000000..c745905 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/triple_validator/README.md" @@ -0,0 +1,21 @@ +# 三元组校验算子 (TripleValidator) + +纯规则的三元组质量治理 DataMate 算子（无需 API，低时延）。 + +## 输入 / 输出 +- 输入：`{"triples":[...]}` JSON 文本（如 MedicalRE 的输出）。 +- 输出：`{"valid":[...], "rejected":[{"triple","reason"}]}`。 + +## 校验规则 +1. Schema 合法性：关系两端实体类型必须匹配本体约束。 +2. 去重归一：大小写/空格归一后去重，保留高置信。 +3. 置信度过滤：低于 `minConfidence` 丢弃。 +4. 冲突检测：互斥关系（如 阳性标志物 vs 阴性标志物）报警拒绝。 + +## 参数 +| 参数 | 说明 | +| --- | --- | +| minConfidence | 最低置信度阈值（默认 0.5） | + +## 打包上传 +压缩包名必须为 `triple_validator.zip`。 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/triple_validator/__init__.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/triple_validator/__init__.py" new file mode 100644 index 0000000..f9ec97f --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/triple_validator/__init__.py" @@ -0,0 +1,7 @@ +# -*- coding: utf-8 -*- +from datamate.core.base_op import OPERATORS + +OPERATORS.register_module( + module_name='TripleValidator', + module_path="ops.user.triple_validator.process", +) diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/triple_validator/metadata.yml" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/triple_validator/metadata.yml" new file mode 100644 index 0000000..9c1a5c4 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/triple_validator/metadata.yml" @@ -0,0 +1,36 @@ +name: '三元组校验' +description: '对候选关系三元组做质量治理：schema合法性校验、去重归一、置信度过滤、冲突检测，输出通过的三元组与每条拒因。纯规则、低时延、无需API。' +language: 'python' +vendor: 'custom' +raw_id: 'TripleValidator' +version: '1.1.0' +modal: 'text' +inputs: 'text' +outputs: 'text' +types: + - 'cleaning' + - 'annotation' +release: + - '1.1.0：与五算子 DataMate 流水线版本同步' + - '1.0.1：与医学抽取流水线版本同步' + - '首次发布' + - 'schema约束 + 冲突检测 + 可解释拒因' +metrics: + - name: '内存使用' + metric: '< 64 MB' + - name: '处理速度' + metric: '> 5000 三元组/秒（纯CPU规则）' +runtime: + memory: 67108864 + cpu: 0.05 + gpu: 0 + npu: 0 +settings: + minConfidence: + name: '最低置信度' + description: '低于该置信度的三元组将被过滤' + type: 'slider' + defaultVal: 0.5 + min: 0 + max: 1 + step: 0.05 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/triple_validator/process.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/triple_validator/process.py" new file mode 100644 index 0000000..6056d1f --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/triple_validator/process.py" @@ -0,0 +1,96 @@ +# -*- coding: utf-8 -*- +"""DataMate operator: triple validation & governance (rule-based, self-contained). + +Reads sample['text'] expected to be JSON {"triples":[...]} (e.g. MedicalRE output) +and applies: schema legality, dedup/normalization, confidence filtering and +conflict detection. Writes {"valid":[...], "rejected":[...]} with reasons. +""" +import json +from typing import Any, Dict + +try: + from loguru import logger +except ImportError: # pragma: no cover + import logging + logger = logging.getLogger(__name__) + +from datamate.core.base_op import Mapper + +_LESION = {"Disease", "Tumor"} +RELATION_CONSTRAINTS = { + "has_symptom": (_LESION, {"Symptom"}), + "recommend_drug": (_LESION, {"Drug"}), + "need_examination": (_LESION, {"Examination"}), + "complication": (_LESION, _LESION), + "contraindication": ({"Drug"}, _LESION | {"Symptom"}), + "treated_in_department": (_LESION, {"Department"}), + "positive_marker": (_LESION, {"Biomarker"}), + "negative_marker": (_LESION, {"Biomarker"}), + "associated_gene": (_LESION, {"Gene"}), + "has_morphology": (_LESION, {"Morphology"}), + "located_in": (_LESION | {"Symptom"}, {"Body"}), + "subtype_of": (_LESION, _LESION), + "treated_by_procedure": (_LESION, {"Procedure"}), + "adverse_reaction": ({"Drug"}, {"Symptom", "Disease"}), +} +_CONFLICTS = {("positive_marker", "negative_marker")} + + +class TripleValidator(Mapper): + def __init__(self, *args, **kwargs): + super().__init__(*args, **kwargs) + self.min_confidence = float(kwargs.get("minConfidence", 0.5)) + + @staticmethod + def _as_float(v: Any) -> float: + try: + return float(v) + except (TypeError, ValueError): + return 0.0 + + def execute(self, sample: Dict[str, Any]) -> Dict[str, Any]: + self.read_file_first(sample) + text = (sample.get(self.text_key, "") or "").strip() + try: + payload = json.loads(text) if text else {} + except json.JSONDecodeError: + payload = {} + triples = payload.get("triples", []) if isinstance(payload, dict) else [] + + valid, rejected = [], [] + seen, pair_rel = set(), {} + for t in triples: + if not isinstance(t, dict): + continue + head, tail = str(t.get("head", "")).strip(), str(t.get("tail", "")).strip() + rel = str(t.get("relation", "")).strip() + ht, tt = str(t.get("head_type", "")).strip(), str(t.get("tail_type", "")).strip() + conf = self._as_float(t.get("confidence", 0.0)) + + if not head or not tail or not rel: + rejected.append({"triple": t, "reason": "missing head/tail/relation"}); continue + if rel not in RELATION_CONSTRAINTS: + rejected.append({"triple": t, "reason": f"unknown relation '{rel}'"}); continue + head_ok, tail_ok = RELATION_CONSTRAINTS[rel] + if ht not in head_ok or tt not in tail_ok: + rejected.append({"triple": t, "reason": f"schema violation {ht}-{rel}->{tt}"}); continue + if conf < self.min_confidence: + rejected.append({"triple": t, "reason": f"low confidence {conf:.2f}"}); continue + key = f"{ht}:{head.lower()}|{rel}|{tt}:{tail.lower()}" + if key in seen: + continue + pair = (head.lower(), tail.lower()) + rels = pair_rel.setdefault(pair, set()) + conflict = next((r for r in rels if (r, rel) in _CONFLICTS or (rel, r) in _CONFLICTS), None) + if conflict: + rejected.append({"triple": t, "reason": f"conflicts with '{conflict}'"}); continue + rels.add(rel) + seen.add(key) + valid.append({ + "head": head, "head_type": ht, "relation": rel, + "tail": tail, "tail_type": tt, "confidence": round(conf, 3), + }) + + logger.info(f"TripleValidator: {len(valid)} valid / {len(rejected)} rejected") + sample[self.text_key] = json.dumps({"valid": valid, "rejected": rejected}, ensure_ascii=False, indent=2) + return sample diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/triple_validator/requirements.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/triple_validator/requirements.txt" new file mode 100644 index 0000000..8367e7d --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/datamate\347\256\227\345\255\220\345\214\205/\346\272\220\347\240\201/triple_validator/requirements.txt" @@ -0,0 +1 @@ +# No third-party dependencies; pure standard library. diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/.dockerignore" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/.dockerignore" new file mode 100644 index 0000000..2da1998 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/.dockerignore" @@ -0,0 +1,34 @@ +.git +.github +.env +.venv +.venv-neural +venv +env +__pycache__ +**/__pycache__ +*.py[cod] +.pytest_cache +.ruff_cache +.coverage +htmlcov + +# Runtime data and results are bind-mounted by compose.yaml. +data +outputs + +# Large or platform-specific artifacts are not required by MCP/A2A images. +finetune/outputs +NPU +datamate_ops/dist +演示视频录制与截图 + +# Local/transient files. +*.log +*.tmp +*.bak +dist +.idea +.vscode +.DS_Store +Thumbs.db diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/.env.example" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/.env.example" new file mode 100644 index 0000000..e245153 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/.env.example" @@ -0,0 +1,81 @@ +# ====== MediGraph-Agent configuration ====== +# Copy this file to ".env" and fill in your keys, then: the code auto-loads it. + +# ---- LLM provider selection ---- +# Which provider to use by default: siliconflow | dashscope | deepseek +LLM_PROVIDER=siliconflow + +# SiliconFlow (default). Get a key at https://siliconflow.cn +SILICONFLOW_API_KEY=sk-xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx +SILICONFLOW_BASE_URL=https://api.siliconflow.cn/v1 +SILICONFLOW_MODEL=Qwen/Qwen3.5-35B-A3B +EMBEDDING_MODEL=Qwen/Qwen3-Embedding-0.6B + +# Aliyun DashScope (fallback / alternative). https://bailian.console.aliyun.com +DASHSCOPE_API_KEY=sk-xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx +DASHSCOPE_BASE_URL=https://dashscope.aliyuncs.com/compatible-mode/v1 +DASHSCOPE_MODEL=qwen-plus + +# DeepSeek official API (another fallback / alternative). https://platform.deepseek.com +DEEPSEEK_API_KEY=sk-xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx +DEEPSEEK_BASE_URL=https://api.deepseek.com +DEEPSEEK_MODEL=deepseek-chat + +# ---- LLM call tuning ---- +LLM_TEMPERATURE=0.2 +LLM_MAX_RETRIES=3 +LLM_TIMEOUT=120 +LLM_ENABLE_THINKING=false # Qwen3 thinking mode; off=faster, on=better planning/NL2SQL + +# ---- Confidence-routed extraction ---- +# auto: neural L1 first, then lexicon/LLM fallback; neural: force GPLinker; fast: offline lexicon only; llm: legacy API only +EXTRACTION_BACKEND=auto +EXTRACTION_LLM_FALLBACK=true +EXTRACTION_ROUTE_THRESHOLD=0.55 +# NEURAL_EXTRACTOR_DIR=data/models/neural_extractor +# NEURAL_EXTRACTOR_THRESHOLD=0.0 +# NEURAL_EXTRACTOR_REL_THRESHOLD=0.0 +# FAST_EXTRACTOR_ARTIFACT=data/models/fast_extractor.json +# ENTITY_LINKER_ARTIFACT=data/models/entity_linker.json +# CALIBRATION_ARTIFACT=data/models/temperature_calibration.json + +# ---- Analytics backend (Task 3 relational layer) ---- +# sqlite -> file DB under outputs/ (zero-config default; CI and demos use this) +# postgres -> pooled PostgreSQL with real indexes; needs the container below: +# docker run -d --name medigraph-pg -e POSTGRES_PASSWORD=... -e POSTGRES_DB=medigraph \ +# -p 5433:5432 -v medigraph-pg-data:/var/lib/postgresql/data pgvector/pgvector:pg16 +# (host port 5433 because 5432/5434 are taken by the DataMate/Nexent stacks) +ANALYTICS_BACKEND=sqlite +POSTGRES_HOST=127.0.0.1 +POSTGRES_PORT=5433 +POSTGRES_USER=postgres +POSTGRES_PASSWORD=change-me +POSTGRES_DB=medigraph +PG_POOL_MIN=1 +PG_POOL_MAX=8 + +# ---- Redis result cache (extraction / NL2SQL responses) ---- +# docker run -d --name medigraph-redis -p 6380:6379 redis:7-alpine redis-server --appendonly yes +# (host port 6380 because 6379 is taken by the Nexent stack's Redis) +CACHE_ENABLED=false +REDIS_URL=redis://127.0.0.1:6380/0 +CACHE_TTL_SECONDS=3600 + +# ---- Knowledge-graph backend ---- +# local -> NetworkX + JSON (zero dependency, runs now) +# neo4j -> use a running Neo4j instance (set NEO4J_* below) +GRAPH_BACKEND=local + +NEO4J_URI=bolt://localhost:7687 +NEO4J_USER=neo4j +NEO4J_PASSWORD=neo4j-password + +# ---- Docker / platform integration ---- +# compose.yaml maps the project services to host ports 8011 and 8100. +MEDIGRAPH_MCP_PORT=8011 +MEDIGRAPH_A2A_PORT=8100 +MEDIGRAPH_A2A_PUBLIC_URL=http://host.docker.internal:8100 +DATAMATE_DOCKER_BASE=http://host.docker.internal:8080/api +FINETUNED_ORCHESTRATOR_DOCKER_URL=http://host.docker.internal:18088/v1/chat/completions +# false = compact deterministic/LLM-fallback image; true = also install torch/transformers. +MEDIGRAPH_INSTALL_NEURAL=false diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/Dockerfile" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/Dockerfile" new file mode 100644 index 0000000..b36f14c --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/Dockerfile" @@ -0,0 +1,31 @@ +# syntax=docker/dockerfile:1 + +ARG PYTHON_VERSION=3.11 +FROM python:${PYTHON_VERSION}-slim + +ARG INSTALL_NEURAL=false + +ENV PYTHONDONTWRITEBYTECODE=1 \ + PYTHONUNBUFFERED=1 \ + PIP_DISABLE_PIP_VERSION_CHECK=1 \ + PIP_NO_CACHE_DIR=1 + +WORKDIR /app + +COPY requirements-docker.txt requirements-docker-neural.txt ./ + +RUN python -m pip install --upgrade pip \ + && python -m pip install -r requirements-docker.txt \ + && if [ "${INSTALL_NEURAL}" = "true" ]; then \ + python -m pip install -r requirements-docker-neural.txt; \ + fi + +COPY . . + +RUN mkdir -p /app/data /app/outputs + +LABEL org.opencontainers.image.title="MediGraph Agent" \ + org.opencontainers.image.description="MediGraph MCP and A2A runtime" \ + org.opencontainers.image.licenses="MIT" + +CMD ["python", "-X", "utf8", "mcp_server/server.py"] diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/compose.yaml" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/compose.yaml" new file mode 100644 index 0000000..d3fa661 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/compose.yaml" @@ -0,0 +1,72 @@ +name: medigraph + +x-medigraph-common: &medigraph-common + build: + context: . + dockerfile: Dockerfile + args: + PYTHON_VERSION: ${MEDIGRAPH_PYTHON_VERSION:-3.11} + INSTALL_NEURAL: ${MEDIGRAPH_INSTALL_NEURAL:-false} + image: medigraph-agent:${MEDIGRAPH_IMAGE_TAG:-local} + env_file: + - path: .env + required: false + environment: + PYTHONUNBUFFERED: "1" + DATAMATE_BASE: ${DATAMATE_DOCKER_BASE:-http://host.docker.internal:8080/api} + FINETUNED_ORCHESTRATOR_URL: ${FINETUNED_ORCHESTRATOR_DOCKER_URL:-http://host.docker.internal:18088/v1/chat/completions} + FINETUNED_ORCHESTRATOR_MODEL: ${FINETUNED_ORCHESTRATOR_MODEL:-qwen3p5-0p8b-orchestrator} + extra_hosts: + - host.docker.internal:host-gateway + volumes: + - ./data:/app/data:ro + - ./outputs:/app/outputs + restart: unless-stopped + +services: + mcp: + <<: *medigraph-common + container_name: medigraph-mcp + command: ["python", "-X", "utf8", "mcp_server/server.py"] + environment: + PYTHONUNBUFFERED: "1" + MEDIGRAPH_MCP_HOST: 0.0.0.0 + MEDIGRAPH_MCP_PORT: "8011" + # Base URL the chat *user's browser* uses to open generated reports/graphs. + # Tools return links built from this, so a container path never leaks to the UI. + MEDIGRAPH_ARTIFACT_BASE_URL: ${MEDIGRAPH_ARTIFACT_BASE_URL:-http://localhost:8011} + DATAMATE_BASE: ${DATAMATE_DOCKER_BASE:-http://host.docker.internal:8080/api} + FINETUNED_ORCHESTRATOR_URL: ${FINETUNED_ORCHESTRATOR_DOCKER_URL:-http://host.docker.internal:18088/v1/chat/completions} + FINETUNED_ORCHESTRATOR_MODEL: ${FINETUNED_ORCHESTRATOR_MODEL:-qwen3p5-0p8b-orchestrator} + ports: + - "${MEDIGRAPH_MCP_PORT:-8011}:8011" + healthcheck: + test: + - CMD + - python + - -c + - "import socket; s=socket.create_connection(('127.0.0.1',8011),2); s.close()" + interval: 10s + timeout: 3s + retries: 12 + start_period: 15s + + a2a: + <<: *medigraph-common + container_name: medigraph-a2a + command: ["python", "-X", "utf8", "integration/a2a/a2a_server.py"] + environment: + PYTHONUNBUFFERED: "1" + MEDIGRAPH_A2A_PUBLIC_URL: ${MEDIGRAPH_A2A_PUBLIC_URL:-http://host.docker.internal:8100} + ports: + - "${MEDIGRAPH_A2A_PORT:-8100}:8100" + healthcheck: + test: + - CMD + - python + - -c + - "import urllib.request; urllib.request.urlopen('http://127.0.0.1:8100/.well-known/agent.json',timeout=2).read()" + interval: 10s + timeout: 3s + retries: 12 + start_period: 10s diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/config/__init__.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/config/__init__.py" new file mode 100644 index 0000000..e69de29 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/config/settings.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/config/settings.py" new file mode 100644 index 0000000..47980a3 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/config/settings.py" @@ -0,0 +1,187 @@ +"""Central configuration for MediGraph-Agent. + +All environment-variable access lives here (single source of truth), so the rest +of the code never reads os.environ directly. Values come from a .env file (loaded +via python-dotenv) or from the real environment. +""" +from __future__ import annotations + +import os +from dataclasses import dataclass +from pathlib import Path + +from dotenv import load_dotenv + +# Project root = the folder holding this config/ package. Load its .env if present. +PROJECT_ROOT = Path(__file__).resolve().parent.parent +load_dotenv(PROJECT_ROOT / ".env") + +OUTPUTS_DIR = PROJECT_ROOT / "outputs" +DATA_DIR = PROJECT_ROOT / "data" +MODEL_DIR = DATA_DIR / "models" +# Raw text corpus for Task-1 ETL + Task-2 extraction (built by data/prep/build_dataset.py +# from CMeIE-V2 + DiaKG + pathology). Name kept as RAW_DEMO_DIR for back-compat. +RAW_DEMO_DIR = DATA_DIR / "corpus" +CORPUS_DIR = DATA_DIR / "corpus" +KG_GRAPH = DATA_DIR / "kg" / "cm3kg_graph.json" +FAST_EXTRACTOR_ARTIFACT = MODEL_DIR / "fast_extractor.json" +ENTITY_LINKER_ARTIFACT = MODEL_DIR / "entity_linker.json" +CALIBRATION_ARTIFACT = MODEL_DIR / "temperature_calibration.json" +NEURAL_EXTRACTOR_DIR = MODEL_DIR / "neural_extractor" + + +@dataclass +class LLMConfig: + """Resolved LLM connection settings for the active provider.""" + + provider: str + api_key: str + base_url: str + model: str + temperature: float + max_retries: int + timeout: int + enable_thinking: bool = False + embedding_model: str = "Qwen/Qwen3-Embedding-0.6B" + + +def _get(name: str, default: str = "") -> str: + return os.getenv(name, default).strip() + + +def get_llm_config(provider: str | None = None) -> LLMConfig: + """Build the LLM config for the requested provider (default from env).""" + provider = (provider or _get("LLM_PROVIDER", "siliconflow")).lower() + + if provider == "dashscope": + api_key = _get("DASHSCOPE_API_KEY") + base_url = _get("DASHSCOPE_BASE_URL", "https://dashscope.aliyuncs.com/compatible-mode/v1") + model = _get("DASHSCOPE_MODEL", "qwen-plus") + elif provider == "deepseek": + api_key = _get("DEEPSEEK_API_KEY") + base_url = _get("DEEPSEEK_BASE_URL", "https://api.deepseek.com") + model = _get("DEEPSEEK_MODEL", "deepseek-chat") + else: + provider = "siliconflow" + api_key = _get("SILICONFLOW_API_KEY") + base_url = _get("SILICONFLOW_BASE_URL", "https://api.siliconflow.cn/v1") + model = _get("SILICONFLOW_MODEL", "Qwen/Qwen3.5-35B-A3B") + + return LLMConfig( + provider=provider, + api_key=api_key, + base_url=base_url, + model=model, + temperature=float(_get("LLM_TEMPERATURE", "0.2") or 0.2), + max_retries=int(_get("LLM_MAX_RETRIES", "3") or 3), + timeout=int(_get("LLM_TIMEOUT", "120") or 120), + enable_thinking=_get("LLM_ENABLE_THINKING", "false").lower() == "true", + embedding_model=_get("EMBEDDING_MODEL", "Qwen/Qwen3-Embedding-0.6B"), + ) + + +@dataclass +class GraphConfig: + backend: str # local | neo4j + neo4j_uri: str + neo4j_user: str + neo4j_password: str + + +def get_graph_config() -> GraphConfig: + return GraphConfig( + backend=_get("GRAPH_BACKEND", "local").lower() or "local", + neo4j_uri=_get("NEO4J_URI", "bolt://localhost:7687"), + neo4j_user=_get("NEO4J_USER", "neo4j"), + neo4j_password=_get("NEO4J_PASSWORD", "neo4j-password"), + ) + + +@dataclass +class AnalyticsConfig: + """Relational analytics backend selection. + + sqlite -> file DB under outputs/ (zero-config default, used by CI and demos) + postgres-> pooled PostgreSQL; same logical schema, adds real indexes/EXPLAIN + """ + + backend: str # sqlite | postgres + pg_host: str + pg_port: int + pg_user: str + pg_password: str + pg_database: str + pool_min: int + pool_max: int + + @property + def pg_dsn(self) -> str: + return ( + f"host={self.pg_host} port={self.pg_port} user={self.pg_user} " + f"password={self.pg_password} dbname={self.pg_database}" + ) + + +def get_analytics_config() -> AnalyticsConfig: + backend = _get("ANALYTICS_BACKEND", "sqlite").lower() or "sqlite" + if backend not in {"sqlite", "postgres"}: + backend = "sqlite" + return AnalyticsConfig( + backend=backend, + pg_host=_get("POSTGRES_HOST", "127.0.0.1"), + pg_port=int(_get("POSTGRES_PORT", "5433") or 5433), + pg_user=_get("POSTGRES_USER", "postgres"), + pg_password=_get("POSTGRES_PASSWORD", ""), + pg_database=_get("POSTGRES_DB", "medigraph"), + pool_min=int(_get("PG_POOL_MIN", "1") or 1), + pool_max=int(_get("PG_POOL_MAX", "8") or 8), + ) + + +@dataclass +class CacheConfig: + """Redis result cache for extraction / NL2SQL responses.""" + + enabled: bool + url: str + ttl_seconds: int + + +def get_cache_config() -> CacheConfig: + return CacheConfig( + enabled=_get("CACHE_ENABLED", "false").lower() == "true", + url=_get("REDIS_URL", "redis://127.0.0.1:6380/0"), + ttl_seconds=int(_get("CACHE_TTL_SECONDS", "3600") or 3600), + ) + + +@dataclass +class ExtractionConfig: + """Confidence-routed local/LLM extraction configuration.""" + + backend: str # auto | neural | fast | llm + neural_model_dir: Path + fast_artifact: Path + linker_artifact: Path + calibration_artifact: Path + route_threshold: float + neural_threshold: float + neural_rel_threshold: float + llm_fallback: bool + + +def get_extraction_config() -> ExtractionConfig: + backend = _get("EXTRACTION_BACKEND", "auto").lower() or "auto" + if backend not in {"auto", "neural", "fast", "llm"}: + backend = "auto" + return ExtractionConfig( + backend=backend, + neural_model_dir=Path(_get("NEURAL_EXTRACTOR_DIR", str(NEURAL_EXTRACTOR_DIR))), + fast_artifact=Path(_get("FAST_EXTRACTOR_ARTIFACT", str(FAST_EXTRACTOR_ARTIFACT))), + linker_artifact=Path(_get("ENTITY_LINKER_ARTIFACT", str(ENTITY_LINKER_ARTIFACT))), + calibration_artifact=Path(_get("CALIBRATION_ARTIFACT", str(CALIBRATION_ARTIFACT))), + route_threshold=float(_get("EXTRACTION_ROUTE_THRESHOLD", "0.55") or 0.55), + neural_threshold=float(_get("NEURAL_EXTRACTOR_THRESHOLD", "0.0") or 0.0), + neural_rel_threshold=float(_get("NEURAL_EXTRACTOR_REL_THRESHOLD", "0.0") or 0.0), + llm_fallback=_get("EXTRACTION_LLM_FALLBACK", "true").lower() == "true", + ) diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_000.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_000.txt" new file mode 100644 index 0000000..f6e6732 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_000.txt" @@ -0,0 +1 @@ +溶血性贫血@ * 获得性溶血性贫血可分为免疫性和非免疫性： * 自身抗体是免疫介导的溶血性贫血的病因，通常包含在其他自身免疫性疾病（例如系统性红斑狼疮、类风湿关节炎、硬皮病）中或与淋巴组织增生性疾病（例如非霍奇金淋巴瘤、慢性淋巴细胞白血病）有关。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_001.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_001.txt" new file mode 100644 index 0000000..148c076 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_001.txt" @@ -0,0 +1 @@ +女孩中约80%的中枢性性早熟患儿为特发性性早熟。 根据性早熟的发病机制和病因，可将之分为中枢性性早熟和外周性性早熟： 1.中枢性性早熟（central precocious puberty，CPP） 亦称完全性或真性性早熟，是指由于下丘脑-垂体-性腺轴功能提前激活，导致性腺发育及功能成熟，与正常青春发育成熟机制完全一致，并可具有一定的生育能力。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_002.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_002.txt" new file mode 100644 index 0000000..1554274 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_002.txt" @@ -0,0 +1 @@ +出生后感染性肺炎可出现发热或体温不升，反应差等全身症状。 维持正常血气 有低氧血症时可根据病情和血气分析结果选用鼻导管、面罩、鼻塞式CPAP给氧，使血气维持在正常范围。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_003.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_003.txt" new file mode 100644 index 0000000..e8616b7 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_003.txt" @@ -0,0 +1 @@ +白喉@## 鉴别诊断 ### 查看全部  ### 化脓性链球菌咽炎 体征/症状 检查 体征/症状 起病急，伴明显喉痛和发热。 白喉@有些患者出现细小的丘疹，伴口周苍白和草莓舌（猩红热）。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_004.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_004.txt" new file mode 100644 index 0000000..5c3a431 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_004.txt" @@ -0,0 +1 @@ +【临床表现】 在室间隔完整的大动脉转位新生儿，两大循环间的交换血流量少，存在着明显的青紫（室间隔完整和血液混合不充分的新生儿青紫明显），可在出生后数小时内即被发现，且大多情况下为唯一症状。随着肺动脉高压的发展，逐渐出现第三心音、心力衰竭引起的奔马律及肺动脉第二音亢进，在心尖处可闻及因肺静脉血流增加而产生的舒张中期杂音。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_005.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_005.txt" new file mode 100644 index 0000000..69e5577 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_005.txt" @@ -0,0 +1 @@ +高血压脑病：由于脑血管痉挛，导致缺血、缺氧、血管渗透性增高而发生脑水肿。年长儿会主诉剧烈头痛、呕吐、复视或一过性失明，严重者突然出现惊厥、昏迷。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_006.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_006.txt" new file mode 100644 index 0000000..e848d56 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_006.txt" @@ -0,0 +1 @@ +转移性乳腺癌@ 三线选择 * 如果考虑进一步激素治疗，则可应用孕酮类药物，例如甲地孕酮。转移性乳腺癌@不过，每一种后续治疗的有效期似乎越来越短，直至不得不进行化疗。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_007.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_007.txt" new file mode 100644 index 0000000..16cac83 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_007.txt" @@ -0,0 +1 @@ +急性淋巴细胞白血病@ ### 案例 #2 一位4岁女孩出现昏睡、呼吸困难、发热及瘀斑。急性淋巴细胞白血病@体格检查显示肝脾肿大，胸片显示纵膈肿块与胸腔积液。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_008.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_008.txt" new file mode 100644 index 0000000..c51c2ab --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_008.txt" @@ -0,0 +1 @@ +消化性溃疡病@## 并发症 ### 查看全部   并发症 table 并发症 | 时间表 | 可能性 ---|---|--- ### 溃疡穿透消化道壁 | 长期 | 低 慢性溃疡可穿透整个胃壁或十二指肠壁，并进入胰腺等邻近器官，但未发生溃破进入腹腔。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_009.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_009.txt" new file mode 100644 index 0000000..612e84e --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_009.txt" @@ -0,0 +1 @@ +1.典型的21-羟化酶缺乏症的临床表现 （1）单纯男性化型： 21-羟化酶缺乏症部分性缺乏，占21-羟化酶缺乏症患者总数25%。出生时外生殖器似正常，少数有轻度的阴茎增大，阴囊色素沉着。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_010.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_010.txt" new file mode 100644 index 0000000..568b713 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_010.txt" @@ -0,0 +1 @@ +第十九章 进行性肌营养不良 进行性肌营养不良（progressive muscular dystrophy）是一组遗传性骨骼肌变性疾病，临床表现为进行性肌无力和肌萎缩，最终完全丧失运动功能。 （二）支持治疗 为保持肌肉功能及预防挛缩，进行适度运动甚为重要，不宜久卧床上。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_011.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_011.txt" new file mode 100644 index 0000000..4f9e41e --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_011.txt" @@ -0,0 +1 @@ +慢性阻塞性肺疾病@[ 结核病 ](/topics/zh-cn/165) ### 细支气管炎 体征/症状 检查 体征/症状 细支气管炎可能累及幼年患者。慢性阻塞性肺疾病@胸部 X 线检查显示过度充气。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_012.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_012.txt" new file mode 100644 index 0000000..2973fb5 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_012.txt" @@ -0,0 +1 @@ +婴儿猝死综合征@### 非意外外伤或虐待性伤害，包括代理型孟乔森综合征 体征/症状 检查 体征/症状 外伤的迹象，包括非常见部位瘀青、肋骨骨折、长骨螺旋型骨折和视网膜出血。 婴儿猝死综合征@存在腹内损伤（例如肝/空腔脏器损伤）。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_013.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_013.txt" new file mode 100644 index 0000000..b490d49 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_013.txt" @@ -0,0 +1 @@ +（二）血氨 部分患者血氨增高。 （四）凝血酶原时间和肝促凝血活酶试验 AHF时，凝血酶原时间（prothrombin time，PT）总是延长的。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_014.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_014.txt" new file mode 100644 index 0000000..84fc86b --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_014.txt" @@ -0,0 +1 @@ +（四）呕吐 患儿可出现呕吐，呕吐物可呈咖啡样或带胆汁。 【X线检查】 腹部X线平片检查对诊断NEC有非常大的价值，但早产儿NEC表现不典型，要多次随访检查，观察动态变化。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_015.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_015.txt" new file mode 100644 index 0000000..720d867 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_015.txt" @@ -0,0 +1 @@ +铅中毒@对于非妊娠成人，如果血铅水平＞3.4 μmol/L (＞70 μg/dL)，可考虑给予琥巯酸或依地酸钙钠单药治疗。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_016.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_016.txt" new file mode 100644 index 0000000..9360365 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_016.txt" @@ -0,0 +1 @@ +在以免疫复合物介导的疾病中，补体下降往往提示疾病活动，免疫复合物介导的肾炎尤其如此，如狼疮肾炎、血清病、链球菌感染后肾炎、冷球蛋白血症及部分与风湿性疾病相关的肾炎（如多动脉炎肾炎）。 （2）抗细胞质抗体： 如抗线粒体抗体、核糖体抗体及溶酶体抗体等，引起相应的病变。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_017.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_017.txt" new file mode 100644 index 0000000..2651ade --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_017.txt" @@ -0,0 +1 @@ +多发性硬化症@ 患者还需要在用药开始后 3 至 4 个月复查 OCT。多发性硬化症@应当监测患者是否发生严重头痛，它可能由血管痉挛及呼吸短促和肺活量下降等肺部问题引起。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_018.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_018.txt" new file mode 100644 index 0000000..70dc368 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_018.txt" @@ -0,0 +1 @@ +近年来推荐新的诊断标准：典型临床特征（呼吸道症状、胃肠道、泌尿生殖系统症状），或同胞中有CF患儿，或新生儿筛查试验阳性，加下列CFTR功能紊乱的实验室证据之一即可诊断：两个不同日期采集的汗液Cl-含量升高，鉴定出两种CF突变，鼻上皮电位差测定异常。设法去除呼吸道内黏稠分泌物，加强肺部物理治疗，尤其是胸部叩打和体位引流，根据病情每天1～4次；注意口服补液或静脉补液，尤其是炎热季节及伴发急性胃肠炎时，防止脱水和气道分泌物干燥黏稠；雾化吸入0. 45～0. 9%氯化钠可湿化气道、稀化痰液，亦可加用人重组DNA酶（2. 5mg，每天1次）雾化吸入。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_019.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_019.txt" new file mode 100644 index 0000000..8fda37a --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_019.txt" @@ -0,0 +1 @@ +细菌性脑膜炎@[ 癫痫发作概述 ](/topics/zh-cn/112) ### 硬膜下积液 | 存在差异 | 中 可见于三分之一患者。细菌性脑膜炎@通常与 _流感嗜血杆菌_ 和 _肺炎双球菌_ 有关。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_020.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_020.txt" new file mode 100644 index 0000000..7def640 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_020.txt" @@ -0,0 +1 @@ +临床上较难发现未累及肺泡与肺泡间壁的纯粹毛细支气管炎，故国内认为是一种特殊类型的肺炎,称为喘憋性肺炎。 【病因】 主要由呼吸道合胞病毒（RSV)引起，副流感病毒、腺病毒、鼻病毒、人类偏肺病毒（hMPV)、博卡病毒（bocavirus)、肺炎支原体也可引起本病。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_021.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_021.txt" new file mode 100644 index 0000000..36c2f4c --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_021.txt" @@ -0,0 +1 @@ +图12-2 Bartter综合征的诊断步骤 【鉴别诊断】 1.原发性醛固酮增多症 可出现低血钾和高醛固酮血症，但有高血压和低肾素血症，对血管紧张素反应敏感。 【治疗】 1.补钾 长期大剂量口服氯化钾以纠正低血钾，剂量＞10mmol/（kg•d），年长儿有时高达500mmol/d，但大剂量可致胃部不适和腹泻，难以耐受。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_022.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_022.txt" new file mode 100644 index 0000000..b591339 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_022.txt" @@ -0,0 +1 @@ +注意排除继发性肺含铁血黄素沉着症，如继发于二尖瓣狭窄以及任何原因引起的左心衰竭，或肺内毛细血管压力长期增高的心脏病患者及结缔组织疾病如结节性多发性动脉炎、类风湿病、过敏性紫癜。肾上腺皮质激素治疗无效者可试用免疫抑制剂，如硫唑嘌呤、环磷酰胺，疗程一般3个月，可与肾上腺皮质激素联合应用。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_023.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_023.txt" new file mode 100644 index 0000000..8c163cd --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_023.txt" @@ -0,0 +1 @@ +抗菌谱广，口服体内吸收良好，毒性反应低，对假丝酵母菌病疗效均显著。 4.氟康唑（fluconazole) 双三唑类抗真菌药，作用机制和抗菌谱与酮康唑相似，体内抗真菌活性比酮康唑强,生物利用度高，口服吸收好,对假丝酵母菌有效。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_024.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_024.txt" new file mode 100644 index 0000000..adfa36a --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_024.txt" @@ -0,0 +1 @@ +对肾实质性ARF，治疗原则如下： （一）少尿期治疗 1.一般治疗 保证热量230～251kJ/（kg•d）［55～60kcal/（kg•d）］，给予低盐、低蛋白、低钾、低磷饮食，蛋白每日摄入量为0. 3～1. 0g/kg，且为优质蛋白，因此可输注5. 53%肾必氨（9R）3～5ml/（kg•d）。 5.促蛋白合成激素 苯丙酸诺龙25mg/d，每周1～2次。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_025.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_025.txt" new file mode 100644 index 0000000..6ff58d0 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_025.txt" @@ -0,0 +1 @@ +第四节 毛细支气管炎 毛细支气管炎（bronchiolitis）是婴儿期常见的下呼吸道炎症性疾病。及时补充液体，维持水、电解质、酸碱平衡。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_026.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_026.txt" new file mode 100644 index 0000000..4986371 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_026.txt" @@ -0,0 +1 @@ +唇腭裂@## 治疗流程 请注意，同一药物不同名称的剂型和剂量可能不同： [ 参见免责声明 ](https://bestpractice.bmj.com/info/disclaimer/) 疾病持续状态 ### 完全性唇腭裂 查看全部   首选 –   特殊喂养 尽管鼻胃管饲很少需要，但若出现喂养困难可能需要延长住院时间。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_027.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_027.txt" new file mode 100644 index 0000000..fdf7f2b --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_027.txt" @@ -0,0 +1 @@ +以上四种并发症多见于金黄色葡萄球菌肺炎、耐药肺炎链球菌肺炎和某些革兰氏阴性杆菌肺炎 (Gram-negative bacillary pneumonia，GNBP ) 0 支气管扩张（bronchiectasis)肺炎部位支气管阻塞，腔内淤滞的分泌物造成对支气管壁的压力，日久造成远端扩张。X线片由于分辨率不高,易遗漏部分支气管扩张病变，而肺部CT，尤其高分辨CT(HRCT)能细致地显示病变，不易漏诊。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_028.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_028.txt" new file mode 100644 index 0000000..c8b3d44 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_028.txt" @@ -0,0 +1 @@ +提示颅内压增高的特征包括颅缝裂开、脑回压迹加深以及蛛网膜颗粒压迹增大加深，蝶鞍扩大，鞍背及前后床突的吸收或破坏等。 （1）20%甘露醇： 0. 25～1. 5g/kg，静脉推入，每4～6小时一次。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_029.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_029.txt" new file mode 100644 index 0000000..bd695b4 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_029.txt" @@ -0,0 +1 @@ +前置胎盘@可以采用经阴道、经腹部或经会阴超声（在大多数情况下没有帮助，但如果可行，也是一种选择，且存在阴道出血和可能导致宫颈扩张的顾虑），但首选经阴道超声。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_030.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_030.txt" new file mode 100644 index 0000000..a0c6635 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_030.txt" @@ -0,0 +1 @@ +夜盲或暗光中视物不清最早出现，持续数周后，开始出现干眼症的表现，外观眼结膜、角膜干燥，失去光泽，自觉痒感,泪减少，眼部检查可见结膜近角膜边缘处干燥起皱褶，角化上皮堆积形成泡沫状白斑，称结膜干燥斑或毕脱斑(Bitot’s spots)。严重时可发生角膜溃疡、坏死引起穿孔,虹膜、晶状体脱出，导致失明。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_031.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_031.txt" new file mode 100644 index 0000000..8765de3 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_031.txt" @@ -0,0 +1 @@ +肝硬化@### 胸壁特征（例如男子女性型乳房） 慢性肝病胸部典型体征包括：男子女性型乳房（乳核发育）、男性丧失第二性征、女性乳房萎缩。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_032.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_032.txt" new file mode 100644 index 0000000..27559e3 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_032.txt" @@ -0,0 +1 @@ +第七节 系统性红斑狼疮性肾炎 系统性红斑狼疮（systemic lupus erythematosus，SLE）是一种公认的自身免疫性疾病，其病变大多累及数个系统或器官。本病多发于青少年女性，男女比例为1∶7～1∶9。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_033.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_033.txt" new file mode 100644 index 0000000..3cdab45 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_033.txt" @@ -0,0 +1 @@ +血管炎综合征@ 和其他风湿病相比，血管炎综合征男孩受累多于女孩。血管炎综合征@过敏性紫癜和川崎病是儿童常见的血管炎，分别影响小血管和中等大小血管；其次为大动脉炎，是唯一影响大血管的血管炎；结节性多动脉炎、变应性肉芽肿（allergic granulomatosis Churg-Strauss syndrome）和韦格纳肉芽肿（Wegner granulosis）则儿童相对少见，其他如白塞病（Bechet syndrome）、Cogan综合征及淋巴瘤肉芽肿，在儿童期更为少见。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_034.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_034.txt" new file mode 100644 index 0000000..85bc7fb --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_034.txt" @@ -0,0 +1 @@ +胃癌@ ### 转移性疾病 化疗联合或不联合放疗 * 对于转移性胃癌患者，化疗与最佳支持治疗相比，可以改善患者的生活质量及生存情况。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_035.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_035.txt" new file mode 100644 index 0000000..ec2db72 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_035.txt" @@ -0,0 +1 @@ +消化性溃疡病@## 监测 胃溃疡者在开始接受治疗后6到8周需要复查胃镜，以此来确定溃疡愈合情况，并且由于小部分胃癌可表现和胃溃疡相似，复查胃镜还可以排除胃癌。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_036.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_036.txt" new file mode 100644 index 0000000..e2e5a32 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_036.txt" @@ -0,0 +1 @@ +类风湿关节炎@### 首次就诊时为高疾病活动度：未妊娠/计划妊娠 查看全部   首选 –   甲氨蝶呤 #### 第一选择 [ 甲氨蝶呤 ](/druglink?dd=MARTINDALE) open_in_new : 7.5mg-25mg，口服/肌内注射，每周1次，每周同一天给药 若患者处于严重疾病状态（如胸膜炎、间质性肺病、心包炎及炎性眼病）并伴有预后不良因素（如RF阳性和/或抗- CCP抗体阳性、初期骨侵蚀的影像学证据等），初始治疗应更为积极，可加用生物制剂（TNF-α抑制剂或阿巴西普） 然而，许多临床医生仍首选尝试单药治疗，且必要时只加用一种生物制剂。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_037.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_037.txt" new file mode 100644 index 0000000..54daf32 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_037.txt" @@ -0,0 +1 @@ +脑面血管瘤病@约90%病人有癫痫发作，多表现为血管痣对侧肢体局限性运动性发作，全身大发作少见，部分患儿也可表现为婴儿痉挛、肌阵挛性发作、失张力性发作或复杂部分性发作等。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_038.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_038.txt" new file mode 100644 index 0000000..fb073f8 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_038.txt" @@ -0,0 +1 @@ +气相色谱-质谱技术（gas chromatography mass spectrometry，GC/MS）对诊断有机酸尿症和某些疾病有重要意义。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_039.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_039.txt" new file mode 100644 index 0000000..ba3275e --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/cmeie_039.txt" @@ -0,0 +1 @@ +【治疗】 （一）复温 是治疗新生儿硬肿症低体温的重要措施。 （三）纠正器官功能紊乱 1. DIC治疗 重症硬肿常伴有DIC是硬肿症死亡的重要原因，抓紧高凝期治疗是关键。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_1.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_1.txt" new file mode 100644 index 0000000..9c7dfae --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_1.txt" @@ -0,0 +1,83 @@ +中国成人2型糖尿病胰岛素促泌剂应用的专家共识 +随着社会经济的发展，糖尿病患病率逐渐增加，已成为严重的世界性问题。糖尿病特别是其慢性并发症影响患者的生活质量，甚至威胁患者的生命，给社会、家庭以及患者带来沉重的经济负担。中国的流行病学调查显示，中国20岁以上人群2型糖尿病患病率达9.7%；且近2/3的患者HbA1c得不到有效控制(HbA1c≤7%)；60.7%的患者因未被诊断而无法及早进行有效的治疗和指导。 +中国成人2型糖尿病发生的病理生理特点与欧美国家存在差异，β细胞胰岛素分泌功能下降比胰岛素敏感性降低更明显，且糖尿病肾病发生率更高(2c级，2b级)。因此根据中国2型糖尿病患者自身特点，进行合理的降糖治疗，努力控制其他多种血管病变危险因素，降低血管并发症风险和提高患者生活质量是目前亟需解决的问题。尽管随着糖尿病防治进展，新降糖药物不断问世，而多数权威指南仍将胰岛素促泌剂作为成人2型糖尿病治疗的一线药物。英国糖尿病前瞻性研究(UKPDS)及其后续研究与糖尿病和心血管疾病行动(ADVANCE)等多个大型临床研究证实，磺脲类促泌剂或以其为基础的降糖治疗可显著提高2型糖尿病患者的血糖达标率，降低糖尿病血管并发症风险(1b级)。由于胰岛素促泌剂的发展，其种类逐渐增多，为了针对中国成人2型糖尿病患者的自身特点，更有效指导临床正确使用胰岛素促泌剂，中华医学会内分泌分会组织专家对胰岛素促泌剂在中国成人2型糖尿病的临床应用进行了多次认真的讨论并达成了共识。 +共识中的证据等级根据牛津循证医学中心的标准分类如(表1)。 +糖尿病发病机制与中国2型糖尿病患者特点 +胰岛素抵抗和β细胞胰岛素分泌缺陷是2型糖尿病发病的两大因素，胰岛素抵抗常常是2型糖尿病发生的始动因素，但如果β细胞胰岛素分泌功能保持其代偿能力，2型糖尿病并不会发生，因此，β细胞胰岛素分泌功能缺陷是2型糖尿病发病病的中心环节之一(5级)。 +事实上在糖尿病诊断前约10~15年，β细胞胰岛素分泌功能已开始逐渐下降(2b级)。 +在中国新诊断2型糖尿病患者中，胰岛素抵抗为主、胰岛素分泌缺陷为主以及胰岛素分泌缺陷伴胰岛素抵抗的患者各占约1/3(2c级)。对中国新诊断2型糖尿病患者的调查发现，随着空腹血糖水平增高，患者胰岛素分泌功能的下降较胰岛素敏感性降低更明显，且非肥胖(体重指数<24kg/m2)的2型糖尿病患者胰岛素分泌功能更差(2c级)。 +因此中国2型糖尿病患者更应关注β细胞胰岛素分泌功能的异常。 +胰岛素促泌剂的分类 +目前国内常用的胰岛素促泌剂分为磺脲类和格列奈类。 +磺脲类促泌剂包括半衰期较短的短效促泌剂(如：格列吡嗪和格列喹酮)和半衰期较长的中长效促泌剂(如普通剂型的格列美脲、格列本脲和格列齐特，以及改良剂型的格列吡嗪控释片和格列齐特缓释片)。 +格列奈类促泌剂半衰期较短，包括瑞格列奈和那格列奈。 +常用的各种胰岛素促泌剂的药理特点如下(表2)。 +胰岛素促泌剂的降糖机制 +一、促胰岛素分泌作用 +现有胰岛素促泌剂均通过与胰岛β细胞膜ATP依赖钾(KATP)通道的磺脲类受体(SUR)-1结合，促使KATP通道关闭，从而刺激内源性胰岛素分泌。 +促胰岛素分泌的差异取决于不同药物的药代动力学特性、与SUR一1结合的亲和力以及解离速度。 +KATP通道也存在于其他许多组织，包括大脑、心机和血管平滑肌细胞。 +不同组织的SUR存在差异，且胰岛素促泌剂会与β细胞不同分子量的SUR受体结合，这些是其产生药效学差异的原因(5级)。 +二、部分胰岛素增敏作用 +近年采用葡萄糖钳夹技术研究发现，磺脲类促泌剂可使人体外周葡萄糖利用增加10%~52%(平均29%)，但大多数学者认为，此作用可能主要是继发于葡萄糖毒性作用的改善 +三、其他降糖机制 +磺脲类促泌剂还可以通过其他机制降低血糖。 +Simonson等和Best等证明了磺脲类促泌剂降低空腹血糖的作用还与其抑制基础肝糖的生成密切相关(5级)。 +胰岛素促泌剂的临床效果 +一、降糖效果 +胰岛素促泌剂降糖作用强，且降糖作用在常规剂量内呈剂量依赖性，除那格列奈外单药治疗一般可平均降低HbA1c2%左右，甚至降低2%以上(5级)；且患者基线HbA1c越高，服用胰岛素促泌剂治疗后HbA1c的降低幅度越大(2b级)。 +1.磺脲类促泌剂：磺脲类促泌剂是一类应用时间长、降糖疗效肯定、安全性高的降糖药物。 +(1)短效促泌剂：短效磺脲类及格列奈类促泌剂半衰期短，作用迅速，主要降低2型糖尿病患者餐后血糖，主要包括：格列喹酮和格列吡嗪、瑞格列奈和那格列奈等。 +(2)中长效促泌剂：中长效磺脲类促泌剂半衰期长，作用较持久，明显降低2型糖尿病患者空腹和餐后血糖。包括自身半衰期较长的普通剂型磺脲类促泌剂，如格列本脲和格列美脲，以及剂型改良后的缓控释制剂，如格列齐特缓释片、格列吡嗪控释片。格列本脲与β细胞膜SUR亲和力强，降糖疗效强，但低血糖的发生率高(1a级)。格列美脲与β细胞膜SUR结合及解离的速度较格列本脲为快，低血糖发生率有所降低(2b级)；且在血糖控制相同的情况下格列美脲较格列本脲治疗时的空腹及餐后胰岛素和C肽水平为低(2b级)。格列吡嗪控释片通过胃肠道治疗系统(GITS)技术实现控释，格列齐特缓释片采用以亲水性羟丙甲纤维素为基质的缓释技术，可保持全天血药浓度平稳。其活性成分的释放更符合2型糖尿病患者24h血糖变化特点，低血糖尤其是严重低血糖的发生更少(4级)。 +2.格列奈类促泌剂：格列奈类促泌剂直接刺激胰岛β细胞分泌胰岛素，其最大特点是改善早相分泌，起效快、作用时间短，以降低餐后血糖为主，且低血糖风险小、受肾功能影响小(3b级)。一般需1日多次服用。 +二、减少或延缓微血管及大血管并发症发生和发展的效果 +2.大血管并发症：对新诊断的2型糖尿病患者，UKPDS以格列本脲和氯磺丙脲为基础的降糖治疗，其后续研究5年随访未显示明显的大血管获益，10年随访心肌梗死风险下降15%(P=0.01，1b级)。对病程较长且合并心血管高危因素的患者，ADVANCE发现以格列齐特缓释片为基础的降糖治疗5年，HbA1c降至6.5%时，心血管死亡相对风险下降12%(P=0.12，1b级)。对伴有持续性微量白蛋白尿的非超重2型糖尿病患者，Steno-2研究结果显示，采用以格列齐特为基础的降糖治疗，结合多因素强化干预，心血管疾病相对风险下降53%(P=0.008，1b级)。对UKPDS和ADVANCE等研究的meta分析结果显示，以氯磺丙脲、格列本脲和格列齐特缓释片为基础的降糖治疗可使2型糖尿病患者非致死性心肌梗死风险显著降低17%、冠心病风险显著降低15%(1a级)。 +三、降低全因死亡的效果 +由于糖尿病使心脏病或卒中风险加倍，多数医生和患者非常关注心脑血管疾病，而糖尿病导致死亡的其他因素却较少受到关注。近期的一项研究显示，40%的糖尿病患者死于非心血管疾病，包括肾病、感染、癌症、老年痴呆症、慢性阻塞性肺疾病、神经系统疾病等，提示关注糖尿病患者全因死亡非常重要(2b级)。 +ADVANCE显示以格列齐特缓释片为基础的强化降糖治疗组，随访5年，，全因死亡有降低的趋势(1b级)。 +UKPDS试验后继续10年的随访结果显示：格列本脲和氯磺丙脲治疗组的患者，全因死亡风险下降13%(P=0.007，1b级)。 +安全性 +一、低血糖风险 +磺脲类促泌剂可导致低血糖的发生，但剂型改良后的缓释、控释制剂、格列奈类及格列美脲低血糖发生率相对较低。GUIDE研究结果显示，在血糖水平控制相似的情况下，不同磺脲类促泌剂所致低血糖发生风险不同(1b级)。ADVANCE以格列齐特缓释片为基础的降糖治疗严重低血糖年发生率仅为UKPDS采用格列本脲和氯磺丙脲为基础的降糖治疗的1/4(1b级)。因此，应根据不同胰岛素促泌剂的特点及糖尿病患者的血糖谱选择合适的胰岛素促泌剂，从而在保证降糖疗效的同时降低低血糖发生风险。 +二、对体重的影响 +肥胖是多种慢性疾病特别是心脑血管疾病发生、进展的危险因素，因此应该高度重视。一般认为磺脲类药物治疗可引起体重增加。 +UKPDS表明，以格列本脲为基础的降糖治疗，患者体重增加1.7kg(1b级)。 +而ADVANCE以格列齐特缓释片为基础的联合降糖治疗，随访5年，平均体重并未增加(1b级)。 +剂型改良后的磺脲类促泌剂、格列奈类及格列美脲对体重影响较小。 +三、对β细胞功能的影响 +UKPDS的结果显示，接受格列本脲和氯磺丙脲治疗的患者β细胞胰岛素分泌功能有下降趋势，但与采用二甲双胍治疗和单纯饮食控制相似(2b级)。糖尿病进展实验(ADOPT)对比了3种不同类型降糖药物(罗格列酮、格列本脲和二甲双胍)在新诊断2型糖尿病患者中的疗效，对该研究分析发现，格列本脲组在治疗早期对β细胞胰岛素分泌功能显著优于罗格列酮和二甲双胍(2b级)。 +因此，磺脲类胰岛素促泌剂并不加速β细胞胰岛素分泌功能的衰竭。 +四、肿瘤风险 +研究表明2型糖尿病患者的肿瘤风险增加，目前没有胰岛素促泌剂增加肿瘤风险的确切证据。 +近期发表的ADVANCE亚组分析显示，以格列齐特缓释片为基础的降糖治疗，并不增加患者肿瘤风险(2b级)。 +五、心血管风险 +美国大学组糖尿病研究项目(UGDP)研究提出，甲苯磺丁脲可能增加2型糖尿病患者心血管死亡风险。 +但UKPDS、ADOPT及ADVANCE并未发现格列本脲和格列齐特缓释片增加心血管风险(1b级，2b级)。 +六、其他不良反应 +胰岛素促泌剂其他少见不良反应包括头晕、乏力、头痛、皮疹、恶心和胃肠道不良反应(呕吐、腹痛、腹泻等)。 +一般对症处理和调理药物剂量后上述症状可以缓解或消失。 +新型的如格列美脲、格列奈类及剂型改良后的磺脲类促泌剂，这些情况更少见。 +胰岛素促泌剂用药原则 +一、胰岛素促泌剂总的用药原则 +1.胰岛素促泌剂的适应证：胰岛素促泌剂可作为2型糖尿病患者的一线用药。一般而言，有一定β细胞功能、无胰岛素促泌剂使用禁忌的2型糖尿病患者可考虑选用胰岛素促泌剂，为不适合使用二甲双胍的2型糖尿病患者的治疗首选，或其他口服降糖药物治疗血糖控制不佳的2型糖尿病患者联合用药方案首选(5级)。 +2.胰岛素促泌剂的禁忌证：药物过敏、1型糖尿病、糖尿病酮症酸中毒、高糖性高渗透压综合征、严重肝或肾损伤和哺乳期患者等。 +3.胰岛素促泌剂的联合用药原则：2型糖尿病患者，若胰岛素促泌剂单药治疗血糖控制不佳，应与其他降糖药物如双胍类、α-糖苷酶抑制剂或噻唑烷二酮类药物联用。 +联合治疗时应注意以下事项：(1)应选择作用机制互补的降糖药物(5级)；(2)一般联合2种药物，最多可联用3种药物，若血糖仍得不到有效控制，应及时启动胰岛素治疗(5级)；(3)联合用药应考虑价效因素，尽量减轻患者经济负担；(4)磺脲类促泌剂与格列奈类促泌剂虽然在分子结构和作用靶位上存在不同，但两者合用的临床证据尚不充分，一般不推荐两者联用。 +二、不同血糖谱的选药原则 +在选择胰岛素促泌剂治疗时，可根据患者血糖选择不同类型胰岛素促泌剂(5级)：(1)以餐后血糖(PPG)升高为主者，宜选择格列吡嗪、格列奈类促泌剂；(2)以空腹血糖(FPG)升高为主者，宜选择依从性好、低血糖发生风险低的中长效磺脲类促泌剂；(3)餐后血糖和空腹血糖均升高者，宜选择依从性好、低血糖发生风险低的中长效磺脲类促泌剂。 +三、老年糖尿病患者(≥65岁) +老年患者应根据脏器功能、认知功能以级预期寿命选择不同胰岛素促泌剂治疗，但总体而言，治疗措施应尽量简单易行，并充分考虑肝肾功能减退程度(5级)。若患者既往有严重低血糖史、合并其他严重疾病、预期生存期较短，宜选择作用时间较短的格列奈类促泌剂；若患者脏器功能和认知能力良好、预期生存期较长，可选择低血糖少等安全性较好的磺脲类促泌剂。 +四、低血糖高危险人群 +糖尿病病程长(>15年)、有“无感知”低血糖病史、存在肝肾功能不全或全天血糖波动较大并反复出现低血糖症状的患者给予胰岛素促泌剂治疗时，应选择格列奈类促泌剂或低血糖风险较低的磺脲类促泌剂(1b级，5级)；一般应小剂量开始使用。 +五、其他情况 +目前关于妊娠期糖尿病或妊娠期显性糖尿病或孕前2型糖尿病患者妊娠期间及哺乳期使用胰岛素促泌剂的临床证据尚不太充分，一般情况下国内不推荐孕妇及哺乳期患者应用胰岛素促泌剂治疗。 +对伴有中度肾功能不全患者，应首选胰岛素，也可选择经肾排泄少的胰岛素促泌剂，如瑞格列奈或格列喹酮，并根据肾功能水平适当降低胰岛素促泌剂的使用剂量。 +对短期接受胰岛素强化治疗后的患者，可选择胰岛素促泌剂治疗。 +对依从性差的患者，尤其是在中国农村地区的患者，宜选择低血糖风险低、对体重影响小及廉价的1日1次磺脲类促泌剂(4级)。 +总结 +迄今为止，胰岛素促泌剂在2型糖尿病治疗中仍占据不可或缺的地位，为多数权威2型糖尿病防治指南中的一线降糖药物。中国成人2型糖尿病患者体重指数较低、糖尿病肾病发生率较高且β细胞胰岛素分泌功能比胰岛素敏感性降低更明显，胰岛素促泌剂更符合中国成人2型糖尿病患者特点。 +磺脲类药物，经长时间应用及大型临床研究证实，降糖疗效肯定且降HbA1c作用强、安全性高，可减少微血管并发症的发生，早期使用还可减少大血管并发症和全因死亡的发生。 +格列奈类有效降低餐后血糖，在中国也广泛使用。 +由于患者的耐受性、依从性及经济条件差别较大，因此，在临床实践中应根据患者特点，选用合适的胰岛素促泌剂。 +1.微血管并发症：UKPDS证实，以氯磺丙脲、格列本脲为基础的降糖治疗，可减少新诊断2型糖尿病患者的微血管复合终点风险25%(P=0.0099)，其中视网膜病变风险下降29%(P=0.0031，1b级)；9年随防时微量白蛋白尿和大量白蛋白尿发生的相对风险分别下降24%(P=0.00062)和33%(P=0.026，1b级)。ADVANCE对病程较长，合并心血管高危因素的2型糖尿病患者采用以格列齐特缓释片为基础的降糖治疗，主要微血管事件减少14%(P=0.01)，肾脏事件减少21%(P=0.006，1b级)。 +优化的降糖治疗不仅只针对胰岛素分泌缺陷，还应同时关注其他发病机制(如胰岛素抵抗、能量摄取等)。胰岛素促泌剂与其他作用机制互补的药物联用，可多方面干预糖尿病发病环节，使患者血糖得到长期、有效、平稳及安全的控制。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_10.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_10.txt" new file mode 100644 index 0000000..f850617 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_10.txt" @@ -0,0 +1,74 @@ +糖尿病周围神经病诊断和治疗共识 +糖尿病周围神经病(diabetic peripheral neuropathy，DPN)是糖尿病的常见并发症，临床表现包括多种类型，其中以远端对称性多发性周围神经病(distal symmetric polyneuropathy，DSPN)和自主神经病最为常见。 +早期识别和治疗DPN，对于改善患者预后具有重要意义。 +一、临床症状和体征 +通过详细的病史询问和体格检查，寻找周围神经受累的证据是诊断DPN的第一步。 +(一)病史 +肢体麻木、疼痛等感觉异常为DPN的常见主诉。 +临床医生应详细追问感觉异常的性质、分布范围和发生发展的规律，同时明确感觉障碍是否符合周围神经分布以及肢体疼痛是否符合神经痛的特点。 +应注意询问是否有排汗异常、腹泻、便秘、性功能障碍等症状，从而了解有无自主神经受累。 +糖尿病患者出现肢体肌肉无力和萎缩通常相对较晚。 +(二)体格检查 +1.感觉检查：应仔细检查患者有无振动觉、痛觉、触压觉、温度觉减退以及痛觉过敏，DPN的感觉障碍通常以下肢远端更为明显，严重者可有感觉共济失调。 +2.运动检查：患者可有足部或手部小肌肉的无力和萎缩，但通常出现较晚。 +3.腱反射检查：通常可出现腱反射减低或消失，尤以跟腱反射为著，是诊断DPN的主要体征之一。 +4.自主神经功能检查：注意有无足部皮肤发凉、干燥以及变薄、溃疡，注意患者卧位和立位的血压和心率变化等。 +(三)注意事项 +1.应重视下肢的感觉障碍和腱反射检查。 +2.询问患者有无偏食、饮酒史、药物或毒物接触史以及家族史等，从而有助于对病因进行鉴别。 +3.中枢神经系统感觉通路病变、功能性疾病或内外科相关疾病也可有感觉异常或某些自主神经症状(如性功能障碍、便秘、排尿困难等)，详细的病史询问和体格检查是鉴别DPN与其他疾病的关键。 +二、辅助检查 +(一)生化检查 +1.血糖相关检查：对于周围神经病患者，应常规进行空腹血糖、葡萄糖负荷后2h血糖和糖化血红蛋白测定，明确患者有无糖尿病。 +2.根据患者临床表现的差异，可选择不同的化验检查进行鉴别，如：血常规、肝肾功能、肿瘤筛查、免疫指标、免疫固定电泳、甲状腺功能、叶酸和维生素B12检测等，必要时可进行毒物筛查、腰椎穿刺脑脊液检查等。 +(二)神经电生理检查。 +神经电生理检查能够确认周围神经病变，并辅助判断其类型以及严重程度；对于无症状的糖尿病患者，电生理检查有助于发现其亚临床周围神经病变。 +当病史和体检已经能够明确周围神经病变及其类型时，神经电生理检查并非必需。 +1.神经传导测定：神经传导测定在DPN的诊断中具有重要作用。感觉和运动神经传导测定应至少包括上、下肢各2条神经。①感觉神经传导测定：主要表现为感觉神经动作电位波幅降低，下肢远端更为明显，传导速度相对正常，符合长度依赖性轴索性周围神经病的特点。当存在嵌压性周围神经病时，跨嵌压部位的感觉神经传导速度可有减慢。在以自主神经表现为主者，感觉传导可以正常。感觉神经传导测定有助于发现亚临床病变。2运动神经传导测定：远端运动潜伏期和神经传导速度早期通常正常，一般无运动神经部分传导阻滞或异常波形离散，后期可出现复合肌肉动作电位波幅降低，传导速度轻度减慢。在单神经病或腰骶丛病变时，受累神经的复合肌肉动作电位波幅可以明显降低，传导速度也可有轻微减慢。在合并嵌压性周围神经病者，跨嵌压部位传导速度可明显减慢。 +2.针极肌电图检查：①针极肌电图检查可见异常自发电位，运动单位电位时限增宽、波幅增高，大力收缩时运动单位募集减少。②针极肌电图能够证实运动神经轴索损害，发现亚临床病变，并协助不同神经病变分布类型的定位。③在以自主神经或感觉神经受累为主的周围神经病变，针电极检测的阳性率较低。 +3.F波和H反射：可有潜伏期延长，以下肢神经为著。 +4.皮肤交感反应测定：有助于发现交感神经通路的异常。 +表现为潜伏期延长，波幅降低或引不出波形。 +5.定量感觉测定：可以定量评估深感觉和痛温觉的异常，常用于DPN的临床研究；对于痛觉纤维的评估，有助于小纤维神经病变的判断，对糖尿病自主神经病的诊断有辅助作用。 +6.其他：心率变异度测定可反映副交感神经的功能，是诊断小纤维受累为主周围神经病变的主要方法之一。 +痛觉诱发电位也可以评估痛觉通路的异常，目前主要用于临床研究。 +(三)影像学检查 +对于神经根或丛病变者，可选择影像学检查排除脊柱与椎管内病变和盆腔内占位性病变。 +(四)神经或皮肤活体组织检查 +皮肤活体组织检查有助于小纤维神经病的诊断，在糖尿病自主神经病的诊断中具有一定价值。神经活体组织检查主要用于鉴别其他疾病，并非诊断DPN的常规手段，仅在病因诊断困难的情况下根据病情选择。 +(五)其他自主神经功能的测定 +不同的自主神经功能有相应的检测方法，如测定卧位和立位或Valsalva试验引起的血压变化和心率变化，可以反映心脏自主神经功能；B超检测膀胱残余尿和尿动力学测定有助于排尿困难的鉴别诊断。 +三、糖尿病周围神经病的诊断标准 +(一)糖尿病周围神经病诊断的基本条件 +1.明确患有糖尿病。 +2.存在周围神经病变的临床和(或)电生理的证据。 +3.排除导致周围神经病变的其他原因。 +(二)糖尿病周围神经病的分类 +糖尿病周围神经病有多种分类方法。按照周围神经受累的分布，可以分为多发性对称性周围神经病和局灶性非对称性周围神经病‘。 +1.远端对称性多发性周围神经病：是DPN最常见的类型。主要表现为隐袭起病，缓慢发展，临床表现对称，多以肢体远端感觉异常为首发症状，可呈现手套.袜套样感觉障碍，早期即可有腱反射减低，尤以双下肢为著，可伴有自主神经受损表现。 +早期肌无力和肌萎缩通常不明显。 +2.糖尿病自主神经病：以自主神经病变为首发症状，一般隐袭起病，缓慢发展，表现有排汗异常、胃肠道症状、性功能减退、排尿困难、直立性低血压以及静息时心动过速等。由于小纤维受累，发生心绞痛或心肌梗死时可无心前区疼痛的表现，发生严重心律失常时猝死的风险增加。 +3.糖尿病单神经病或多发单神经病：以正中神经、尺神经、腓总神经受累多见，常隐袭发病，也有急性起病者。 +主要表现为神经支配区域的感觉和运动功能障碍。 +在神经走行易受嵌压部位(如腕管、肘管、腓骨小头处)更容易受累。 +脑神经亦可受累，如动眼神经、外展神经、面神经等，通常为急性起病。 +4.糖尿病神经根神经丛病：也称糖尿病性肌萎缩或痛性肌萎缩，为少见的糖尿病并发症，常见于腰骶神经根神经丛分布区。急性或亚急性起病，表现为受累神经支配区的疼痛和感觉障碍，相继出现肌肉无力和萎缩，以下肢近端为主，可以单侧或双侧受累，诊断时需要首先除外其他原因的神经根或神经丛病变。 +5.其他糖尿病相关周围神经病：糖尿病前周围神经病是糖耐量异常或空腹血糖受损相关的周围神经病，临床特点和DPN相似。 +糖尿病治疗相关的周围神经病较为少见。 +通常在采用胰岛素或其他方法过于快速地控制血糖后出现，主要表现为急性远端对称性神经痛，疼痛往往较为难治，部分患者在1—2年后可自发缓解。 +四、鉴别诊断 +在DPN诊断过程中，需要与多种其他病因导致的周围神经病进行鉴别，特别是当临床存在明显的肢体无力或神经电生理显示传导速度明显减慢时，诊断DPN应该慎重。临床常需要与其鉴别的疾病包括：慢性炎性脱髓鞘性多发性神经根周围神经病、营养缺乏、中毒、异常球蛋白血症、肝功能不全、肾功能不全、甲状腺功能减退、恶性肿瘤、结缔组织病、感染性疾病以及遗传病等。 +DPN为排除性诊断，但临床表现典型时，通常不需要进行各种复杂的检查。 +五、糖尿病周围神经病的治疗 +(一)病因治疗 +积极控制血糖和糖化血红蛋白水平，保持血糖稳定。 +建议将糖化血红蛋白控制在7%以内，但具体控制程度应个体化。 +(二)针对发病机制的治疗 +目前有多种药物在临床上用于DPN的治疗，包括具有抗氧化应激作用的药物(如α-硫辛酸)，改善代谢紊乱类药物(如醛糖还原酶抑制剂)以及各种改善微循环的药物等。但是，临床研究显示当DPN发生后，目前尚无药物能够逆转周围神经病变的进展。 +(三)神经营养修复药物 +临床可选择多种B族维生素类(如硫胺素和甲钴胺等)作为针对神经营养修复的辅助治疗药物。 +(四)对症治疗 +神经痛是影响DPN患者生活质量的主要因素之一，临床有多种药物可以改善患者神经痛的症状，如阿米替林、加巴喷丁、普瑞巴林、度洛西汀、文拉法辛等，具体参见中华医学会神经病学分会制定的痛性周围神经病的诊断和治疗共识。对于自主神经病变引起各系统受累的症状，可根据情况分别治疗，如胃肠道排空功能减退者，可适当选择胃肠动力药物，需注意降糖药的使用，防止低血糖的发生；对于存在明显直立性低血压者，可使用弹力袜，但需注意下肢的血液循环情况。 +应避免使用可能加重自主神经病症状的药物。 +(五)预防 +加强健康教育，提高患者自我护理能力。积极控制高血压和高脂血症，改变生活方式，控制体重，避免吸烟和过度饮酒。早期发现空腹血糖受损以及糖耐量异常的患者，并进行积极干预。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_11.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_11.txt" new file mode 100644 index 0000000..b00b547 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_11.txt" @@ -0,0 +1,111 @@ +基于胰高血糖素样肽1降糖药物的临床应用共识 +自从2005年国际上第一个肠促胰素类药上市以来，此类药物的研究和临床应用有了飞速的发展。目前在我国已经上市2种胰高血糖素样肽1(GLP-1)受体激动剂和5种二肽基肽酶Ⅳ(DPP-4)抑制剂，为了便于使用者全面和快速地了解此类药物的基本知识以及在我国的临床研究和应用情况，中华医学会糖尿病学分会达成以下共识。 +—、肠促胰素类药物的发现和发展 +胃肠道是机体重要的内分泌器官，肠道内分泌细胞在代谢调节中的作用日益受到重视。 +二十世纪初期，人们发现营养物质摄入后，从肠道分泌的某种激素可以刺激胰岛素分泌从而产生降低血糖的作用。 +1929年，中国学者冯德培、侯祥川、林可胜教授在国际上率先发现并命名了肠抑胃素(enterogastrone)。 +同年，Zunz和LaBarre教授发现在狗身上应用这种物质后可引发低血糖，进而将该物质命名为"肠促胰素"(incretin)。 +1969年，Unger和Eisentraut等首先以“肠-胰岛轴”来描述肠道与胰岛之间的关联，提示这样一个系统能够整合从肠道到胰岛细胞之间的营养、神经和激素信号，从而调控胰岛素、胰高糖素、生长抑素或胰多肽的分泌。 +营养物质尤其是碳水化合物可刺激这类激素的释放，当血糖升高时刺激胰岛素释放。 +Elrick等发现，在血糖变化水平相同的情况下，与静脉注射葡萄糖相比，口服葡萄糖可引起更多的胰岛素分泌，这种现象被称为“肠促胰素效应”。 +人体内主要有两种肠促胰素：葡萄糖依赖性胰岛素释放肽(GIP)和GLP-I。 +GIP早在1930年被发现，是第一个被发现的肠促胰素，它是从猪小肠提取物中分离出来的物质，由于其具有抑制胃酸和胃蛋白酵分泌的作用，早期被命名为抑胃肽。 +但在1973年，Pederson等学者发现它在狗、大鼠乃至人体内呈现出葡萄糖依赖性刺激胰岛素释放的特性，即被更名为葡萄糖依赖性胰岛素释放肽。 +1986至1987年间，Drucker等和Orskov等分别在对哺乳动物胰高糖素原基因的克隆和序列测定过程中，发现第二个可以刺激胰岛素释放的肠促胰素，即GLP-1。 +肠促胰素引起的胰岛素分泌能力约占全部胰岛素分泌量的50%-70%，而且肠促素刺激胰岛素分泌的作用具有葡萄糖浓度依赖的特点，故在调节血糖的同时，引起低血糖的风险很低。GIP是人17号常染色体长臂基因编码的具有42个氨基酸的肽类物质，在碳水化合物和脂类刺激下，主要由十二指肠和空肠近端的K细胞分泌。GIP与胰腺β细胞上的特异性受体结合，促进胰岛素分泌。但2型糖尿病患者的循环CIP水平正常或升高，同时GIP对β细胞的促胰岛素分泌作用显著降低，对a细胞也没有作用，因而限制了其临床应用。GLP-1是人2号常染色体长臂的胰高血糖素原基因编码，而后经修饰的具有30个氨基酸的肠肽类激素，在食物的刺激下由回肠和结肠的L细胞分泌释放入血，从而发挥葡萄糖依赖性促进胰岛素的合成和分泌、抑制β细胞凋亡、抑制胰高糖素分泌等生理作用。1993年，在Nauck等发表的文章中，提示对磺脲类药物不能有效控制的2型糖尿病患者，持续静脉输注CLP-1后，能够显著降低血糖；当血糖达到正常水平时，持续输注GLP-1并未继续刺激胰岛素分泌、血糖呈稳定状态，进一步表明了GLP-1的葡萄糖浓度依赖性降糖的特征。 +此外，研究还发现肠促胰素，尤其是GLP-1可抑制胰腺α细胞分泌胰高糖素，并有减轻体重、改善β细胞功能和在动物模型中增加β细胞量的作用，可对2型糖尿病患者的代谢异常进行多方面的调控。 +二、作用机制 +GLP-1通过与其广泛存在于器官上的特异受体相结合，从而发挥相应的作用。 +目前明确存在GLP-1受体的器官包括胰岛细胞、胃肠、肺、脑、肾脏、下丘脑、心血管系统等。 +另外，肝脏、脂肪组织和骨骼肌也可能存在GLP-1受体。 +不像其他胰岛素促泌剂通过KATP通道释放胰岛素,GLP-1还通过刺激胰岛素前体基因表达面合成胰岛素。 +这个效应主要是通过GLP-1与β细胞的GLP-1受体结合后激活了cAMP依赖的PKA信号通路。 +另外，GLP-1也可以通过抑制胰岛α细胞释放胰高糖素而降低血糖。 +这个机制尚不明确，可能是通过存在于α细胞上的GLP-1受体直接作用或间接通过刺激分泌的胰岛素和生长抑素的旁路效应。 +在临床前研究中发现，GLP-1对胰腺的作用还包括保护β细胞、增加β细胞量(可能是通过促进β细胞分化、增殖、抑制细胞凋亡通路)。 +GLP-1除了对胰腺作用外，还通过与存在于其他脏器上的特异受体结合发挥胰腺外作用，其胰腺外作用可能通盖多个方面： +1.作用于胃肠道，延缓胃挂空和肠道蠕动的作用，并可以抑制胃酸和五肽胃泌素分泌，从而减少餐后血糖波动和减轻体重。 +2.作用于中枢神经系统，发挥抑制食欲、增加饱感等作用.从而达到减少摄食的目的。 +3.作用于心血管系统，降低收缩压、改善心肌缺血和心肌收缩功能。 +4.作用于肝、肾，抑制肝脏葡萄糖生成、降低肝酶、降低血脂，改善肝功能。 +5.增加肥胖者的钠排泄、减少H+分泌、降低肾小球高滤过，从而对肾脏可能起到保护作用。 +三、药物分类 +目前有两大类药物：分别为GLP-1受体激动剂和DPP-4抑制剂。 +CLP-1受体激动剂通过模拟天然CLP-1激活GLP-1受体而发挥作用，且不容易被DPP-4快速降解，延长了半衰期，增加了活性GLP-1在体内的浓度。 +GLP-1受体激动剂主要通过外源性补充GLP-1以使体内的GLP-1水平达到药理浓度而发挥作用，其降糖效果显著，降低HbA1c幅度约0.8%~1.5%。 +目前，在中国上市的GLP-1受体激动剂有两种：一种是短效GLP-1受体激动剂艾塞那肽(exenatide，商品名百泌达)，是两栖动物美洲毒蜥唾液中多肽exendin-4的人工合成多肽，其与人GLP-1的同源性为53%；另一种是长效人GLP-1类似物利拉鲁肽(liraglutide，商品名诺和力)，通过对人GLP-1分子结构局部修饰加工而成，与GLP-1的同源性为97%。 +另外，根据降糖作用时间长短，可以把GPL-I受体激动剂分为短效和长效制剂，短效制剂对延迟胃排空作用较强，餐后血糖降低明显，长效制剂对延迟胃排空作用较弱，但通过刺激胰岛素分泌和抑制胰高糖素分泌，对空腹血糖降低明显。短效制剂有艾塞那肽，每天注射两次；利司那肽(lixisenatide)，每天一次。 +长效制剂有利拉鲁肽，每天一次；艾塞那肽周制剂，每周一次；阿必鲁肽(albiglutide)，每周一次；dulaglutide，每周一次。 +DPP-4抑制剂通过阻止DPP-4酶降解体内CLP-1，使得CLP-1在生理浓度范围内有一定程度的升高，其降低HbA1c幅度约为0.4%~1.0%。 +目前在中国已上市的DPP-4抑制剂药物有西格列汀(sitagliptin,商品名捷诺维)、沙格列汀(saxagliptin，商品名安立泽)、维格列汀(vildagliptin，商品名佳维乐)、利格列汀(linagliptin，商品名欧唐宁)和阿格列汀(alogliptin，商品名尼欣那)。 +四、临床应用 +(一)GLP-1受体激动剂 +CLP-1受体激动剂不但具有显著的降糖效果，还同时兼有低血糖发生率低的优点。 +另外具有降低体重、收缩压，改善血脂紊乱的作用。 +1.CLP-1受体激动剂的临床疗效 +目前国内上市的GLP-1受体激动剂为艾塞那肽和利拉鲁肽，均需皮下注射。包括我国2型糖尿病患者在内的临床试验显示艾塞那肽可以使HbA1c降低0.8%，利拉鲁肽的疗效和格列美脲相当。 +2.GLP-1受体激动剂的适应证 +GLP-1受体激动剂适用于成人2型糖尿病患者。艾塞那肽是在国内最早上市的GLP-1受体激动剂，用于改善2型糖尿病患者的血糖控制，适用于单用二甲双胍、磺脲类，以及二甲双胍合用磺脲类，而血糖仍控制不佳的患者(表1)。 +在国外，艾塞那肽还可与噻唑烷二酮类、二甲双胍合用磺脲类、二甲双胍合用噻唑烷二酮类、以及基础胰岛素联合使用等。 +利拉鲁肽在国内适用于单用二甲双胍或磺脲类药物最大可耐受剂量治疗后血糖仍控制不佳的患者，与二甲双胍或磺脲类药物联合应用(表1)。 +在国外，利拉鲁肽在此应用基础上还有单药使用，与二甲双胍合用磺脲类或与二甲双胍合用噻唑烷二酮类或与胰岛素联合应用的适应证等。 +3.GLP-1受体激动剂的不良反应及注意事项 +(1)不良反应：GLP-1受体激动剂的主要不良反应为恶心、呕吐、腹泻、消化不良、食欲下降、低血糖等。 +罕见的不良反应包括胰腺炎、皮疹等。 +详细信息请参考各种GLP-1受体激动剂的说明书。 +(2)注意事项 +①GLP-1受体激动剂不能替代胰岛素，不适用于1型糖尿病患者或糖尿病酮症酸中毒的治疗。 +②严重胃肠道疾病患者、妊娠期和哺乳期妇女以及儿童不推荐使用。 +③艾塞那肽和利拉鲁肽使用中有少数急性胰腺炎病例报道，应当告知患者急性胰腺炎的特征性症状。 +如果怀疑发生了腹腺炎，应该立即停用。 +⑤艾塞那肽有罕见肾功能改变报告，不推荐艾塞那肽用于终末期肾病或严重肾功能不全(肌酐清除率<30ml/min)的患者；利拉鲁肽由于经验有限，不推荐利拉鲁肽用于肾脏终末期患者。 +⑥利拉鲁肽在纽约心脏病学会(NYHA)分级Ⅰ-Ⅱ级的充血性心力衰竭的患者中的治疗经验有限，尚无在Ⅲ-Ⅳ级充血性心力衰竭患者中的应用经验。 +⑦利拉鲁肽不得用于有甲状腺髓样癌(MTC)既往史或家族史患者以及2型多发性内分泌肿瘤综合征患者(MEN2)。 +4.禁忌证 +GLP-1受体激动剂禁用于对该类产品活性成分或任何其他辅料过敏者。 +(二)DPP-4抑制剂 +DPP-4抑制剂可抑制DPP-4活性，有效减少GLP-1的失活，在生理范围内增加有活性的GLP-1水平，以葡萄糖浓度依赖的方式促进胰岛素释放，并降低胰高糖素水平，发挥降低糖化血红蛋白(HbA1c)、空腹血糖及餐后血糖的作用。最近临床试验的研究结果证实了阿格列汀和沙格列汀对心血管疾病(CVD)的长期良好安全性。 +1.DPP-4抑制剂的临床疗效(表2) +DPP-4抑制剂国内注册研究的主要疗效见表1。此外，在以二甲双胍为基础治疗，再加用DPP-4抑制剂与其他多种降糖药物，包括磺脲类、噻唑烷二酮类的许多对比研究中，显示DPP-4抑制剂在降低HbA1c方面，与对照药的疗效相当。在中国2型尿病人群的对比研究中维格列汀与阿卡波糖降低HbA1c的作用相似。 +需要注意的是DPP-4抑制剂降低HbA1c程度与基线HbA1c水平有一定的关系，即基线HbA1c水平高的降低幅度明显。 +2.DPP-4抑制剂的适应证 +DPP-4抑制剂适用于成人2型糖尿病患者的血糖控制。目前国内批准该类药物的适应证为：西格列汀可配合饮食控制与运动，进行单药或与二甲双胍联合使用治疗改善血糖控制；沙格列汀和阿格列汀可在饮食和运动基础上单药治疗，亦可在单独使用二甲双胍血糖控制不佳时与二甲双胍联合使用；维格列汀在二甲双胍作为单药治疗用至最大耐受剂量仍不能有效控制血糖时，与二甲双胍联合使用；利格列汀可配合饮食控制和运动，与二甲双胍和磺脲类药物联合使用改善血糖控制(表2)。 +3.DPP-4抑制剂的不良反应和注意事项 +(1)不良反应 +DPP-4抑制剂的主要不良反应有鼻咽炎，头痛、上呼吸道感染、低血糖等，低血糖的发生率比磺脲类低。其他一些很少见的不良反应有超敏反应、血管神经性水肿、肝酶升高、腹泻、咳嗽、淋巴细胞绝对计数降低等。最近完成的临床研究结果显示，沙格列汀可明显增加心力衰竭住院的风险，但不增加相关的死亡率。 +详细信息请参考各种DPP-4抑制剂的说明书。 +(2)注意事项 +①DPP-4抑制剂不能用于1型糖尿病或糖尿病酮症酸中毒的患者；不推荐用于妊娠期、哺乳期妇女以及儿童。 +②DPP-4抑制剂在肾功能不全患者中的应用： +a.西格列汀通过肾脏代谢，用于中、重度肾功能不全及需要透析的终末期肾病的患者时需要根据肌酐清除率调整剂量。 +b.维格列汀均在中度或重度肾功能不全患者或需要接受血液透析治疗的终末期肾脏疾病(ESRD)患者中的应用经验有限，因此不推荐此类者使用。 +c.沙格列汀在轻度肾功能不全的患者中无需调整剂量。中重度肾功能不全的患者应将剂量调整为2.5mg，每日1次。在重度肾功能不全的患者中临床研究经验有限，因此不推荐使用。 +d.利格列汀极少经过肾脏排泄，在不同程度肾功能不全的患者中使用，均不需要调整剂量。 +e.阿格列汀在中度肾功能受损患者中使用剂量为推荐剂量减半，重度肾功能受或终末期肾功能衰竭患者中使用剂量为推荐量的四分之一。 +推荐在开始使用阿格列汀前评估肾功能并定期复查。 +③DPP-4抑制剂在肝功能不全患者中的应用 +a.西格列汀用于轻度或中度肝功能不全的患者，不需要进行剂量调整；尚无严重肝功能不全患者使用的临床经验。 +b.维格列汀不推荐用于开始给药前血清谷丙转氨酵或谷草转氨酶大于正常上限3倍的患者；罕见有肝功能障碍(包括肝炎)报告，需要进行定期检测肝酶； +对于用药中发生肝酶异常者，在肝功能检测恢复正常后，不建议重新使用。 +c.沙格列汀用于中度肝功能不全的患者时需谨慎，不推荐用于重度肝功能不全的患者。 +d.利格列汀在不同程度肝功能不全的患者中使用，均不需要调整剂量。 +e.阿格列汀在肝功能检查结果异常的患者中应慎重使用。如果患者报告发生可能提示肝损伤的症状，迅速进行肝功能检查。如果患者出现具有临床意义的肝酶升高，和肝功能检查异常结果持续或恶化，应停用阿格列汀。 +如果未发现引起肝功能检查异常的其他原因，不要在此类患者中再次使用阿格列汀。 +④超敏反应 +a.西格列汀在上市后发现有严重超敏反应，包括过敏反应、血管性水肿和脱性皮肤损害，包括Stevens-Johnson综合征。如怀疑发生超敏反应，应停止使用。 +b.维格列汀和沙格列汀在对猴子进行的毒理学研究中，出现四肢皮肤的损伤报告，尽管未在临床中观察到皮肤损伤的发生率升高，但在合并有糖尿病皮肤并发症的患者中经验有限。 +建议观察皮肤病变，如水疱、皮疹或溃疡等情况。 +c.阿格列汀在上市后发现严重皮肤不良反应，如怀疑发生严重过敏反应，停用阿格列汀。 +d.沙格列汀和阿格列汀上市后有报告严重超敏反应(包括速发过敏反应和血管性水肿)。如果疑有沙格列汀严重超敏反应，则停止使用，评估是否还存在其他可能的原因，并改用别的方案治疗糖尿病。 +e.利格列汀治疗的临床研究中报告的其他不良反应有高敏反应(例如荨麻疹、血管性水肿、局部皮肤剥脱或支气管高敏反应)。 +⑤沙格列汀及维格列汀含有乳糖，罕见的半乳糖不耐受遗传疾病、Lapp乳糖酶缺乏症或葡萄糖-半乳糖吸收不良患者不得服用。 +⑥维格列汀和沙格列汀在纽约心功能分级(NYHA)为Ⅰ-Ⅱ级的充血性心力衰竭的患者中经验有限，此类患者中慎用；尚未在Ⅲ-Ⅳ级充血性心力衰竭的患者中进行临床试验，不推荐在此类患者中使用。 +⑦药物相互作用：西格列汀在与磺脲类药物合用时低血糖风险增加，需适当减少磺脉类药物的剂量。利格列汀在与胰岛素、磺脲类合用时低血糖风险增加，需适当减少胰岛素和磺脲类药物的剂量。沙格列汀的代谢主要由CYP3A4/5介导。沙格列汀的主要代谢产物也是DPP-4抑制剂，其抑制活性作用是沙格列汀的二分之一。因此，CYP3A4/5强抑制剂和强诱导剂能改变沙格列汀及其代谢物的药代动力学。与强效CYP3A4/5抑制剂(如酮康唑、阿扎那韦、克拉霉素、茚地那韦、伊曲康唑、奈法唑酮、奈非那韦、利托那韦、沙奎那书和泰利霉素)合用时，应将沙格列汀的剂量限制为2.5mg/d。 +4.DPP-4抑制剂的禁忌证 +已知对药物或药物中任何一成分过敏者禁用。 +五、小结 +基于GLP-1类降糖药物的应用是2型糖尿病治疗中的一个重要发展，其药物作用的特点弥补了传统降糖药物治疗中的一些不足之处。多项研究结果显示CLP-1受体激动剂具有葡萄糖浓度依赖性降低血糖作用的特点，低血糖发生率低，还可减轻体重、降低收缩压、减少心血管疾病危险因素。 +目前GLP-1受体激动剂艾塞那肽和利拉鲁肽在国内均被批准可在一种口服药(二甲双胍或磺脲类)治疗失效后开始使用，艾塞那肽还可在二甲双胍与磺脲类联合治疗失效后开始使用。 +这为我国2型糖尿病忠者降糖治疗提供了一种新的选择。 +DPP-4抑制剂均为口服制剂，使用方便，也具有葡萄糖浓度依赖性降低血糖作用，低血糖发生率低，对体重的影响小，已有报告阿格列汀和沙格列汀对CVD的长期安全性良好，胃肠道不良反应少。目前DPP-4抑制剂在国内被批准用于单药或与二甲双胍或与磺脲类联合治疗。综上所述，作为新一类2型糖尿病的治疗药物，基于GLP-1的降糖药物为临床控制糖尿病提供了新的治疗手段。 +④GLP-1受体激动剂在与磺脲类药物合用时低血糖发生率升高，适当减少磺脲类药物的剂量可减少低血糖风险。在联合使用GLP-1受体激动剂与磺脲类药物时，应告知患者在驾驶或操作机械时采取必要措施防止发生低血糖。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_12.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_12.txt" new file mode 100644 index 0000000..42df72d --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_12.txt" @@ -0,0 +1,88 @@ +二甲双胍临床应用专家共识 +二甲双胍自1957年问世，应用于临床已有50多年的历史，是当前全球应用最广泛的口服降糖药之一。近年来有许多种新型降糖药物上市，但二甲双胍仍是在全球使用量迅速增加的经典口服降糖药物。二甲双胍具有良好的单药/联合治疗的疗效和安全性证据，以及良好的卫生经济学效益证据。无论对于血糖控制，还是糖尿病心血管并发症的预防，其都有明确的临床证据。 +因此，该药已成为全球控制糖尿病的核心药物。 +二甲双胍在我国已经有近20年的使用经验。1995年，FDA正式批准二甲双胍用于治疗T2DM，2004年欧盟正式批准二甲双胍用于治疗10岁以上的儿童T2DM。国内外主要糖尿病指南均建议：无论患者超重与否，除非有肾损害的证据或风险，否则均应从开始就使用二甲双胍治疗，且联合治疗的方案中都应包括二甲双胍，这体现了二甲双胍在糖尿病治疗中的“基石“地位。然而,在临床工作中，仍有部分医生和患者对二甲双胍的使用(有效性、剂量、用法、安全性、疗效与体重的关系等)存在误区，如因担心胃肠道反应未能发挥二甲双胍的剂量优势：因担心其损害肝肾功能和引起乳酸酸中毒等，使一些原本可从二甲双胍治疗中获益的患者错失治疗良机，为此，我们组织内分泌临床专家、药学专家共同制定《二甲双胍临床应用专家共识》，以指导临床医生和患者正确认识并合理使用二甲双胍。 +循证医学证据分级、常见缩略语及主要推荐意见见表1~3。 +一、临床地位与使用时机 +1.治疗T2DM的一线首选用药：二甲双胍具有可靠的短期和长期降糖疗效，单独使用可有效降低T2DM患者的FPG、PPG，可使HbA1c下降1%~2%，可使中国新诊断T2DM患者的HbA1c降低1.8%(可能含安慰剂效应)，且不受体重影响。在相似的基线HbA1c条件下，最佳有效剂量(2000mg/d)的降糖疗效显著强于其他口服降糖药。二甲双胍单药治疗疗效不佳的患者，联合其他口服降糖药可进一步获得明显的血糖改善(Ⅰ级)。联合胰岛素可降低血糖、改善血脂，同时减轻胰岛素引起的体重增加，减少胰岛素用量。该药具有心血管保护作用，是目前唯一被糖尿病指南推荐为有明确心血管获益证据的降糖药物。二甲双胍的长期治疗与新诊断的T2DM患者及已经发生了心血管疾病的T2DM患者的心血管疾病发生风险下降相关(Ⅰ级)。二甲双胍具有良好的安全性和耐受性，低血糖的发生率低，胃肠道反应多为一过性，不导致肾脏损害，长期使用不增加高乳酸血症和乳酸酸中毒的风险。 +与其他降糖药物相比，具有更好的成本效益比(Ⅰ级)。 +如无禁忌症，二甲双胍是T2DM药物治疗的首选药物，且应一直保留在糖尿病治疗方案中。 +2.超重或肥胖T2DM患者的首选用药：回顾性和前瞻性的临床研究结果均显示，二甲双胍在正常体重、超重、肥胖的T2DM患者中的疗效相当， +因此，体重不是使用二甲双胍治疗与否的决定因素(Ⅰ级)。无论对于超重患者还是体重正常的患者，国内外主要糖尿病指南均推荐二甲双胍为治疗T2DM的首选用药。 +3.对于糖尿病的预防作用：二甲双胍是第一个被证明能预防糖尿病或延缓糖尿病发生的药物。二甲双胍能有效地降低糖尿病前期人群发生T2DM的风险，且具有良好的耐受性和长期的有效性。但在我国预防糖尿病尚不是二甲双胍的适应证。DPP研究显示，二甲双胍干预治疗3年可使糖尿病的发生率降低31%，且在中年腹型肥胖的患者中干预效果最佳(Ⅰ级)。IDPP研究显示，二甲双胍单独或与强化生活方式干预联合应用均能降低发生糖尿病的危险(Ⅱ级)。2012年IDF全球T2DM指南推荐，预防糖尿病最好选择生活方式干预，对于IFG、年龄<60岁的肥胖人群，可给予二甲双胍干预。 +DPP研究随访显示，生活方式干预组和二甲双胍治疗组与安慰剂组相比，10年内糖尿病病发生率分别降低了34%和18%(Ⅰ级)。 +二、作用机制 +1.二甲双胍的降糖作用机制：二甲双胍治疗糖尿病的作用机制包括(1)通过直接抑制肝脏的糖异生降低FPG；(2)通过提高外周组织(肌肉、脂肪)对葡萄糖的摄取和利用，降低PPG；(3)减少小肠内葡萄糖吸收；(4)通过抑制线粒体复合物Ⅰ和线粒体氧化磷酸化，减少ATP合成，激活AMPK，促进脂肪酸进入线粒体进行脂肪酸β氧化，减少脂肪合成，从而减轻IR；(5)改善IS，提高胰岛β细胞对血糖的应答；(6)升高GLP-1水平。 +2.二甲双胍是一种胰岛素增敏剂：《Joslin糖尿病学》将二甲双胍归为增敏剂一类。IR是T2DM的主要病理生理特征之一。 +机体在IR的代偿反应是分泌更多的胰岛素，以维持正常的糖代谢。 +胰岛素增敏剂通过改善IR，增加胰岛素刺激的葡萄糖利用，减少脂肪酸氧化代谢，抑制肝糖输出。 +二甲双胍通过抑制肝糖原分解，降低肝糖异生，增强胰岛素与外周组织胰岛素受体的亲合力，促进葡萄糖的摄取和利用，改善组织对胰岛素的敏感性。 +三、剂量与临床疗效 +1.最小、最大及最佳使用剂量：二甲双胍的降糖效果与剂量(500~2000mg/d)呈正相关。500mg/d二甲双胍可降低HbA1c0.6%(减去安慰剂效应后，以下同)，2000mg/d可降低HbA1c2%，且胃肠道反应与1000或1500mg/d差异无统计学意义(Ⅰ级)。UKPDS研究中二甲双胍强化治疗剂量中位数达到2550mg/d，缓释剂型推荐最大用量为2000mg/d，普通片推荐成人最大剂量为2550mg/d。二甲双胍起效的最小推荐剂量500mg/d，成人最大量2550mg/d，最佳有效剂量2000mg/d。 +2.剂量调整原则：二甲双胍的剂量调整原则为“小剂量起始，逐渐加量”。开始时服用500mg/d或<1000mg/d，1~2周后加量至1000mg/d，继续1~2周加量1次。最佳剂量为2000mg/d(1000mg，2次/d或2000mg/d，3次/d)。二甲双胍可在进餐时或餐后立即服用，缓释剂型1次/d，晚餐时或餐后立即服用。考虑药物的临床疗效及患者依从性，可采用简化的剂量方案：建议起始500mg，2次/d，如无明显胃肠道不良反应，2周后可增加至1000mg，2次/d可根据患者状况个体化治疗，每日总剂量1500~2550mg，分2~3次服用。老年人及肝肾功能不全的患者需要调整剂量，具体调整方法详见“四”中，二甲双胍在特殊人群的使用。 +3.剂型：目前国内外主要有单一成分的二甲双胍普通片(250mg/片，500mg/片或850rag/片)、二甲双胍缓释片或胶囊(500mg/片或500mg/胶囊)、二甲双胍肠溶片或胶囊(250mg/片或250mg/胶囊)、二甲双胍粉剂，以及与其他口服降糖药[如磺脲类药物或DPP-4抑制剂]组成的复方制剂。 +4.不同剂型的疗效区别：(1)各种剂型的主要区别在于给药后制剂中药物的溶出释放行为不同。 +普通片剂在胃内崩解释放；肠溶片在从胃排空到肠道后崩解释放；缓释片和缓释胶囊在肠道内缓慢地溶出、释放；肠溶胶囊在肠道内溶出、释放；(2)普通片剂在胃内的溶出速度较快，肠溶片和肠溶胶囊次之，缓释片再次之。 +因每种制剂给药后血药浓度峰值、达峰时间、表观半衰期等参数存在一定的差异，所以多剂量给药后的达稳时间也不一致；(3)缓释片/胶囊和肠溶片/胶囊相对于普通片剂而言，可减少给药后的胃肠道反应，提高患者的用药依从性；(4)合格的药物制剂，在相同的给药剂量下，各种剂型间应具有生物等效性；(5)不同剂型的临床疗效是否一致，尚需更多的大样本临床研究证实。 +5.单药治疗的降糖疗效：一项双盲、安慰剂对照、剂量效应研究显示，在减去安慰剂效应后，不同剂量的二甲双胍单药治疗可使FPG降低1.05~4.33mmol/L，HbA1c下降0.9%~2.o%。另有研究显示，二甲双胍可使PPG降低2.58mmol/L。中国新诊断T2DM患者中，二甲双胍可使HbA1c降低1.8%(可能含安慰剂效应)(Ⅰ级)。在新诊断的经过短期胰岛素治疗后的中国T2DM患者中开展的随机分组、前瞻性对照研究结果显示，二甲双胍(2000mg/d)的疗效与甘精胰岛素的降糖疗效相当。 +6.联合磺脲类药物的疗效：二甲双胍可改善IR，降低肝糖输出，磺脲类药物可促进胰岛素分泌，两类药物联合，作用机制互补，具有更全面针对T2DM的病理生理缺陷的特点。一项随机、双盲、平行对照研究显示，二甲双胍联合格列本脲治疗组比单用二甲双胍或单用格列本脲组能更好地控制FPG和HbA1c。针对磺脲类药物血糖控制不佳的患者治疗18周后，格列吡嗪/二甲双胍复合制剂治疗组的血糖达标率(HbA1c<7.0%)为36.3%，分别是单用二甲双胍治疗组(8.9%)和单用格列吡嗪治疗组(9.9%)的4.1和3.7倍，同时可更好地控制FPG(Ⅰ级)。在中国T2DM患者中开展的一项随机、平行对照研究显示，二甲双胍联合格列喹酮治疗组的HbA1c降幅(1.7%)显著高于二甲双胍联合阿卡波糖治疗组的HbA1c降幅(0.9%)，且两组间低血糖、体重增加无差异无统计学意义。另有随机、双盲、双模拟、平行对照研究显示，在二甲双胍的基础上联合含有格列本脲的中药固定复方制剂与相同剂量的格列本脲相比，降糖效果相当，但低血糖发生的风险显著减低。 +7.联合噻唑烷二酮类药物的疗效：对于严重IR，二甲双胍联合噻唑烷二酮类药物能更好地降低HbA1c，显著改善胰岛功能和IR，且有剂量依赖性趋势，但不良反应(体重增加、升高LDL-C)高于二甲双胍单用组；罗格列酮/二甲双胍的复合制剂与单用二甲双胍比较，复合制剂降低HbA1c和FPG更显著，故在IR严重，且排除两药的使用禁忌时，可考虑二甲双胍联合噻唑烷二酮类药物的治疗方案(Ⅰ级)。 +8.联合格列奈类药物的疗效：格列奈类药物属于短效促胰岛素分泌剂，与二甲双胍联用具有协同作用。在新诊断的血糖水平较高(HbA1c水平接近11.0%)的T2DM患者中瑞格列奈和二甲双胍联合比单用瑞格列奈能更有效降低HbA1c，而低血糖发生率差异无统计学意义。那格列奈联用二甲双胍和格列齐特联用二甲双胍的降糖强度差异无统计学意义，但低血糖事件更少(Ⅰ级)。故在二甲双胍联合磺脲类且低血糖发生风险较高时，可考虑选用二甲双胍联合格列奈类药物。 +另有研究显示，在二甲双胍的基础上加用米格列奈，可进一步降低HbA1c、FPG和PPG，并提高达标率，而不良事件的发生率差异无统计学意义。 +9.联合α糖苷酶抑制剂的疗效：二甲双胍与α糖苷酶抑制剂联合，可兼顺FPG和PPG，超重的T2DM患者在二甲双胍疗效不佳时，加用阿卡波糖能更好地控制HbA1c、FPG和体重。一项在中国T2DM人群中的对照研究显示，二甲双胍和阿卡波糖联用的降糖效果劣于二甲双胍和磺脲类联用。 +这两种药物都有一定的胃肠道不良反应，联合应用有可能增加胃肠不适。 +10.联合DPP-4抑制剂的疗效：二甲双胍联合DPP-4抑制剂在降低FPG、HbA1c、体重的幅度均强于两药单用，但是对心血管危险因素、低血糖、胃肠道作用差异无统计学意义，二甲双胍联合DPP-4抑制剂的疗效与二甲双胍联合磺脲类药物的疗效相当，但体重增加和低血糖发生的风险低于二甲双胍联合磺脲类药物，由于DPP-4抑制剂上市时间较短，关于二甲双胍和DPP-4抑制剂的联合用药的疗效和安全性，还需要更多的研究验证。 +11.联合GLP-1受体激动剂的疗效：目前中国临床应用的GLP-1受体激动剂主要包括利拉鲁肽和艾塞那肽。在二甲双胍治疗基础上加用GLP-1受体激动剂，可进一步降低FPG、HbA1c，血糖达标率更高：改善胰岛素β细胞功能：改善IR，降低体重和SBP，无严重低血糖事件(Ⅰ级)。在我国T2DM人群中开展的随机分组、对照性研究显示，利拉鲁肽联合二甲双胍与格列美脲联合二甲双胍相比降糖疗效相当，体重和血压显著降低，低血糖发生风险显著减少。 +但患者对利拉鲁肽联合二甲双胍治疗所导致的不良反应的耐受性更差。 +12.联合胰岛素的疗效：二甲双胍可增强肝脏和肌肉组织的IR，因此在开始胰岛素治疗的同时应该继续维持二甲双胍治疗。与胰岛素单药治疗相比，二甲双胍联合胰岛素可进一步降低HbA1c，减少胰岛素用量，还可减少使用胰岛素之后出现的体重增加(Ⅰ级)，一项随机对照研究人组了接受胰岛素单药治疗但HbA1c≥7.0%的T2DM患者，受试者随机接受胰岛素单药(n=31)或胰岛素联合二甲双胍(n=27)治疗4个月。结果显示，二甲双胍联合胰岛素治疗，在保证相同降精疗效的同时，可减少胰岛素用量，从而降低低血糖的发生风险。Yki-Jarvinen等将96例接受磺脲类药物治疗血糖控制不佳的T2DM患者，随机分为睡前胰岛素+二甲双胍+安慰剂组、睡前胰岛素+格列本脲+安慰剂组、睡前胰岛素+二甲双胍+格列本脲和睡前胰岛素+清晨胰岛素组。治疗1年后，睡前胰岛素+二甲双胍组体重无明显变化，而其他组的体重均有所增加，且与其他组相比，睡前胰岛素+二甲双胍组HbA1c降幅最大，每日胰岛素用量最少，低血糖的发生率最低。 +13.应尽早足量使用以维持更长的达标时间：在500~2000mg剂量范围，二甲双胍疗效呈现剂量依赖效应，且相比其他降糖药物，二甲双胍具有更好的成本效益比(Ⅰ级)。ADOPT研究显示，在新诊断的T2DM患者中，二甲双胍(2000mg/d)单药治疗可以在4年内使受试者平均HbA1c水平维持在7%以下。 +在一项长达104周的对照临床研究中，与西格列汀(100mg/d)单药治疗相比，二甲双胍(2000mg/d)单药治疗使受试者平均HbA1c水平维持在7%以下的时间增加了约24周。 +因此，在患者可以耐受的情况下，使用单药最佳剂量(2000mg/d)的二甲双胍治疗不但可以使血糖控制尽早达标，且可使血糖得到更长时间的良好控制，如果出现可耐受的不良反应时，可适当减量；如果不能耐受，建议尽早更换其他降糖药。 +14.用于正在接受胰岛素治疗的T1DM患者：对于T1DM患者可联用二甲双胍。临床研究发现其不仅能减少胰岛素用量，还可进一步降低血脂水平(与降低血糖无关)，尤其是LDL-C；对于单用胰岛索治疗血糖控不佳的患者，如果联合二甲双胍，可降低胰岛素用量10%，减少使用胰岛素所带来的体重过度增加。中国T1DM诊治指南也支持T1DM在使用胰岛素治疗的前提下联用二甲双胍。 +15.减重效果：二甲双胍具有控制体重的作用。研究表明，新诊断T2DM患者二甲双胍单药治疗16周，可使正常(BMI18.5~23.9kg/m2)、超重(BMI24.0~27.9kg/m2)、肥胖(BMI≥28.0kg/m2)患者的体重分别下降(可能包含部分安慰剂效应)1.47、2.81及2.92kg(Ⅰ级)，磺脲类、格列酮类和胰岛素治疗伴有体重增加，以二甲双胍为基础的联合治疗减轻上述药物对体重增加的影响。 +HOME研究证实，以二甲双胍为基础联合胰岛素治疗，体重少增加2.28~3.85kg。 +四、特殊人群用药 +1.心力衰竭患者使用注意事项：需要药物治疗的充血性心力衰竭(CHF)是二甲双胍使用的禁忌证，但回顾性研究显示，二甲双胍本身不会导致心力衰竭，也不会对心力衰竭患者造成不良影响。2014年ADA糖尿病指南也指出，如果肾功能正常，二甲双胍可用于病情稳定的CHF患者(Ⅴ级)。 +2.65岁以上老年患者使用注意事项：2013年IDF老年糖尿病指南和中国老年糖尿病诊疗措施专家共识都把二甲双胍作为一线首选用药，对二甲双胍的使用没有具体年龄限制。老年糖尿病患者合理应用二甲双胍治疗可以达到良好的降糖效果，较少的低血糖风险对老年人有一定益处，但需要定期监测肾功能(3~6个月检查1次)。 +80岁以上患者[eGFR<45ml/(min·1.73m2)除外]，如掌握好适应证，从小剂量起始，在合理监测条件下，应用二甲双胍仍可取得良好的效果(Ⅰ级)。 +因此，年龄并非二甲双胍治疗的禁忌，但需要监测肾功能。 +老年患者的eGFR在45~60ml/(min·1.73ml2)者，应减少剂量，如果eGFR<45ml/(min·1.73m2)则不能使用]。 +适合我国CKD患者的eGFR评估公式为：cG FR[ml/(min·1.73m2)]=175×Scr-1.234(mg/dI)×年龄-0.179(女性X0.79)。 +3.儿童和青少年糖尿病及糖尿病前期患儿使用注意事项：无需以胰岛素作为起始治疗的10岁及以上T2DM患儿，应立即开始给予生活方式干预，不达标者以二甲双胍作为起始治疗药物。10岁及以上的糖尿病前期(IFG或lGT)患儿经3个月有效的生活方式干预(饮食控制、150min/周运动，减轻体重5%~10%)后，代谢异常指标仍无法逆转，建议使用二甲双胍治疗，起始剂量500mg，3次/d，最大剂量2000mg/d(V级)。二甲双胍可用于10岁及以上的T2DM的儿童或青少年，且最高剂量不超过2000mg/d，不推荐用于10岁以下的儿童。 +4.妊娠期糖尿病(GDM)患者使用注意事项：有GDM史的患者发现为糖尿病前期时，应接受生活方式干预或二甲双胍以预防糖尿病。患者一旦妊娠，建议改用胰岛素治疗(V级)。二甲双胍可降低PCOS患者妊娠早期的流产率和GDM的发生率。在控制孕妇体重和治疗IR方面有优势，孕早期口服二甲双胍没有增加胎儿重大畸形和新生儿并发症的风险，二甲双胍在FDA妊娠期用药分级中为B类药物。 +但我国药监部门尚未批准二甲双胍用于妊娠期妇女。 +5.肝功能不全的T2DM患者使用注意事项：二甲双胍不经过肝脏代谢，无肝脏毒性。 +目前肝功能不全患者使用二甲双胍的临床资料较少。 +肝功能严重受损会明显限制乳酸的清除能力，建议血清转氨酶超过3倍正常上限时应避免使用，血清转氨酶轻度升高的患者使用时应密切监测肝功能。 +7.造影或全麻术前患者使用注意事项：肾功能正常患者，造影前不必停用二甲双胍，但使用对比剂后应在医生的指导下停用48~72h，复查肾功能正常后可继续用药；而对于肾功能异常的患者，使用对比剂及全身麻醉术前48h应当暂时停用二甲双胍，之后还需停药48~72h，复查肾功能结果正常后可继续用药(V级)。 +五、安全性 +1.禁忌证：(1)血清肌酐水平，男≥132μmol/L(1.5mg/dl)女≥124μmol/L(1.4mg/dl)，或eGFR<45ml/(min·1.73m2)禁用；(2)需要药物治疗的CHF和其他严重心、肺疾患；(3)严重感染和外伤、外科大手术、临床有低血压和缺氧等；(4)已知对盐酸二甲双胍过敏；(5)急、慢性代谢性酸中毒，包括有或无昏迷的糖尿病酮症酸中毒；(6)酗酒者；(7)接受血管内注射碘化对比剂者，应暂时停用；(8)维生素B12、叶酸缺乏未纠正者。 +2.常见不良反应：常见不良反应包括腹泻、恶心、呕吐、胃胀、乏力、消化不良、腹部不适及头痛。 +这些不良反应的发生常见于药物治疗的早期， +绝大多数患者可耐受。 +随着治疗时间的延长，上述不良反应可基本消失。 +小剂量开始，逐渐增加剂量是减少治疗初期不良反应发生的有效方法。 +3.胃肠道反应与剂量的关系及处理原则：二甲双胍引起的胃肠道反应发生多出现在治疗的早期(绝大多数发生于前10周)，多数患者随着治疗时间的延长，可逐渐耐受或症状消失。国外报道，即使二甲双胍较大剂量(1000mg/d)起始治疗，其胃肠道反应发生率为28%，在1000mg增至2000mg/d时胃肠道反应差异无统计学意义。 +国内报道，二甲双胍的胃肠道反应发生率为15%(Ⅰ级)，如果增加剂量后发生严重胃肠道反应，可以降至之前较低的剂量，耐受后可再尝试增大剂量，缓释制剂也可减少患者的胃肠道症状。 +4.对维生素B12的吸收的影响：已有多项交叉横断面试验及随机对照研究显示，长期服用二甲双胍可引起维生素B12水平的下降。其机制可能与以下因素有关(1)小肠蠕动的改变刺激肠道细菌过度生长，竞争性抑制维生素B12的吸收；(2)维生素B12内因子水平的变化及钴胺素内吞受体的相互作用；(3)二甲双胍可抑制回肠末端维生素B12内因子复合物钙依赖性吸收(这种抑制作用可以通过补充钙剂逆转)。二甲双胍治疗引起巨幼红细胞性贫血罕见，如发生应排除维生素B12缺乏。 +建议在长期使用二甲双胍治疗患者中适当补充维生素B12。 +不建议在服用二甲双胍的患者中常规监测维生素B12的水平。 +5.是否损伤肝肾：二甲双胍主要以原形由肾脏从尿中排出，清除迅速，12~24h大约可清除90%。二甲双胍肾清除率约为肌酐清除率的3.5倍，且经肾小管排泄是二甲双胍清除的主要途径。因此，二甲双胍对肾脏没有损害。有研究提示，二甲双胍可能具有肾脏保护作用。二甲双胍通过胃肠道吸收进行血液循环，几乎不与血浆白蛋白结合，不经过肝脏代谢，不竞争P450酶，在体内也不降解，面是直接作用于肝脏和肌肉，减少肝糖异生，增加肌肉葡萄糖酵解。因此二甲双胍无肝毒性，推荐剂量范围内用药的肝功能正常者，不会造成肝损害。但肝功能受损者使用二甲双胍时应谨慎，因为肝功能受损会明显限制其对乳酸盐的清除能力。 +6.二甲双胍与乳酸酸中毒：目前尚无确切的证据支持二甲双胍的使用与乳酸酸中毒有关，肝肾功能正常患者长期应用不增加乳酸酸中毒风险。COSMIC研究显示，使用二甲双胍的乳酸酸中毒发生率与其他降糖治疗差异无统计学意义(Ⅰ级)。荟萃分析显示，在肾功能正常的患者中使用二甲双胍不增加乳酸酸中毒风险，且二甲双胍发生乳酸酸中毒的概率并不比其他口服降糖药物高。因二甲双胍直接以原形经肾脏排泄，因此有肾功能损害时易发生二甲双胍与乳酸在体内蓄积，有可能会增加乳酸酸中毒风险。建议肾功能受损[eGFR<45ml/(min·1.73m2)]和低氧血症患者应避免使用。 +7.与非降糖药物的相互作用：(1)使用氨氯吡咪、地高辛、吗啡、普鲁卡因胺、奎尼丁、奎宁、雷尼替丁、氨苯蝶啶、甲氧苄氨嘧啶和万古霉素等经肾小管排泌的阳离子药物，其影响肾功能或二甲双胍分布，应密切监测血糖并调整二甲双胍和/或相互作用的剂量；(2)同时服用噻嗪类药物或其他利尿剂、糖皮质激素、吩噻嗪、甲状腺制剂、雌激素、口服避孕药、苯妥英、烟碱酸、拟交感神经药、钙离子通道阻滞剂和异烟肼等可引起血糖升高的药物需密切监测血糖。而在这些药物停用后，要密切注意低血糖的发生：合并服用氯磺丙脲的患者在换用二甲双胍的最初2周要密切监测血糖，氯磺丙脲在体内有较长潜留，易发生低血糖；(3)二甲双胍有增加华法林的抗凝血倾向；(4)树脂类药物，如苏合香、血竭、乳香等与二甲双胍合用会减少其吸收。 +六、心血管益处 +1.心血管保护作用：二甲双胍通过有效改善糖尿病和非糖尿病患者的IR，降低基础和负荷后胰岛素水平，起到直接或间接的心血管保护作用(Ⅰ级)。UKPDS显示，使用二甲双胍的肥胖T2DM患者的全因死亡风险相对下降35%，心肌梗死风险下降39%；UKPDS10年随访显示，二甲双胍治疗组大血管并发症及死亡风险的获益具有延续效应，且降低死亡和心肌梗死的作用优于磺脲类和胰岛素。 +REACH研究结果提示，二甲双胍治疗2年，全因死亡相对风险下降24%，HOME研究结果提示，二甲双胍联合胰岛素比单用胰岛素可以减少大血管事件风险，中国SPREAD研究结果显示，对于有冠心病病史的T2DM患者，与格列吡嗪组相比，二甲双胍组的主要终点事件发生风险降低46%(Ⅰ级)。 +二甲双胍是目前唯一被2013AACE指南推荐有心血管获益证据的降糖药物。 +2.心血管保护作用机制：二甲双胍可能通过减少心血管疾病的危险因素而达到心血管保护。心血管疾病的危险因素包括血脂异常、IR、肥胖、高血压、NAFLD等。控制危险因素是心血管保护的重要方式之一。二甲双胍目前已经被证实可以降低血糖、改善NAFLD和IR(尤其是肝脏和肌肉)、减轻体重、改善血脂(主要是改善TG、LDL-C及TC水平，对HDL-C改变不明显)和抗凝等此外，二甲双胍可以直接改善血管内皮细胞功能，增加血流量。 +七、降糖外益处 +1.在改善血脂方面的作用：二甲双胍能够改善脂肪的合成与代谢。多项研究显示，二甲双胍治疗T2DM患者，可降低患者血浆TG、LDL-C及TC水平，但对HDL-C改变不明显。 +2.在治疗NAFLD方面的作用：中华医学会肝病学分会脂肪肝和酒精性肝病学组布《中国非酒精性脂肪性肝病诊疗指南(2010年修订版)》提出：除非存在明显的肝损害(如血清转氨大于3倍正常值上限)、肝功能不全或失代偿期肝硬化等情况，否则NAFLD患者可安全使用胰岛素增敏剂(二甲双胍和噻唑烷二酮类)等药物(V级)。有14项临床研究评价了二甲双胍对NAFLD患者肝脏组织学、血清酶学和IR等指标的改善情况，所有研究均显示HOMA-IR明显改善，13项研究显示血清酶学(谷丙转氨酶、谷草转氨酶)明显下降；5项研究显示二甲双胍对肝脏炎症、脂肪变性和纤维化有改善。 +3.在治疗PCOS方面的作用：PCOS不是二甲双胍的适应证，但国内外应用二甲双胍治疗PCOS已有十余年的历史。美国内分泌学会推荐二甲双胍可作为PCOS合并T2DM/IGT患者，生活方式干预(一线治疗)失败或月经不规则且无法应用避孕药(二线治疗)的情况下的一种治疗药物。循证医学证据表明二甲双胍可降低血浆胰岛素水平，增加IS，降低雄激素水平，提高雌二醇水平，改善PCOS患者的多毛症，使月经规律，诱导排卵，PCOS患者可从500mg/d开始，每周加量500mg，直到2000mg/d(分二次餐时或餐后服用)，维持数月，直至排卵，恢复月经，待发现怀孕时停药。 +国外甚至用到2500mg/d，安全性依然良好。 +4.抗肿瘤作用：糖尿病可能是多种肿瘤，如乳腺癌、胰腺癌、结直肠癌、子宫内膜癌等的危险因素。多项研究显示，二甲双胍可激活AMP激活的蛋白激(AMPK)通路。 +而AMPK通路的激活除了影响代谢外，也可能抑制肿瘤的发生和发展。 +英国一项大型病例对照研究显示，二甲双胍治疗与癌症的危险性下降具有相关性，并观察到随着使用时间的延长和使用次数的增加，二甲双胍的保护效应具有逐渐增强的趋势(Ⅱ级)。 +6.肾功能不全的T2DM患者使用注意事项：二甲双胍本身不会对肾功能有影响，但临床存在仅根据蛋白尿就停用二甲双胍的使用误区。 +建议根据eGFR的水平调整二甲双胍的使用。 +患者eGFR≥60ml/(min·1.73m2)无需减量，eGFR 45~60ml/(min·1.73m2)时减量，当eGFR<45ml/(min·1.73m2)时停用(V级)。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_13.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_13.txt" new file mode 100644 index 0000000..bff6491 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_13.txt" @@ -0,0 +1,119 @@ +中国2型糖尿病合并血脂异常防治专家共识(2017年修订版) +一、前言 +2型糖尿病(T2DM)患者合并血脂异常，可进一步增加大血管和微血管并发症的风险。为了进一步做好T2DM患者的血脂管理工作，中华医学会内分泌学分会曾于2011年颁布了《中国2型糖尿病合并血脂异常防治专家共识》。近年来，一系列新研究结果的发表、新指南的颁布，促使了血脂异常管理理念进一步发展。为了进一步优化我国T2DM患者的血脂管理，为临床医生提供更为科学合理的诊疗建议，中华医学会内分泌学分会根据中国患者的疾病特点，参考国内外新的循证证据和指南，对2011年版的《中国2型糖尿病合并血脂异常防治专家共识》进行修订，以更好地规范我国T2DM患者的血脂管理，预防动脉粥样硬化性心直管疾病(ASCVD)的发生。 +相较于2011版《专家共识》，本共识中我们对下列内容进行了更新：(1)血脂异常特点及流行病学中补充了中国血脂研究的数据。(2)对于国外指南建议非空腹血脂监测，本共识未做推荐。(3)ASCVD危险度评估和治疗目标中更新危险因素。(4)对T2DM患者的血脂管理的流程图进行合并，更简单明了，易于操作。(5)基于疗效、耐受性及治疗费用的考虑，中国证据显示中等强度他汀类药物治疗适合于我国多数T2DM合并血脂异常患者。(6)经过中等强度的他汀类药物治疗后非高密度脂蛋白胆固醉(non-HDL-C)仍不达标者，特别是三酰甘油(TG)≥2.3mmol/L，可在他汀类药物治疗基础上加用贝特类药物，如非诺贝特或苯扎贝特，或高纯度鱼油。(7)胆固醇吸收抑制剂依折麦布和人类前蛋白转化酶枯草溶菌素9(PCSK9)抑制剂可作为他汀不耐受或单药治疗低密度脂蛋白胆固醇(LDL-C)不能达标时的联合用药。(8)对于T2DM患者特殊情况下的血脂管理，如合并肝病或肝功能异常、合并慢性肾脏病(CKD)、老年T2DM时的处理进行了更新。(9)评价了长期服用他汀类药物对血糖影响和增加新发糖尿病风险的获益和风险。 +(10)本共识增加T2DM患者常用药物对血脂的影响。 +为了便于读者了解某一项诊疗措施的价值和证据等级，本共识制订了分级体系(附表1)，用来阐明和编纂各项建议的证据。 +二、T2DM患者的血脂异常特点及流行病学 +推荐1：T2DM患者的血脂诸以混合型血脂紊乱多见，其特征性的血脂谱包括：(1)空腹和餐后TG水平升高.即使在空腹血糖和TG水平控制正常后往往还存在餐后高TG血症；(2)HDL-C水平降低；(3)血清总胆固醇(TC)水平和LDL-C正常或轻度升商，且LDL-C发生质变，小而致密的LDL-C水平升高；(4)富含TG脂蛋白的载脂蛋白(apo)B-100和apoB-48水平升高，apo-CⅢ水平升高，apo-CII/apo-CIII以及apo-CIII/apo-E的比值升高。 +推荐2：中国T2DM患者合并血脂异常的比例高，治疗率、达标率低，临床上应加强对T2DM患者的血脂管理。 +T2DM是危害人类健康的主要疾病之一，是ASCVD的独立危险因素。T2DM患者血脂异常的发生率明显高于非糖尿病患者，是T2DM患者心血管并发症发生率增加的重要危险因素。英国前瞻性糖尿病研究(UKPDS)的结果显示，血脂异常是T2DM患者发生致死性和非致死性心肌梗死的首要危险因素。 +T2DM患者的脂代谢异常与胰岛素抵抗和腹型肥胖等代谢综合因素有关。导致患者血脂异常的主要原因是由于胰岛素作用不足、胰岛素抵抗等所致的极低密度脂蛋白(VLDL)、TG的产生过多和清除缺陷。T2DM患者的血脂谱以混合型血脂紊乱多见，其特征性的血脂谱包括：空腹和餐后TC水平升高，即使在空腹血糖和TG水平控制正常后往往还存在餐后高TG血症；HDL-C水平降低；血清TC水平和LDL-C正常或轻度升高，且LDL-C发生质变，小而致密的LDL-C水平升高。 +富含TG脂蛋白(triglyceride- rich lipoprotein) 的apoB-100和apoB-48水平升高，apo- CIII水平升高，apo-CII/apo-CIII以及apo-CIII/apo-E的比值升高。 +中国人群血脂控制现状不容乐观，据研究显示，我国人群血清总胆固醇及低密度脂蛋白胆固醇水平增高，如无有效的干预措施，在不久的将来，动脉硬化性心血管疾病的患病率将飞速增长。CCMR-3B研究对全国104家医院的25817例中国T2DM门诊患者进行了调查，结果发现42%的T2DM忠者合并血脂异常，其中仅有55%的患者接受了调脂治疗。 +此外，该研究中TC<4.5mmol/L、TG<1.5mmol/L、LDL-C<2.6mmol/L和HDL-C>1.04mmol/L的患者比例分别为36.1%、46.6%、42.9%和71.9%，四项指标均达标的患者比例仅为12%。 +CCMR-3B研究真实地反映了当前我国T2DM患者血脂异常患病及控制情况，并提示临床上应加强对T2DM患者的血脂管理。 + +三、T2DM者血脂检测时机及监测频率 +推荐3：在确诊T2DM的同时均应检测患者的空血脂(包括TG、TC、HDL-C和LDL-C)(推荐；E级证据)。 +推荐4：对于血脂位于正常范围内的患者，如果无其他心血管风险。在T2DM治疗过程中每年至少要进行1次血脂谱的检测：如果伴有多重心血管风险因素，则在诊断T2DM后每3个月监测血脂谱1次。对于合井血脂谱异常的T2DM患者，则在起始生活方式干预和药物治疗，以及药物剂量调整期间每1~3个月监测1次血脂谱，此后则建议每3~12个月监测1次血脂谱。 +由于血脂异常通常没有明显症状，往往通过体检或发生了心脑血管事件后才得以发现，因而及早发现T2DM患者合并血脂异常，并给予早期干预，可防治动脉粥样硬化、减少心脑血管事件、降低死亡率。 +为了及早发现T2DM患者的血脂异常，在确诊T2DM的同时均应检测患者的空腹血脂谱(包括TG、TC、HDL-C和LDL-C)(推荐；E级证据)，根据基线血脂水平以制定相应的监测策略(图1)：对于血脂位于正常范围内的患者，如果无其他心血管风险，在T2DM治疗过程中每年至少要进行1次血脂谱的检测；如果伴有多重心血管风险因素(男性≥40岁或绝经期后女性、吸烟、肥胖和早发缺血性心血管病家族史等).则在诊断T2DM后每3个月监测血脂谱1次。对于合并血脂谱异常的T2DM患者，则在起始生活方式干预和药物治疗，以及药物剂量调整期间每4~12周监测1次血脂谱，此后则建议每3~12个月监测1次血脂谱。 +鉴于有关血脂控制目标和心血管风险分层、血脂治疗等研究数据均基本来自于空腹血脂监测，目前亦缺乏非空腹血脂监测的中国人群的研究数据，因此目前暂不宜在我国临床工作中推广非空腹血脂监测，仍应继续采用空腹血脂监测。 +建议采取以下措施可提高标本采集的质量：(1)受试者准备：采集标本前受试者处于稳定代谢状态，至少2周内保持非高脂饮食习惯和稳定体重。 +(2)采集标本前受试者24小时内不进行剧烈身体活动、避免情绪紧张、饮酒、饮咖啡等。 +(3)采集标本前受试者禁食约12小时。 +(4)除特殊情况外，受试者可取坐位或半卧位接受采血，采血前至少休息5min。 +(5)静脉穿刺时止血带使用不超过1min。 +(6)血液标本保持密封，避免震荡，及时送检。 +床疾患等进行综合评估，并根据评估结果制定相应的血脂管理目标和治疗措施(推荐；C级证据)。值得关注的是，虽然T2DM患者的血脂谱特征是LDL-C正常或轻度升高，但小而致密的LDL颗粒数量增加。事实上，小而密LDL颗粒更容易被氧化形成过氧化脂质，易通过非受体通路摄取，被单核-巨噬细胞的清道夫受体识别、吞噬，形成泡沫细胞，促进ASCVD的发生，具有很强的致ASCVD作用。UKPDS研究结果也显示，LDL-C是T2DM患者发生冠心病和心肌梗死的首要预测因素，LDL-C每上升1mmo/L，冠脉事件发生率增加57%。胆固醇治疗试验(CTT)协作组的meta分析结果也显示，LDL-C每降低1.0mmol/L分别显著下降主要血管事件、血管性死亡和缺血性卒中事件风险达21%、13%和21%。由此证明，T2DM患者降低LDL-C心血管获益确切。低HDL-C水平往往与TG水平升高相关，也是T2DM患者常见的血脂异常。 +而靶向升高HDL-C治疗药物的证证远远不如他汀类药物充分。 +因此，当前各糖尿病指南中虽然建议T2DM患者需全面控制血脂，但LDL-C仍是首要的 +降脂治疗目标(表1)。 +四、T2DM患者的ASCVD危险度评估和治疗目标 +推荐5：T2DM患者ASCVD高危人群调脂的主要目标为LDL-C<2.6mmol/L，次要目标Non-HDL-C<3.4mmol/L，其他目标TG<1.7mmo/L。 + +推荐6：T2DM患者ASCVD极高危人群调脂的主要目标为LDL-C<1.8mmol/L，次要目标Non-HDL-C<2.6mmol/L，其他目标TG<1.7mmol/L。 + +基于ASCVD危险程度的分层管理策略是当前血脂管理的总体趋势，因此，全面评估ASCVD危险度是T2DM患者进行血脂管理的前提。在确诊T2DM后，应对患者的血脂水平、所具有的心血管危险因素及临床疾患等进行综合评估，并根据评定结果指定相应的血脂管理目标和治疗措施（推荐：C级证据）。值得关注的是，虽然T2DM患者的血脂谱特征是LDL-C正常或轻度升高，但小而致密的LDL颗粒数量增加。事实上，小而密LDL颗粒更容易被氧化形成过氧化脂质，易通过非受体通路摄取，被单核-巨噬细胞的清道夫受体识别、吞噬，形成泡沫细胞，促进ASCVD的发生，具有很强的致ASCVD作用。UKPDS研究结果也显示，LDL-C是T2DM患者发生冠心病和心肌梗死的首要预测因素，LDL-C每上升1mmol/L，冠脉事件发生率增加57%。胆固醇治疗试验（CTT）协作组的meta分析结果也显示，LDL-C每降低1.0mmol/L分别显著下降主要血管事件、心血管死亡和缺血性卒中事件风险达21%、13%和21%。由此证明，T2DDM患者降低LDL-C心血管获益确切。低HDL-C水平往往与TG水平升高相关，也是T2DM患者常见的血脂异常。而靶向升高HDL-C治疗药物的循证证据远远不如他汀类药物充分。因此，当前各糖尿病指南中虽然建议T2DM患者全面控制血脂，但LDL-C仍是首要的降脂治疗目标（表1）。 +五、T2DM合并血脂异常患者的血脂管理 +(一)T2DM患者的血脂管理流程 +推荐7：所有T2DM合并血脂异常患者均应进行生活方式干预，在此基础上血脂仍未达标者接受中等强度的他汀类药物治疗。若他汀类药物不耐受，则换用另一种他汀类药物、减低他汀剂量或给药频次、或小剂量他汀合用胆固醇吸收抑制剂依折麦布或PCSK9抑制剂。若LDL-C未达到预期目标，则进一步强化调整生活方式，并中等强度他汀合用胆固醇吸收抑制剂折麦布或PCSK9抑制剂。若他汀治疗前TG>5.6hmol/L，服用降TG药物(如贝特类或高纯度鱼油)，以减少发生急性胰腺炎的风险；若他汀治疗后TG≥2.3mmol/L，可在他汀类药物治疗基上合用贝特类或高纯度鱼油。 +T2DM患者的血脂管理需基于其血脂异常情况及心血管危险程度，确定个体化的治疗目标及措施(图2)。 +(二)生活方式干顶 +推荐8：T2DM患者的血脂管理均应以生活方式干预为基础，并贯穿T2DM治疗的全过程(推荐；A级证据)。 +T2DM患者的血脂管理均应以生活方式干预为基础(表2)，并贯穿T2DM治疗的全过程(推荐；A级证据)。生活方式干预不仅有助于降低胆固醇水平，还可对血压、血糖以及整体心血管健康状况产生有益的影响，因此是糖尿病患者血脂管理的基础。一些轻度血脂异常的T2DM患者，经有效生活方式干预可将其血脂参数控制在理想范围。 +但经过积极生活方式干预仍不能改善血脂参数的患者，则需加用调脂药物治疗，而积极的生活方式干预有助于减少用药剂量。 +(三)调脂药物治疗 +既往的研究已充分证实，合并血脂异常可进一步增加T2DM患者的大血管和微血管并发症风险。因此，T2DM患者除了重视血糖控制外，还应重视血脂管理。经过积极的生活方式干预仍不能改善血脂水平者(基于ASCVD危险程度制定的目标)，需加用调脂药物治疗。 +目前常用的调脂药物包括：他汀类药物、贝特类药物，胆固醇吸收抑制剂，烟酸类等(表3)。 +1.降胆固醇治疗 +推荐9：对于绝大多数T2DM患者，中等强度他汀(可使LDL-C水平降低30%~50%)是可选的降胆固醇治疗药物(推荐；A级证据)。 +在目前临床常用的降胆固醇治疗药物中，他汀类药物是具有最充分随机化临床研究(RCT)证据的显著改善患者预后的词脂药物。特别是，斯堪地那维亚辛伐他汀生存研究(4S)、心脏保护研究(HPS)、协作阿托伐他汀糖尿病研究(CARDS)、CTT协作组进行的一项meta分析等多项研究均证实他汀拥有充分的循证证据证明可显著降低T2DM患者心血管疾病风险(附表2)，被各糖尿病指南推荐为首选的降胆固醇治疗药物。 +临床上选择他汀类药物剂量，在LDL-C达标的前提下，还需考虑安全性、耐受性和治疗费用。对于绝大多数T2DM患者，中等强度他汀(可使LDL-C水平降低30%~50%)是可选的降胆固醉治疗药物(推荐；A级证据)。中国胆固醇教育计划专家建议中指出：与白种人比较，我国人群平均胆固醇水平较低。中国国家糖尿病和代谢紊乱研究表明，中国居民的平均LDL-C水平为2.68mmol/L，明显低于欧美国家。因此，大多数中国患者经过中等强度他汀类药物治疗即可使LDL-C达标。此外，中国患者对于高强度他汀类药物治疗的耐受性也较差，发生肝毒性、肌肉毒性的风险明显高于欧美患者。基于疗效、耐受性及治疗费用的考虑，中等强度他汀类药物治疗适合于我国多数T2DM合并血脂异常患者，推荐临床选择效价比高的中等强度他汀，如辛伐他汀20~40mg、匹伐他汀2~4mg、阿托伐他汀10~20mg等。 +对于其基线LDL-C水平如何，均应在生活方式干预的基础上使用中等强度他汀(推荐；B级证据)。对于无ASCVD，且不合并其他心血管危险因素的T2DM患者，如果LDL-C≥2.6mmo/L，也应在生活方式干预的基础上使用中等强度他汀(推荐；A级证据)。 +若出现他汀类药物不耐受情况，可换用另一种他汀类药物，减低剂量或给药频次或加用非他汀类的降LDL-C药物依折麦布。 +若血脂未达预期目标，则在强化生活方式干预的同时，合用胆固醇吸收抑制剂依折麦布或PCSK9抑制剂。 +极高危的T2DM患者，除非存在禁忌证，无论 +2.降TG治疗 +推荐10：如果患者TG>5.6mmol/L时，可在生活方式干预的基础上首选隆TG药物治疗(如贝特类，或高纯度鱼油)，以减少发生急性胰腺炎的风险(推荐；C级证据)。 +经过中等强度的他汀类药物治疗后non-HDL-C仍不达标者，特别是TG≥2.3mmo/L，可在他汀类药物治疗基础上加用贝特类药物(建议；B级证据)。 +高TG血症可引发急性胰腺炎，因此若患者TG>5.6mmol/L时，可在生活方式干预的基础上首选降TG药物治疗(如贝特类，或高纯度鱼油0.5~1.0g/次)，以减少发生急性胰腺炎的风险(推荐；C级证据)。 +前瞻性流行病学研究和meta分析均证实，高TG水平与ASCVD发生相关，与T2DM患者的大血管和微血管事件的剩留风险相关。多项RCT也检验了此类药物预防CHD的作用。非诺贝特干预及减少糖尿病心脏事件研究(FIELD)和糖尿病患者心血管风险干预研究(ACCORD)的亚组分析均提示在高TG/低HDL-C的糖尿病患者中，非诺贝特治疗可使ASCVD风险减少30%左右。Meta分析表明，贝特类药物可使CHD风险降低约25%，CHD死亡率降低约10%。苯扎贝特心肌梗死预防研究(BIP)和苯扎贝特冠状动脉粥样硬化干预研究(BECAIT)证实，苯扎贝特治疗可以缓解ASCVD的进展。因此，经过中等强度的他汀类药物治疗后non-HDL-C仍不达标者，特别是TG≥2.3mmol/L，可在他汀类药物治疗基础上加用贝特类药物(建议；B级证据)，如非诺贝特或苯扎贝特，或高纯度鱼油。但在老年、严重肝肾疾病、甲状腺功能减退等特殊情况者，应慎用他汀联合贝特类药物，并严密监测和随访，一旦出现异常，及时停药。 +3.其他药物 +推荐11：胆固醇吸收抑制剂依折麦布和PCSK9抑制剂可作为他汀不耐受或单药治疗LDL-C不能达标时的联合用药(建议；A级证据)。 +在T2DM患者中进行的终止糖尿病患者动脉粥样硬化研究(SANDS)、依折麦布/辛伐他汀疗效国际试验(IMPROVE-IT)研究显示，选择性胆固醇吸收抑制剂依折麦布联合他汀治疗进一步降低主要心血管终点事件风险(HR：0.936，P=0.016)，且安全性良好。PCSK9抑制剂是一类新型的降胆固醇治疗药物，Meta分析结果显示，PCSK9抑制剂可降低心肌梗死(OR：0.49，P=0.03)和全因死亡率(OR：0.45，P=0.015)。胆固醇吸收抑制剂依折麦布和PCSK9抑制剂可作为他汀不耐受或单药治疗LDL-C不能达标时的联合用药(建议；A级证据)，但其长期以及在糖尿病患者中的疗效和安全性仍有待进一步的探讨。 +Meta分析证明.烟酸单药或联合他汀治疗可有效改善糖尿病患者的血脂异常，但长期治疗可升高空腹血糖(+0.085mmo/L，P<0.05)。此外，目前没有确切证据证明烟酸用于糖尿病患者中可降低心血管事件风险，而烟酸与他汀联合的终点事件研究——干预对全球卫生健康的影响研究(AIM-HIGH)，因可能增加缺血性卒中风险(1.6%对0.9%)而提前终止。因此，不推荐T2DM合并血脂异常患者使用烟酸。 +(四)长期维持治疗 +推荐12：T2DM血脂异常患者的调脂治疗在血脂达标后，仍需长期维持治疗(推荐；A级证据)。T2DM血脂异常患者的调脂治疗在血脂达标后，仍需长期维持治疗(推荐；A级证据)。已有证据表明，长期调脂治疗可给患者带来更大的获益。由于炎症和不稳定状态会持续一段时间，如T2DM患者发生了急性冠状动脉综合征(ACS)事件后，他汀类药物强化治疗应至少坚持2年，此后用有效剂量长期治疗。而在治疗期间，需对T2DM患者加强健康教育与管理，强调血脂异常的危害、达标及长期治疗的获益等.提高患者长期治疗依从性。 +(五)提高患者治疗依从性 +T2DM患者往往需要长期降胆固醇治疗，而不依从用药占据治疗失败的30%~50%，并导致各种不良后果，包括增加住院率和医疗费用等。因此，在T2DM患者就诊时应评估其生活方式干预及药物治疗的依从性，发现其(可能)存在的问题、障碍或不良反应，并将血脂水平及控制目标等信息持续向惠者反馈。必要时组建多学科治疗团队，包括内分泌代谢病科医师、心血管病科医师、脑血管病科医师、营养专家、运动医学专家、护师、药剂师等，以帮助患者解决依从性问题。 +六、T2DM患者特殊情况下的血脂管理 +(一)T2DM合并肝病或肝功能异常 +推荐13：当血清丙氨酸氨基转移酶(ALT)或天门冬氨酸氨基转移酶(AST)<2.5x正常上限值(ULN)，同时总胆红素(TBil)正常，可观察，无需调整剂量；如血清ALT或AST2.5~3.0xULN时，可减量；如血清ALT或AST≥3.0xULN时，应停药；当ALT恢复正常时，可酌情再次加量或换药。 +1.T2DM合并慢性肝炎、非酒精性脂肪性肝病、非酒精性脂肪性肝炎(NASH)、代偿期肝硬化患者在无肝功能不全征象时可安全使用他汀类药，通常无需减小剂量。在糖尿病前期/T2DM患者以及活检证实的NASH患者中采用他汀类药物治疗是安全的。考虑到他们心血管疾病的高风险，对这类人群应该鼓励服用他汀类药物治疗。他汀类药物与治疗感染(如乙型和丙型肝炎)的药物同时使用时，应了解两类药物之间的相互作用，如果存在药物的相互作用，应更换一种与治疗感染无相互影响的他汀类药物或者限制其在最低的剂量使用。 +2.他汀类药物本身可引起肝功能受损，主要表现为转氨酵升高，发生率约0.5%~3.0%，常见于开始用药或增大剂量的12周内，且呈剂量依赖性，极少引起肝衰竭；当血清ALT或AST<2.5xULN，同时TBil正常，可观察，无需调整剂量；如血清ALT或AST2.5~3.0xULN时可减量；如血清ALT或AST≥3.0xULN时应停药：当ALT恢复正常时.可酌情再次加量或换药。 +3.失代偿性肝硬化及急性肝功能哀竭是他汀类药物应用禁忌证。 +(二)T2DM合并CKD +推荐14：当合并CKDI~2期，他汀类药物的使用无须减量；当合并CKD3期，除普伐他汀限制使用，阿托伐他汀、辛伐他汀、氟伐他汀、瑞舒伐他汀均无须减量：当合并CKD4期，阿托伐他汀可无须减量，辛伐他汀应减量使用，而氟伐他汀、瑞舒伐他汀、普伐他汀均应限制使用；当合并CKD5期，透析前使用他汀治疗的患者，他汀类药物慎续用；不推荐在此期起始他汀治疗。 +Meta分析结果显示他汀对肾功能无不良影响，在患者可耐受的前提下，推荐T2DM合并CKD患者在血脂异常时应接受他汀治疗。 +当合并CKDI~2期，他汀类药物的使用无须减量(图3)；当合并CKD3期，除普伐他汀限制使用，阿托伐他汀、辛伐他汀、氟伐他汀、瑞舒伐他汀均无须减量；当合并CKD4期，阿托伐他汀可无须减量，辛伐他汀应减量使用，而氟伐他汀、瑞舒伐他汀、普伐他汀均应限制使用；当合并CKD5期，透析前使用他汀治疗的患者.他汀类药物谨慎续用；不推荐在此期起始他汀治疗。 +CKD患者是他汀引起肌病的高危人群，尤其是在肾功能进行性减退或肾小球滤过率(glomerular filtration rale，GFR)<30ml·min-1·1.73m2)时，并且发病风险与他汀剂量密切相关，故应避免大剂量应用。 +中等强度他汀治疗LDL-C不能达标时，推荐联合应用依折麦布。 +(三)老年T2DM +老年人大多有不同程度的肝肾功能减退，或常患多种慢性疾病，需服用多种药物，需注意药物间的相互作用和不良反应；调脂药物剂量的选择需要个体化，起始剂量不宜太大；当老年患者年龄>75岁时，不推荐高强度他汀治疗，推荐中等强度他汀治疗，并根据治疗效果调整调脂药物剂量和监测肝肾功能、肌酸激酶。 +七、T2DM患者血脂管理中药物不良事件的监测和处理 +推荐15：大多数患者对他汀类的耐受性良好。 +推荐16：在服用他汀类药物期间出现肌肉不适或无力症状以及排褐色尿时，应及时监测肌酸激酵(CK)，注意排除甲状腺功能低下、过度运动等导致的肌肉症状和/或肌酶升高。如果发生或高度怀疑肌炎，应立即停止他汀治疗。 +推荐17：长期服用他汀类药物可能引起血糖异常和增加新发糖尿病的风险。 +推荐18：Meta分析和中国多中心研究数据显示，他汀与非诺贝特联用，可进一步改善血脂谱、显著提高血脂达标率，且耐受性良好。 +因此，可使用他汀与非诺贝特合用，避免与吉非贝齐合用，应用时应加强临床监测，警惕不良反应的发生。 +使用调脂药过程，尤其联合用药者应密切监测安全性，特别在高龄、低体重、多系统疾病、同时使用多种药物、围手术期等患者更应加强监测。 +大多数患者对他汀类的耐受性良好。常见不良反应包括头痛、失眠、抑郁、以及消化不良、腹泻、腹痛、恶心等消化道症状，通常较轻且短暂.常不需要特殊治疗。 +但仍有极少数病例发生肝脏转氨酶如ALT和AST升高，且呈剂量依赖性。 +因此建议在治疗前和开始治疗后4-8周复查肝功能，如无异常，则逐步调整为6-12个月复查1次；如AST或ALT超过3倍正常上限值，应暂停给药，且仍需每周复查肝功能，直至恢复正常。 +轻度的肝酶升高小于正常值上限2.5倍并不是治疗的禁忌证，患者可以继续服用他汀，部分患者升高的ALT可能今自行下降。 +用药过程仅有血CK升高而不伴肌痛或肌无力等其他肌损伤证据，则不考虑他汀所致肌损伤。在服用他汀类药物期间出现肌肉不适或无力症状以及排褐色尿时，应及时检测CK，注意排除甲状腺功能低下、过度运动等导致的肌肉症状和(或)肌酶升高。如果发生或高度怀疑肌炎，应立即停止他汀治疗。如果患者有肌肉触痛、压痛或疼痛，CK不升高或中度升高(3~10xULN)，应进行随访、每周检测CK水平，直至排除了药物作用；如肌肉症状恶化，应及时停药。如果患者有肌肉触痛、压痛或疼痛，且连续检测CK呈进行性升高，应慎重考虑减少他汀剂量或暂时停药。然后决定是否或何时再开始他汀类药物治疗。一旦患者发生横纹肌溶解，应停止他汀类药物治疗，必要时住院进行静脉内水化治疗。 +长期服用他汀类药物可能引起血糖异常和增加新发糖尿病的风险。对13项随机对照临床研究进行的meta分析中，他汀治疗组新发糖尿病风险增加9%。关于他汀类药物的类效应的研究发现，阿托伐他汀、瑞舒伐他汀、辛伐他汀、氟伐他汀在正常人和T2DM患者中都具有类似的对血糖调控的不良影响，而匹伐他汀和普伐他汀对血糖调节具有较中性的作用。目前发现他汀引发新发糖尿病的可能机制有：增加其他致糖尿病的危险因素、损伤胰岛β细胞、降低胰岛素敏感性等。一个遗传学随机试验发现他汀类药物通过抑制HMG-CoA还原酶活性，可引起体重增加，从而增加新发糖尿病的风险。在另一项meta分析中，高剂量他汀治疗比中等剂量他汀增加新发糖尿病的风险12%，提示他汀引发新发糖尿病与剂量相关。但他汀对心血管疾病的总体益处与新发糖尿病风险之比是9：1，他汀类药物对心血管疾病的保护作用远大于新发糖尿病风险。使用中等强度他汀不仅有效降低心脑血管事件，同时安全性和耐受性良好。现有数据表明，如果有在使用他汀类出现血糖不良反应，通常反应小且可通过调整血糖控制方案减弱该反应。而他汀减少有糖尿病风险患者的心血管事件的获益已得到充分肯定。因此，T2DM患者使用他汀治疗期间，着重于通过减轻体重或降糖药物来控制血糖和HbA1c，并提供适当的饮食与运动建议。 + +贝特类最常见的不良反应为胃肠道不适，多为轻微的恶心、腹泻和腹胀等。另外，偶见皮肤强痒、荨麻疹、皮疹、脱发、头痛、失眠和性欲减退等。长期服用贝特类时，需要警惕药物引起的肝、肾功能损害，因此在治疗开始后半个月应该监测肝、肾功能；个别患者服药后可能发生药物性横纹肌溶解症，若有上述症状，则应该立即检测血CK水平。另外，贝特类可使胆结石的发生率升高，个别患者服药后白细胞、红细胞和嗜酸性粒细胞可能减少，因此若有相应的症状和体征，应该进行相应的监测。 +烟酸可导致糖代谢异常或糖耐量恶化，一般不推荐在糖尿病患者中使用。若必须使用，应该定期监测血糖水平。 +T2DM患者常为混合型血脂异常，临床可能需要他汀类与贝特类药物联合应用，两药联用可能会增加不良反应的几率。Meta分析共纳人13项非诺贝特他汀联用随机对照临床研究中的7712例受试者数据，结果显示，联合治疗组尽管肝酶升高发生率有所升高，但因肝功能异常停药的患者比例并未增加，且CK升高、因肌病停药发生率在联合治疗组和单药组间无统计学差异，说明他汀与非诺贝特联用耐受性良好。 +中国多中心研究数据显示，他汀与非诺贝特联用，可进一步改善血脂谱、显著提高血脂达标率，且耐受性良好。 +因此，可使用他汀与非诺贝特合用，避免与吉非贝齐合用，应用时应加强临床监测，警惕不良反应的发生。 +八、T2DM患者常用药物对血脂的影响 +推荐19：在临床中，T2DM患者一些常用的药物会影响患者的血脂水平，临床医师在处方药物时应该考虑到这些潜在的药物作用。 +在临床中，T2DM患者一些常用的药物会影响患者的血脂水平，可能会对患ASCVD的风险产生影响。有些药物对血脂的影响可能显著，但大多数影响较小(附表5)。当T2DM患者同时服用多种药物时，其累积效应不容忽视。 +因此，临床医师在处方药物时，应该考虑到这些潜在的药物作用，以免使患者承受不必要的风险。 +九、T2DM患者的血脂异常预防策略 +推荐20：治疗性生活方式改变不仅是治疗T2DM患者血脂异常的基础，更是预防T2DM患者血脂异常的根本手段。 +治疗性生活方式改变不仅是治疗T2DM患者血脂异常的基础，更是预防T2DM患者血脂异常的根本手段。因此，应教育患者调整饮食结构，并提倡健康生活方式。调整饮食结构包括控制总热量、减少饱和脂肪酸的摄入、增加不饱和脂肪酸的摄入、控制胆固醇的摄入、增加富含维生素、纤维等食物。 +健康生活方式包括减肥、戒烟、控制酒精、限制食盐、坚持有氧运动、注重心理健康、保持乐观达的生活态度等。 +这些均可以有效预防T2DM患者的血脂异常。 + +十、总结 +总之，遵循专家共识中血脂异常的个体化处理原则，确定T2DM患者调脂治疗的具体目标值，选用合适的调脂药物、剂量及疗程，是改善T2DM伴血脂代谢异常患者临床预后的关键所在。 +他汀类药物是首选的降脂药物，在兼顾疗效、安全及费用的基础上可选用中等强度他汀，适合大部分T2DM合并血脂异常患者降脂治疗。 +若血脂未达预期目标，则在强化生活方式干预的同时，加用其他非他汀类药物如贝特类药物或依折麦布。 +血脂达标后，仍需长期维持治疗。 +治疗性生活方式改变不仅是治疗T2DM患者血脂异常的基础，更是预防T2DM患者血脂异常的根本手段。 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_14.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_14.txt" new file mode 100644 index 0000000..5846ebe --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_14.txt" @@ -0,0 +1,79 @@ +围术期血糖管理专家共识(快捷版) +血糖异常增高是围术期的常见问题。一方面，手术创伤应激诱发机体分泌儿茶酚胺、皮质醇和炎性介质等胰岛素拮抗因子，促使血糖增高。另一方面，合并糖尿病、代谢综合征等胰岛素抵抗或胰岛素分泌障碍疾病的患者更容易发生围术期高血糖。另外，围术期经常使用的激素、含糖营养液等进一步增加了高血糖的风险。值得注意的是，长时间禁食和不恰当的降糖治疗也有引起患者低血糖和血糖剧烈波动的可能。 +大量证据表明，围术期血糖异常(包括高血糖、低血糖和血糖波动)增加手术患者的死亡率，增加感染伤口不愈合以及心脑血管事件等并发症的发生率，延长住院时间，影响远期预后。 +合理的血糖监测和调控是围术期管理的重要组成部分，应当得到重视。 +据此，中华医学会麻醉学分会于2014年组织专家组起草和制订了《围术期血糖管理专家共识》，本文是在此基础上进一步修订的2015年快捷版本。 +围术期血糖管理的基本原则 +识别围术期血糖异常的高危人群围术期血糖异常以高血糖为主，可分为合并糖尿病的高血糖和应激性高血糖两类(stress-induced hyperglycemia)。一般手术围术期高血糖以合并糖尿病者居多。目前我国糖尿病患病率逐年增高，合并糖尿病的外科手术患者也日趋增多，其中相当比例的患者术前并未得到正确诊断和有效控制。有国外研究报道，择期手术中10%以上的患者合并隐匿性糖尿病。与普通人群相比，合并糖尿病尤其是未发现、未治疗的糖尿病患者血糖升高更加显著，围术期死亡率和并发症发生率更高，应当在术前加以识别。 +而单纯由于应激导致血糖显著增高者往往提示手术应激很强，或合并感染、败血症等并发症，可能为危重患者。 +合理的血糖控制目标大量循证医学证据表明，血糖控制有利于减少外科重症患者术后感染等并发症，但控制过于严格(如降至“正常”范围)则增加低血糖风险，对降低总死亡率并无益处。 +尽管目前的结论主要来源于对ICU重症患者以及体外循环心脏手术患者的研究，对一般外科手术患者的理想血糖值尚缺乏高级别的研究证据，但采用适当宽松的血糖控制目标已得到了广泛的共识。 +围术期血糖管理的要点围术期血糖管理的要点在于控制高血糖，同时避免发生低血糖，维持血糖平稳。因禁食、降糖方案未及时调整或降糖治疗中断等因素造成的围术期血糖波动比稳定的高血糖危害更大。 +严密的血糖监测、及时调整降糖治疗方案是保持围术期血糖平稳的关键。 +应根据患者术前血糖水平、治疗方案、有无并发症、手术类型等进行全面评估，制定个体化的管理方案。 +血糖术前评估与术前准备 +术前评估 +1.糖化血红蛋白HbA1c反映采血前三个月的平均血糖水平，可用于术前筛查糖尿病和评价血糖控制效果。对既往无糖尿病病史者，如果年龄≥45岁或体重指数BMI≥25kg/m2，同时合并高血压、高血脂、心血管疾病、糖尿病家族史等高危因素，行心脏外科、神经外科、骨科、创伤外科、器官移植等高危手术者，推荐术前筛查HbA1c；HbA1c≥6.5%即可诊断糖尿病。既往已有明确糖尿病病史的患者，HbA1c≤7%提示血糖控制满意，围术期风险较低；HbA1c>8.5%者建议考虑推迟择期手术。单纯应激性高血糖者HbA1c正常。 +注意贫血、近期输血等因素可能干扰HbA1c测量的准确性。 +2.对合并糖尿病的患者，术前还应了解糖尿病类型、病程、目前的治疗方案、低血糖发作情况，特别是有无糖尿病并发症。合并糖尿病酮症酸中毒、高渗综合症是非急诊手术的禁忌。病程长的糖尿病患者可能并发冠心病等心脑血管疾病，且心肌缺血症状往往不典型、容易漏诊，应引起警惕。 +3.手术类型与围术期高血糖风险相关。手术越大、应激越强，血糖增高越明显。与区域麻醉比较，全身麻醉特别是吸入性麻醉药刺激血糖升高的作用更显著，但目前并没有证据证明糖尿病患者必须首选区域麻醉。 +术前准备 +胰岛素是围术期唯一安全的降糖药物。 +术前应将原有降糖方案过渡至胰岛素，并根据禁食情况减去控制餐后血糖的胰岛素剂量。 +1.糖尿病患者手术当日停用口服降糖药和非胰岛素注射剂。磺脲类和格列奈类口服降糖药可能造成低血糖，术前应停用至少24小时；二甲双胍有引起乳酸酸中毒的风险，肾功能不全者术前停用24~48小时。 +停药期间监测血糖，使用常规胰岛素控制血糖水平。 +术前住院时间超过3天的患者可在入院后即换用短效胰岛素皮下注射控制血糖，术前调整到适合的剂量。 +无需禁食水的短小局麻手术可保留口服降糖药。 +2.入院前长期胰岛素治疗者，方案多为控制基础血糖的中长效胰岛素联合控制餐后血糖的短效胰岛素皮下注射。长时间大手术、术后无法恢复进食的糖尿病患者，手术日换用短效胰岛素持续静脉泵注控制血糖。短小门诊手术者，手术当日可保留中长效胰岛素，剂量不变或减少1/3~1/2，停用餐前短效胰岛素。 +3.术前控制餐前血糖≤140mg/dl(7.8mmol/L)，餐后血糖≤180mg/dl(10.0mmol/L)。 +手术风险越高，术前血糖控制达标的重要性越强。 +另一方面，术前血糖长期显著增高者，围术期血糖不宜下降过快。 +因此，应当综合评估风险，合理选择手术时机，可适当放宽术前血糖目标上限至空腹≤180mg/dl(10mmol/L)，随机或餐后2小时≤216mg/dl(12mmol/L)。 +4.避免术前不必要的长时间禁食，糖尿病患者择期手术应安排在当日第一台进行。禁食期间注意血糖监测，必要时输注含糖液体。由于术前精神紧张应激，手术患者发生低血糖的风险低于普通住院患者。 +围术期血糖监测和控制目标 +围术期血糖测量方法床旁快速血糖仪测量指血(毛细血管血)血糖用于血流动力学稳定的患者。血糖仪需定期校准。严重低血糖时血糖仪所测得的数值可能偏高，应与中心实验室测量的静脉血结果进行对照。动脉或静脉血气分析是围术期血糖监测的金标准。在低血压、组织低灌注、贫血以及高血脂、高胆红素血症等代谢异常的情况下，指血血糖准确性下降，应使用动脉血气监测血糖。 +生理情况下，动脉血糖较毛细血管血糖高0.3mmol/L。 +围术期血糖监测频率正常饮食的患者监测空腹血糖、三餐后血糖和睡前血糖。禁食患者每4~6小时监测一次血糖。术中血糖波动风险高，低血糖表现难以发现，应1~2小时监测一次血糖。危重患者、大手术或持续静脉输注胰岛素的患者，每0.5~1小时监测一次。体外循环手术中，降温复温期间血糖波动大，每15分钟监测一次。血糖≤70mg/dl(3.9mmol/L)时每5~15分钟监测一次直至低血糖得到纠正。 +病情稳定的门诊手术患者，如手术时间≤2小时，在入院后和离院前分别监测一次血糖。 +围术期血糖控制目标 +1.推荐围术期血糖控制在140mg/dl(7.8mmol/L)~180mg/dl(10.0mmol/L)，不建议控制过严。 +正常饮食的患者控制餐前血糖≤140mg/dl(7.8mmol/L)，餐后血糖≤180mg/dl(10.0mmol/L)。 +2.术后ICU住院时间≥3d的危重患者，推荐血糖目标值≤150mg/dl(8.4mmol/L)。 +3.根据患者手术类型、术前血糖水平、脏器功能，建立围术期血糖控制的个体化目标。整形手术对伤口愈合要求高，血糖目标降低至108mg/dl(6.0mmol/L)~144mg/dl(8.0mmol/L)有利于减少术后伤口感染。脑血管疾病患者对低血糖耐受差，血糖目标值可适当放宽至≤214mg/dl(12.0mmol/L)。 +高龄、有严重合并症、频繁发作低血糖的患者，血糖目标值也可适当放宽。 +原则上血糖最高不宜超过250mg/dl(13.9mmol/L)。 +血糖管理实施方案 +高血糖 +1.糖尿病患者围术期需要输注葡萄糖者，建议液体中按糖(g)：胰岛素(U)=3~4：1的比例加用胰岛素中和。肠内外营养的患者应注意营养液中的糖负荷，选用糖尿病专用型制剂，适当降低糖与脂肪的比例，缓慢输注，通过降低糖类总量、减慢吸收速度，降低血糖峰值，减少血糖波动。 +2.尽量避免引起血糖升高的其他因素。 +地塞米松常用于预防术后恶心呕吐，可升高血糖水平。 +使用其他糖皮质激素、儿茶酚胺类药物、生长抑素和免疫抑制剂也可能造成血糖增高。 +3.血糖>180mg/dl(10.0mmol/L)开始胰岛素治疗。静脉给胰岛素起效快，方便滴定剂量，术中和术后ICU期间适宜静脉给药。持续静脉泵注胰岛素有利于减少血糖波动，糖尿病患者以及术前已经使用静脉胰岛素的患者术中首选持续静脉泵注胰岛素。应激性高血糖的患者可选择单次或间断静脉推注胰岛素，如血糖仍高，则予持续泵注。通常使用短效胰岛素加入生理盐水，浓度1U/ml配泵，参照患者的血糖水平、术前胰岛素用量、手术刺激大小等因素来确定胰岛素的用量，密切监测，根据血糖升降适当调整泵速，注意个体化给药，避免发生低血糖。 +胰岛素皮下注射适合病情稳定的非重症患者，常用于术前术后过渡；注意避免短时问内反复给药造成降糖药效叠加。 +4.严重高血糖可能造成渗透性利尿，引起高渗性脱水和低钾血症，应注意维持水电解质平衡。术中由于多数患者血糖水平增高，一般输注无糖液体。术后和过长时间的手术当中，为了减少酮体合成和酸中毒风险，在血糖<250mg/dl(13.9mmol/L)的前提下，静脉泵注胰岛素的同时可泵注加入中和比例胰岛素的含糖液体，根据测得的血糖水平调节泵速。胰岛素+糖双泵同时输注有利于减少血糖波动，但可能促使钾向细胞内转移，进一步加重低钾血症。因此，持续静脉泵注胰岛素时应注意监测血钾，可预防性补钾。 +低血糖 +1.低血糖的危害超过高血糖。 +血糖≤50mg/dl(2.8mmol/L)时出现认知功能障碍，长时间≤40mg/dl(2.2mmol/L)的严重低血糖可造成脑死亡。 +发生一次低血糖围术期死亡率即可增加。 +2.低血糖重在预防和及时发现。 +衰弱、严重感染、肝肾功能不全的患者低血糖风险增加。长期未得到有效控制的糖尿病患者可能在正常的血糖水平即发生低血糖反应。脑损伤患者难以耐受100mg/dl(5.6mmol/L)以下的血糖水平。 +需要警惕的是，全麻镇静患者的低血糖症状可能被掩盖，不易及时发现。 +3.静脉输注胰岛素的患者血糖≤100mg/dl(5.6mmol/L)应重新评估，调整泵速。血糖≤70mg/dl(3.9mmol/L)立即停用胰岛素，开始升血糖处理。可进食的清醒患者立即口服10~25g快速吸收的碳水化合物(如含糖饮料)，不能口服的静脉推注50%葡萄糖20~50rnl，之后持续静脉点滴5%或10%葡萄糖维持血糖，每5~15分钟监测一次直至血糖≥100mg/dl(5.6mmol/L)。 +仔细筛查引起低血糖的可能原因。 +血糖术后管理 +术后早期管理 +1.术后因疼痛应激、感染、肠内外营养液输注，是血糖波动的高危时期，也是血糖管理的重要时期。 +2.术中持续静脉泵注胰岛素者，建议术后继续泵注24小时以上。机械通气和应用血管活性药物的ICU患者容易出现血糖波动，胰岛素应静脉泵注。 +3.病情稳定后过渡到皮下注射胰岛素。根据过渡前静脉泵速推算皮下胰岛素剂量。皮下注射和静脉泵注应有2小时左右的重叠，便于平稳过渡。 +积极预防术后恶心呕吐，尽早恢复正常饮食，根据进食情况逐步增加餐前短效胰岛素剂量。 +出院前准备 +1.长期胰岛素治疗的患者在出院前1~2天恢复原有方案。 +2.饮食正常规律、器官功能稳定后，如无禁忌证，可恢复口服降糖药。 +二甲双胍在肾功能稳定后加用，并且不早于术后48小时。 +3.对于围术期新发现的糖尿病患者以及调整了治疗方案的患者，应进行出院前宣教，安排内分泌科随诊。 +4.门诊手术术后监测直至排除低血糖风险后方可离院。皮下注射速效胰岛素1.5小时内、常规胰岛素3~4小时内有发生低血糖的危险。 +离院途中应随身携带含糖饮料。 +常规降糖治疗需推迟到恢复正常饮食以后。 +小结 +围术期血糖管理对于减少血糖异常相关的并发症、促进患者术后快速康复、改善手术患者预后具有重要意义。术前筛查糖化血红蛋白有助于识别围术期高血糖相关不良事件的高危人群。“合理、有效、安全”是血糖管理的宗旨，围术期血糖目标值定为140mg/dl(7.8mmol/L)~180mg/dl(10.0mmol/L)兼顾了血糖管理的有效性和安全性，较为合理。血糖>180mg/dl(10.0mmol/L)即可启动胰岛素治疗，短效胰岛素持续静脉泵注便于及时调整剂量，减少血糖波动，是高危患者围术期血糖控制的首选方案。 +严密监测血糖，个体化管理，方可实现围术期平稳过渡。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_15.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_15.txt" new file mode 100644 index 0000000..02bd5a3 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_15.txt" @@ -0,0 +1,106 @@ +2型糖尿病合并动脉粥样硬化性心血管疾病患者降糖药物应用专家共识 +随着经济高速发展、生活方式改变及人口老龄化，我国糖尿病患病率呈快速上升趋势。2007~2008年流行病学调查显示，我国20岁以上成人糖尿病患病率为9.7%。2010年流行病学调查显示，我国18岁以上成人糖尿病患病率为11.6%。在我国糖尿病患者中，90%以上为2型糖尿病(T2DM)。动脉粥样硬化性心血管疾病(ASCVD)包括冠心病、缺血性卒中及外周动脉疾病。T2DM与ASCVD关系密切，两者共存可进一步增加心血管事件和死亡风险，半数以上糖尿病患者的死亡与ASCVD相关。近年来，随着临床研究证据的不断积累和更新，关于降糖药物与T2DM患者心血管结局之间的关系也日益明确。因此，合理规范应用降糖药物对于T2DM合并ASCVD患者显得尤为重要。 +为了指导我国临床医师对T2DM合并ASCVD患者进行规范化管理，并且充分了解T2DM合并ASCVD患者的综合管理策略、降糖治疗原则、血糖控制目标及常用降糖药物合理应用，由我国内分泌科、心内科、肾内科及临床流行病学专家联合制定了本共识。 +一、T2DM合并ASCVD的流行病学 +2006年中国心脏调查发现，52.9%的冠心病住院患者合并糖尿病。另一方面，在全国三甲医院住院T2DM患者中，17.1%合并心血管疾病，13.2%合并脑血管疾病。 +在我国大型城市住院T2DM患者中，25.1%合并冠心病，17.3%合并脑血管疾病。 +中国“3B”研究显示，门诊就诊的T2DM患者中，14.6%合并心血管疾病，10.1%合并包括缺血性卒中在内的脑血管疾病。 +上述研究数据表明，我国T2DM患者合并ASCVD的情况非常普遍，已日益成为糖尿病管理的一个巨大挑战，值得临床医生给予高度重视。 +二、T2DM患者中ASCVD危险因素的综合管理 +除高血糖外，T2DM患者往往合并有高血压、血脂异常、肥胖等多重心血管危险因素。因此，对于大多数T2DM患者，特别是合并ASCVD的患者，应采取综合管理策略，在控制血糖的同时，全面管理好各种心血管危险因素，具体措施包括生活方式干预、降压、调脂、抗血小板治疗、减重等，以期最大程度降低心血管事件和死亡风险。 +(一)生活方式干预 +对于所有T2DM合并ASCVD患者，生活方式干预应作为综合管理策略的基础性措施，并贯穿于综合治疗的全过程。 +生活方式干预包括健康教育、戒烟限酒、限盐(<6g/d)、合理饮食、规律运动、注意保持心理平衡等。 +(二)降压治疗 +高血压与高血糖并存可使ASCVD发生和发展风险显著增加，从而增加T2DM患者的病死率。研究显示，控制高血压可显著降低ASCVD发生和发展的风险，降压治疗的心血管获益主要源自血压控制本身。因此，对于大多数T2DM合并高血压患者，血压控制目标为<140/80mmHg；对于年轻、没有并发症、合并白蛋白尿或糖尿病慢性肾脏病(CKD)患者，可将收缩压控制在<130mmHg。 +选择降压药物时，应综合考虑疗效、心肾保护作用、安全性、依从性、对代谢的影响等因素。 +大多数患者需要至少两种不同作用机制的降压药物的联合治疗。 +(三)调脂治疗 +T2DM患者通常合并多项血脂异常，主要表现为TG升高、LDL-C升高及HDL-C降低、三者均与T2DM患者ASCVD发生风险增高相关。T2DM合并ASCVD患者属于极高危人群，调脂治疗的首要干预靶点IDL-C目标值为<1.8mmol/L，次要干预靶点非HDL-C目标值为<2.6mmol/L，为了达到上述目标-应首选他汀类药物。经他汀类治疗后，如非HDL-C仍不能达到目标值.可在他汀类基础上加用贝特类、高纯度鱼油制剂。对于严重高TG血症(空腹TG≥5.7mmol/L)患者，应首先考虑使用贝特类、高纯度鱼油制剂或烟酸类药物治疗，以预防急性胰腺炎的发生。 +(四)抗血小板治疗 +T2DM患者的高凝血状态是发生心血管事件的重要原因之一。在ASCVD或伴有心血管高危因素的患者中，阿司匹林可有效预防卒中、心肌梗死等心脑血管事件。对于T2DM合并ASCVD患者应常规使用阿司匹林作为二级预防措施，最佳剂量为75~150mg/d；对于阿司匹林过敏或不耐受的患者，可考虑使用氯吡格雷(75mg/d)作为替代治疗。对于急性冠状动脉综合征(ACS)患者，可使用阿司匹林和氯吡格雷双联抗血小板治疗1年。 +(五)体重管理 +超重或肥胖、腹型肥胖可增加胰岛素抵抗(IR)，使ASCVD发生风险显著增加。体重控制目标包括体重指数(BMI)<24kg/m2和腰围(WC)达标(男<90cm，女<85cm)。不同降糖药对体重和内脏脂肪的影响存在差异，胰岛素、磺脲类药物(SUs)及噻唑烷二酮类(TZDs)可导致体重增加；二甲双胍可减轻体重，对内脏脂肪的影响尚不明确；胰升糖素样肽1(GLP-1)受体激动剂和钠-葡萄糖协同转运蛋白2(SGLT-2)抑制剂既可减轻体重，又可减少内脏脂肪。因此，对于合并超重或肥胖(尤其是腹型肥胖)的T2DM患者，应优先考虑使用兼具减轻体重和减少内脏脂防的降糖药物。 +(六)血糖管理 +糖尿病是ASCVD的独立危险因素，不同类型的高血糖状态，包括空腹血糖(FPG)、餐后血糖(PPG)以及HbA1c的升高，均是ASCVD的危险因素。因此，血糖管理是T2DM合并ASCVD患者综合管理策略中的重要组成部分，以下将对此进行详细阐述。 +三、T2DM合并ASCVD患者的血糖管理策略和控制目标 +对于T2DM合并ASCVD患者，血糖管理的总原则是必须兼顾降糖有效性和心血管安全性，并且优先考虑选择具有心血管获益证据的降糖药物。英国糖尿病前瞻性研究(UKPDS)及其后续的10年随访研究显示，在新诊断的T2DM患者中，严格血糖控制(HbA1c<7.0%)对降低心血管事件的远期风险非常重要。然而，退伍军人糖尿病研究(VADT)、控制糖尿病患者心血管风险行动研究(ACCORD)、糖尿病与血管疾病行动研究(AD-VANCE)等随机对照临床试验(RCTs)均显示，在年龄较大、病程较长或合并ASCVD的T2DM患者中，强化降糖治疗并不能显著降低心血管事件风险。此外，对于合并ASCVD的T2DM患者，一旦发生低血糖还可能诱发心律失常、心肌梗死、卒中、猝死等。 +因此，对于这类患者而言，降糖治疗的安全性可能比降糖疗效更为重要，应尽量在避免低血糖的前提下使血糖控制达标。 +本共识建议，T2DM合并ASCVD患者的血糖控制目标应该遵循个体化原则-综合考虑患者的年龄、糖尿病病程、ASCVD病史、其他并发症或合并症、低血糖风险等因素，充分平衡严格血糖控制的利弊得失。 +基于现有的循证医学证据，本共识推荐T2DM合并ASCVD患者的血控制目标如下： +1.对于大多数患者，HbA1c目标应控制在<7.0%。 +2.对于年龄较大、糖尿病病程较长、存在低血糖高危因素的患者，HbA1c目标应控制在<7.5%或<8.0%. +3.对于慢性疾病终末期患者，如纽约心脏学会(NYHA)心功能Ⅲ-IV级、终末期肾病、恶性肿瘤伴有转移、中重度认知功能障碍等，HbA1c控制目标可适当放宽至<8.5%。 +四、T2DM合并ASCVD患者的降糖药物治疗 +(一)降糖药物的心血管安全性评价 +2008年，美国食品药品监督管理局(FDA)发布了强制性指导意见，要求所有新批准上市的降糖药都必须进行心血管安全性评估。 +根据这一要求.目前全球已开展了一系列新型降糖药物的心血管结局研究(CVOT)。 +传统降糖药物由于不受这条强制性要求的制约，故缺少CVOT证据，其心血管安全性评估通常基于针对降糖治疗策略的大型RCT数据或基于针对降糖疗效的多项RCTs荟萃分析结果。 +根据目前已有的CVOT证据(表1)，本共识将降糖药物的心血管安全性分为获益、中性及其他3大类。 +1.具有心血管获益证据的降糖药物 +目前，明确具有心血管获益的降糖药物包括二甲双胍、恩格列净及利拉鲁肽。二甲双胍是T2DM降糖治疗的一线药物，其心血管安全性证据来自UKPDS及其后续的10年随访研究。UKPDS研究纳人1704例合并超重或肥胖的新诊断T2DM患者，随机分为给予传统治疗(饮食控制为主，n=411)、二甲双胍强化降糖治疗(n=342)或其他药物(SUs或胰岛素)强化降糖治疗(n=951)，中位随访时间为10.7年。结果显示，与传统治疗相比，二甲双胍可显著降低心血管事件风险，其中心肌梗死风险下降39%(P=0.010)，心血管事件复合终点(心肌梗死、猝死、心绞痛、卒中或周围血管疾病)风险下降30%(P=0.020)；二甲双胍与其他药物的两种强化降糖治疗方案之间相比，心血管事件风险差异无统计学意义。UKPDS研究结束后继续随访10年仍发现，二甲双胍的心血管获益具有延续效应，与传统治疗相比，其心肌梗死风险下降33%(P=0.005)。 +SGLT-2抑制剂恩格列净是第一个通过CVOT证实具有明确心血管获益的新型降糖药物，但目前尚未在我国上市。恩格列净心血管事件结局(EM-PA-REG OUTCOME)研究纳入7020例伴有心血管疾病的T2DM患者，中位随访时间为3.1年。结果显示，在常规治疗基础上，与安慰剂相比，恩格列净可显著降低3终点的主要心血管不良事件(3终点MACE，包括心血管死亡、非致死性心肌梗死或非致死性卒中)风险14%(P=0.04)，降低心血管死亡风险38%(P<0.001)，降低心力衰竭住院风险35%(P=0.002)。 +GLP-1受体激动剂利拉鲁肽是目前在中国上市的降糖药物中唯一被CVOT证实具有心血管获益的降糖药物。利拉鲁肽在糖尿病患者中的心血管结局评估(LEADER)研究纳入9340例伴有心血管疾或心血管危险因素的T2DM患者，其中81.3%的患者既往有心血管病史(包括心肌梗死、卒中或短暂性脑缺血发作、曾行血运重建术、冠状动脉或颈动脉或下肢动脉狭窄≥50%)，中位随访时间为3.8年。结果显示，在常规治疗基础上，与安慰剂相比利拉鲁肽可使3终点MACE风险降低13%(P<0.001)-心血管死亡风险降低22%(P=0.007)，扩展的心血管事件复合终点(心血管死亡、非致死性心肌梗死、非致死性卒中、血运重建、不稳定性心绞痛住院或心力衰竭住院)风险降低12%(P=0.005)，且不增加心力衰竭住院风险。 +EMPA-REG OUTCOME和LEADER均为大型、多中心、随机、双盲、安慰剂对照的CVOT，这两项研究分别为恩格列净和利拉鲁肽的心血管保护作用提供了可靠证据，对于T2DM合并ASCVD患者的降糖治疗策略制定具有里程碑意义。 +2.具有心血管效应为中性证据的降糖药物 +在T2DM患者中CVOT证实心血管效应为中性的降糖药物包括罗格列酮、吡格列酮、甘精胰岛素、西格列汀、沙格列汀、阿格列汀及利司那肽。 +评估罗格列酮对糖尿病患者心血管结局和血糖控制影响(RECORD)研究是一项开放标签的RCT研究，4447例二甲双胍或SUs单药治疗血糖控制不佳的T2DM患者随机分为两组：在原有治疗基础上联合罗格列酮或在原有治疗基础上联合SUs或双胍类，平均随访时间为5.5年。结果显示与二甲双胍联合SUs治疗组相比，罗格列酮联合二甲双胍或SUs组的首要心血管终点事件(心血管疾病住院或心血管死亡)风险达到非劣效性标准(HR为0.99.95%CI为0.85~1.16)；心力衰竭住院或死亡的相对风险显著增加(HR2.10，95%CI 1.35~3.27) +吡格列酮对大血管事件影响的前瞻性临床试验(PROactive)是一项随机、双盲、安慰剂对照的临床研究，在5238例伴有心血管疾病的T2DM患者中评估吡格列酮的心血管安全性。受试者在常规治疗基础上联合吡格列酮或安慰剂治疗，平均随访时间为34.5个月。结果显示，与安慰剂组相比，吡格列酮组的首要复合事件终点(全因死亡、非致死性心肌梗死、卒中、ACS、冠状动脉或下肢动脉的血运重建、踝关节以上的下肢截肢)风险差异无统计学意义(HR 0.90，95%CI 0.80~1.02，P=0.095)，主要次级终点(全因死亡、非致死性心肌梗死或卒中)相对风险下降16%(P=0.027)。 +PROactive研究结束后继续随访7.8年发现，两组间在首要终点和主要次级终点方面比较，差异均无统计学意义。 +甘精胰岛素初始干预转归(ORIGIN)研究采用随机、双盲、2×2析因设计，纳入12537例有心血管高危因素的IFG、IGT或T2DM患者，随机分为甘精胰岛素或常规治疗，中位随访时间为6.2年。 +结果显示，与常规治疗组相比，甘精胰岛素治疗组3终点MACE的风险差异无统计学意义(HR 1.02，95%CI 0.94~1.11，P=0.63)。 +在二肽基肽酶4(DPP-4)抑制剂中进行的3项随机、双盲、安慰剂对照的CVOT均显示，DPP-4抑制剂既不增加也不降低心血管事件发生风险。评估T2DM患者中西格列汀心血管安全性(TECOS)研究纳入14671例有心血管病史的T2DM患者，中位随访时间为3年。结果显示，在常规降糖治疗基上，与安慰剂组相比，西格列汀组首要心血管事件复合终点(3终点MACE+不稳定型心绞痛住院)的风险达到非劣效性标准(HR 0.98，95%CI 0.88~1.09)。且不增加心力衰竭住院风险。评价沙格列汀在糖尿病患者中的心血管结局(SAVOR-TIMI53)研究纳入16492例伴有心血管疾病或心血管危险因素的T2DM患者，中位随访时间为2.1年。结果显示，在常规降糖治疗基础上，与安慰剂组相比，沙格列汀组3终点MACE的风险达到非劣效性标准(HR 1.00，95%CI 0.89~1.12)，但心力衰竭住院相对风险增加27%(P=0.007)。阿格列汀与标准治疗在T2DM合并ACS患者中心血管结局比较(EXAMINE)研究在5380例既往15~90d内发生过ACS的T2DM患者中评估阿格列汀的心血管安全性，中位随访时间为18个月。 +结果显示，在常规降糖治疗基上，与安慰剂组相比，阿格列汀组3终点MACE的风险达到非劣效性标准(HR 0.96，单侧重复CI上限1.16)。 +利司那肽治疗T2DM合并ACS患者的心血管事件评估(ELIXA)研究是一项随机、双盲、安慰剂对照的临床试验，纳入6068例在既往180d内发生过ACS的T2DM患者，中位随访时间为25个月。结果显示，在常规降糖治疗基础上，与安慰剂组相比，利司那肽组首要心血管事件复合终点(3终点MACE+不稳定性心绞痛住院)的风险达到非劣效性标准( HR 1.02，95%CI 0.89~1.17)，且不增加心力衰竭住院风险。 +上述研究数据表明，罗格列酮、毗格列酮、甘精胰岛素、西格列汀、沙格列汀、阿格列汀及利司那肽的心血管效应为中性，既不增加也不降低心血管事件发生风险。 +3.其他降糖药物 +(1)目前缺少在T2DM患者中评估心血管安全性的CVOT证据的降糖药物 +对于那些未进行CVOT的传统降糖药物而言，其心血管安全性证据主要源自针对降糖治疗策略的RCT研究数据或基于针对降糖疗效的多项RCTs的荟萃分析结果，这些药物包括SUs、格列奈类、维格列汀及大部分胰岛素制剂。 +47项RCTs研究的荟萃分析显示，与安慰剂或活性对照药相比，SUs不增加T2DM患者全因死亡、心血管死亡、心肌梗死及卒中的风险.。 +那格列奈和缬沙坦在IGT人群中的结局研究(NAVIGATOR)显示，在有心血管事件病史或心血管危险因素的IGT患者中，与安慰剂相比，那格列奈治疗5年后，首要心血管事件复合终点(3终点MACE+心力衰竭住院)风险差异无统计学意义( HR 0.94，95%CI 0.82~1.09，P=0.43)。 +25项Ⅲ期临床试验的荟萃分析显示，与安慰剂或活性对照药相比，维格列汀不增加T2DM患者心脑血管事件风险，其中50mg/d组的相对风险为0.88(95%CI 0.37~2.11)、100mg/d组的相对风险0.84(95%CI 0.62~1.14).。 +T2DM心血管结局(HEART2D)研究显示，在急性心肌梗死后的T2DM患者中，餐时胰岛素或基础胰岛素治疗2.7年后，首要心血管事件复合终点(3终点MACE+冠状动脉血运重建或ACS住院)的风险相似( HR 0.98，95%CI 0.88~1.21)。事后亚组分析提示，在年龄>65.7岁亚组中，与基础胰岛素组相比，餐时胰岛素组首次心血管事件的发生风险更低(HR 0.69，95%CI 0.49~0.96)，表现为发生比例更低、时间更晚。 +(2)CVOT尚在进行中的降糖药物 +目前，正在进行CVOT的降糖药物包括阿卡波糖、利格列汀、艾塞那肽(周制剂)、度拉唐肽、阿必鲁肽、达格列净、坎格列净及德谷胰岛素。 +(二)降糖药物的用药原则 +降糖治疗的目标不仅仅是单纯控制血糖，更重要的是减少糖尿病并发症（特别是心血管事件）、降低死亡风险，从而改善患者的远期预后。生活方式干预是T2DM患者降糖治疗的基础性措施，应贯穿于降糖治疗的始终。如果单纯生活方式干预不能使血糖达标，应开始药物治疗。对于合并ASCVD的T2DM患者，尤应注意心血管安全性问题，并且优先考虑选择具有心血管获益证据的降糖药物。 +1.一线治疗 +大多数国内外指南均推荐二甲双胍作为T2DM +患者单药治疗的一线首选药物和联合治疗的基本用药，如无禁忌证且能够耐受，二甲双胍应一直保留在T2DM患者的降糖治疗方案中。 +若存在禁忌证或无法耐受，建议视患者的具体情况考虑选择具有心血管保护或中性的降糖药物. +2.联合治疗 +若一线降药物单药治疗3个月不能使血糖控制达标，需考虑两种降糖药物联合治疗。根据患者的不同情况，选择个体化的联合用药方案。对于T2DM合并ASCVD患者，可优先考虑联合具有明确心血管获益证据的降常药物(如利拉鲁肽或恩格列净)治疗， +以最大限度降低患者心血管事件和死亡的风险。 +若两种降糖药物联合治疗3个月不能使患者血糖控制达标，可考虑联合第3种降糖药物或者联合胰岛素治疗.。 +(三)降糖治疗的药物选择 +1.非胰岛素降糖药 +表2总结了常用非胰岛素降糖药的作用机制、使用方法、降糖疗效、低血糖风险、对体重的影响、注意事项等主要信息。 +(四)其他特殊情况 +1.ASCVD急性期 +对于处在ASCVD急性期(如ACS、缺血性卒中急性期、冠状动脉血运重建围手术期等)的T2DM患者，其降糖治疗方案需要充分考虑疾病特点、机体应激状况以及严格降糖治疗的获益/风险比。对于合并ACS的患者，若血糖>10.0mmol/L，可采用以胰岛素为基础的降糖治疗方案，使血糖水平控制在7.8~10.0mmol/L，同时注意避免发生低血糖。对于接受经皮冠状动脉介人治疗(PCI)的患者，使用对比剂前可以不停用二甲双胍，但应密切监测肾功能，造影后应连续两日检验血清肌酐(Scr)。若Scr值比造影前上升26.5μmol/L，则应考虑对比剂肾病发生，应立即停用二甲双胍，直至肾功能恢复至基础水平，方可重新开始二甲双胍治疗。 +目前尚无充分的证据提示，不同降糖药物对接受PCI治疗患者的预后存在不同的影响。 +对于接受冠状动脉旁路移植术(CABG)的患者，围手术期不 +推荐口服降糖药，应使用胰岛素治疗。 +2.心力衰竭 +T2DM和ASCVD患者常合并心力衰竭。对于合并心力衰竭的T2DM患者，制定降糖治疗方案时，应关注某些降糖药物对心力衰竭的潜在不良影响。 +二甲双胍：在定期检查心、肾功能的情况下，稳定期的慢性心力衰竭患者可以服用二甲双胍，但因存在乳酸性酸中毒的潜在风险，急性、病情不稳定或住院的心力衰竭患者禁用。 +TZDs：可引起水钠潴留和血容量扩张，诱发或加重心力衰竭，故急性心力衰竭、NYHA心功能Ⅱ~IV级的慢性心力衰竭患者禁用。 +DPP-4抑制剂：SAVOR-TIMI53研究显示，对于伴有心血管事件病史或心血管危险因素的T2DM患者，沙格列汀可增加心力衰竭住院风险。EXAMINE研究事后分析显示，对于无心力衰竭病史、近期发生过ACS的T2DM患者，阿格列汀增加心力衰竭住院风险( HR 1.76，P=0.026)。 +2015年4月，美国FDA对沙格列汀和阿格列汀提出警示，要求在说明书中增加对心力衰竭风险的标示。TECOS研究显示，在有心血管病史的T2DM患者中，西格列汀不增加心力衰竭住院风险，维格列汀的相关研究证据尚不充分.。 +GLP-1受体激动剂：LEADER和ELIXA研究显示，在心血管事件高危的T2DM患者中利拉鲁肽和利司那肽治疗不增加心力衰竭住院风险。 +SGLT-2抑制剂：EMPA-REG OUTCOME研究显示，在伴有心血管疾病的T2DM患者中，恩格列净可降低心力衰竭住院风险。 +胰岛素：胰岛素治疗不增加心力衰竭患者的死亡风险。ORIGIN研究显示，在有心血管高危因素的糖代谢异常患者中，与二甲双胍或SUs相比，甘精膝岛素治疗不增加心力衰竭住院风险。 +其他降糖药物在心力衰竭患者中应用的安全性尚待进一步评估。 +3.低血糖 +低血糖对心血管系统具有显著的不良影响.其短期风险包括诱发心律失常、心血管事件，长期风险为认知障碍和痴呆，严重低血糖甚至可导致患者猝死。因此，对于合并ASCVD的T2DM患者，在降糖治疗过程中尤其应尽量避免出现低血糖。胰岛素和胰岛素促泌剂均可引起低血糖，与SUs相比，格列奈类药物的低血糖风险相对较低。二甲双胍、a-糖苷酶抑制剂、TZDs、GLP-1受体激动剂、DPP-4抑制剂以及SGLT-2抑制剂单独使用时通常不会导致低血糖，在接受降糖治疗的患者中，一旦发生低血糖，应迅速补充葡萄糖或含糖食物，以使血糖水平恢复正常，并及时调整降糖治疗方案。 +4.肾功能不全 +T2DM和ASCVD患者常合并CKD。当患者存在肾功能不全[eGFR<60ml/(min.1.73m2)]时，大多数非胰岛素降糖药物的药代动力学会发生 +改变。 +因此，对于合并CKD的患者.降糖药物的选择应基于药物的药代动力学特征和患者肾功能状态进行综合判断，以确保在有效降糖的同时不增加低血糖风险，并避免诱发乳酸性酸中毒.。 +瑞格列奈和利格列汀在CKD1~5期全程均可使用，且无需调整剂量。其他非胰岛素降糖药的使用均可因肾功能不全的不同程度而受到一定的影响。二甲双胍在CKD3a期[eGFR45~59ml/(min.1.73m2)]时应减量，在CKD3b期[eGFR30--45ml/(min.1.73m2)]时证据相对有限，谨慎观察下减量使用，在CKD4期[eGFR<30ml/(min.1.73m2)]时禁用。基于LEADER研究和LIRA-RENAL研究的数据.推荐利拉鲁肽可用于CKD1~3期，从CKD4期开始禁用。根据美国FDA批准的药品说明书，恩格列净可用于CKD1~3a期，从3b期开始不推荐使用。 +在CVOT中，包括肾脏不良事件在内的微血管事件通常作为研究的次要终点。在LEADER研究中，24.7%的患者基线时合并CKD3期或以上，利拉鲁肽可使肾脏事件复合终点(包括新发大量蛋白尿、Scr倍增、终末期肾病或肾病导致的死亡)的风险显著降低22%(P=0.003)。在EMPA-REGOUTCOME研究中，25.9%的患者基线时伴有CKD3期，恩格列净可使肾脏事件复合终点(Scr倍增、起始肾脏替代治疗或因肾病死亡)的风险显著降低46%(P<0.001)。 +2016年6月，美国FDA修改坎格列净和达格列净的药物说明书，新增急性肾损伤风险的标签警示信息，建议处方这两种药物之前全面考虑增加急性肾损伤风险的各种因素，并在服药期间监测肾功能的动态变化。 +表4总结了T2DM合并ASCVD患者降糖药物使用应着重关注的主要安全性问题，其中包括药物的心血管效应、低血糖风险、对体重的影响、在心力衰竭或肝肾功能不全等特殊患者中应用的注意事项。 +五、结语与展望 +对于T2DM合并ASCVD患者，应采取综合管理策略，全面控制高血糖、高血压、血脂异常、超重或肥胖等多重心血管危险因素。在血糖管理方面，临床医师应充分考虑降糖药物的疗效与安全性之间的平衡，并且全面了解常用降糖药物的心血管安全性，这样才能熟练掌握其应用原则。 +随着CVOT的广泛开展，其研究结果将陆续公布。最新公布的SUSTAIN-6研究显示，新型长效GLP-1受体激动剂索马鲁肽(semaglutide，尚未被批准上市)同样也可显著降低心血管事件风险。因此，有理由相信未来将会出现越来越多可为T2DM患者带来心血管保护作用的降糖药物，这将推动T2DM(特别是合并ASCVD)患者的治疗策略和理念发生巨大的变革。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_2.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_2.txt" new file mode 100644 index 0000000..cb462e7 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_2.txt" @@ -0,0 +1,39 @@ +中国成人2型糖尿病HbA1c控制目标的专家共识 +目前，2型糖尿病及其并发症已经成为危害公众健康的主要疾病之一，控制血糖是延缓糖尿病进展及其并发症发生的重要措施之一。虽然HbA1c是评价血糖控制水平的公认指标，但应该控制的理想水平即目标值究竟是多少还存在争议。糖尿病控制与并发症试验(DCCT，1993)、熊本(Kumamoto，1995)、英国前瞻性糖尿病研究(UKPDS，1998)等高质量临床研究已经证实，对新诊断的糖尿病患者或病情较轻的患者进行严格的血糖控制会延缓糖尿病微血管病变的发生、发展，其后续研究DCCT-EDIC(2005)、UKPDS一80(2008)还证实早期有效控制血糖对大血管也有保护作用。这些研究终点的HbA1c控制在7.5%左右，那么年龄较大、糖尿病病程较长、部分已有心血管疾病(CVD)或伴CVD极高危因素的糖尿病人群进一步降低血糖，对CVD的影响将会如何?糖尿病患者心血管风险干预研究(ACCORD)、退伍军人糖尿病研究(VADT)和糖尿病与心血管疾病行动研究(ADVANCE)等对该类人群平均5年左右的干预，结果显示强化降糖治疗使HbA1c<6.5%，患者死亡风险和大血管事件发生并无进一步减少，ACCORD甚至表明控制HbA1c水平接近正常值(<6.4%)会增加这类患者死亡率。这些与理论或预期不一致结果产生的原因尚不确定，可能与人组人群差异、低血糖、体重增加、随访时间长短及评估方法等诸多因素有关，但过分苛求血糖正常化可能是主要原因之一。ACCORD、VADT数据分析提示对病程长、有低血糖史、有CVD或合并CVD极高危的患者，盲目地进行强化达标治疗，会明显增加低血糖和心血管事件发生。各权威组织推荐的血糖控制目标HbA1c的水平也不尽相同，美国糖尿病协会(ADA)认为一般情况下血糖控制目标值HbA1c<7%；国际糖尿病联盟(IDF)、美国内分泌医师协会/美国内分泌协会(AACE/ACE)、英国健康与临床优化研究所(NICE)、全球有效管理糖尿病合作组织(GPEDM)和加拿大糖尿病协会(CDA)则建议一般情况时HbA1c<6.5%；中华医学会糖尿病分会推荐的一般HbA1c目标值为<6.5%。 +糖尿病患者血糖控制目标应该遵循个体化原则，即对血糖控制的风险(risk)与获益(benefit)、成本(cost)与效益(effectiveness)和可行性(feasibility)方面进行科学评估，寻找较为合理的平衡，这一点已是专家共识。在我国，多数糖尿病患者居住在县以下及农村地区，经济、受教育程度、医疗保障及医疗水平等诸多影响血糖控制的因素差别极大，地域差别较强，因此临床医生在设定糖尿病血糖控制目标时除考虑病理生理因素即病情外，还必须考虑社会因素，社会因素的重要性在某些特定患者甚至超过病情。比如自我血糖监测(SMBG)在我国开展不普遍，因此防范严重低血糖的发生必须放在首位，HbA1c目标的制定应统筹考虑安全性、可行性和科学性。我们不主张笼统推荐成人2型糖尿病的HbA1c控制目标，而是根据病情分层和社会因素的差异建议相对合理的HbA1c值，力争做到安全达标。 +从病情因素考虑，大致将患者分为以下6类。 +一、无糖尿病并发症和严重伴发疾病的非老年(<65岁)患者 +1.一般将HbA1c控制于<6.5%，若降糖治疗无低血糖或体重增加等不良反应者可使HbA1c<6%。目前，新诊断糖尿病患者的人数逐年增加，越来越年轻化，尤其是30—39岁比例增加引起了临床医生的关注。这些患者绝大多数除糖尿病外并无并发症和其他疾病，考虑对患者预期寿命和生活质量的影响，应该严格控制血糖，目标值HbA1c<6.5%，我们也同意并推荐IDF的建议，对于年轻、病程较短、治疗后无低血糖或体重增加等不良反应发生的患者，血糖控制目标值应该尽量使HbAIc<6%。 +研究表明，随着HbA1c水平的升高，发生CVD的危险性相对增加，而且糖尿病病史越长的患者治疗后CVD危险性减低越小；流行病学调查结果的meta分析显示，HbA1c每增加1%，2型糖尿病心血管事件的相对危险性为1.18，1型糖尿病为1.15；ACCORD亚组分析也提示，既往无CVD且HbA1c<8%的患者强化治疗后CVD的发生及其死亡率明显下降，这与总体患者(平均病程10年，35%发生过CVD)的研究结果恰恰相反。另一方面，DCCT-EDIC经过后续8年的随访证实1型糖尿病患者早期强化治疗对微血管有持久的保护作用，并延缓动脉粥样硬化的发展；UKPDS-80经过后续10年的长期随访发现对新诊断的2型糖尿病患者，强化降糖治疗不仅能减少微血管并发症的发生，还能显著降低患者的心肌梗死发生率和总死亡率。所以，观察到严格控制血糖对大血管的保护作用可能需要较长的时间。总之，不管从病理生理还是流行病学的角度，在糖尿病诊断时就严格控制血糖，同时控制体重、血脂、血压，抗血小板治疗，全面降低CVD危险因素会延缓慢性并发症的发生、发展。 +2.口服降糖药物未达标加用或改用胰岛素的患者，其血糖控制目标值可适当放宽至HbA1c<7%，以减少低血糖和体重增加这两大不良反应。Miller等对1055例2型糖尿病患者(平均年龄61岁，病程10.8年)的低血糖发生情况调查显示，在随访的7个月中有24.5%的患者至少发生过一次低血糖(有低血糖症状并且血糖<3.3mmol/L)，其中生活方式干预组(HbA1c<6%)占11.8%，口服药物治疗组(HbA1c<7%)占16.2%，胰岛素治疗组(HbA1c<8.1%)占30.5%，而且随访过程中发生的5例严重低血糖事件(0.5%)均在胰岛素治疗组。UKPDS和ACCORD均发现胰岛素使体重增加，若体重增加，可能加重胰岛素抵抗，增加CVD风险。 +调查结果和临床经验提示对应用胰岛素治疗的患者适当放宽控制目标，也许患者受益更多。 +3.目前不必使用降糖药物的患者，即经过一定时间的降糖治疗后已经停用降糖药物，仅使用生活方式干预血糖控制很好，其目标值应该更严格(HbA1c<6%)。 +这些患者达到目标值的过程中仍存在低血糖风险，但其发生率较低，更严格的血糖控制能显著减缓慢性并发症的发生、发展，因此获益/风险比明显增加。 +二、已有CVD或CVD极高危患者 +糖尿病病史长，已患CVD或处于CVD极高危，我们推荐HbA1c≤7.5%，因为他们发生或再次发生CVD风险明显增加，低血糖风险较高，目前还没有足够的证据证明HbA1c控制在7%以下对大血管的益处。大规模随机对照试验，如ACCORD、VADT和ADVANCE的结果表明，强化降糖5年内并未发现大血管受益，ACCORD甚至显示总死亡风险反而有所增加。分析ACCORD的研究资料发现对病情较重的入组患者(平均年龄62岁，病程10年，伴CVD占35%)进行强化降糖，可能是主要原因之一。对这些年龄大、病程长、并发症和伴发疾病多的患者严格控制血糖，若发生低血糖可能诱发CVD，增加患者的死亡风险。 +ACCORD中3或4种降糖药物同时应用力求快速达到控制目标(HbA1c<6.0%)，这明显增加低血糖的发生率和总死亡率。 +ADVANCE与ACCORD不同，其血糖控制力求平稳，低血糖发生率较低，效果也更好，至少没有增加CVD事件和死亡率。 +另外，虽然DCCT-EDIC和UKPDS-80提示，对病情较轻的患者进行早期强化降糖治疗大血管受益较多，但即使是新诊断的糖尿病人群观察到降糖对大血管的保护作用也需要10年以上。 +对伴CVD或CVD极高危患者血糖控制目标要适当放宽，治疗过程中要避免血糖下降速度过快和发生低血糖；并且该组患者多同时服用其他干预CVD危险因素的药物，应慎重选择降糖药物，注意药物的禁忌证和药物间的相互作用。 +三、老年糖尿病患者 +多数指南并未单独设定老年糖尿病患者(>65岁)的血糖控制目标，这是因为老年患者的身体健康状况、脏器功能、认知功能以及预期寿命差异较大，不能一概而论；同时缺乏相关的循证医学证据指导制定个体化治疗目标。本共识专家认为应该就此特殊人群制定血糖控制目标，本共识专家认为应该就此特殊人群制定血糖控制目标，参考国外文献，建议血糖控制目标：若患者脏器功能和认知能力良好、预期生存期>15年，应严格控制HbA1c<7%；若患者合并其他疾病、预期生存期5~15年，可适当放宽HbA1c<8%；若患者既往有严重低血糖史、合并其他严重疾病、预期生存期<5年，美国退伍军人事务局推荐控制目标可放宽到HbA1c<9%。HbA1c较高者应避免发生高血糖症状、急性代谢紊乱和感染。 +对老年尤其高龄(>80岁)患者的血糖控制目标总体放宽主要原因是，老年人的神经反应比较迟钝或存在神经病变，容易发生无感知低血糖，患者常常在没有任何征兆的情况下发生低血糖昏迷，这种情况如果发生在夜间非常危险，往往因错过抢救时机导致严重脑损伤甚至死亡；而且老年人多伴有心脑血管动脉粥样硬化，一旦发生低血糖可诱发心肌梗死及脑卒中。 +即使是轻微的低血糖也可能引起患者摔伤、骨折等机体损伤，导致患者入院，增加心理和经济负担。 +老年患者的预期寿命也很重要，严格的强化治疗会使生活质量下降、心理压力明显增大，如果预期生存期<5年，则获益/风险比显著下降。 +因此，对老年糖尿病患者的血糖控制目标放宽程度应该因人而异，治疗措施应该简单易行，控制高血糖药物选择还需充分考虑患者脏器功能的减退程度。 +糖尿病病程>15年、有无感知低血糖病史、有严重伴发病如肝肾功能不全或全天血糖波动较大并反复出现低血糖症状的患者，很难设定其HbA1c的靶目标，最重要的是避免低血糖的发生，也许HbA1c控制在7%~9%是可以接受的。因为Stratton等对4585例2型糖尿病患者10年的随访表明，HbA1c<7%患者慢性并发症的发生和死亡风险最低；HbA1c控制在7%~9%，上述风险虽然增加，但是相对增长缓慢；一旦HbA1c>9%，风险明显增加甚至翻倍。 +四、低血糖高危险人群 +所有大样本随机对照研究都证实强化治疗使低血糖的发生率明显增加，虽然严重低血糖事件发生率少，但对UKPDS、前瞻性吡格列酮对大血管事件影响的临床研究(PROactive)、ADVANCE、VADT和ACCORD五大临床研究的meta分析显示强化治疗组的严重低血糖发生率为2.3%，常规治疗组为1.2%，可见，强化治疗增加低血糖发生率是不可避免的。但是，如前面所述，低血糖除了直接造成相应的严重临床后果外，频繁或严重的低血糖影响糖尿病患者的治疗。调查表明患者一旦出现频繁或严重的低血糖会明显降低患者对血糖控制达标的积极性。 +因此低血糖高危人群的个体化血糖控制格外重要。 +五、妊娠期高血糖 +对于计划妊娠的糖尿病患者，应严格控制血糖目标值HbA1c<6.5%，如应用胰岛素可适当放宽HbA1c<7%以防止低血糖发生。不建议HbA1c>8%的患者妊娠，这些患者应首先应控制血糖，因为高血糖会明显增加早期流产和胎儿畸形风险。 +妊娠期高血糖包括糖尿病合并妊娠(妊娠前糖尿病)、妊娠期发现的糖尿病(overt diabetes，指妊娠期HbA1c或血糖达到糖尿病诊断标准)和妊娠糖尿病(GDM)三种情况。 +妊娠前糖尿病或妊娠期发现的糖尿病在不发生低血糖前提下孕期血糖控制，理想目标值为HbA1c<6%；毛细血管血糖餐前、睡前及夜间不高于5.4mmol/L，餐后峰值不高于7.1mmol/L。GDM毛细血管血糖餐前<5.3mmol/L，餐后1h<7.8mmol/L或2h<6.7mmol/L。 +临床研究显示，相对于餐前血糖而言，餐后血糖的良好控制可更好地减少并发症，尤其是巨大儿出生；相对于餐后2h血糖，控制好餐后1h血糖，产科结局更好。 +六、其他情况 +与2型糖尿病并存的其他疾病比较多，这些情况下血糖控制目标目前缺乏相应的循证医学证据和共识。比如：恶性肿瘤、老年痴呆症、癫痫等。若患者预期寿命<5年者，HbA1c不应超过9%；预期寿命更长者，HbA1c可控制在7%左右。执行治疗方案较困难的情况，如精神或智力障碍者、视力障碍者、老年、高龄及独居者等，其血糖的控制目标应适当放宽，HbA1c不应超过9%，主要防止血糖过高引起的症状、急性代谢紊乱、感染和低血糖的发生。 +社会因素是决定血糖控制目标的另一个重要且必须考虑的问题，对美国不同种族的糖尿病患者在降糖治疗过程中的依从性和血糖控制情况的调查表明，那些医疗保障差的患者，治疗的依从性、血糖的自我管理能力和血糖的控制水平明显下降。 +但是，医疗保障差的人群总花销并不比平均水平低，这主要是因为忽视糖尿病治疗导致血糖过低或过高，引起相关疾病发生而入院诊治。 +在我国，很多糖尿病患者居住在县以下及农村地区，家庭收入和受教育程度较低、医疗保障及医疗条件差，他们对糖尿病相关知识知之甚少，对糖尿病的危险性认识不够、依从性差、几乎不能进行血糖自我监测(SMBG)，这类患者的血糖控制目标应依据患者的病情综合考虑，适当放宽，尽量避免因严重的低血糖或高血糖发生，加重患者病情和经济负担。 +对中国成人2型糖尿病HbA1c目标值的适用人群以HbA1c水平分层，总结于表1。 +总之，糖尿病患者的血糖控制目标要因人而异，像GPEDM倡导的“量体裁衣”(tailoring)式管理血糖，有些患者可适当放宽，不要因为过分强调HbA1c达标或正常化增加患者低血糖和死亡风险。HbA1c受检测方法和血红蛋白、红细胞转换、年龄等诸多因素的影响，也不能反映瞬时血糖水平及血糖波动，常规开展HbA1c测定还有困难，且目前国内尚缺乏检测方法的标准化，因此必须充分结合血糖监测才能真正了解糖代谢的控制情况。HbA1c的监测可依据病情每3~6个月进行一次。应该依据病情、治疗方案的不同结合患者的经济、文化、对治疗的依从性、医疗条件等多种因素，制定个体化的降糖策略，达到安全平稳降糖。必须强调血糖以外的CVD风险因素如血压、血脂、体重以及促凝状态等控制，戒烟及生活方式干预对防止、延缓或减少糖尿病并发症的发生同样十分重要。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_3.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_3.txt" new file mode 100644 index 0000000..86ce7e1 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_3.txt" @@ -0,0 +1,43 @@ +成人2型糖尿病胰岛素临床应用的中国专家共识 +糖尿病已成为严重威胁国人健康的最重要的慢性非传染性疾病之一，但糖尿病控制状况在我国并不容乐观，甚至按纵向比较，血糖控制情况亦无显著改善。2011年公布现状调查显示口服药联合胰岛素治疗的患者中85%HbA1c控制未达标(≥7.o%)糖尿病相关治疗费用中约80%用于糖尿病并发症的治疗。 +众所周知，2型糖尿病患者胰岛β细胞功能随病程进展逐渐恶化。由此推论，随病程进展，为取得血糖最佳控制，大部分2型糖尿病患者似乎最终均需胰岛素治疗。 +然而，由于社会、经济和心理因素，胰岛素使用不足和使用过度的情况在我国同时并存。 +因此，规范胰岛素治疗对于改善糖尿病管理、提高广大医护人员的临床实践水平具有重要意义。 +目前临床应用的胰岛素包括动物胰岛素、人胰岛素及胰岛素类似物。其中，人胰岛素具有免疫原性低、长期使用安全可靠、效价比高等优点，在临床中应用最为广泛，在2型糖尿病血糖管理中作用突出。 +胰岛素类似物通过改变人胰岛素结构从而改变其药代动力学特性，可分为超短效胰岛素类似物和长效胰岛素类似物。 +因起效和持续时间不同，胰岛素类似物有其各自的特点，但其使用和剂量调整原则与人胰岛素基本相同（表1）。 +一、合理选择胰岛素治疗时机 +对于2型糖尿病患者而言，尽早启动胰岛素治疗能减轻胰岛β细胞的负荷，尽快纠正高血糖状态，迅速解除高糖毒性，改善胰岛素抵抗，保护甚至逆转残存β细胞功能。 +对于胰岛素起始治疗的时机，不同学术组织的推荐有所不同(表2)。 +多项研究表明，亚裔不仅胰岛β细胞胰岛素分泌储备能力较西方白种人低，糖脂毒性及氧化应激等对β细胞毒害作用亦更为显著。因此，中国2型糖尿病患者应适时启动胰岛素治疗。 +本共识建议，对于2型糖尿病患者，以下情况应给予胰岛素治疗：(1)急性并发症或严重慢性并发症；(2)应激情况(感染、外伤、手术等)；(3)严重合并症，肝肾功能不全；(4)妊娠期间。 +以下情况可给予胰岛素单药治疗，亦可给予口服药和胰岛素联合应用：(1)新诊断2型糖尿病患者，HbA1c≥9.0%且糖尿病症状明显；(2)在采用有效的生活方式干预及2种或2种以上口服降糖药物次大剂量治疗3个月后血糖仍不达标(HbA1c≥7.0%)的患者；(3)病程中出现无明显诱因的体重下降者。 +二、初始胰岛素治疗方案的制定 +临床医师在制定胰岛素方案、剂量调整和设定糖尿病血糖控制目标时，除考虑病理生理因素外，还必须考虑社会经济因素，并统筹考虑安全性、可行性和科学性，制定个体化的血糖控制目标和起始治疗方案。 +同时，在治疗过程中，应及时进行临床评价，进行适当调整。 +1.制定个体化的治疗目标：(1)长期血糖控制目标：一般而言，以反映最近2~3个月血糖控制情况的HbA1c为主要目标，兼顾空腹和餐后血糖达标(具体可参照《中国成人2型糖尿病Hbh1c控制目标的专家共识》，表3)。 +(2)短期血糖控制目标：一般住院患者，降糖治疗以即时血糖达标为主要目标。 +一般推荐7.8~10mmol/L(140~180mg/d1)为宜。 +2.各种治疗方案的特点：目前临床中常见的胰岛素治疗方案有1天1次或2次基础胰岛素联合口服药、1天2次预混胰岛素方案、基础+餐时胰岛素方案。 +各种方案适用于不同的临床情况(根据患者的治疗意愿、能力、生活方式和血糖状况做出选择)，具体详见表4。 +3.不同治疗方案的选择：目前尚无循证医学证据证实何种胰岛素起始治疗方案更优，各权威学术组织推荐的胰岛素启动治疗方案不尽相同。多数国家和地区[美国糖尿病学会(ADA)/欧洲糖尿病研究协会(EASD)联合共识、中国台湾糖尿病临床照护指引、英国国家健康与临床优化研究所(ICE)临床指南、国际糖尿病联盟(IDF)欧洲指南]推荐起始使用基础胰岛素。若血糖控制不达标，可加用餐时胰岛素。美国临床内分泌医师协会(AACE)/美国内分泌学院(ACE)专家共识推荐基础胰岛素、预混胰岛素、基础-餐时胰岛素或餐时胰岛素1日多次注射、餐时胰岛素加二甲双胍这4种胰岛素方案中任一种均可作为起始治疗。 +总体而言，预混胰岛素治疗达标率更高，基础胰岛素治疗低血糖发生率相对较低。亚裔糖尿病患者中以餐后血糖增高更常见，餐后血糖在血糖控制中的作用尤为重要。中国2型糖尿病防治指南(2010年版)指出，每日1次基础胰岛素或每日1~2次预混胰岛素均可作为胰岛素起始治疗方案，如基础胰岛素或预混胰岛素与口服药物联合治疗控制血糖不达标则应将治疗方案调整为多次胰岛素治疗(基础胰岛素加餐时胰岛素或每日3次预混胰岛素。 +图1)。 +三、不同类别胰岛素的选择 +药物经济学已经成为评价临床治疗方案的重要手段之一。在选择2型糖尿病治疗方案时，应综合考虑控制医疗费用、患者病情及其支付能力等多方面因素。作为发展中国家，我国医疗资源仍相对匮乏，且糖尿病患者人数众多且增长迅猛，在为2型糖尿病制定胰岛素治疗方案时需考虑以上诸多因素。 +人胰岛素经济、安全、有效，在2型糖尿病治疗中发挥重要的作用。 +正是基于成本和效益比基础上，《国家基本医疗保险、工伤保险和生育保险药品目录(2009年版)》亦对胰岛素的选择做出规定(表5)。 +目前用于临床的胰岛素包括动物胰岛素、人胰岛素和胰岛素类似物。由于潜在免疫原性等问题，动物胰岛素在大多数地区使用逐渐减少，人胰岛素和胰岛素类似物使用逐渐增多。人胰岛素与人体自身分泌的胰岛素结构完全相同，胰岛素类似物通过改变胰岛素结构而改变胰岛素药代动力学特性。短期研究表明，胰岛素类似物与人胰岛素相比，控制HbA1c的能力相似，但使用更方便，在减少低血糖发生的潜在危险方面胰岛素类似物优于人胰岛素，这一优势主要表现在1型糖尿病患者。目前尚缺乏胰岛素类似物对患者长期终点事件，如死亡率、糖尿病相关微血管和大血管并发症等方面的证据。多项meta分析及临床研究显示，在2型糖尿病患者中，胰岛素类似物在HbA1c达标率、胰岛素剂量、体重、日问低血糖、严重低血糖和不良反应方面与人胰岛素相当，长效胰岛素类似物对夜间低血糖的改善优于NPH。 +四、胰岛素应用中应注意的问题 +1.在积极使用胰岛素的同时，应合理使用胰岛素，避免过度应用。对于肥胖(体重指数>28kg/m2)的患者，应在口服药充分治疗的基础上起始胰岛素治疗。 +2.合理的联合用药，避免药物不良反应的产生和叠加。单独使用胰岛素的主要不良反应是低血糖和体重增加。推荐采用胰岛素/口服药联合方案，以增加降糖疗效，同时减少低血糖和体重增加的不良反应。二甲双胍与胰岛素联用可减少体重增加，减少外源性胰岛素用量。α-葡萄糖苷酶抑制剂与胰岛素联用在有效改善血糖的同时，减少胰岛素使用剂量，减少体重增加的幅度和趋势。因此，在无禁忌证的2型糖尿病患者中均可采用二甲双胍或α糖苷酶抑制剂与胰岛素联用。 +促泌剂可发生低血糖和体重增加的不良反应，因此，除基础胰岛素外，不建议胰岛素和促泌剂联合使用。 +3.对已合并心脑血管疾病或危险因素的2型糖尿病患者，或老年糖尿病患者，过于激进的降糖治疗策略可能产生潜在的风险，进而抵消或掩盖其潜在的心血管获益。由于脑组织代谢的特殊性，卒中患者对低血糖的耐受性更低，在使用胰岛素时，应采取相对宽松的降糖治疗策略与目标值，避免低血糖的发生。 +4.肾功能不全时肾脏对胰岛素的降解明显减少，同时胰岛素排出速率下降，胰岛素可能在体内蓄积，患者出现氮质血症即血液中的尿素氮达9mmol[/L(25mg/d1)以上、肌酐达178μmol/L以上时，应根据血糖的监测及时减少和调整胰岛素的用量，使血糖维持在适当的范围内。 +胰岛素应优先选择短效、速效剂型。 +5.在治疗过程中，应加强患者教育，通过多学科的专业合作，提升患者的自我管理能力。 +6.对于注射胰岛素的患者，必须进行自我血糖监测。监测的频率取决于治疗的目标和方式[具体可参考：中国血糖监测临床应用指南(2011年版)]。 +基于以上，成人2型糖尿病胰岛素临床应用中国专家共识推荐如下： +合理把握胰岛素启动治疗时机。新诊断2型糖尿病患者HbA1c≥9.0%同时合并明显临床症状，或合并严重并发症，2种或2种以上口服降糖药次大剂量治疗3个月后仍不达标者(HbA1c≥7.0%)，应启动胰岛素治疗。 +基础胰岛素或预混胰岛素均可作为胰岛素起始治疗方案。 +应综合考虑患者病情、经济能力等各方面的因素，对血糖控制的风险与益处、成本与效益以及可行性进行科学评估，选择合理的胰岛素。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_4.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_4.txt" new file mode 100644 index 0000000..f58b228 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_4.txt" @@ -0,0 +1,51 @@ +2型糖尿病合并慢性肾脏病患者口服降糖药用药原则中国专家共识 +慢性肾脏病(CKD)是严重威胁人类健康的常见慢性病，病因多种多样，由糖尿病所引发的肾脏病称为糖尿病肾脏病(DKD)。T2DM常合并CKD，高血糖是CKD发展的主要原因之一，降糖治疗至关重要。 +口服降糖药作为临床最常用的降糖手段，对于血糖控制具有重要意义。 +近年来，T2DM合并CKD患者中口服降糖药治疗证据不断丰富，国外糖尿病及肾脏病权威指南规范了口服降糖药的应用，但我国尚缺乏T2DM合并CKD用药指南或共识。 +为规范临床用药，中国医师协会内分泌代谢科医师分会组织国内的内分泌科和肾内科领域专家共同制定了本共识。 +对于口服降糖药在T2DM合并CKD患者的应用，参考药品说明书、近期国际指南及经典专著，如“The Kidney”，若缺乏用药经验，则依据从严原则，以保护医患利益。 +一、T2DM合并CKD的流行病学 +我国糖尿病患病率逐年升高，目前糖尿病患者约9240万，其中T2DM占90%以上。糖尿病与CKD关系密切。糖尿病患者CKD发生风险较非糖尿病者增加2.6倍。近年，各地CKD流行病学调查成年人CKD的患病率存在一定差异，为9%~14%。近期全国CKD流行病学调查显示，我国成年人中CKD患病率为10.8%，据此估算18岁以上人群CKD患者人数约1.195亿。在发达国家，糖尿病已是导致CKD的主要病因，而且在发展中国家，糖尿病正逐渐成为CKD的主要致病原因。美国流行病学调查显示，年龄≥20岁的T2DM患者有39.7%合并CKD。对我国住院糖尿病患者的回顾性研究表明，33.6%的糖尿病患者合并肾脏并发症。 +上海市区30岁以上T2DM患者CKD患病率可达63.9%。 +二、T2DM合并CKD的诊断与分期 +CKD是指肾脏结构或功能异常持续超过3个月，其诊断标准见表1。目前国内外大部分指南是根据GFR来进行CKD的肾功能分期。 +(表2) +GFR是评价肾脏功能的重要指标之一，我国估算肾小球滤过率(eGFR)课题协作组改良简化MDRD方程，制定了适合我国CKD患者的eGFR的评估公式：eGFR[ml/(min·1.73m2)]=175×Scr-1.234(mg/dL)×年龄-0.179(女性×0.79)。 +三、T2DM合并CKD的口服降糖药选择 +1.选药原则：T2DM合并CKD的理想降糖治疗策略是在有效降糖的同时，不增加低血糖发生的风险，也应避免诱发乳酸性酸中毒或增加心力衰竭风险。 +口服降糖药的选择应基于药物的药代动力学特征以及患者的肾功能水平综合判断。 +在使用某些低血糖风险较大的口服降糖药时需严格监测血糖，确保随机血糖>5mmol/L以避免低血糖的发生。 +2.血糖控制目标值：对T2DM合并CKD患者的血糖控制目标应遵循个体化原则，尽量避免低血糖的发生。《中国成人2型糖尿病HbA1c控制目标的专家共识》建议对T2DM合并CKD患者的HbA1c可适当放宽控制在7%~9%，一方面避免血糖水平控制过低而出现低血糖，另一方面避免血糖水平过高而出现代谢异常及感染。当CKD导致红细胞寿命缩短时，HbA1c检测结果可能被低估。在晚期CKD患者，使用糖化血清蛋白反映血糖控制水平可能更可靠。 +应监测空腹及餐后血糖以更好地了解血糖控制情况。 +3.口服降糖药的选择：口服降糖药作为临床最常用的降糖手段，对于T2DM合并CKD患者的血糖控制具有重要意义。 +但口服降糖药种类繁多，各类药物的药代动力学差异显著，某些CKD患者对经肾排泄药物或其活性代谢产物的清除减少，因而伴随着不同程度的低血糖风险。 +因此，必须充分了解各种药物的药代动力学特点，结合患者肾功能情况进行个体化选择，确保在有效降糖的同时不增加低血糖风险。 +对于大多数药物，当GFR低于60ml/(min·1.73m2)时需酌情减量或停药。 +常用口服降糖药的药代动力学特征及其在T2DM合并CKD人群中应用的临床证据以及适用人群见图1及表3。 +(1)双胍类：目前，国内外指南均一致推荐二甲双胍作为T2DM控制血糖的一线用药，其主要药理作用是通过减少肝糖输出和改善外周胰岛素抵抗而降低血糖。二甲双胍可使HbA1c降低1%~2%，并可减轻体重且不增加低血糖风险。英国前瞻性糖尿病研究(UKPDS)显示，二甲双胍可降低肥胖T2DM患者心血管事件和死亡风险。二甲双胍直接以原形经肾脏排泄，当肾功能损害时易发生二甲双胍与乳酸在体内蓄积，从而增加乳酸性酸中毒风险。二甲双胍用于CKD3a期患者时减量，当GFR<45ml/(min·1.73m2)停用。 +(2)磺脲类：为胰岛素促泌剂，主要药理作用是通过刺激胰岛β细胞释放胰岛素，增加体内的胰岛素水平而降低血糖。磺脲类药物可降低HbA1c1%~2%，是目前国内外指南中推荐的控制T2DM患者高血糖的主要用药。 +第一代磺脲类药物(如氯磺丙脲、妥拉磺脲、甲苯磺丁脲)的药物原型及其活性代谢产物主要依赖肾脏排泄，在CKD患者应用时半衰期延长，低血糖风险明显增加，因此禁用于该类患者，目前此类药物在临床上已基本被淘汰。在第二代磺脲类药物中，格列本脲的半衰期较长，其活性代谢产物约50%经肾脏排泄，可在CKD患者体内积聚，可能引起严重的低血糖，且持续时间超过24h。格列本脲仅可用于CKD1~2期的患者；3~5期禁用。 +格列美脲的代谢产物仍有降糖活性，其代谢产物及原型的60%经肾脏排泄。格列美脲用于CKD1~2期患者无需调整剂量；3a期减量；3b~5期禁用。 +格列吡嗪和格列齐特的代谢产物均无降糖活性，虽然主要经肾脏排泄，但低血糖风险小于格列本脲和格列美脲。格列吡嗪用于CKD1~2期患者无需调整剂量；3期减量，4~5期禁用。格列齐特用于CKD1~2期患者无需调整剂量；在3a期减量，3b期用药经验有限，需谨慎用药；4~5期禁用。 +格列喹酮的代谢产物无降糖作用且大部分从粪便排泄，仅5%经肾脏排泄，受肾功能影响较小，但用于CKD患者的临床证据有限，格列喹酮曾用于GFR10~50ml/(min·1.73m2)患者，但试验设计不尽完善。格列喹酮可用于CKD1~3期的患者且无需调整剂量；4期用药经验有限，需谨慎用药；5期禁用。 +(3)格列奈类：格列奈类降糖药为非磺脲类胰岛素促泌剂，主要通过刺激早相胰岛素分泌而降低餐后血糖，具有吸收快、起效快和作用时间短的特点，可降低HbA1c0.5%~2.0%，其低血糖的风险和程度较磺脲类药物轻。格列奈类主要代表药物为那格列奈和瑞格列奈。那格列奈及其代谢产物83%经肾脏排泄，随着肾功能的降低，那格列奈的活性代谢产物水平增加，而瑞格列奈却未发现此现象。瑞格列奈及其代谢产物仅8%经肾脏排泄。瑞格列奈Ⅰ期临床试验表明，使用瑞格列奈7d后，肾功能正常患者与不同程度CKD患者相比，血药浓度没有明显差别，提示瑞格列奈在CKD患者体内无蓄积。一项入选281例伴或不伴肾功能不全T2DM患者的多中心研究提示，使用瑞格列奈替换原有降糖治疗，不同程度肾功能不全亚组患者(正常、轻、中、重、极重肾功能损害)低血糖发生率均低于2%，且瑞格列奈治疗期低血糖发生率与肾功能损害程度无关。瑞格列奈用于CKD1~5期的患者无需调整剂量；如起始用药，应0.5mg起始。那格列奈用于CKD1~3a期患者时，无需调整剂量；3b~4期减量；5期禁用。 +(4)噻唑烷二酮类：噻唑烷二酮类为胰岛素增敏剂，主要通过增加靶细胞对IS而降低血糖，可降低HbA1c1.0%~1.5%。主要代表药物为吡格列酮和罗格列酮，均经肝脏代谢，不增加低血糖风险。该类药物的常见不良反应是液体潴留，因而对于重度心力衰竭患者应慎用。此外，绝经后妇女服用该类药物发生骨折及骨质疏松的风险增加，因此慎用于潜在骨疾病的患者(如肾性骨营养不良)。吡格列酮用于CKD1~3a期患者时，无需调整剂量；3b~5期患者用药经验有限，需谨慎用药。罗格列酮因增加心血管风险的安全性问题引起了国内外的警惕，目前美国食品药品监督管理局(FDA)已严格限制其使用。 +(5)α-糖苷酶抑制剂：α-糖苷酶抑制剂通过延缓碳水化合物在小肠上段的吸收而降低餐后血糖，适用于饮食结构以碳水化合物为主且餐后血糖升高的患者，可降低HbA1c0.5%~0.8%，不增加体重且有减轻体重的趋势。主要代表药物有阿卡波糖、伏格列波糖等。阿卡波糖口服后很少部分被吸收，随着肾功能的降低，阿卡波糖及其代谢产物的血药浓度显著增加。阿卡波糖可用于CKD1~3期患者；4~5期禁用。 +伏格列波糖可用于CKD1~3期患者；4~5期禁用。 +(6)二肽基肽酶-4(DPP-4)抑制剂：DPP-4抑制剂通过抑制DPP-4而减少胰升糖素样肽-1(GLP-1)在体内的失活，从而增加体内GLP-1的水平。 +GLP-1以葡萄糖浓度依赖的方式增强胰岛素分泌，抑制胰升血糖素分泌，并能延缓胃排空，通过中枢性食欲抑制来减少进食量。 +这一类降糖药由于上市较晚，缺乏临床用药经验，因此用于合并CKD的患者时应酌情减量。 +DPP-4抑制剂降低HbA1c弱于其他胰岛素促泌剂。 +目前在国内上市的DPP-4抑制剂为西格列汀、沙格列汀、维格列汀和利格列汀。 +西格列汀用于GFR≥50ml/(min·1.73m2)的CKD患者时无需调整剂量；GFR在30~50ml/(min·1.73m2)时减量至50mg，qd；GFR<30ml/(min·1.73m2)时用药经验有限，减量至25mg，qd。 +沙格列汀用于GFR≥50ml/(min·1.73m2)的CKD患者时无需调整剂量，当GFR在30~49ml/(min·1.73m2)时减量；CKD4~5期患者禁用。 +维格列汀用于GFR≥50ml/(min·1.73m2)的CKD患者时无需调整剂量，当GFR<50ml/(min·1.73m2)时禁用。 +一项为期52周的随机、双盲试验评估了利格列汀的疗效及安全性。受试者为既往接受其他降糖药治疗的T2DM患者，GFR<30ml/(min·1.73m2)，分别给予利格列汀或安慰剂，结果显示与安慰剂组相比，利格列汀降低HbA1c达0.6%，但利格列汀组低血糖发生率高于安慰剂组。 +利格列汀用于CKD1~4期患者时无需调整剂量，5期患者用药经验有限。 +需谨慎用药。 +4.特殊人群的治疗： +(1)儿童和青少年T2DM合并CKD患者：在儿童和青少年T2DM合并CKD患者中，缺乏对高血糖、高血压和血脂异常治疗的相关数据。但是生活方式的改变(饮食、锻炼、减肥)对减少以上危险因素有益，因此对高血糖的起始干预应从改变生活方式开始。若生活方式干预不能控制血糖，应考虑降糖药治疗。尽管ADA推荐口服降糖药作为儿童和青少年T2DM患者的一线治疗，但其中仅二甲双胍被FDA批准用于10岁以上的儿童，其使用注意事项与成人相同。 +(2)老年T2DM合并CKD患者：老年T2DM合并CKD患者通常有多种合并症，尤其是心血管疾病以及认知功能障碍，因此应加强对多种危险因素的管理。 +对该类患者尤其应注意避免低血糖的发生，适当调整降糖目标，并视患者的具体情况而选用口服降糖药；应从小剂量开始逐渐增加剂量并注意观察患者的反应和可能的不良反应。 +四、小结 +我国T2DM合并CKD患者是一个数量庞大且不容忽视的人群，患者预后较仅有T2DM或仅有CKD患者更差。在临床实践中，应重视T2DM合并CKD患者口服降糖药的正确选择和规范使用。一旦GFR<60ml/(min·1.73m2)，大多数口服降糖药的药代动力学特征将会改变，低血糖及其他不良反应风险显著增加。遵循指南可使降糖达标率显著升高，低血糖风险显著降低，且入院率和治疗费用均显著下降。因而，对于T2DM合并CKD患者的口服降糖药治疗，尤应重视指南推荐和规范应用。在临床实践中，T2DM合并CKD患者应监测血糖，依据患者的肾功能分期选择合适降糖药并调整剂量，以保证有效控制血糖的同时能够最大程度减少低血糖风险。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_5.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_5.txt" new file mode 100644 index 0000000..d1e5f7a --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_5.txt" @@ -0,0 +1,21 @@ +针对中国肥胖与糖尿病外科手术规范的立场声明 +我国肥胖与糖尿病外科(减重代谢外科)事业起源于2000年郑成竹教授开展的第一例腹腔镜垂直胃绑带术，经过近20年的发展，国内开展手术的医院已经超过200家，手术例数近年也呈现快速增长，这是令人可喜也值得欣慰的事。为了指导及规范该学科的健康发展，经过一定的临床实践，中华医学会外科学分会内分泌外科学组联合腹腔镜与内镜外科学组、胃肠外科学组及外科手术学学组分别于2007年和2010年先后制订和颁布了《中国肥胖病外科治疗指南(2007)》及《中国糖尿病外科治疗专家指导意见(2010)》。2012年中国医师协会外科医师分会肥胖和糖尿病外科医师委员会(Chinese Society for Metabolic and Bariatric Surgery，CSMBS)组建成立，2014年11月CSMBS发表了《中国肥胖和2型糖尿病外科治疗指南(2014)》，2014年12月人民卫生出版社出版了《肥胖与代谢病外科学》，旨在规范该学科的发展及应用。 +但是在学科蓬勃发展的同时，少部分医生缺乏学科专业培训，特别是在少部分基层医院，存在一些不规范的问题，如：不注意手术适用证范围，超手术指征盲目追求手术量的增加；夸大手术治疗效果，不应用创伤小并发症少的腹腔镜手术而仍然采用传统的开腹手术方法；手术方式不规范如将胃旁路的胃囊体积加大，将一些探索性的实验性手术作为治疗性手术；围手术期管理及术后随访不规范不重视，甚至缺失等情况，导致术后效果不佳或者出现一些营养问题。 +本声明旨在从开展手术医院及术者资质、手术指征、手术方式及术后随访管理等方面对减重代谢手术的应用做出规范。 +一、医院及术者资质 +肥胖与糖尿病外科手术的开展必须得到多学科协作的支持，可参考《上海市2型糖尿病外科手术管理规范》，即“手术应在三级综合性医疗单位开展，二级医院原则上不能开展，具备条件的二级医院可向省级医师协会申请并接受审核。 +术者应具备中级及中级以上技术职称，并具有普外科执业资质，须了解各种术式的治疗原理和操作准则，并须登记成为全国或者省级医师协会会员，经系统指导、培训获得资质后方可施行手术。 +”我们认为该要求对肥胖与糖尿病外科的安全和质量提供了保障，且切实可行，故建议当地医师协会根据此要求审核开展肥胖与糖尿病外科手术的医院及术者资质。 +二、手术指征 +肥胖与糖尿病外科手术开展的适应证及禁忌证均应参照《中国肥胖和2型糖尿病外科治疗指南(2014)》。针对肥胖伴有2型糖尿病的治疗，该版指南强调了胰岛功能储备，即T2DM病程小于15年，且空腹血清C肽水平高于正常值下限的二分之一。对于体质量指数(body mass index，BMI)介于25.0~27.5kg/m2的患者，即使合并T2DM及其他肥胖相关疾病，也应慎重开展手术。 +建议此类病人应先选择内科治疗，若内科治疗效果不佳或不能耐受，且病人强烈要求手术治疗，可在充分告知后，依据临床试验的路径行手术治疗。 +《中国肥胖和2型糖尿病外科治疗指南(2014)》中将建议手术年龄定为16~65岁。 +然而根据循证医学证据，手术对于肥胖及相关代谢综合征的治疗效果，年龄并不是一个显著的影响因素，且对于青少年而言，生理、心理发育程度与生物学年龄不一定相符。 +故我们认为对于年龄的建议可根据临床评估结果适当放宽，特别是对于青少年，在经过对肥胖程度及代谢性疾病严重程度的评估、患者及家庭成员心理评估、术后管理依从性评估之后可慎重考虑手术。 +三、手术方式 +目前推荐的手术方式包括：(1)腹腔镜Roux-en-Y胃旁路术(laparoscopic Roux-en-Y gastric bypass，LRYGB)；(2)腹腔镜胃袖状切除术(laparoscopic sleeve gastrectomy，LSG)；(3)胆胰分流并十二指肠转位术(biliopancreatic diversion with duodenal switch，BPD-DS)，其中BPD-DS虽然效果最好，但其并发症发生率有所增加，术后常见维生素和微量元素的缺乏，术后随访和维生素微量元素补充要求严格且长期，故需慎重选择。 +另外，目前国内外报道多种新术式，包括在胃旁路术基础上发展的mini-bypass、袖状胃切除术基础上发展的“SG+X术”、以及胃折叠术、空回肠侧侧吻合术等，这些指南推荐之外的术式均尚缺乏中长期疗效数据，不建议临床推广，仅限于临床研究。 +四、术后随访 +接受肥胖与糖尿病外科手术患者均需终身随访，临床实践中不少医疗机构对接受减重代谢手术的病人缺少规律的随访，致使手术的安全性和有效性缺乏保障。指南确定术后1年内应至少进行4次随访，建议门诊随访，另需更多次的电话或其他方式随访，术后1个月起应对糖尿病改善进行较为完善的评估，包括血糖、糖化血红蛋白、胰岛素、C肽等，术后6个月起应对血生化、营养状况及心理、精神评估进行完善，内容应包括骨密度、维生素及微量元素水平，同时监测是否有手术并发症，进行必要的干预。 +五、总结 +综上所述，肥胖与糖尿病外科手术的开展必须遵循指南，以确保医疗质量和安全，各地医师协会对肥胖与糖尿病外科的发展应起到监管作用，规范肥胖与糖尿病外科手术的管理。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_6.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_6.txt" new file mode 100644 index 0000000..f864470 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_6.txt" @@ -0,0 +1,96 @@ +糖尿病肾病防治专家共识(2014年版) +糖尿病肾病是糖尿病最主要的微血管并发症之一，是目前引起终末期肾病(end-stage renal disease，ESRD)的首要原因。国外研究资料显示，20年以上病程的糖尿病肾病患者发展为ESRD的发生率为40.8/1000人年，需要进行透析或移植等肾脏替代治疗。我国糖尿病肾病的患病率亦呈快速增长趋势，2009至2012年我国2型糖尿病患者的糖尿病肾病患病率在社区患者中为30%~50%，在住院患者中为40%左右。糖尿病肾病起病隐匿，一旦进入大量蛋白尿期后，进展至ESRD的速度大约为其他肾脏病变的14倍，因此早期诊断、预防与延缓糖尿病肾病的发生发展对提高糖尿病患者存活率，改善其生活质量具有重要意义。为规范糖尿病肾病的诊断和治疗，中华医学会糖尿病学分会微血管并发症学组组织国内的内分泌和肾内科领域专家共同制定本共识。 +一、糖尿病肾病的定义与诊断 +糖尿病肾病是由糖尿病引起的肾脏损伤，以往用DN(diabetic nephropathy)表示，2007年美国肾脏病基金会(NKF)制定了肾脏病生存质量指导指南，简称NKF/KDOQI。该指南建议用DKD(diabetic kidney disease)取代DN。2014年美国糖尿病协会(ADA)与NKF达成共识，认为DKD是指由糖尿病引起的慢性肾病，主要包括肾小球滤过率(GFR)低于60ml·min-1·1.73m-2或尿白蛋白/肌酐比值(ACR)高于30mg/g持续超过3个月。糖尿病性肾小球肾病(diabetic glomerulopathy)专指经肾脏活检证实的由糖尿病引起的肾小球病变。 +糖尿病肾病的诊断分为病理诊断和临床诊断。肾脏病理被认为是诊断金标准。糖尿病主要引起肾小球病变，表现为肾小球系膜增生、基底膜增厚和K-W(Kimmelstiel-Wilson)结节等，是病理诊断的主要依据。糖尿病还可引起肾小管间质、肾微血管病变，如肾间质纤维化、肾小管萎缩、出球动脉透明变性或肾微血管硬化等，这些改变亦可由其他病因引起，在诊断时仅作为辅助指标。目前糖尿病肾病临床诊断的依据有尿白蛋白和糖尿病视网膜病变。糖尿病肾病早期可表现为尿白蛋白阴性，症状不明显，易被忽略，但目前仍缺乏比尿微量白蛋白更可靠敏感的糖尿病肾病早期检测指标。 +(一)糖尿病肾病临床诊断依据 +1.尿白蛋白：微量白蛋白尿是糖尿病肾病早期的临床表现，也是诊断糖尿病肾病的主要依据。其评价指标为尿白蛋白排泄率(UAE/AER)或ACR。个体间UAE的差异系数接近40%，与之相比ACR更加稳定且检测方法方便，只需要检测单次随机晨尿即可，故推荐使用ACR。尿白蛋白排泄异常的定义见表1，因尿白蛋白排泄受影响因素较多，需在3-6个月内复查，3次结果中至少2次超过临界值，并且排除影响因素如24h内剧烈运动、感染、发热、充血性心力衰竭、明显高血糖、怀孕、明显高血压、尿路感染，可作出诊断。然而，尿白蛋白对诊断2型糖尿病肾病的特异性不足，对预测病情的转归也存在局限性。 +长期观察结果发现，微量白蛋白尿的患者在10年中仅有30%~45%转变为大量白蛋白尿，有30%转变为尿白蛋白阴性，该现象在2型糖尿病患者中更为显著。 +因此，尿白蛋白作为诊断依据时需进行长期随访、多次检测，结果重复时方可做出判定，且需排除其他可引起白蛋白尿的病因。 +2.糖尿病视网膜病变：糖尿病视网膜病变常早于糖尿病肾病发生，大部分糖尿病肾病患者患有糖尿病视网膜病变，但在透析的糖尿病肾病患者中，糖尿病视网膜病变的发病率反而减少，糖尿病视网膜病变被NKF/KDOQI指南作为2型糖尿病患者糖尿病肾病的诊断依据之一。 +2007年NKF指南荟萃大量研究后指出，在大量白蛋白尿者中，糖尿病视网膜病变对糖尿病性肾小球肾病的阳性预测值为67%~100%，阴性预测值为20%~84%，灵敏度为26%~85%，特异度为13%~100%；在微量白蛋白尿者中，阳性预测值为45%左右，但阴性预测值接近100%，灵敏度为100%，特异度为46%~62%。Meta分析结果表明糖尿病视网膜病变预测2型糖尿病肾病的灵敏度为0.65(95%CI：0.62~0.68)，特异度为0.75(95%CI：0.73~0.78)，阳性为0.72(95%CI：0.68~0.75)，阴性预测值为0.69(95%CI：0.67~0.72)，提示糖尿病视网膜病变是2型糖尿病肾病诊断和筛查的有用指标。 +近来，发现一些因子对糖尿病肾病的诊断有价值，如转化生长因子β1(TGF-β1)、免疫球蛋白G(IgG)、转铁蛋白(TRF)、细胞外基质(ECM)、肾损伤分子1(Kim-1)及中性粒细胞明胶酶相关脂质运载蛋白(NGAL)。利用糖尿病肾病的患者血清蛋白质指纹图谱的比较中筛选到22个上调、24个下调的蛋白质或多肽，并建立诊断决策树模型，盲法验证模型的敏感性90.9%，特异性89.3%。 +上述检测方法被认为比微量白蛋白尿能更早地发现糖尿病肾病，可能作为糖尿病肾病早期诊断的工具，但其可靠性、特异性、敏感性仍需更多研究证实，目前尚未作为诊断依据。 +(二)糖尿病肾病的筛查和肾功能评价 +肾功能改变是糖尿病肾病的重要表现，反映肾功能的主要指标是GFR，根据GFR和其他肾脏损伤证据可进行慢性肾病(CKD)的分期(表2)。横断面调查结果显示，部分糖尿病患者无尿白蛋白排泄异常，但已经存在GFR下降，提示尿白蛋白阴性者也可能存在肾病，GFR可作为糖尿病肾病的诊断依据之一。 +GFR的评估方法分为外源性标志物的肾清除率测定法(如同位素稀释质谱法)和内源性标志物估算法。 +后者更经济实用，更适合于临床应用。 +估算GFR最常用的指标是血清肌酐，基于血清肌酐的肾小球滤过率的常用计算公式有CG(Cockcrofl-Gauh)公式和肾脏饮食修正公式(MDRD)，2009年又提出了CKD-EPI公式，被认为比CG公式和MDRD公式能更准确地估算2型糖尿病患者的GFR，但存在争议。 +本共识推荐使用2006年我国预估肾小球滤过率(eGFR)协作组制定的适用于中国人的改良MDRD公式：eGFR(ml·min-1·1.73m-2)=175x血清肌酐(SCr)·1.234×年龄-0.179(如果是女性×0.79)。 +血清肌本酐在估算GFR中存在灵敏度不足，受个体肌肉量、蛋白质摄入、体内代谢水平、溶血、脂血等因素干扰等局限性。近年来，胱抑素C(CysC)被认为在预测2型糖尿病肾病进展为ESRD的作用上比血清肌酐更好，CysC是由有核细胞以恒速产生的，可自由滤过，被肾小管上皮细胞重吸收和细胞内降解，但不会被肾小管上皮细胞分泌，可更准确地反映肾功能，但其检测的准确性尚未得到保障。一些学者提出了基于CysC的eGFR计算公式和CKD分期。 +目前有研究提出，联合使用血清肌酐与CysC公式比单独使用基于其中一项指标的公式更好。 +由于尿白蛋白和GFR对糖尿病肾病的重要性，对这两项的检测是目前糖尿病肾病的筛检项目，一旦确诊糖尿病，应每年都进行筛检：(1)所有2型糖尿病患者应从确诊时和1型糖尿病患者病程超过5年时每年检查1次以评估UAE/AER。(2)所有成人糖尿病患者，不管UAE/AER如何，每年应至少检查1次血清肌酐，并用血清肌酐估计GFR。 +如果有CKD，需进行分期。 +(三)糖尿病肾病临床诊断标准 +糖尿病肾病的国外诊断标准有美国肾脏基金会(NKF)肾脏病预后质量倡议(K/DOQI)指南标准(2007年)和英国国民医疗服务(NHS)标准(2010年)。我国目前仍无统一的糖尿病肾病诊断标准，本共识推荐采用表3诊断标准，符合任何一项者可考虑为糖尿病肾脏病变(适用于1型及2型糖尿病)： +诊断时，出现以下情况之一的应考虑其CKD是由其他原因引起的：(1)无糖尿病视网膜病变；(2)GFR较低或迅速下降；(3)蛋白尿急剧增多或有肾病综合征；(4)顽固性高血压；(5)尿沉渣活动表现；(6)其他系统性疾病的症状或体征；(7)血管紧张素转换酶抑制剂(ACEI)或血管紧张素II受体拮抗剂(ARB)类药物开始治疗后2~3个月内肾小球滤过率下降超过30%。 +根据NKF-K/DOQI指南、NHS等标准，强调白蛋白尿是2型糖尿病肾脏病变诊断的必要依据，但不能涵盖正常白蛋白尿的糖尿病肾病，忽略了GFR的诊断价值。考虑到ADA指南建议每年检测CKD，本共识提出糖尿病视网膜病变并CKD任何一期的诊断标准，避免遗漏那些白蛋白尿正常但eGFR下降的糖尿病肾病。 +(四)糖尿病肾病的临床分期和病理分级 +1987年Mogensen建议，根据糖尿病肾病的病理生理特点和演变过程，将1型糖尿病患者的糖尿病肾病分为5期。I期：急性肾小球高滤过期，肾小球入球小动脉扩张，肾小球内压增加，GFR升高，伴或不伴肾体积增大；II期：正常白蛋白尿期，UAE正常(<20μg/min或<30mg/24h)(如休息时)，或呈间歇性微量白蛋白尿(如运动后、应激状态)，病理检查可发现肾小球基底膜轻度增厚；Ⅲ期：早期糖尿病肾病期(UAE 20~200μg/min或30~300mg/24h)，以持续性微量白蛋白尿为标志，病理检查肾小球基底膜(GBM)增厚及系膜进一步增宽；IV期：临床(显性)糖尿病肾病期，进展性显性白蛋白尿，部分可进展为肾病综合征，病理检查肾小球病变更重，如肾小球硬化，灶性肾小管萎缩及间质纤维化；V期：肾衰竭期。 +2型糖尿病患者的糖尿病肾病可参考以上标准分期。 +病理活检被认为是糖尿病肾病诊断的金标准，不能依据临床病史排除其他肾脏疾病时，需考虑进行肾穿刺以确诊。2010年，肾脏病理学会研究委员会首次提出了糖尿病肾病病理分级标准，在1型和2型糖尿病患者中均适用。根据肾脏组织光镜、电镜及免疫荧光染色的改变对肾小球损害和肾小管/肾血管损伤分别进行分级、分度。肾小球损伤分为4级：Ⅰ级：GBM增厚；Ⅱa级：轻度系膜增生；Ⅱb级：重度系膜增生；Ⅲ级：一个以上结节性硬化(K-W结节)；Ⅳ级：晚期糖尿病肾小球硬化。肾小管间质用间质纤维化和肾小管萎缩、间质炎症的程度评分，肾血管损伤按血管透明变性和大血管硬化的程度评分。 +二、糖尿病肾病的防治 +糖尿病肾病的防治分为三个阶段。第一阶段为糖尿病肾病的预防，对重点人群进行糖尿病筛查，发现糖耐量受损或空腹血糖受损的患者，采取改变生活方式、控制血糖等措施，预防糖尿病及糖尿病肾病的发生。第二阶段为糖尿病肾病早期治疗，出现微量白蛋白尿的糖尿病患者，予以糖尿病肾病治疗，减少或延缓大量蛋白尿的发生。第三阶段为预防或延缓肾功能不全的发生或进展，治疗并发症，出现肾功能不全者考虑肾脏替代治疗。糖尿病肾病的治疗以控制血糖、控制血压、减少尿蛋白为主，还包括生活方式干预、纠正脂质代谢紊乱、治疗肾功能不全的并发症、透析治疗等。 +(一)生活方式指导 +改变生活方式包括饮食治疗、运动、戒酒、戒烟、控制体重，有利于减缓糖尿病肾病进展，保护肾功能。近期研究证明控制多种危险因素(降糖、降脂、降压并注意生活干预后)糖尿病肾病发展至肾功能衰竭的比例明显下降，生存率明显增加。 +1.医学营养治疗：医学营养治疗应强调饮食结构合理，包括对碳水化合物、蛋白质、脂肪、钠、钾、磷等营养素的管理。每日摄入的总热量应使患者维持接近理想体重，肥胖者可适当减少热量，消瘦者可适当增加热量。高蛋白摄入(超过总热量20%)与轻度肾损伤糖尿病患者中肾功能的下降、糖尿病合并高血压患者中微量白蛋白尿的发展相关联。因此糖尿病肾病患者应避免高蛋白饮食，严格控制蛋白质每日摄入量，不超过总热量的15%，微量白蛋白尿者每千克体重应控制在0.8~1.0g，显性蛋白尿者及肾功能损害者应控制在0.6~0.8g。有随机对照试验的meta分析表明，低蛋白饮食治疗对蛋白尿的控制有益，但对GFR或内生肌酐清除率(Ccr)的改善无显著作用。由于蛋白质的摄入减少，摄入的蛋白质应以生物学效价高的优质蛋白质为主，可从家禽、鱼、大豆及植物蛋白等中获得。有研究表明，ARB/ACEI类药物在低钠饮食下对糖尿病。肾病及心血管疾病的改善作用更明显，但在高钠饮食下则可能存在危害，此应限制钠盐摄入，每日摄入量控制在2000~2400mg，高血压者可配合降压药物治疗。 +尚无明确证据表明富含纤维的蔬菜的摄入对糖尿病肾病有益。 +与执业营养师一起完成营养控制目标，可改善糖尿病肾病患者的预后。 +2.运动：体力活动可诱导糖尿病肾病早期的尿蛋白暂时升高，长期规律的运动可通过提高胰岛素敏感性、改善糖耐量，减轻体重，改善脂质代谢，改善内皮功能，控制血糖、血压，，减缓糖尿病及糖尿病肾病的发生发展。糖尿病控制和并发症防治试验(DCCT)的回顾分析却表明运动对1型糖尿病微血管病变的预后无改善作用，但无证据表明运动带来危害，故仍建议1型糖尿病患者运动。FinnDiane研究结果显示，低频率低强度体育锻炼的1型糖尿病患者发生糖尿病肾病的比例更高。因此糖尿病肾病患者运动的频率强度应达到一定的要求。患者每周应至少进行150min以上中等强度的有氧运动(运动时心率达到最高值的50%~70%)，每周至少运动3d，每周至少安排2次对抗性训练。不适当的运动可因胰岛素水平不足诱发酮症，也可因过度耗能诱发低血糖，因而运动强度、持续时间、频率、项目的选择都要个体化，建议糖尿病肾病患者在专业人士的指导下制定合理的运动方案，或参加运动计划，提高依从性，减少运动不良后果的发生。对于进展至ESRD的糖尿病肾病患者，每周2~3次以上的有氧运动、对抗性运动有利于控制血压、减轻炎症、改善生活质量，但证据大多来自小样本试验。 +3.戒烟：吸烟是糖尿病肾病患者蛋白尿及肾功能进展的危险因素，戒烟或减少吸烟是糖尿病患者预防或控制糖尿病肾病进展的重要措施。 +(二)控制血糖 +DCCT及其后续的糖尿病干预和并发症流行病学研究(EDIC)、英国2型糖尿病前瞻性研究(UKPDS)及美国退伍军人合作研究(VAC)分别验证了在1型糖尿病和2型糖尿病患者中，严格控制血糖可减少糖尿病肾病的发生或延缓其病程进展。 +1.血糖控制目标：糖尿病肾病患者的血糖控制应遵循个体化原则。血糖控制目标：糖化血红蛋白(HbA1c)不超过7%。对中老年患者，HbA1c控制目标适当放宽至不超过7%~9%。由于CKD患者的红细胞寿命缩短，HbA1c可能被低估。在CKD4~5期的患者中，用果糖胺或糖化血清白蛋白反映血糖控制水平更可靠一。 +2.抗高血糖药物的选择：包括双胍类、磺脲类、格列奈类、噻唑烷二酮类、α-糖苷酶抑制剂、二肽基肽酶IV(DPP-4)抑制剂、胰高血糖素样肽1(GLP-1)类似物及胰岛素。某些在肾脏代谢或排泄的药物，在糖尿病肾病尤其是肾功能不全的患者中，经肾排泄减少或其活性代谢产物的清除减少，可引起低血糖等不良反应，这些药物在GFR低于60ml·min·-1·1.73m-2时需酌情减量或停药(图1)。 +(1)双胍类：目前，二甲双胍被推荐作为2型糖尿病控制血糖的一线用药，首选用于单纯饮食控制或体育锻炼无效的2型糖尿病，尤其适用于肥胖患者，也与胰岛素联合用于1型和2型糖尿病。其主要药理作用是通过减少肝糖输出和改善外周胰岛素抵抗而降低血糖，二甲双胍可以使HbA1c降低1%~2%，并可减轻体重且不增加低血糖风险。UKPDS研究显示，二甲双胍可降低伴有肥胖的2型糖尿病患者的心血管事件和死亡风险。糖尿病结果预防试验(ADOPT)研究显示，二甲双胍可延缓糖尿病患者微量白蛋白尿的进展。二甲双胍不经肝脏代谢，直接以原形经肾脏排泄，当肾功能受损时，易发生二甲双胍和乳酸在体内堆积，增加乳酸性酸中毒风险。因此二甲双胍用于CKD3a期以上的患者时应减少剂量，eGFR<45ml·min-1·1.73m-2时停用。肾功能受损的患者应用二甲双胍时应注意肾功能变化，每年至少检查一次肾功能。 +(2)磺脲类：第一代磺脲类药物(如氯磺丙脲、妥拉磺脲、甲苯磺丁脲)的药物原型及其活性代谢产物主要依赖肾脏排泄，应用于CKD患者时半衰期延长，低血糖风险明显增加，因此禁用于该类患者，目前此类药物在临床上已基本被淘汰。第二代磺脲类药物包括格列本脲、格列吡嗪、格列奇特、格列喹酮和格列美脲等。格列本脲和格列美脲的代谢产物仍有降糖活性，尤其是格列本脲的半衰期较长，其活性代谢产物可在CKD患者体内积聚，可能引起严重的低血糖反应，且持续时间可超过24h。因而格列本脲仅可用于CKD1~2期的患者；格列美脲用于CKD3~4期的患者时，应从小剂量开始用药，即起始剂量为每日1mg；由于还未积累关于透析患者的用药经验，在透析患者禁用。格列吡嗪和格列齐特的代谢产物均无降糖活性，虽然主要经肾脏排泄，但低血糖风险小于前两者。格列喹酮的代谢产物无降糖作用且大部分从粪便排泄，仅5%由肾脏排泄，受肾功能影响较小。因而格列吡嗪、格列齐特和格列喹酮于CKD1~3期患者无需调整剂量。 +(3)格列奈类：格列奈类药物是非磺脲类胰岛素促泌剂，其具有葡萄糖依赖性，需餐前服用。由于其对基础胰岛素分泌物无明显刺激作用，其引起低血糖的风险和程度较磺脲类药物轻。其他不良反应有过敏反应、胃肠道不适、眼睛异常、肝功能损害等，均较罕见。格列奈类的主要代表药物有那格列奈和瑞格列奈。瑞格列奈及其代谢产物主要经肝脏代谢，仅<8%经肾排泄。瑞格列奈I期临床试验表明，使用瑞格列奈7d后，肾功能正常患者与不同程度的CKD患者相比，血药浓度没有明显差异，提示瑞格列奈在CKD患者体内无蓄积。一项入选281例伴或不伴肾功能不全2型糖尿病患者的多中心研究提示，使用瑞格列奈替换原有降糖治疗，不同程度肾功能不全亚组患者(正常、轻、中、重、极重肾功能损伤)低血糖发生率均低于2%，且瑞格列奈治疗期低血糖发生率与肾功能损伤程度无关。因此瑞格列奈应用于CKD3、4期或肾脏移植、透析者，均无需调整剂量。在Ccr15~50ml·min-1·1.73m-2的糖尿病患者中，那格列奈的生物利用度和半衰期与健康人相比其差别未达到具有临床意义的程度，但随着肾功能的下降，那格列奈的活性代谢产物水平增加。有观点认为那格列奈应用于肾功能不全的糖尿病患者时无需调整剂量，但ADA仍建议CKD4期应从小剂量每次餐前60mg开始。 +(4)噻唑烷二酮类：该类药物的常见不良反应是液体潴留，因而对于重度心衰患者应慎用。使用该类药物发生骨折及骨质疏松的风险增加，需慎用于潜在骨疾病的患者(如肾性骨营养不良)，尤其是绝经后女性；其他不良反应包括肝酶升高、体重增加等。该类药物不刺激内源性胰岛素分泌，单独使用低血糖风险低(1%~2%)。该类药物主要代表为吡格列酮和罗格列酮。由于其经过肝脏代谢，吡格列酮用于肾功能不全无需调整剂量；罗格列酮因增加心血管风险的安全性问题引起了国内外的警惕，美国食品药品监督管理局(FDA)和欧洲药品管理局建议在心功能不全和严重骨质疏松患者慎用已限制其使用(图1)。 +(5)α-糖苷酶抑制剂：α-糖苷酶抑制剂适用于饮食结构以碳水化合物为主且餐后血糖升高的患者，可将HbA1c降低0.5%~0.8%，其主要药理作用是抑制碳水化合物在小肠上段的吸收而降低餐后血糖，不增加体重且有减轻体重的趋势。该类药物口服后被胃肠道吸收不到1%，故全身性不良反应不多见，主要不良反应是胃肠道不适，表现为腹胀、腹泻等，其主要代表药物有阿卡波糖、伏格列波糖等。随肾功能的降低，阿卡波糖及其代谢产物的血药浓度显著增加，Ccr低于25ml·min-1·1.73m-2者禁用。伏格列波糖仅微量被吸收，分布于肠黏膜和肾脏，可用于CKD 1~3期患者，慎用于CKD4~5期患者，不必调整剂量。 +(6)GLP-1：GLP-1半衰期短，GLP-1类似物的半衰期延长，其代表药物有艾塞那肽、利拉鲁肽等。艾塞那肽经肾排泄，GFR低于45ml·min-1·1.73m-2时，其清除率下降36%，GFR低于30ml·min-1·1.73m-2时，其清除率下降64%且透析患者不能耐受胃肠道不良反应，因此艾塞那肽不推荐用于CKD4~5期的患者。利拉鲁肽也仅可用于CKD1~2期患者，在中度肾功能损害患者中的治疗经验有限，不推荐用于包括ESRD患者在内的重度肾功能损害患者。 +包括ESRD患者在内的重度肾功能损害患者。 +(7)DPP-4抑制剂：DPP-4是GLP-1降解酶，DDP-4抑剂通过减少GLP-1在体内的降解，增加体内GLP-1的水平。这一类降糖药由于上市较晚，缺乏临床用药经验，因此用于糖尿病肾病患者时应酌情减量。DPP-4抑制剂降低HbA1c弱于其他胰岛素促泌剂。目前在国内上市的DPP-4抑制剂为西格列汀、沙格列汀、维格列汀和利格列汀。西格列汀用于GFR>50ml·min-1·1.73m-2的CKD患者时无需调整剂量，当GFR在30~50ml·min-1·1.73m-2时减量至50mg每日1次，GFR<30ml·min-1·1.73m-2或透析的患者可减量至每日25mg，但相关的临床经验尚不丰富。沙格列汀和维格列汀可用于CKD 1~2期患者，用于中重度肾功能不全患者的临床试验数据有限，不推荐用于3~5期患者，仅有利格列汀在CKD 4~5期时无需减量。 +(8)胰岛素：胰岛素是糖尿病的基础用药，适用于1型糖尿病、有急性并发症或严重合并症或处于应激状态或口服降糖药物疗效不佳或有口服降糖药禁忌的2型糖尿病、妊娠糖尿病、继发于严重胰腺疾病的糖尿病、严重营养不良等。不良反应主要有低血糖发作、体重增加、治疗初期的外周组织水肿、过敏反应等。肾功能受损者胰岛素的排泄减少，故CKD3期以上的患者胰岛素用量需减少。 +(三)控制血压 +血压升高不仅是加速糖尿病肾病进展的重要因素，也是决定患者心血管病预后的主要风险因素。在2型糖尿病肾病患者中，血压对肾功能的影响更加突出，收缩压超过140mmHg(1mmHg=0.133kPa)的患者，其肾功能下降速度为每年13.5%，而收缩压<140mmHg者每年肾功能下降的速度是1%。UKPDS研究显示，在处于糖尿病早期的糖尿病患者中采用强化的血压控制，不但可以显著减少糖尿病大血管病变发生的风险，还显著减少了微血管病变发生的风险。大量临床观察也证实，严格控制高血压能明显减少糖尿病肾病患者尿蛋白水平，延缓肾功能损害的进展。 +强化血压控制还可使心血管病终点事件的风险下降20%~30%。 +1.血压控制目标：糖尿病患者的血压控制目标为140/90mmHg，对年轻患者或合并肾病者的血压控制目标为130/80mmHg。 +2.降压药物的选择：ACEI或ARB在糖尿病肾病中有控制血压、减少蛋白尿、延缓肾功能进展的作用，是目前治疗糖尿病肾病的药物中临床证据最多的，被推荐作为治疗糖尿病肾病的一线药物。糖尿病肾病或糖尿病合并高血压的患者首选使用其中一种，不能耐受时以另一种替代，使用期间应监测血清肌酐及血钾水平。 +ACEI或ARB降压效果不理想时，可联合使用钙通道阻滞剂(CCB)、噻嗪类或袢利尿剂、β受体阻滞剂等降压药物。 +ACEI及ARB应用于糖尿病肾病的一级预防治疗存在争议。一项临床试验研究将伴有高血压的2型DM患者分为群多普利组、维拉帕米组、群多普利联合维拉帕米组及安慰剂组，发现群多普利组及群多普利+维拉帕米组两组患者微量白蛋白尿的出现明显延迟，提示ARB对2型糖尿病患者微量白蛋白尿的发生可能具有一级预防作用。糖尿病视网膜坎地沙坦临床试验-肾脏研究(DIRECT-Renal)和肾素-血管紧张素系统研究(RASS)的结果却表明ACEI或ARB改善微量白蛋白尿、保护肾脏的作用并不明显。 +因此，本共识暂不推荐应用该类药物作为糖尿病肾病的一级预防。 +(1)ACEI：ACEI主要药理作用是抑制血浆及组织中的血管紧张素转换酶，减少血管紧张素II的生成，减少血管收缩和醛固酮的分泌。在用药过程中需要注意观察患者肾功能及血钾的变化，对伴有肾动脉狭窄的患者要慎用或禁用。有报道显示该药物在妊娠早期可能对胎儿有害(新生儿急性肾损伤、肺毒性作用、先天心血管系统畸形、中枢神经系统畸形、肾脏畸形、头颅发育不全等)。培哚普利在糖尿病及肾功能减退患者中无不良代谢作用，但在透析中可被清除，中重度肾功能损害患者应根据肾小球滤过率变化调整剂量，起始剂量2mg/d，最大剂量不超过8mg/d，在透析患者中培哚普利清除率同肾功能正常患者。卡托普利在肾功能严重减退患者中应谨慎使用。 +贝那普利的药代动力学和生物利用度在轻中度肾功能不全中不受影响，重度肾功能不全患者需减量，透析对贝那普利的浓度无影响，透析后无需补充药物。 +雷米普利在中度肾功能不全患者中需减量，且不能应用于聚丙烯腈或甲基烯丙基硫化钠高通量滤膜或血液透析。 +福辛普利在肾功能不全患者中应减量或停药，它在透析中不可清除，但在高流量透析膜进行血液透析时较易引起类过敏反应。 +赖诺普利在严重的肾功能不全患者中半衰期可达40h以上，可在体内发生蓄积，蓄积的原药可在透析中去除。 +(2)ARB：ARB通过双重方式降低血压：其一是阻断血管紧张素Ⅱ(AngⅡ)与血管紧张素II 1型受体(AT1R)结合，从而直接或间接抑制血管收缩，减少血管加压素和醛固酮释放，减少肾脏水钠重吸收；其二是促使AngⅡ与AT2R结合，使血管舒张，抑制细胞分化生长，抑制钠水重吸收和交感神经活性。氯沙坦在肾功能不全患者中无需调整剂量，缬沙坦在肾功能减退的大部分患者中都无需调整用药，但在严重肾功能不全患者中用药经验不足，应谨慎用药。替米沙坦及坎地沙坦在轻中度。肾功能不全患者中无需调整用量，重度肾功能不全患者禁用。厄贝沙坦在肾功能不全及血液透析的患者中可能需要调整剂量。 +(3)CCB：非二氢吡啶类钙拮抗剂地尔硫?和维拉帕米能够减少蛋白尿；二氢吡啶类钙拮抗剂能维持和增加肾血流量，改善Ccr和GFR；可以抑制内皮素对肾脏的影响以及预防肾脏肥大。国际拜新同抗高血压干预研究(INSIGHT)证明，与利尿剂相比，硝苯地平胃肠控释系统能显著提高肾小球滤过率，保护肾功能。一般认为，CCB延缓高血压患者的肾功能进展的机制，主要是通过降低血压减轻了体循环对肾小球内压力的传导，从而改善肾小球内高滤过、高灌注状态。在肾功能受损时，长效钙通道阻滞剂无需减低剂量，尤其适用于合并冠心病、肾动脉狭窄、重度肾功能不全、存在ACEI或ARB使用禁忌的患者。CCB是治疗CKD合并高血压最常用的选择之一，但若尿蛋白持续增多，需加用ACEI或ARB药物才能达到保护肾功能的作用。有临床研究表明，二氢吡啶类CCB氨氯地平联合贝那普利在降低糖尿病患者心血管事件及延缓肾病进展方面优于贝那普利与噻嗪类利尿剂组合，非二氢吡啶CCB类药物在降低糖尿病肾病患者尿蛋白水平，延缓肾病进程方面明显优于ACEI及β受体阻滞剂，且不受血压控制的影响。 +(4)利尿剂：60%~90%糖尿病肾病合并高血压的患者使用噻嗪类或袢利尿剂。GUARD临床研究表明ACEI与氢氯噻嗪联合用药在降低患者尿蛋白水平方面优于ACEI与CCB组合。对收缩期高血压患者应用联合治疗以预防心血管事件(ACCOMPLISH)临床研究的结果却表明，在糖尿病高血压高危患者中，ACEI与氢氯噻嗪联合用药对减缓患者肾小球滤过率下降的作用不及ACEI与CCB组合。虽然噻嗪类或袢利尿剂作为联合用药是否强于CCB存在争议，多数糖尿病肾病合并高血压的患者，尤其血压高于130/80mmHg者需要一种以上药物控制血压，故推荐噻嗪类或袢利尿剂作为联合用药。氢氯噻嗪促进钾钠排泄，造成低钠血症时可引起反射性肾素和醛固酮分泌，在无尿或肾功能损害患者的效果差，大剂量使用易导致药物蓄积，增加毒性，故其慎用于该类患者，应从小剂量每日25mg开始。 +(5)β受体阻滞剂：尽管ACEI在降低糖尿病患者蛋白尿方面较β受体阻滞剂更有优势，但两种药物均可延缓患者肾功能的衰退。UKPDS研究亦认为ACEI与β受体阻滞剂在降低2型糖尿病患者微血管和大血管并发症方面临床价值相当。β受体阻滞剂可作为降压治疗的联合用药。第一类为非选择性β受体阻滞剂，主要代表药物是普萘洛尔，目前已较少使用。第二类主要作用于β1受体，代表药物有美托洛尔、比索洛尔。美托洛尔主要经肝脏代谢，5%以原型经肾排泄，用于肾功能损害者剂量无需调整。比索洛尔50%通过肝脏代谢为无活性的代谢产物然后从肾脏排出，剩余50%以原形药的形式从肾脏排出，轻中度肾功能不全患者剂量不需调整，当GFR<20ml·min-1·1.73m-2时每日剂量不超过10mg，肾透析患者使用经验较少。第三类主要作用于β和α1受体，代表药物有卡维地洛、拉贝洛尔。拉贝洛尔55%~60%的原形药物和代谢产物由尿排f也，血液透析和腹膜透析均不易清除，应慎用于肾功能不全者。 +(6)其他肾素-血管紧张素系统(RAS)阻断剂：ACEI或ARB类药物可以降低患者血浆醛固酮水平，但有研究发现有40%服用上述药物的患者其血浆醛固酮水平并未下降，反而升高到了其治疗前的浓度水平，称之为“醛固酮逃避”现象，这可能与肾病进展过程有关，具体机制尚不明确。早期一些短期临床研究表明，ACEI/ARB与醛固酮受体拮抗剂(MRA)联合治疗在降低1型DN患者尿白蛋白水平方面的益处，但是需要更多临床研究证实。赖诺普利联合螺内酯组与赖诺普利+安慰剂组患者相比，其尿白蛋白水平明显降低。因螺内酯可使血钾升高的风险增高，应用时需监测血钾。 +抑制糖尿病肾病患者体内的肾素活性，可显著降低其血压和蛋白尿水平。2型糖尿病患者中，肾素抑制剂阿利吉仑联合氯沙坦与单用氯沙坦相比，尿蛋白更低。然而，近期一项在2型糖尿病患者中进行的阿利吉仑临床试验却因阿利吉仑与ACEI/ARB的联合应用所导致的严重不良事件所终止，不良反应包括肾功能衰竭、高血钾及低血压等。 +因此FDA仍将阿利吉仑禁用于已使用ACEI/ARB的糖尿病患者。 +(7)联合用药：糖尿病肾病患者在血压控制不佳时，可在ACEI/ARB的基础上选择其他降压药物联合使用。一些早期小型临床研究结果表明，ACEI联合ARB在糖尿病肾病患者中具有较高的耐受性和有效率，可使糖尿病患者的尿蛋白水平显著降低，有效降低了患者舒张压。然而，较新的研究表明ACEI与ARB联合治疗疗效并不优于单药治疗，联合ARB及ACEI后，糖尿病患者血清肌酐水平、ESRD发生及死亡率方面并无明显差异。 +本共识不推荐联合使用ACEI和ARB。 +如果已在联合使用ACEI和ARB，则需要检测和随访血钾和肾功能。 +(四)纠正脂质代谢紊乱 +高脂血症不仅直接参与糖尿病胰岛素抵抗和心血管并发症的发生，低密度脂蛋白胆固醇(LDL-C)还可以通过作用于肾小球系膜细胞上的LDL受体，导致系膜细胞和足细胞的损伤，加重蛋白尿和肾小球及肾小管间质纤维化的进展。糖尿病患者出现肾病综合征和肾功能不全，又会进一步加重高脂血症。因此，积极纠正糖尿病肾病患者体内脂代谢紊乱，亦对糖尿病肾病具有重要意义。 +1.血脂控制目标值：糖尿病肾病患者血脂干预治疗切点：血LDL-C>3.38mmol/L(130mg/d1)，甘油三酯(TG)>2.26(200mg/d1)。治疗目标：LDL-C水平降至2.6mmol/L以下(并发冠心病将至1.86mmol/L以下)，TG降至1.5mmol/L以下。 +2.降脂药物的选择：研究表明他汀类药物可减少糖尿病血管疾病的发生率和肾功能减退，建议所有糖尿病患者均应首选口服他汀类药物，以TG升高为主时可首选贝特类降脂药。2型糖尿病患者常见混合性高脂血症。单一降脂药大剂量时不良反应增加，为了提高调脂治疗的达标率，往往需不同类别调脂药联合应用。他汀类和贝特类联用：混合性高脂血症经单用他汀类或贝特类未达标者，可考虑两药联合治疗。尽管目前有证据表明两药合理联用是安全的(ACCORD已经证明是安全的)，但除非特别严重的混合性血脂异常，一般应单药治疗；必要时谨慎联合，但剂量应小；两药分开时间服用；他汀类和贝特类联用时，首选非诺贝特。有以下特殊情况者慎用，包括老年、严重肝肾疾病、甲状腺功能减退等，并严密监测和随访，一旦发现异常，及时停药。他汀类和依折麦布联用：单用他汀类调脂药治疗后LDL-C仍未达标者，可考虑他汀类和依折麦布联用。现有证据表明依折麦布和小剂量他汀类联合应用比单独增加他汀类剂量能更好地改善血脂紊乱，且安全性好。 +(1)三羟基三甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂(他汀类)：抑制细胞内胆固醇合成早期阶段的限速酶即HMG-CoA还原酶，造成细胞内游离胆固醇减少，并通过反馈性上调细胞表面LDL受体的表达，因而使细胞LDL-C受体数目增多及活性增强，加速了循环极低密度脂蛋白(VLDL)残粒[或中间密度脂蛋白(IDL)]和LDL-C的清除。轻至中度肾功能患者无需调整辛伐他汀、氟伐他汀等他汀类的药物用量，但在重度肾功能不全(如Ccr<30ml/min)时需减量或禁用。肾脏疾病不影响阿托伐他汀的血浆浓度和其降低LDL-C的效果，故肾功能不全患者均无需调整其用药剂量，同时，由于阿托伐他汀与血浆蛋白的广泛结合，血液透析并不能显著提高其清除率，但目前由于缺乏其在透析患者中的用药经验，故仍需谨慎用药。 +(2)胆汁酸螯合剂：包括考来烯胺、考来替泊，主要为碱性阴离子交换树脂，在肠道内能与胆酸呈不可逆结合，因而阻断胆酸的肠肝循环，促进胆酸随大便排出体外，阻断胆汁酸中胆固醇的重吸收，能降低血总胆固醇(TC)及LDL-C水平，但对TG无降低作用。 +胆汁酸螯合剂在此肠道内不吸收，不参与肾脏代谢。 +(3)烟酸：烟酸的降脂作用机制尚不明确，可能与抑制脂肪组织中的脂解和减少肝脏中VLDL合成和分泌有关，此外，烟酸还具有促进脂蛋白酶的活性，加速脂蛋白中TG的水解的作用，因而其降低TG的作用明显。但烟酸可导致糖代谢异常或糖耐量恶化，一般不推荐在糖尿病患者中使用，若必须使用，应该定期监测血糖水平。烟酸和阿昔莫司在。肾功能减退患者中应用证据有限，应谨慎或减量使用。 +(4)苯氧芳酸类：能增强脂蛋白酯酶的活性，加速VLDL分解代谢，并能抑制肝脏中VLDL的合成与分泌，可降低TG22%~43%、TC6%~15%，并有不同程度升高高密度脂蛋白胆固醇(HDL-C)的作用。有证据显示贝特类药物将会升高增加心血管事件风险的血清肌酐和同源半胱氨酸(Hcy)水平。肾功能减退的糖尿病患者应根据其GFR水平减少非诺贝特、吉非贝齐及苯扎贝特等贝特类药物，并在严重的肾功能不全患者中禁用。 +如非诺贝特不能用于透析，且当GFR<50ml·min-1·1.73m-2时禁用。 +当患者的GFR<60ml·min-1·1.73m-2时应将吉非贝齐的用量减至600mg/d，GFR<15ml·min-1·1.73m-2时禁用吉非贝齐。 +(5)胆固醇吸收抑制剂：依折麦布附着于小肠绒毛刷状缘，抑制胆固醇的吸收，从而降低小肠中的胆固醇向肝脏中的转运，使得肝脏胆固醇贮量降低从而增加血液中胆固醇的清除。 +本品不增加胆汁分泌(如胆酸螯合剂)，也不抑制胆固醇在肝脏中的合成(如他汀类)。 +依折麦布在不同肾功能水平下均无需调整剂量。 +(五)肾脏替代治疗 +GFR低于15ml·min-1·1.73m-2的糖尿病肾病患者在条件允许的情况下可选择肾脏替代治疗，包括血液透析、腹膜透析和肾脏移植等。 +(六)其他治疗药物应用、研制及展望 +1.微循环扩张剂：(1)胰激肽原酶肠溶片(怡开)：有改善微循环作用。主要用于微循环障碍性疾病，如糖尿病引起的肾病、周围神经病、视网膜病。脑出血及其他出血性疾病的急性期禁用。(2)羟苯磺酸钙(导升明)可用于糖尿病性微血管病变：视网膜病及肾小球硬化症(基·威氏综合征)，严重肾功能不全需透析的患者应减量。 +2.探索中药和中西医结合治疗糖尿病肾病：中药抽提物(如大黄酸、雷公藤甲素等)及中成药(如复方血栓通胶囊、金水宝等)对降低尿白蛋白及改善肾功能有一定的疗效，目前正在积累更多循证医学的依据。 +3.开发针对糖尿病肾病发病机制的药物：如抗AGE药物Pyridorin、抗纤维化类药物舒洛地昔，内皮受体拮抗剂阿曲生坦进入临床试验，但其应用尚缺乏经验。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_7.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_7.txt" new file mode 100644 index 0000000..06e6ac7 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_7.txt" @@ -0,0 +1,84 @@ +心血管疾病合并糖尿病口服降糖药物应用专家共识 +2008年中国糖尿病流行病学调查显示，中国20岁及以上人群2型糖尿病患病率为9.7%。 +2010年调查的全国成年人糖尿病患病率为11.6%。 +2013年国际糖尿病联盟发布的第6版“糖尿病地图”公布，中国糖尿病的患病人数为9840万，居全球首位，而全球成年人糖尿病患病率为8.3%。 +心血管疾病与糖尿病关系密切。2006年的”中国心脏调查”发现，慢性稳定性心绞痛和急性冠状动脉综合征(ACS)的住院患者中，约80%存在不同程度的糖代谢异常，其中糖尿病占52.9%，糖尿病前期占26.4%。中国医院门诊高血压患者中，糖尿病患病率为24.3%。中华医学会糖尿病学分会慢性并发症调查组报告，1991—2000年部分三级甲等医院住院的2型糖尿病患者合并高血压者占34.2%，合并其他心血管疾病者占17.1%。荟萃分析表明，糖化血红蛋白(HbA1c)在5%以上的患者，HbA1c每增加1%，心血管事件风险增加21%。 +血糖控制情况影响心血管疾病(CVD)患者预后。英国前瞻性糖尿病研究(UKPDS)提示，早期严格血糖控制对降低大血管并发症非常重要；但目前还没有足够的临床研究证明，更加严格的血糖控制(如HbA1c<6.5%)可使所有CVD合并糖尿病患者有更进一步的心血管获益。对随机对照研究如退伍军人糖尿病事件研究(VADT)、控制糖尿病患者心血管危险行动(ACCORD)、糖尿病治疗和血管保护行动：百普乐与达美康缓释片对照评估研究(ADVANCE)进行的荟萃分析，也未发现口服降糖药强化治疗可降低心血管事件风险。同时，强化血糖控制会增加低血糖事件发生率，低血糖可诱发合并CVD的糖尿病患者发生心肌梗死及卒中等。因此，重视低血糖的危害、预防低血糖的发生，对心血管疾病合并糖尿病患者尤为重要。 +为进一步提高我国心血管专科医师对心血管疾病合并糖尿病患者的综合防治能力与水平，让工作在一线的临床医师能够充分了解心血管疾病患者的糖尿病筛查流程和诊断标准、常用口服降糖药物选择以及血糖控制目标值，中国医师协会心血管内科医师分会组织心内科、内分泌科以及肾内科等领域专家，共同制订此共识。 +一、心血管疾病患者糖尿病筛查流程及诊断标准 +(一)筛查对象 +成年人具有下列任何一个及以上危险因素，可被定义为糖尿病高危人群，应进行糖尿病的筛查。(1)有糖调节受损史(定义见诊断标准)；(2)年龄≥40岁；(3)超重(BMI≥24kg/m2)或肥胖(BMI≥28kg/m2)和/或中心性肥胖(男性腰围≥90cm，女性腰围≥85cm)；(4)2型糖尿病患者的一级亲属；(5)高血压(血压≥140/90mmHg，1mmHg=0.133kPa)，或正在接受降压治疗；(6)血脂异常[HDL-C≤0.91mmol/L(35mg/dI)或TG≥2.26mmol/L(200mg/dI)]，或正在接受调脂治疗；(7)动脉粥样硬化性心脑血管疾病患者；(8)其他：①静坐生活方式；2有巨大儿(出生体重≥4kg)生产史，妊娠期糖尿病史；③有一过性类固醇诱导性糖尿病病史者；④多囊卵巢综合征患者；⑤严重精神病和/或长期接受抗抑郁症药物治疗的患者。 +(二)筛查方法 +1.空腹静脉血浆血糖(FPG)：FPG是评价糖代谢状态和血糖控制水平最常用的指标，要求受试者至少空腹8h后，在次日上午取血。仅通过FPG筛查糖尿病的优点是简便、易行，但存在漏诊的可能性。 +如不能确诊，且病情允许时可行口服葡萄糖耐量试验(OGTT)。 +2.OGTT：如果FPG无法确诊糖尿病，推荐采用OGTT进行糖尿病筛查：依据FPG和糖负荷后2h血糖(2hPG)水平进行诊断。 +OGTT方法：(1)空腹至少8h，在次日上午检查前，配制口服葡萄糖溶液(无水葡萄糖粉75g，或国内常用的含1分子结晶水的葡萄糖粉82.5g，溶于300ml水内)备用；(2)第1次抽血应在服糖前，前臂采血标本测定血糖。 +抽血时间最好是7：00—9：00。 +随后，应在5min内顺利喝完备好的葡萄糖溶液。 +第2次抽血应在服糖后2h整，前臂采血标本测定血糖(从服糖第一口开始计时，到2h整，为2hPG)。 +注意事项：(1)试验过程中，受试者不喝茶及咖啡，不吸烟，不做剧烈运动，安静休息，但也无须绝对卧床；(2)血标本采集后尽早送检；(3)试验前3天内，每日碳水化合物摄入量不少于150g；(4)试验前3~7天停用可能影响血糖水平的药物，如避孕药、利尿剂或苯妥英钠等。 +3.HbA1c：HbA1c测定值可以反映近3个月内平均血糖水平，结果稳定、可靠、变异性小。 +不受进食时间、应激状态及短期生活方式改变的影响，是糖尿病监测和疗效评估的重要指标。 +糖尿病患者应每3~6个月监测1次。 +2009年国际专家委员会和2010年美国糖尿病学会(ADA)指南均提出，将HbA1c作为糖尿病的诊断标准之一，诊断糖尿病的切点为≥6.5%，糖尿病高危状态的切点介于5.7%~6.4%。目前美国和欧洲已认可HbA1c在糖尿病诊断和监测中的作用。由于HbA1c检测在我国尚未实现全国标准化，并且部分医院HbA1c的检测方法未通过美国国家糖化血红蛋白标准化计划(NGSP)标准体系的认证，故HbA1c目前在我国主要用于血糖监测。WHO的意见是，如果HbA1c检测方法通过NGSP认证，可将HbA1c作为糖尿病的诊断指标之一，以6.5%做为糖尿病的诊断切点。 +考虑到我国目前存在的上述实际状况，以及中国人群中HbA1c诊断糖尿病的切点需要进一步的研究，《中国2型糖尿病防治指南》尚未推荐在我国采用HbA1c诊断糖尿病。 +(三)糖尿病和糖代谢异常的诊断标准 +1.糖尿病：若有代谢紊乱症状(包括多饮、多尿、多食和不明原因的体重下降)，一次FPG≥7.0mmol/L或2hPG≥11.1mmol/L或随机血糖≥11.1mmol/L，即可诊断糖尿病。无糖尿病症状者，需两次血糖值达到上述诊断标准(表1)。 +2.糖尿病前期：空腹血糖受损(IFG)或糖耐量受损(IGT)统称为糖调节受损(IGR，即糖尿病前期)。若FPG6.1~<7.0mmoL/L，2hPG<7.8mmol/L诊断为IFG；FPG<7.0mmoL/L，2hPG7.8~<11.1mmol/L诊断为IGT(表1)。 +(四)筛查流程(图1) +二、心血管疾病合并糖尿病患者口服降糖药物选择 +(一)常用口服降糖药物 +1.双胍类：常用药物为二甲双胍，起始剂量500mg/d，随餐服用，逐渐加量，最大剂量2000mg/d。主要通过减少肝脏葡萄糖的输出和改善肝脏、肌肉胰岛素抵抗而降低血糖。二甲双胍可以使HbA1c下降1%~2%，并可减轻体重。单独使用二甲双胍极少发生低血糖。常见的副作用为胃肠道反应，绝大多数患者均能耐受；严重的副作用是乳酸性酸中毒。因此，禁用于肾功能不全[血肌酐水平男性>132.6μmol/L(1.5mg/dI)，女性>123.8μmol/L(1.4mg/dI)；或肾小球滤过率<45ml·min-1·1.73m-2]、肝功能不全、严重感染、缺氧或接受大手术的患者。 +以往使用对比剂之前停用二甲双胍的建议缺乏足够的循征医学证据。 +因此，使用对比剂前可不停用，但需密切监测肾功能，若肾功能恶化，应立即停用二甲双胍。 +2.胰岛素促分泌剂：(1)磺脲类：常用药物有格列吡嗪、格列齐特、格列喹酮及格列美脲。多从小剂量开始应用，而后根据血糖监测结果进行剂量调整。主要通过刺激胰岛β细胞分泌胰岛素，增加体内的胰岛素水平而降低血糖。磺脲类药物可以使HbA1c降低1%~2%。磺脲类药物如果使用不当可以导致低血糖，特别是老年患者和肝、肾功能不全者。磺脲类会增加体重。轻度、中度肾功能不全的患者，宜选择格列喹酮。(2)格列奈类：常用药物有瑞格列奈和那格列奈。多从小剂量开始应用，而后根据血糖监测结果进行剂量调整。主要通过刺激胰岛素的早时相分泌而降低餐后血糖，具有吸收快、起效快和作用时间短的特点，可降低HbA1c0.3%~1.5%。常见副作用是低血糖和体重增加，但与磺脲类药物相比，发生频率较低、程度较轻。 +3.α-糖苷酶抑制剂：常用药物有阿卡波糖和伏格列波糖，多从小剂量开始应用，而后根据血糖监测结果进行剂量调整。通过抑制碳水化合物在小肠上部的消化和吸收而降低餐后血糖，适用于以碳水化合物为主要食物和餐后血糖升高的患者。α-糖苷酶抑制剂可使HbA1c下降0.5%~0.8%，不增加体重。单独使用时不导致低血糖，但与胰岛素促泌剂或胰岛素合用时需要注意低血糖的防治，纠正低血糖只能使用葡萄糖制剂。 +常见不良反应为胃肠道反应，如有疝气或曾行胃肠道外科手术应禁用。 +4.噻唑烷二酮类：常用药物有罗格列酮和吡格列酮。每日早餐前1次服用。主要通过改善外周组织胰岛素抵抗而降低血糖。噻唑烷二酮类药物可以使HbA1c下降1.0%~1.5%。噻唑烷二酮类药物单独使用时不导致低血糖。但体重增加和水肿是其常见副作用。临床研究发现噻唑烷二酮类药物与骨折和心力衰竭风险增加相关。有心力衰竭[纽约心脏病协会(NYHA)心功能Ⅱ级以上]的患者、活动性肝病或转氨酶增高超过正常上限2.5倍的患者，以及有严重骨质疏松和骨折病史的患者，应禁用本类药物。 +5.二肽基肽酶4(DPP-4)抑制剂：目前我国上市的药物有西格列汀、维格列汀、沙格列汀、阿格列汀和利格列汀。 +多每日1次服用，通过抑制DPP-4而减少胰高血糖素样肽-1(GLP-1)在体内的失活，增加内源性GLP-1水平。 +GLP-1以葡萄糖浓度依赖的方式增强胰岛素分泌，抑制胰高血糖素分泌。 +临床试验显示，DPP-4抑制剂可降低HbA1c0.5%~1.0%。 +DPP-4抑制剂单独使用不增加低血糖发生的风险，不增加体重。 +表2总结了各种口服降糖药物的作用机制、使用方法、疗效、安全性、注意事项等主要信息。 +(二)口服降糖药物用药原则 +1.一线药物治疗：许多国家和国际组织制定的糖尿病指南推荐：若无禁忌且能耐受，二甲双胍是2型糖尿病患者的基础用药。UKPDS还显示二甲双胍可减少超重或肥胖2型糖尿病患者的心血管事件和死亡。 +若存在禁忌或不能耐受，可考虑应用胰岛素促分泌剂或α-糖苷酶抑制剂。 +如果HbA1c在10.0%~12.0%，或血糖>16.7~19.4mmoL/L，需应用胰岛素治疗。 +2.联合用药：若起始HbA1c≥9.0%，单药治疗很难使血糖达标，需联合口服降糖药物治疗；若生活方式干预联合一线口服降糖药物单药治疗3个月不能使血糖达标，需考虑联合用药。 +根据患者的情况选择联合用药方案，如胰岛素促分泌剂或α-糖苷酶抑制剂或DPP-4抑制剂或噻唑烷二酮类药物。 +餐后血糖升高为主者，可优先选用格列奈类降糖药、α-糖苷酶抑制剂或DPP-4抑制剂。 +若两种口服降糖药物联合治疗3个月不能使患者血糖达标，可考虑联合第三种口服降糖药物，或者联合胰岛素或GLP-1受体激动剂治疗。 +三、心血管疾病合并糖尿病患者的血糖控制目标 +随机对照临床试验已证实，严格的血糖控制可降低糖尿病的微血管并发症，但对大血管并发症的直接获益存在不同观点，有待进一步证实。早期临床研究如UKPDS报道，严格血糖控制可明显降低微血管并发症，心肌梗死风险降低16%(P=0.052)；在延长观察阶段，心肌梗死和全因性死亡的风险减少13%。近年，对于2型糖尿病患者的口服降糖药物强化血糖控制的随机对照研究，如VADT、ACCORD、ADVANCE，均未发现口服降糖药物强化降糖治疗可降低心血管事件风险，但对VADT、ACCORD和ADVANCE的心血管终点事件的综合荟萃分析后，HbA1c每下降1%，非致命性心梗相对风险降低15%，但未降低卒中或全因死亡风险。 +UKPDS研究中患者糖尿病史较短，血糖控制尤其早期控制更为重要；而VADT、ACCORD和ADVANCE研究中患者病史相对较长。所以对于糖尿病病程较短，无并发症的患者，强化血糖控制可带来更多的血管并发症获益；而对于病史较长，合并症较多的患者，强化血糖控制并不能带来更多的心血管获益。糖尿病治疗的目的要兼顾用心血管获益和用药安全，合并CVD的糖尿病患者，一旦发生低血糖可诱发心肌梗死及卒中等，因而对于这类人群应尽量在避免低血糖的情况下使血糖控制达标。综合循证医学研究结果，并充分平衡风险和血管获益，结合患者的年龄、糖尿病病程以及CVD病史等，将血糖控制目标个体化。 +糖尿病患者的血糖控制可根据自我血糖监测(SMBG)的结果和HbA1c水平综合判断。 +在治疗之初或血糖未达标时，应每3个月进行1次HbA1c的测定，血糖控制达标者至少每半年进行1次HbA1c测定。 +1.已证实HbA1c<7.0%可减少糖尿病患者微血管并发症，故推荐血糖控制目标：HbA1c<7.0%，FPG<7.0mmol/L，2hPG<10.0mmol/L。 +2.糖尿病病史较短、预期寿命较长、没有并发症的患者，在不发生低血糖的情况下可考虑将HbA1c控制在6.5%以下。 +3.有严重低血糖病史，或预期寿命较短，或有显著微血管或大血管并发症的患者，可放宽血糖目标值：HbA1c<7.5%~8.0%。 +4.慢性疾病终末期(如心功能NYHA Ⅲ-Ⅳ级、慢性肾功能不全、恶性肿瘤伴转移、中重度认知功能障碍等)患者的HbA1c可放宽至<8.5%。 +四、特殊情况说明 +(一)心血管疾病 +1.ACS：若血糖>10.0mmol/L，可使用以胰岛素为基础的治疗方案，使血糖水平控制在7.8~10.0mmol/L，同时注意避免低血糖发生。 +应激情况下可出现暂时性血糖升高，对于既往没有糖尿病病史(特别是HbA1c在正常范围者)，不能以此血糖值诊断糖尿病，须在应激消除后复查，必要时行OGTT明确。 +2.经皮冠状动脉介入治疗(PCI)：接受PCI的患者使用对比剂前可不停用二甲双胍，但应密切监测肾功能，若48h内肾功能恶化，应立即停用二甲双胍，直至肾功能恢复至基础水平，方可恢复使用。 +3.冠状动脉旁路移植术(CABG)：围手术期不推荐口服降糖药，应使用胰岛素治疗。 +4.心力衰竭：急性心力衰竭伴有缺氧情况，禁用双胍类药物、噻唑烷二酮类药物。对于慢性心力衰竭患者，需根据肾功能、血氧状态以及基础心功能等情况，选择应用口服降糖药物，还应注意监测血清乳酸水平和血气分析指标。心功能NYHAII~IV级的患者，应避免使用噻唑烷二酮类药物。DPP-4抑制剂在心功能NYHAⅡ~Ⅲ级临床经验有限，III~IV级无临床经验，故心力衰竭时应慎用或禁用。目前缺乏其他药物在心力衰竭患者中的用药证据。 +(二)肾功能不全 +心血管疾病和糖尿病患者常合并慢性肾脏病(CKD)，而CKD患者应基于药物的药代动力学特征和患者的肾功能水平综合判断，选择合适的降糖药物，并适当调整剂量，确保在有效降糖的同时不增加低血糖风险。 +瑞格列奈、利格列汀在肾功能不全时无需调整剂量；二甲双胍在GFR45~59ml·min-1·1.73m-2时应减量，GFR<45ml·min-1·1.73m-2禁用；α-糖苷酶抑制剂在GFR<30ml·min-1·1.73m-2时禁用。其他药物在肾功能不全中的应用详见图2。 +(三)阻塞性睡眠呼吸暂停综合征(OSAHS) +对于OSAHS伴发2型糖尿病的患者，常用降糖药均可选用，但应尽可能使用不增加体重的药物。由于OSAHS易发生夜间缺氧，对于低氧血症严重者慎用或禁用双胍类药物。 +(四)老年糖尿病患者 +老年患者降糖目标应个体化，考虑个人功能状态、共患或伴发疾病，尤其应考虑是否发生过心血管疾血、低血糖、微血管并发症等。 +生活自理的老人，HbA1c为7.0%~7.5%；生活无法自理者，以≤8.0%为宜；对于虚弱患者，可放宽至≤8.5%。 +老年糖尿病患者病情复杂、发生并发症或合并症的风险高、器官功能逐渐衰退。 +因此，对于老年糖尿病患者而言，治疗方案需更有针对性、更符合个体情况、更重视安全性。 +(五)低血糖 +糖尿病患者血糖水平低于3.9mmol/L(70mg/dI)时，定义为低血糖。 +在口服降糖药物中，胰岛素促泌剂均可引起低血糖，其中磺脲类药物尤为常见，格列奈类药物因其药理作用时间短，相对较少见。 +常见原因包括：药物剂量、剂型或给药时间，甚至治疗方案需要调整，均可能与低血糖相关；过强的身体运动时肌肉等外周组织对葡萄糖摄取和利用增加，而消耗血糖；未正常进食，或隔夜禁食时间偏长等，导致食物来源的外源性葡萄糖摄入减少或延迟所致；因肾功能不全等疾病，使体内胰岛素或胰岛素促泌剂清除能力下降，血中胰岛素或胰岛素促泌剂浓度过高，血糖被过度降低。 +二甲双胍、α-糖苷酶抑制剂、噻唑烷二酮类及DPP-4抑制剂单独使用时一般不会导致低血糖。 +五、结语 +糖尿病与心血管疾病关系密切，糖尿病是心血管疾病的主要危险因素之一。血糖管理是心血管疾病综合防控的重要内容之一。心血管专科医师应熟练掌握心血管疾病合并糖尿病患者常用口服降糖药物的应用原则。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_8.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_8.txt" new file mode 100644 index 0000000..2c7b60d --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_8.txt" @@ -0,0 +1,75 @@ +DPP-4抑制剂超药物说明书用法专家共识 +中国20岁以上人口的2型糖尿病的患病率已经达到9.7%。传统降糖药物在2型糖尿病的防治中发挥了重要作用，但仍存在低血糖、体重增加、增加心血管风险以及药物继发失效使血糖控制进行性恶化等局限性。二肽基肽酶-4(dipeptidyl peptidase-4，DPP-4)抑制剂是近年研发的口服降糖药，因作用机制独特、疗效确定、低血糖发生率少、对体重中性作用或轻度降低、心血管安全性良好等特点受到普遍关注，临床应用越来越广泛。 +DPP-4抑制剂减少体内胰高血糖素样肽-1(glucagon-like peptide-1，GLP-1)降解而增加循环GLP-1浓度2~3倍，GLP-1通过血糖依赖性刺激胰岛β细胞分泌胰岛素，抑制胰岛α细胞分泌胰高血糖素而发挥降低血糖的作用。 +国内批准临床应用的DPP-4抑制剂有5种，包括西格列汀(sitagliptin)、沙格列汀(saxagliptin)、维格列汀(vildagliptin)、阿格列汀(alogliptin)、利格列汀(linagliptin)。 +虽然不同的DPP-4抑制剂在结构和药物代谢动力学上存在明显差异，但是所有DPP-4抑制剂均显示出相近的降糖效果(降低HbA1c0.5%~1.0%)和良好的安全性。 +由于各种药物说明书批准的适应证存在一定差异，而且中国大多数医生目前还缺乏实际应用经验，所以为了更好、更合理地应用这类药物，消除可能的误解，造福糖尿病患者，本共识基于国内外药物说明书、临床研究证据、以及国内外2型糖尿病防治指南，对可能出现的超药物说明书用药(药品说明书之外用法)提供参考意见。 +超药物说明书用法，又称为“药品未注册用法”或“药品说明书之外的用法”(unlabeled uses，off-label uses，out-of label usage or outside of labeling）是指药品使用的适应证、给药方法、剂量或给药途径不在药品监督管理部门批准的说明书之内的用法。 +美国等国家的药品管理机构同意在一定条件下，允许医师进行超药物说明书用法。 +我国对此没有相应的管理法规。 +存在超药物说明书用法的主要原因是药品说明书用法往往滞后于科学知识和文献的更新和发展。 +药物说明书依然是临床安全使用药物的基础，药物说明书用法不是“试验性用法(experimental uses)或试验性用药”，是建立在充分循证证据和权威指南推荐的基础上，完全是为了患者的利益使用。 +在具体使用前应该获得所在执业单位的药事管理委员会和伦理委员会批准备案，并签署患者知情同意书。 +DPP-4抑制剂的适应证和超药物说明书用法 +中国批准的各种DPP-4抑制剂的说明书的适应证为2型糖尿病患者饮食运动不能控制血糖的单药、联合二甲双胍以及联合二甲双胍和磺脲类药物治疗。 +大多为单药或与二甲双胍联用，只有利格列汀与二甲双胍和磺脲类药物联合使用。 +西格列汀的适应证单药治疗：本品配合饮食控制和运动，用于改善2型糖尿病患者的血糖控制；联合治疗：当单独使用盐酸二甲双胍血糖控制不佳时，可与盐酸二甲双胍联合使用，在饮食和运动基础上改善2型糖尿病患者的血糖控制。 +维格列汀的适应证适用于治疗2型糖尿病。单药治疗：本品配合饮食控制和运动，用于改善2型糖尿病患者的血糖控制；当二甲双胍作为单药治疗用至最大耐受剂量仍不能有效控制血糖时，本品可与二甲双胍联合使用。 +沙格列汀的适应证用于2型糖尿病。单药治疗：可作为单药治疗，在饮食和运动基础上改善血糖控制；联合治疗：当单独使用盐酸二甲双胍血糖控制不佳时，可与盐酸二甲双胍联合使用，在饮食和运动基础上改善血糖控制。 +利格列汀的适应证利格列汀与二甲双胍和磺脲类药物联合使用，配合饮食控制和运动，可用于成年2型糖尿病患者的血糖控制。 +阿格列汀的适应证适用于治疗2型糖尿病：单药或联合二甲双胍用于成人2型糖尿病患者的血糖控制。 +超出说明书范围，如与其他2种及以上的不同类别降糖药物联合使用；或在1型糖尿病患者中使用即属超药物说明书使用。 +除维格列汀未在美国上市外，美国FDA批准上述药物的适应证均为饮食运动不能控制血糖的2型糖尿病患者，药物说明书提供单药以及多种联合治疗方案的详细资料。 +我国药物说明书的形式与欧盟更接近，需要分别批准单药或与其他降糖药的不同联合，详见表1。 +诊断早期或病情较轻的2型糖尿病患者可能1种降糖药即可控制血糖，但由于2型糖尿病是进展性疾病，随病程延长需要2种以上不同种类的降糖药联用。 +如果药物说明书只是批准单药或与部分药物联用，而改变说明书适应证需要严格的审批，并花费大量时间和费用，往往滞后于严格的临床研究数据；如果局限于说明书可能使其临床应用受到严重限制。 +故国内外的2型糖尿病防治指南均按药物的作用机制和循证证据等进行推荐临床应用。 +DPP-4抑制剂在国内外指南中的地位 +2011年国际糖尿病联盟(IDF)的2型糖尿病治疗路径、2013年中华医学会糖尿病分会的中国2型糖尿病防治指南、美国糖尿病协会(ADA)/欧洲糖尿病研究协会(EASD)和美国临床内分泌协会(AACE)制定的2型糖尿病治疗流程均认可DPP-4抑制剂可与多种传统降糖药物联合或单药治疗，即在二甲双胍或其他药物联合治疗不能达标加用(联用)，或不能耐受二甲双胍时选择(单药)。IDF指南和中国2型糖尿病防治指南建议在选择二甲双胍、磺脲类药物、α-糖苷酶抑制剂控制不佳后加用；AACE 治疗流程和ADA/EASD专家共识认为二甲双胍治疗不能达标或不能耐受时即可选用，也可与多种降糖药联合使用，包括胰岛素。 +指南均未推荐在1型糖尿病患者中使用。 +DPP-4抑制剂的安全性及有效性的临床研究证据 +1. 单药治疗 +目前在中国，西格列汀、维格列汀、阿格列汀和沙格列汀已获批了单药治疗的适应证，可用于饮食和运动治疗基础上不能良好控制血糖的2型糖尿病患者。国外研究也显示利格列汀对绝大多数2型糖尿病患者有明显降低血糖的效果。 +多项安慰剂对照、双盲、为期24周以上的研究显示DPP-4抑制剂降低HbA1c0.5%~1.0%，均显著优于对照组。 +由于不同的研究所选择的入组人群、基线HbA1c水平和研究方案的不同，不同DPP-4抑制剂在降低HbA1c方面可能存在微小差异。 +对于那些基线HbA1c较高的患者，DPP-4抑制剂的降糖幅度较大。 +目前认为DPP-4抑制剂中并无某一特定药物在降糖方面比其他药物更具优势。 +2. 联合应用 +2.1 DPP-4抑制剂联合二甲双胍大多数DPP-4抑制剂最常见的联合用药指征是用于二甲双胍不能取得良好血糖控制的患者，主要原因在于二甲双胍是国内外指南推荐治疗2型糖尿病的一线用药。此外，这2种药物联合使用可优势互补，针对了2型糖尿病最重要的病理生理基础，即DPP-4抑制剂改善β细胞功能，二甲双胍改善胰岛素抵抗。众多的研究已经证实这种联治疗的有效性和安全性。DPP-4抑制剂联合二甲双胍可以进一步降低患者HbA1c0.5%~1.1%。DPP-4抑制剂联合二甲双胍的低血糖发生率与安慰剂组相似，胃肠道反应与二甲双胍单药治疗相比无显著差异。目在中国获批与二甲双胍联合应用的DPP-4抑制剂有沙格列汀、维格列汀、阿格列汀、西格列汀。利格列汀获得了FDA和EMA的批准用于与二甲双胍的联合治疗。目前国外已有DPP-4抑制剂与二甲双胍的复合制剂，可直接用于需要二者联合使用的患者。对于二甲双胍单药治疗不满意的患者联合DPP-4抑制剂的低血糖发生率明显低于联合磺脲类药物，且具有体重控制方面的优势。 +2.2 DPP-4抑制剂联合噻唑烷二酮类噻唑烷二酮类是选择性PPAR-γ(peroxisome proliferator-activated receptor-gamma)受体激动剂，主要通过增加糖尿病患者外周组织对胰岛素的敏感性来改善胰岛素抵抗。DPP-4抑制剂与噻唑烷二酮类药物联合直接针对2型糖尿病最重要的两个发病因素，部分基础研究显示两者联合治疗能够增加胰岛β细胞再生，联合治疗可能会提供更好和更持久的血糖控制和β细胞功能的保护。研究显示不同的DPP-4抑制剂与TZD类药物的联用均可降低空腹和餐后血糖，24周联合治疗HbA1c水平与对照组相比可降低约1.0%，HbA1c达标率更高。FDA已经批准了西格列汀、利格列汀、阿格列汀以及沙格列汀与TZD类药物联合应用，但是目前中国尚未批准任何DPP-4抑制剂与TZD类药物的联用。对于二甲双胍不能耐受或严重胰岛素抵抗的患者，TZD和DPP-4抑制剂的联合治疗也是一种可能的选择。 +国内外指南的治疗流程也推荐两者合用。 +2.3 DPP-4抑制剂与磺脲类药物的联合应用磺脲类药物是我国使用最广泛的口服降糖药物之一，通过刺激内源性胰岛素分泌从而降低血糖。许多患者需要在磺脲类药物治疗效果不满意或药物继发失效的基础上添加其他口服药物。众多临床研究均显示在使用磺脲类单药治疗血糖控制不良的患者中加用DPP-4抑制剂可进一步改善血糖，提高HbA1c的达标率。但需要注意的是DPP-4抑制剂自身单独使用并不引起低血糖，但与磺脲类药物联合使用时发生低血糖的风险增加。FDA已经批准西格列汀、利格列汀和沙格列汀与磺脲类药联合使用，但是上述药物尚未在中国申请与磺脲类的联合使用。从血糖控制以及低血糖风险等综合因素来看，目前的临床证据支持DPP-4抑制剂与磺脲类药物联用，指南也推荐二甲双胍不能耐受时两者的联用。 +2.4 DPP-4抑制剂与胰岛素的联合应用DPP-4抑制剂另一个潜在的应用方法是与胰岛素联合，这种联合可以改善血糖控制，减少血糖波动而不增加低血糖的发生，并且可减少胰岛素的用量。在使用稳定剂量胰岛素治疗的患者中加用DPP-4抑制剂可进一步降低血糖，但不增加低血糖发生风险和体重，甚至降低低血糖发生率和严重程度。目前西格列汀、利格列汀和格列汀在美国FDA和欧洲EMA均获批了与胰岛素的联用适应证。中国尚未批准上述药物与胰岛素的联用。国内外指南推荐在口服药疗效不佳时可联合胰素使用。 +2.5 DPP-4抑制剂多药联合应用由于胰岛β细胞功能逐年减退，导致血糖难以持续达标，常常需要2种以上的药物联合使用以增加疗效。 +既往药物相互作用的研究数据未显示2种以上降糖药物联用时，在进一步降糖的同时会出现特殊的安全性问题。 +有研究显示2种药物联合使用基础上加用DPP-4抑制剂可获得更好的血糖控制，而药物相关的不良反应与对照组相当。 +由于大部分DPP-4抑制剂通过肾脏排泄(利格列汀由胆汁及肠道排出)，药代动力学数据提示药物和药物之间干扰作用较小，联合应用的时候不需要调整剂量。 +总之，现有的临床证据提示DPP-4抑制剂与其他多种降糖药物的多重联合有进一步疗效和安全性良好。 +利格列汀、西格列汀和沙格列汀在FDA和EMA均获得了与胰岛素和二甲双胍的联合使用适应证。 +在中国利格列汀获得和二甲双胍与磺脲类药物联合治疗的适应证。 +指南也推荐必要时3种药物联用。 +DPP-4抑制剂的安全性 +DPP-4抑制剂是一类耐受性良好的降糖药物，单独使用基本无低血糖风险。临床试验显示其不良事件总体水平与安慰剂相当。通常DPP-4抑制剂增加内源性GLP-1 2~3倍，胃肠道反应也较少。既往曾有该类药物在临床使用后发生胰腺炎的病例报道，但大样本的回顾性分析以及新近发布的大型前瞻性研究结果均未显示DPP-4抑制剂增加胰腺炎发生风险。 +虽然DPP-4酶也存在于T淋巴细胞膜上(CD26)，但尚无证据表明DPP-4抑制剂会导致人类免疫功能异常。 +但需要指出，由于DPP-4抑制剂在临床的使用时间较短，需要更多的上市后研究来发现其潜在的不良反应。 +DPP-4抑制剂在特殊人群中的应用 +1. 1 型糖尿病患者 +GLP-1除葡萄糖依赖性刺激胰岛素分泌、抑制胰高血糖素分泌外，还具有延缓胃肠排空以及保护β细胞的作用。胰高糖素分泌相对增多也是1型糖尿病血糖升高的主要机制之一。虽然有研究提示1型糖尿病患者使用DPP-4抑制剂可降低患者HbA1c水平，并减少胰岛素的用量，但现有数据并没有显示DPP-4抑制剂具有延缓1型糖尿病进展的作用。 +因此，DPP-4抑制剂是否能够用于1型糖尿病的治疗尚需要更多的临床研究证实，也没有相应的适应证，国内外指南也未推荐使用。 +本共识不主张在临床使用DPP-4抑制剂治疗1型糖尿病患者。 +2.2 型糖尿病合并肾功能不全患者 +大部分DPP-4抑制通过肾脏排泄，因此DPP-4抑制剂的暴露浓度会随着肾功能下降而相应的增加。药物说明书和国内外指南认为西格列汀、沙格列汀、维格列汀以及阿格列汀在轻度肾功能不全的患者中不需要调整剂量，但对于中到重度肾功能不全的患者需要减少剂量，利格列汀不需要调整剂量。 + +3.2型糖尿病合并肝功能不全患者 +肝功能受损的患者对DPP-4抑制剂具有良好的耐受性。肝功能受损基本不会对DPP-4抑制剂产生有临床意义的药代动力学影响，对于大部分DPP-4抑制剂，在轻到中度肝功能受损的患者中均无需调整剂量。 +但是在针对维格列汀的临床试验中发现肝酶的暂时性升高，因此对丙氨酸氨基转移酶和(下转第17页)(上接第13页)天门冬氨酸氨基转移酶高于正常上限3倍的患者不能使用。 +利格列汀在肝功能不全患者中无需调整剂量。 +相当，达标率相当。阿卡波糖降低餐后2h血糖的作用显著优于二甲双胍，其降低餐后胰岛素、减轻体重和降低三酰甘油的作用也优于二甲双胍。二甲双胍是新诊断2型糖尿病患者药物治疗的一线选择，但如果患者以餐后血糖升高为主要特点时，可考虑首选阿卡波糖。 +MARCH研究为比较阿卡波糖和二甲双胍的疗效和获益提供了非常有价值的信息，为指南的制定提供了循证医学证据参考，并跨出了历史性的一步。 +MARCH研究以坚实的临床数据赢得了世界的尊重，在探索中国糖尿病治疗的长征路上迈出了坚实的一步。 +4.老年2型糖尿病患者 +老年糖尿病患者是高度差异化的人群，常常合并多种疾病，需要服用多种药物。低血糖以及整体安全性考虑在老年人群药物的选择中占有越来越重的地位。DPP-4抑制剂单独或联合使用低血糖风险较低，而且对体重的影响中性，适于在这类人群中使用。临床研究显示DPP-4抑制剂在老年人群中具有良好的有效性及安全性，甚至有荟萃分析提示DPP-4抑制剂在老年患者中的血糖控制效果优于年轻患者。总体而言，这类药物良好的安全性使其适合应用于老年2型糖尿病患者。 +5.糖尿病合并心血管高危因素患者 +心血管并发症是导致糖尿病患者死亡的最主要原因，因此，在选择糖尿病治疗药物的过程中，药物的心血管安全性是非常重要的考量因素。临床研究的数据汇集分析(pooled analysis)显示，DPP-4抑制剂不增加心血管事件。最新发表的SAVOR-TIMI53研究和EXAMINE研究为评估沙格列汀和阿格列汀心血管安全性的多中心、随机、双盲、对照的前瞻性临床研究。研究纳入未接受过肠促胰素类降糖药物的2型糖尿病(HbA1c≥6.5%)合并心血管高危风险患者，随机分为安慰剂组和治疗组。研究结果显示主要复合终点事件(包括心血管疾病导致的死亡、非致死性心肌梗死、非致死性缺血性脑卒中)发生率与安慰剂组相似，进一步明确了沙格列汀和阿格列汀心血管安全性良好。其他关注DPP-4抑制剂心血管安全性的诸多大型前瞻性临床研究正在进行中，如西格列汀的TECOS研究、利格列汀的CAROLINA，CARMELINA研究等。但现有的研究数据显示DPP-4抑制剂不增加2型糖尿病患者的心血管风险。 +总结 +DPP-4抑制剂是一种新型的口服降糖药，疗效确切，安全性良好。中国FDA批准的适应证主要为单药或与二甲双胍联用，或与二甲双胍和磺脲类药物联用。临床应用应该以药物说明书为基础，但临床证据和国内外权威指南支持与多种传统降糖药双药以上的联合使用。暂不主张在1型糖尿病患者中应用DPP-4抑制剂，因为需要更充分的临床证据。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_9.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_9.txt" new file mode 100644 index 0000000..e56a768 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/diakg_9.txt" @@ -0,0 +1,42 @@ +2型糖尿病合并慢性肾脏病口服降糖药用药原则中国专家共识(2015年更新版) +慢性肾脏病是严重威胁人类健康的常见慢性病，病因多种多样，由糖尿病所引发的慢性肾脏病称为糖尿病肾脏病变。2型糖尿病常合并慢性肾脏病，高血糖是慢性肾脏病发生和发展的主要原因之一.因此良好控制血糖至关重要。 +口服降糖药是良好控制血糖最常用的降糖药物。 +中国医师协会内分泌代谢科医师分会于2013年组织国内的内分泌科和肾内科领域专家,共同制定了“2型糖尿病合并慢性肾脏病口服降糖药用药原则中国专家共识”。 +近年来2型糖尿病合并慢性肾脏病患者中口服降糖药治疗证据不断丰富,国内外糖尿病及肾脏病权威指南对2型糖尿病合并慢性肾脏病的口服降糖药应用规范也进行了相应更新,加之同时陆续有新的口服降糖药上市。 +因此,本分会再次组织相关专家对原有共识进行了更新完善。 +一、2型糖尿病合并慢性肾脏病的流行病学 +流行病学调查显示各地成年人慢性肾脏病的患病率存在差异,为9.0%~14.0%。近期中国慢性肾脏病流行病学调查显示，我国成年人中慢性肾脏病患病率为10.8%，据此估算18岁以上人群慢性肾脏病患者人数约1.195亿。一项中国健康与养老追踪调查研究表明，45岁以上中年及老年人群中，慢性肾脏病患病率达到11.5%，且城市患病率高于农村。另一方面，糖尿病的患病率也很高。2010年中国糖尿病流行病学调查显示成人糖尿病患病率已达11.6%，据此估计我国糖尿病患者人数约1.139亿。糖尿病与慢性肾脏病关系密切，糖尿病患者慢性肾脏病发生风险较非糖尿病患者增加2.6倍。在发达国家,糖尿病已是导致慢性肾脏病的主要病因,美国流行病学调查显示,年龄≥20岁的2型糖尿病患者有39.7%合并慢性肾脏病。而且在发展中国家,糖尿病正逐渐成为慢性肾脏病的主要致病原因。我国住院糖尿病患者的回顾性研究表明，52.25%的糖尿病患者合并肾脏并发症,上海市区30岁以上2型糖尿病患者慢性肾脏病患病率可达63.9%，提示糖尿病合并慢性肾脏病也是我国糖尿病研究和治疗领域面临的重大问题。 +二、2型糖尿病合并慢性肾脏病的诊断与分期 +慢性肾脏病是指肾脏结构或功能异常持续超过3个月,其诊断标准见表1。肾小球滤过率(GFR)是评价肾脏功能的重要指标之一，我国估算肾小球滤过率(eGFR)课题协作组改良简化肾脏病饮食改良 (modification of diet in renal disease，MDRD)方程，制定了适合我国慢性肾脏病患者的eGFR的评估公式。目前国内外大部分指南根据GFR来进行慢性肾脏病的肾功能分期(表2)。 +三、2型糖尿病合并慢性肾脏病的口服降糖药选择 +1.选药原则：治疗2型糖尿病合并慢性肾脏病的理想降糖策略是在有效降糖的同时，不增加低血糖发生的风险，同时避免诱发乳酸性酸中毒或增加心力衰竭风险。 +口服降糖药的选择应基于药物的药代和药效动力学特征以及患者的肾功能水平综合判断。 +在 +使用某些低血糖风险较大的口服降糖药时需严格监测血糖,确保随机血糖>5.0mmol/L以避免低血糖的发生。 +2.血糖控制目标值：对2型糖尿病合并慢性肾脏病患者的血糖控制目标应遵循个体化原则，尽量避免低血糖的发生。《中国成人2型糖尿病HbA1c控制目标的专家共识)建议对2型糖尿病合并中重度慢性肾脏病患者的HbA1c可适当放宽控制在7.0%~9.0%，以此一方面避免血糖水平控制过低而出现低血糖，另一方面避免血糖水平过高而出现代谢异常及感染。当慢性肾脏病导致红细胞寿命缩短时,HbA1c检测结果可能被低估。在晚期慢性肾脏病患者，使用糖化白蛋白可更可靠地反映血糖控制水平，同时应监测空腹及餐后血糖以更全面地了解血糖控制情况。 +3.口服降糖药的选择：口服降糖药是临床最常用的降糖手段，对于2型糖尿病合并慢性肾脏病患者的血糖控制不可或缺。然而,口服降糖药种类繁多，各类药物的药代动力学差异显著，加之慢性肾脏病患者对经肾排泄的药物或其活性代谢产物的清除能力下降，这使得对口服降糖药物使用不当将不同程度地增加低血糖以及其它不良事件的风险。因此临床工作中，必须充分了解各种降糖药物的药代和药效动力学特点，结合患者肾功能情况进行个体化选择，确保有效降糖的同时不增加低血糖风险。一般而言，当GFR低于60ml.min-1.(1.73m2)-1时大多数口服降糖药物需酌情减量或停药。常用口服降糖药的药代动力学特征、其在2型糖尿病合并慢性肾脏病人群中应用的临床证据以及适用人群见图1及表3。 +◆双胍类：此药的主要作用是通过减少肝糖输出和改善外周胰岛素抵抗而降低血糖，可使HbA1c降低1.0%-2.0%，同时减轻体重且不增加低血糖风险。英国前瞻性糖尿病研究(UKPDS)显示，二甲双胍可降低肥胖2型糖尿病患者心血管事件和死亡风险，目前国内外指南均推荐二甲双胍作为2型糖尿病控制血糖的一线用药。研究显示，二甲双胍以原形经肾脏直接排泄，当肾功能严重损害时二甲双胍与乳酸易在体内蓄积,从而增加乳酸性酸中毒的风险。因此,二甲双胍用于慢性肾脏病3a期患者时减量，当GFR<45ml.min-1(1.73m2)-1不推荐使用，当GFR<30ml.min-1.(1.73m2)-1禁用。 +◆磺脲类：为胰岛素促泌剂，可降低HbA1c1.0%-2.0%，是目前国内外指南中推荐的控制2型糖尿病患者高血糖的主要用药之一。 +第一代磺脲类药物(如甲苯磺丁脲等)目前临床上已基本被淘汰。第二代磺脲类药物中，格列本脲的半衰期较长，其活性代谢产物约50.0%经肾脏排泄，故其易在慢性肾脏病患者体内积聚，从而可能引起严重的低血糖，且低血糖的持续时间可超过24h。故仅推荐格列本脲用于慢性肾脏病1~2期的患者；3~5期禁用。 +格列美脲的代谢产物仍有降糖活性，其代谢产物及原型的60.0%经肾脏排泄。格列美脲用于慢性肾脏病1~2期患者无需调整剂量；3a期减量；3b~5期禁用。 +格列吡嗪和格列齐特的代谢产物均无降糖活性，虽然主要经肾脏排泄，但低血糖风险小于格列本脲和格列美脲。推荐格列吡嗪用于慢性肾脏病1~2期患者无需调整剂量；3期减量，4~5期禁用。格列齐特用于慢性肾脏病1~2期患者无需调整剂量；在3a期减量，3b期需谨慎用药；4~5期禁用。 +格列喹酮的代谢产物无降糖作用且大部分从粪便排泄，仅5.0%经肾脏排泄，受肾功能影响较小，但用于慢性肾脏病患者的大型临床研究有限。曾有研究观察格列喹酮用于GFR10~50mlmin-1.(1.73m2)-1患者，但试验设计不尽完善。格列喹酮可用于慢性肾脏病1~3期的患者且无需调整剂量；4期需谨慎用药；5期禁用。 +◆格列奈类：格列奈类降糖药为非磺脲类胰岛素促泌剂，可降低HbA1c0.5%~2.0%，其导致低血的风险和程度低于磺脲类。 +格列奈类的主要代表药物为那格列奈和瑞格列奈，近期有米格列奈用于临床。 +那格列奈83.0%在尿中排泄，所服药物的6.0%~16.0%以原型在尿中排泄。药代动力学研究显示，中度及重度肾功能损害的糖尿病患者中，包括在血液透析患者，那格列奈暴露无显著变化。有研究显示那格列奈的活性代谢产物在肾功能不全患者中仅少量增加，但降糖效力仅为原药1/5。一项纳人1170例老年糖尿病患者的回顾性研究显示，在合并肾功能不全的老年糖尿病患者中，那格列奈可降低HbA1c1.1%，低血糖发生率仅3.0%。基于以上资料，推荐那格列奈在肾功能损害患者中无需调整剂量：对于起始用药的GFR<30ml.min-1.(1.73m2)-1患者，应从每餐60mg开始。 +瑞格列奈及其代谢产物的8.0%经肾脏排泄此药的I期临床试验表明，使用瑞格列奈7d后，与肾功能正常患者相比，不同程度慢性肾脏病患者的血药浓度没有明显差别，提示瑞格列奈在慢性肾脏病患者体内无蓄积。一项以瑞格列奈替换原有降糖治疗、共人组281例伴或不伴肾功能不全2型糖尿病患者的多中心研究显示，不同程度肾功能不全亚组患者(正常、轻、中、重、极重育功能损害)的低血糖发生率均低于2.0%，且瑞格列奈治疗期低血糖发生率与肾功能损害程度无关。推荐瑞格列奈用于慢性肾脏病1~5期的患者无需调整剂量；如系起始用药患者，应0.5mg起始。 +米格列奈临床应用时间短且不够广泛.其用药方法及特点见表3。 +◆噻唑烷二酮类：此药为胰岛素增敏剂，可降低HbA1c1.0%~1.5%。此类药物包括毗格列酮和罗格列酮；二者均经肝脏代谢，不增加低血糖风险。此类药物的常见不良反应是体重增加、水钠潴留和心力衰竭[纽约心脏学会(NYHA)功能分级2级以上]患者禁用。此外，绝经后妇女服用该类药物增加骨折和骨质疏松风险，因此慎用于潜在骨疾病的患者(如肾性骨营养不良)。吡格列酮用于慢性肾脏病1~3a期患者时，无需调整剂量；3b~5期患者用药经验有限，需谨慎用药。肾功能损伤的患者可以单用罗格列酮，无需调整剂量。 +◆糖苷醇抑制剂：此类药物可降低HbA1c，0.5%~0.8%。同时，此类药物不增加体重且有减轻体重的趋势。主要代表药物有阿卡波糖、伏格列波糖和米格列醇。阿卡波糖口服后很少部分被吸收，随着肾功能的降低，药物本身及其代谢产物的血药浓度增加显著。阿卡波糖可用于慢性肾脏病1~3期患者：4~5期禁用。伏格列波糖可用于慢性肾脏病1~3期患者；4~5期慎用。 +米格列醇临床应用时间短且不够广泛，其用药方法及特点见表3 +◆二肽基肽酶-IV(DPP-4)抑制剂：此类药物通过抑制DPP-4活性而减少胰升糖素样肽1(GLP-1)在体内的灭活，从而增加内源性GLP-1的水平达到降糖目的。 +在以二甲双胍为基础治疗，多个联用DPP-4抑制剂或包括磺脲类、噻唑烷二酮类在内的其他多种降糖药物对比研究中，显示DPP-4抑制剂在降低HbA1c方面与阳性对照药的疗效相当。 +目前在国内上市的DPP-4抑制剂为西格列汀、沙格列汀、维格列汀、利格列汀和阿格列汀。 +西格列汀大约79.0%从尿中排泄，中度肾功能不全的患者使用西格列汀后其血浆曲线下面积(AUC)约增加2倍，重度肾功能不全和终末期肾病的患者大约增加4倍：同时西格列汀可以少量被透析清除，因此为了达到与正常肾功能患者相似的血浆浓度，中、重度和终末期肾病患者需要减少药物剂量。推荐西格列汀用于GFR≥50ml.min-1.(1.73m2)-1的慢性肾脏病患者时无需调整剂量；GFR在30~50ml.min-1.(1.73m2)-1时减量至50mg，每日1次(qd)；GFR<30ml.min-1.(1.73m2)-1时减量至25mg，qd。 +沙格列汀通过肾和肝排泄，此药用于轻度肾功能不全患者时无需调整剂量；中或重度肾功能不全的患者应将剂量调整为2.5mg，qd；在重度肾功能不全的患者中用药经验非常有限，使用应谨慎。 +被代谢消除是维格列汀在人体内的主要清除途径，约占给药剂量的69.0%；其主要代谢产物(LAY151)没有药理活性，约有23.0%的维格列汀原形药物从肾脏中排泄。与正常健康受试者相比，维格列汀在轻度、中度和重度肾功能不全患者中的AUC均值分别增加1.4、1.7和2倍。对于中度或重度肾功能不全患者，维格列汀的峰浓度无明显增加，由于半衰期(TI/2)延长致使暴露水平增加约2倍，因此，对于中、重度肾功能不全患者，维格列汀50mgqd就可以维持24h对DPP-4的抑制作用。 +60.0%-71.0%的阿格列汀以原型通过尿液排泄。轻度肾功能受损患者中，阿格列汀的血浆AUC升高程度不具有临床相关性。中度肾功能受损患者中阿格列汀的血浆AUC约升高2倍。重度肾功能受损和终末期肾病患者中，阿格列汀的血浆AUC分别约升高3倍和4倍，透析3h可清除体内7.0%的药物。因此中重度糖尿病合并慢性肾脏病患者应谨慎用药。大部分(约90.0%)的利格列汀以原型排泄，肾排泄低于给药剂量的5.0%，因此此药的使用不受肾功能降低的影响。利格列汀用于慢性肾脏病1~5期的患者时无需调整剂量。 +4.特殊人群的治疗：(1)儿童和青少年2型糖尿病合并慢性肾脏病患者中，缺乏高血糖、高血压和血脂异常治疗方面的相关数据；但是生活方式干预(饮食、锻炼、减肥)是各种治疗的基础，因此对高血糖的控制应从改善生活方式开始。若生活方式干预不能控制血糖，应考虑降糖药治疗。尽管美国糖尿病协会(ADA)推荐口服降糖药作为儿童和青少年2型糖尿病患者的一线治疗，但其中仅二甲双胍被美国食品药品监督管理局(FDA)批准用于10岁以上的儿童，其使用注意事项与成人相同。(2)老年2型糖尿病合并慢性肾脏病患者：老年2型糖尿病患者除合并慢性肾脏病之外，还通常合并其他多种并发症和伴随症，尤其是心血管疾病以及认知功能障碍；因此应加强对多种危险因素的管理。 +对此类患者尤其应注意避免低血糖的发生，适当放宽降糖目标，并视患者的具体情况而选用口服降糖药；如选择使用具有低血糖风险的药物时，应从小剂量开始，逐渐加量并注意观察患者的降糖疗效和不良反应。 +四.结束语 +2型糖尿病合并慢性肾脏病患者的预后较单纯2型糖尿病或单纯慢性肾脏病患者更差。临床实践中，应重视2型糖尿病合并慢性肾脏病患者口服降糖药的正确选择和规范使用。一旦GFR<60ml.min-1(1.73m2)-1，大多数口服降糖药的药代和药效动力学特征将发生改变，低血糖及其他不良反应风险显著增加。研究显示遵循指南可显著提高降糖达标率，显著降低低血糖风险，且入院率和治疗费用均显著下降。因而，对于2型糖尿病合并慢性肾脏病患者的口服降糖药治疗，尤应重视指南推荐和规范应用。临床实践中，应密切监测2型糖尿病合并慢性肾脏病患者的血糖，依据患者的肾功能分期合理选择降糖药物的种类并积极调整剂量，以便有效控制血糖，同时减少低血糖等多种不良风险。 \ No newline at end of file diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/pathology_\345\204\277\347\247\221\345\233\264\344\272\247\346\234\237\347\227\205\347\220\206\345\255\246_cleaned.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/pathology_\345\204\277\347\247\221\345\233\264\344\272\247\346\234\237\347\227\205\347\220\206\345\255\246_cleaned.txt" new file mode 100644 index 0000000..af9e0aa --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/pathology_\345\204\277\347\247\221\345\233\264\344\272\247\346\234\237\347\227\205\347\220\206\345\255\246_cleaned.txt" @@ -0,0 +1,438 @@ +## 1. Cleft lip, gross {#item-1} +![](../../images/pediatric_9b94a6c6.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Examination of a stillborn fetus or neonate should consist of a careful and detailed physical examination. You must note the presence of any anomalies, as well as detail size and gestational age. The anomaly seen in this photograph, a large bilateral cleft lip, is not so subtle, but some anomalies are. Call a clinical geneticist for consultation. The presence of one anomaly suggests that additional anomalies may be present, including internal anomalies such as congenital cardiac defects that may be life-threatening. +## 2. Lateral cleft lip, gross {#item-2} +![](../../images/pediatric_9b18d8d5.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is alateral cleftin a child with multiple congenital anomalies. In this case, the constellation of anomalies suggested a possible chromosomal anomaly, and a karyotype revealed 47, XY, +18 (trisomy 18). +## 3. Facial abnormalities, gross {#item-3} +![](../../images/pediatric_b7fe4c7c.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +![](../../images/pediatric_7981e08e.jpg) +The facial features shown in the 3rd trimester fetus above and the 2nd trimester fetus below are typical for trisomy 18 (e.g., 47, XY, +18). The face is small in proportion to the head, with micrognathia. +## 4. Hands with abnormal crease, gross {#item-4} +![](../../images/pediatric_99183c84.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +There is an abnormaltransverse creaseacross the palm of each hand seen here. Together with thesingle flexion creaseon the 5th digit, this is quite typical for trisomy 21 (e.g., 47, XX, +21). +## 5. Syndactyly, hand and foot, gross {#item-5} +![](../../images/pediatric_90bdc6ea.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +![](../../images/pediatric_8e697ad3.jpg) +Syndactyly represents fusion of two or more digits. It can be an isolated finding or part of syndromes that define patterns of anomalies. Most of these syndromes do not have a specific genetic defect yet defined, though some do. Seen above are the digits of the hand fused together. Below, the foot has rudimentary, partially fused digits. +## 6. Syndactyly, hand, gross {#item-6} +![](../../images/pediatric_05d3128c.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is an example ofsyndactylyin which the 3rd and 4th fingers are fused into one large digit. This particular pattern can be seen with triploidy (69 chromosomes) as part of a malformation syndrome with multiple anomalies. It may also be an isolated defect. +## 7. Clenched hand, gross {#item-7} +![](../../images/pediatric_5502aee4.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +These are clenched hands resulting from camptodactyly (fingers bent over) and clinodactyly (fingers inclined to one side or the other). This particular appearance is very suggestive of trisomy 18. Note how digits 2 and 5 curve inward to overlapdigits 3 and 4of the right hand. The presence of external anomalies suggests an increased likelihood for internal organ anomalies that may impact health and survival. When multiple anomalies are present, a malformation syndrome may be present, and some have a genetic basis. +## 8. 'Rocker bottom' foot, gross {#item-8} +![](../../images/pediatric_49d998d2.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is the appearance of a "rocker bottom" foot with aprominent calcaneusand rounded profile to the bottom of the foot. Such an anomaly may suggest a chromosomal abnormality such as trisomy 18. +## 9. Sirenomelia, gross {#item-9} +![](../../images/pediatric_9cfc7fe1.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is sirenomelia. The term comes from "siren" or "mermaid" because of the characteristicfusion of the lower extremitiesthat results from a failure in the development of a normal vascular supply to lower extremities from the lower aorta in utero. +## 10. Intrauterine fetal demise, external features, gross {#item-10} +![](../../images/pediatric_57f95f83.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Note the features of intrauterine fetal demise:skin slippageand reddening. These features are those of maceration and not trauma or birth defect. Note the shortened lower extremities, known asphocomelia. It was idiopathic in this case, but in the 1950's the drug thalidomide was responsible for many cases when pregnant women took it. Thus, it is very important that pregnant mothers be advised that drugs (including cigarette smoking and alcohol consumption) may have profound effects on the fetus. +## 11. Hydrops fetalis, gross [XRAY] {#item-11} +![](../../images/pediatric_c8e610b1.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Generalized edema from fluid collection in the soft tissues results in hydrops fetalis. There are many causes for fetal hydrops. The most common are "non-immune" types that include infections, congestive failure (from anemia or cardiac abnormalities), and congenital anomalies. Immune hydrops, from maternal antibody formed against fetal red blood cells, is not common when Rh immune globulin is employed in cases of potential Rh incompatibility. +## 12. Omphalocele, gross {#item-12} +![](../../images/pediatric_1f1a7ed2.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is a ventral abdominal wall defect. This defect involves the region of the umbilical cord, so this is anomphalocele. Note that there is a thin membrane covering the herniated abdominal contents (loops of bowel can be seen under the membrane). This defect would have to be repaired over a period of time. Since the bowel has mainly developed outside of the abdominal cavity, it is malrotated and the cavity is not properly formed (too small). +## 13. Gastroschisis, gross {#item-13} +![](../../images/pediatric_d926149b.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is large lateralabdominal wall defectdoes not involve the intactumbilical cordand is not covered by a membrane. This is a gastroschisis. Much of thebowel, as well as thestomach, and also theliverare herniated outside the abdominal cavity. This may be the consequence of an early amnion disruption, a rare sporadic event. +## 14. Limb-body wall complex, gross [XRAY] {#item-14} +![](../../images/pediatric_351aae20.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is a gastroschisis in association with a limb-body wall (LBW) complex. Most of theliverhas herniated through the large lateral abdominal wall defect. This complex is sometimes called "amnionic band syndrome" but suchfibrous bandsmay only be present in half of cases of LBW complex. Seen here in association with LBW complex are reductions of the extremities, particularly theleft upper extremity +## 15. Limb-body wall complex, gross {#item-15} +![](../../images/pediatric_960e4fea.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is limb-body wall (LBW) complex with constrictingamnionic bandsamnionic bands. The bands, as well as the other defects, may arise from early embryonic disruption with formation of adhesions and subsequent abnormal formation and loss of structures such as extremities and abdominal wall defect (gastroschisis). The suffix -schisis denotes a cleft with open defect. +## 16. Bowel atresia, gross {#item-16} +![](../../images/pediatric_1a6a85e5.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The meconium-filled bowel ends in ablind pouch. This is atresia of the bowel. Such a defect, like many anomalies, often happens along with other anomalies. Bowel atresias are accompanied by polyhydramnios, since the swallowing and absorption of amniotic fluid by the fetus is impaired. +## 17. Duodenal atresia, gross [XRAY] {#item-17} +![](../../images/pediatric_f176ca5d.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +There is a point of marked narrowing indicative of congenitalduodenal atresiadepicted here. Interestingly, half of all duodenal atresias occur with Down syndrome, although conversely, few cases of Down syndrome have duodenal atresia. By ultrasound, there is a "double bubble" sign fromduodenal enlargementproximal to the atresia accompanying thenormal stomachbubble. The normalesophagus,liver, andgallbladderare seen here as well. +## 18. Colonic atresia, gross {#item-18} +![](../../images/pediatric_b7d5ce11.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is acolonic atresiaaccompanied by additional anomalies, including apersistent cloacathat resulted from failure of the urogenital septum to form. Theright testisand theleft testisare cryptorchid, and there is absence of the penis. The presence of one anomaly suggests that others are present as well, and the term "multiple congenital anomalies" applies. +## 19. Tracheo-esophageal fistula and atresia, gross {#item-19} +![](../../images/pediatric_5cac6af8.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is a tracheo-esophageal fistula with esophageal atresia. Theesophageal atresiais present in the mid-esophagus. Thetracheoesophageal fistulais located below the carina. +## 20. Diaphragmatic hernia, gross {#item-20} +![](../../images/pediatric_130f1a91.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +In this case, the diaphragmatic dome is missing on the left, allowing herniation of the abdominal contents into the chest cavity. The metal probe in the photograph is behind the left lung, which has been displaced by thestomach. Below the stomach is a dark spleen (at the white arrow). The white arrow overlies the left lobe of liver which is extending upward. +## 21. Diaphragmatic hernia, gross {#item-21} +![](../../images/pediatric_2b7a0071.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +A diaphragmatic hernia on the left allowsherniation of bowelinto the left chest cavity. The herniatingliver has become tilted vertically. Incursion of abdominal contents into the chest cavity will result in pulmonary hypoplasia. Though diaphragmatic hernia may occur as an isolated defect that is potentially repairable, most are associated with multiple anomalies, and often with chromosomal abnormalities. +## 22. Recessive polycystic kidney disease, gross {#item-22} +![](../../images/pediatric_24ed3c52.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The two enormous masses beneath the liver arecystic kidneys. This is an example of autosomal recessive polycystic kidney disease (ARPKD). +## 23. Renal agenesis, gross {#item-23} +![](../../images/pediatric_d31e8989.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Agenesis refers to the absence of formation of a body part in embryogenesis. Here the kidneys are absent from the retroperitoneum, and this renal agenesis will result in oligohydramnios, because amniotic fluid is mainly derived from fetal urine. The oligohydramnios leads to deformations such as a constricted chest, diminished lung development, and pulmonary hypoplasia. +## 24. 'Potter facies' from oligohydramnios, gross {#item-24} +![](../../images/pediatric_43a29887.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This baby demonstrates the typical "Potter's facies" with prominentinfraorbital foldsresulting from oligohydramnios in utero. This is an example of a deformation sequence in which an anomaly (here the lack of normal kidneys) leads to lack of fetal urine output with resultant oligohydramnios that causes deformation through constraint. +## 25. 'Potter facies' and 'glove-like' hand from oligohydramnios, gross {#item-25} +![](../../images/pediatric_b8e9d206.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Seen in the right panel is the characteristic facial appearance with oligohydramnios, with prominentinfraorbital creasesand a flattened nose. In the left panel the hand appears to have excessive skin folds, like a loose glove. Oligohydramnios restricts fetal movement. The umbilical cord may be short. +## 26. Normal chest cavity, gross {#item-26} +![](../../images/pediatric_29187dd2.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is the normal appearance of the chest cavity in a neonate. Note the prominent pinkthymusabove theheartin the mediastinum. Note the size of the heart in relation to thelungsand chest cavity. Thediaphragmatic leavesare intact. Theliveris normally quite large in neonates in relation to other organs. +## 27. Pulmonary hypoplasia, gross {#item-27} +![](../../images/pediatric_f7e6ab58.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The most serious consequence of oligohydramnios is pulmonary hypoplasia. Note the extremelysmall lungsin this case on each side of theheartin the middle of the chest. The chest cavity is opened here at autopsy and the lung appear small in comparison to chest size, but in utero the constriction from diminished amnionic fluid would have decreased the chest cavity size. +## 28. Pulmonary hypoplasia, microscopic {#item-28} +![](../../images/pediatric_b2e5f322.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Microscopic examination of the lung reveals no alveolar development, onlytubular bronchiolesincapable of significant gas exchange, in this premature baby with pulmonary hypoplasia from oligohydramnios. This results in insufficient gas exchange from respiration following birth. +## 29. Varus deformities, feet, gross {#item-29} +![](../../images/pediatric_2dc734c6.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Deformation from constraint with oligohydramnios in utero can result in the appearance of theclub feet(varus deformity) seen here. The feet are turned inward. +## 30. Alobar holoprosencephaly, gross [MRI] {#item-30} +![](../../images/pediatric_1b082b71.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is holoprosencephaly, often accompanied by the failure of fetal facial midline structures to form properly. Hence, there are usually midline facial defects (cleft lip, cleft palate, cyclopia, etc) accompanying this condition. The "alobar" form of holoprosencephaly is shown here in which there asingle large ventricle, because there is no attempt to form separate cerebral hemispheres. This condition may be associated with trisomy 13. It may rarely occur in association with maternal diabetes mellitus. +## 31. Semilobar holoprosencephaly, gross {#item-31} +![](../../images/pediatric_ef4dee46.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The skull is opened here to reveal the "semilobar" form of holoprosencephaly, because there is asmall cleftrepresenting an attempt to separate the hemispheres. There is no gyral pattern here because this stillborn fetus was under 20 weeks gestation. Holoprosencephaly is a grave condition with little or no brain function. Holoprosencephaly can be associated with chromosomal anomalies (such as trisomy 13), with maternal diabetes mellitus, and can be seen sporadically. +## 32. Holoprosencephaly, gross {#item-32} +![](../../images/pediatric_e834fb2e.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is a cross section though a brain with holoprosencephaly, revealing a single ventricle. Toward the base of the brain are thefused thalamitypical of this process. +## 33. Hydranencephaly, gross {#item-33} +![](../../images/pediatric_32d811e9.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This ishydranencephaly. Note that watery fluid fills the cerebral hemispheres shown here with the skull opened at the vertex in this stillborn. The brain is essentially a bag of water covered by a thin meningeal layer, because an intrauterine vascular accident involving the brain led to lack of blood flow and subsequent loss of cerebral tissue. +## 34. Conjoined twins (craniothoracopagus), gross {#item-34} +![](../../images/pediatric_de21cb1d.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is an uncommon complication of monozygous twinning in which there is fusion of the twins. The general term is conjoined twinning. The scientific term applicable in the case shown here involving two stillborns is craniothoracopagus, or twins joined at the head (cranio) and chest (thoraco). There is only one brain, and the hearts and gastrointestinal tracts are fused as well. The location and amount of fusion can vary. Separation is possible with simple fusion of superficial structures. +## 35. Conjoined twins (thoracopagus ), gross {#item-35} +![](../../images/pediatric_b1f159cc.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is an example of conjoined twins called thoracopagus. Note the largeomphalocelein the lower abdomen shared by these monozygous twins. These twins also shared a heart, and liver and several other organs were partially fused. Attempts at separation of such twins is challenging. The survival rate with significant fusion of organs is essentially nil. +## 36. Acardius acephalus (chorangiopagus parasiticus), gross {#item-36} +![](../../images/pediatric_d8c59016.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is another abnormality of twinning in which one fetus is essentially a poorly formed blob attached to, or separate from, a complete fetus. This condition is called acardius-acephalus because there is typically no heart or brain in the "blob" twin. The photograph here reveals an acardiac twin that consists mainly of just lower extremities. Such a non-viable twin can be surgically removed if attached to the viable twin. +## 37. Acardius anceps (chorangiopagus parasiticus), gross {#item-37} +![](../../images/pediatric_65b6ca1b.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is a more complete acardiac twin in which actual body regions are present. There were few poorly formed internal organs present. Nonetheless, it is non-viable. +## 38. Twin-twin transfusion syndrome, gross {#item-38} +![](../../images/pediatric_907c4060.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +If there is a vascular connection across a monochorionic twin placenta, then a twin-twin transfusion syndrome can develop via blood flow between the fetuses. In this condition, there is diminished blood flow to one twin (the "donor") and increased blood flow to the other twin (the "recipient"). The pale appearing donor is smaller and may die for lack of sufficient blood flow. More commonly, the larger plethoric recipient may die from congestive heart failure. +## 39. Meningomyelocele, gross {#item-39} +![](../../images/pediatric_12831f84.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Neural tube defects are are one of the more common congenital anomalies to occur. Such defects result from improper embryonic neural tube closure. The most minimal defect is called spina bifida, with failure of the vertebral body to completely form, but the defect is not open. Open neural tube defects with lack of a skin covering, can include a meningocele, in which meninges protrude through the defect. Here is a largemeningomyelocelein which the defect is large enough to allow meninges and a portion of spinal cord to protrude through the defect. Such defects can be suggested by an elevated maternal serum alpha-fetoprotein (MSAFP). +## 40. Meningomyelocele, gross {#item-40} +![](../../images/pediatric_bfb12a21.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is a fetus from a termination of pregnancy via dilation and extraction, which is done in the second trimester. Note the largeneural tube defectin the lower back. +## 41. Anencephaly, gross {#item-41} +![](../../images/pediatric_51929219.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is anencephaly. This condition occurs when there isfailure of formationof the fetal cranial vault. The brain cannot form properly when exposed to amniotic fluid. Note that this fetus died in utero--there are signs of maceration, with skin slippage andreddening. +## 42. Anencephaly, gross {#item-42} +![](../../images/pediatric_a4144a5a.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Note theabsence of the cranial vaultin this fetus with anencephaly. Supplementing the maternal diet with folate prior to and during pregnancy can reduce the incidence of neural tube defects. +## 43. Anencephaly, gross {#item-43} +![](../../images/pediatric_e6665bc0.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The eyes appear proptotic with anencephaly because of thelack of the skull. Note the low set external ear. Such a condition would be suggested by an elevated prenatal maternal serum alpha-fetoprotein. +## 44. Iniencephaly, gross {#item-44} +![](../../images/pediatric_b2eb921f.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is a slight variation of a neural tube defect known as iniencephaly in which there is lack of proper formation of occipital bones with a short neck and defect of the upper cord. The head is tilted back. +## 45. Rachischisis, gross {#item-45} +![](../../images/pediatric_2b15f072.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +A severe rachischisis is shown here in a fetus that also has iniencephaly. This large open defect has a reddish base and involves much of the spinal column extending to the skull. +## 46. Iniencephaly, encephalocele, rachischisis, gross {#item-46} +![](../../images/pediatric_c20faf00.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Seen protruding from the back of the head is a largeencephalocelethat merges with the scalp above. The encephalocele extends down to partially cover a rachischisis on the back. This fetus also has a retroflexed head from iniencephaly. +## 47. Exencephaly, gross {#item-47} +![](../../images/pediatric_45195bc3.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This form of neural tube defect is known as exencephaly. The cranial vault is not completely present, but a brain is present, because it was not completely exposed to amniotic fluid. Such an event is very rare. It may be part of craniofacial clefts associated with the limb-body wall complex, which results from early amnion disruption. +## 48. Nasopharyngeal teratoma, congenital, gross {#item-48} +![](../../images/pediatric_db45a0c0.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Congenital and pediatric neoplasms are uncommon. One type that can occur is a teratoma. Shown here is a large nasopharyngeal teratoma that is protruding from theoral cavity. Though histologically benign, the large mass effect severely impacts survival. +## 49. Teratoma, congenital, low power microscopic {#item-49} +![](../../images/pediatric_e8bd5285.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The microscopic appearance of a teratoma is seen here. This neoplasm, though benign from a microscopic standpoint, can become a large mass that has severe consequences for a small fetus, infant, or child. The three embryologic germ layers are represented byskin(ectoderm) at the top,cartilage(mesoderm) at the bottom left center, and acolonic gland(endoderm) at the right. +## 50. Lymphangioma, congenital, gross {#item-50} +![](../../images/pediatric_1f013507.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +There is alarge massinvolving the left upper arm and left chest of this fetus. This congenital neoplasm turned out to be a lymphangioma. +## 51. Lymphangioma, congenital, medium power microscopic {#item-51} +![](../../images/pediatric_6594a459.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is the microscopic appearance of the lymphangioma at medium power, with largelymphatic spaceslined by a thin endothelium. The adjacent stroma haslymphoid nodules. Lymphangiomas in the pediatric age range tend to involve head, neck, and chest. +## 52. Lymphangioma, congenital, medium power microscopic {#item-52} +![](../../images/pediatric_b2b6b649.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +At high magnification, the histologically benign nature of the lymphangioma is apparent. There are enlarged lymphatic spaces lined by a thin endothelium. However, such lesions tend to be poorly circumscribed and extend widely into surrounding soft tissues, making their surgical removal difficult. +## 53. Hemangioma, congenital, gross {#item-53} +![](../../images/pediatric_a7514c18.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Beneath the skin surface at the left are manydilated vascular channelsfilled with many red blood cells. This is a neoplasm known as a hemangioma. +## 54. Wilms tumor, gross {#item-54} +![](../../images/pediatric_374dee19.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This lobulated tan-white mass involving the kidney of a child is a Wilms tumor. There is adjacent surrounding residual compressed brown renal parenchyma. This pediatric neoplasm manifests most often as an abdominal mass. Over 90% of Wilms tumors are diagnosed during the first 6 years of life. About a fourth of cases are associated with hypertension. +## 55. Wilms tumor, medium power microscopic {#item-55} +![](../../images/pediatric_ed6ceedf.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Wilms tumor microscopically resembles the primitive nephrogenic zone of the fetal kidney, with primitiveglomeruloid structuresglomeruloid structures and a cellular stroma. Wilms tumor is associated with mutations involving theWT1tumor suppressor gene on chromosome 11. This neoplasm is very treatable with an excellent prognosis and >80% cure rate overall. +## 56. Neuroblastoma, gross [MRI] {#item-56} +![](../../images/pediatric_0a672596.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is the gross appearance of a neuroblastoma arising in the right adrenal gland. It is the most common pediatric malignancy in infancy, and 75% of cases are diagnosed in children less than 4 years old. These tumors most often present as an abdominal or mediastinal mass. +## 57. Neuroblastoma, medium power microscopic {#item-57} +![](../../images/pediatric_3fb20c97.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Microscopically, neuroblastoma is a "small round blue cell" tumor. Histologic variations, as well as staging and cytogenetic characteristics help to determine the prognosis. +## 58. Rhabdomyosarcoma, low power microscopic [CT] {#item-58} +![](../../images/pediatric_b3b1ff4b.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +A rare neoplasm that appears most commonly in the first decade of life is the rhabdomyosarcoma. This malignant neoplasm has skeletal muscle derivation. The alveolar variant is shown here. These neoplasms occur most frequently in the head and neck area, as well as the genitourinary tract. +## 59. Rhabdomyosarcoma, medium power microscopic [MRI] {#item-59} +![](../../images/pediatric_d7d343e4.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This alveolar rhabdomyosarcoma is composed of primitive round blue cells (rhabdomyoblasts) arranged in nests with spaces and surrounded by a fibrous stroma. A variant of this neoplasm seen in the genital tract is the sarcoma botryoides. +## 60. Congenital syphilis, gumma in heart, gross {#item-60} +![](../../images/pediatric_b0d336a8.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is an example of a granulomatous process known as a"gumma"in a case of congenital syphilis. The gumma shown here is located in the heart of a fetus. Syphilis can be acquired in utero in the third trimester. congenital syphilis is increasing in incidence in the U.S. +## 61. Spirochetes (Treponema pallidum), microscopic {#item-61} +![](../../images/pediatric_32eab10a.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Spirochetes are seen here. These areTreponema pallidumorganisms and are the causative agents for syphilis. +## 62. Cytomegalovirus, congenital, kidney, microscopic {#item-62} +![](../../images/infection_09173092.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here within the tubular epithelium of a fetal kidney can be seen many large violetintranuclear inclusionscharacteristic of congenital cytomegalovirus (CMV) infection. The inclusions may appear in the urine of a liveborn infant with CMV. CMV infections tend to be disseminated to multiple organs. There may be fetal hydrops from organ failure. +## 63. Parvovirus, congenital, spleen, microscopic {#item-63} +![](../../images/pediatric_9ec4a62f.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The largepink inclusionin the erythroid precursor seen here in fetal spleen is evidence for parvovirus infection. Parvovirus, or "fifth" disease, produces a mild illness in children, marked by a light reddish "slapped cheek" facial rash. In adults, the illness often goes unnoticed, but pregnant women can pass the virus to the fetus, where it may produce marked fetal anemia and hydrops in some cases. +Veterinarians are aware that one form of parvovirus (canine parvovirus type 2) is highly contagious in dogs and can produce gastrointestinal infection with severe bloody diarrhea, as well as cytopenias. Young dogs and puppies are most affected. A vaccine is available. +## 64. Congenital pneumonia, microscopic {#item-64} +![](../../images/pediatric_eea3470c.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +One of the most common forms of perinatal congenital infection arises from bacterial agents that ascend the birth canal and may be seen in association with premature rupture of membranes (PROM) and acute chorioamnionitis. Seen here is a congenital pneumonia with manyneutrophilsfilling immature bronchioles. +## 65. Hyaline membrane disease, lung, microscopic [XRAY] {#item-65} +![](../../images/pediatric_0c30a43e.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is hyaline membrane disease due to prematurity and lack of surfactant production from type II pneumonocytes within the immature lung. Note thethick pink membraneslining the alveolar spaces. +## 66. Bronchopulmonary dysplasia, lung, microscopic [MRI] {#item-66} +![](../../images/pediatric_3c865018.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +A later complication of prematurity should the baby survive the immediate neonatal period, during which time mechanical ventilation was necessary, is bronchopulmonary dysplasia (BPD). With BPD, there isinterstitial fibrosisand inadequate alveolar development for good pulmonary function. Respiratory distress can continue for months to years. +## 67. Germinal matrix, brain, normal and with hemorrhage, low power microscopic {#item-67} +![](../../images/pediatric_6b3523eb.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +![](../../images/pediatric_4e3a6878.jpg) +The dense layer of small dark blue cells seen here below the ependyma of the lateral ventricle is the germinal matrix. The germinal matrix is a highly cellular and highly vascularized region from which cells migrate out during brain development, mainly between 22 and 30 weeks gestation. This area is highly vulnerable to birth injury and changes in blood pressure following birth. If severe and if survival occurs, the hemorrhage may organize and lead to obstructive hydrocephalus. Agerminal matrix hemorrhageis shown below. +## 68. Intraventricular hemorrhage, gross {#item-68} +![](../../images/pediatric_54d77bc2.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This coronal section of a premature neonatal brain showsintraventricular hemorrhage (IVH)extending from a germinal matrix hemorrhage. Such hemorrhages occur from a variety of factors that afflict neonates, including difficulty regulating blood pressure. Such hemorrhages can be devastating. +## 69. Intraventricular hemorrhage, severe, gross {#item-69} +![](../../images/pediatric_c5120b02.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Intraventricular hemorrhage (IVH) can be minimal, but can also be severe as shown here with blood filling and distending all of the lateral ventricles, extending intobrain parenchyma, and extending down the third ventricle and out into thesubarachnoid space. The prognosis is grim. With survival, organization of the blood may lead to obstructive hydrocephalus +## 70. Kernicterus, brain, gross {#item-70} +![](../../images/pediatric_33a1b995.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The yellow staining in the brain of a neonate is known as kernicterus. There is a coronal section of medulla on the left and cerebral hemisphere on the right demonstratingkernicterusin deep grey matter of hemisphere and brain stem. Increased unconjugated bilirubin, which accounts for the kernicterus, is toxic to the brain tissue. Kernicterus is more likely to occur with prematurity, low birth weight, and increased bilirubin levels. [Image contributed by Jeannette J. Townsend, MD, University of Utah] +## 71. Neonatal necrotizing enterocolitis (NEC), gross {#item-71} +![](../../images/pediatric_bd0567e9.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +A complication of prematurity and low birth weight is neonatal necrotizing enterocolitis (NEC) in which ischemia results in focal to confluent areas ofbowel necrosis, most often in the terminal ileum. Seen at autopsy here is a dark red appearance to the small intestine of a premature neonate. [Image contributed by Ted Pysher, MD, University of Utah] +## 72. Neonatal necrotizing enterocolitis (NEC) and normal bowel, low power microscopic {#item-72} +![](../../images/pediatric_f6813db3.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The clinical manifestations of neonatal necrotizing enterocolitis (NEC) in premature neonates include abdominal distension, ileus, and bloody stool at several days of age. Compared to normal bowel at the left, bowel involved by NEC at the right shows hemorrhagic necrosis, beginning in the mucosa and extending to involve the muscular wall, with the potential for perforation. With NEC, the intestinal villi are seen to be disintegrating, with loss of cell nuclei, and reddish cytoplasm. +## 73. Pyloric stenosis, gross {#item-73} +![](../../images/pediatric_da17fe23.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is pyloric stenosis. Note the prominenthypertrophied musclewith elongation and narrowing of the pylorus at the gastric outlet on the left. Pyloric stenosis is uncommon, but is a cause for "projectile" vomiting in an infant about 3 to 6 weeks of age. Males are affected more than females. The overall incidence is approximately 3 per 1000 livebirths.The "pacemaker" interstitial cells of Cajal (ICC) regulate motility, and contain the enzyme heme oxygenase-2 which generates carbon monoxide (CO) as a neurotransmitter to cause relaxation in adjacent smooth muscle cells. The lack of ICCs in pyloric stenosis results in deficient CO production leading to motility dysfunction. +The "pacemaker" interstitial cells of Cajal (ICC) regulate motility, and contain the enzyme heme oxygenase-2 which generates carbon monoxide (CO) as a neurotransmitter to cause relaxation in adjacent smooth muscle cells. The lack of ICCs in pyloric stenosis results in deficient CO production leading to motility dysfunction. +## 74. Meconium ileus, gross {#item-74} +![](../../images/pediatric_7c00bf16.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Meconium ileus is most often seen in the first few days of life in neonates with cystic fibrosis, but can rarely occur in infants with a normal pancreas. In cystic fibrosis, the abnormal pancreatic secretions lead to inspissated meconium that produces intestinal obstruction. The dilated coils of ileum are opened here to reveal the inspissated green meconium (which may also be tarry or gritty), while the unopened colon at the upper left and the appendix at the lower left beyond the ileocecal valve are not dilated, and little or no meconium is passed per rectum. [Image contributed by Ted Pysher, MD, University of Utah] +## 75. Meconium ileus with peritonitis, gross {#item-75} +![](../../images/pediatric_90b3c84b.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Meconium peritonitis shown here as a greenish exudate overlying the serosal surfaces of the peritoneal cavity can complicate meconium ileus in utero, particularly in fetuses with cystic fibrosis. The bowel ruptures and leaks meconium, which produces a chemical peritonitis. Calcifications in the spilled meconium may be seen radiographically. Another complication of meconium ileus is volvulus. [Image contributed by Ted Pysher, MD, University of Utah] +## 76. Hirschsprung disease, gross {#item-76} +![](../../images/pediatric_6b52d367.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Shown here is dilation of bowel (megacolon) proximal to the affected region of narrowing at the lower left center in sigmoid colon. Mucosal damage and secondary infection may follow.Hirschsprung disease results from an absence of ganglion cells in both submucosal and myenteric plexuses and can occur in either a segment of colon (short segment disease) or the entire colon (long segment disease). The aganglionic segment becomes narrowed, causing obstruction, with proximal dilation. Affected newborns may develop focal inflammation at the point of obstruction, with fever and diarrhea. Colonic perforation may occur. Infants with the disease may have alternating diarrhea and constipation, while children mainly have constipation. Treatment consists of surgical correction with resection of the aganglionic segment.Hirschsprung disease is thought to result from mutation of susceptible genes interacting with environmental and other factors, resulting in variable penetrance. Multiple genetic mutations have been found, but about half of familial cases and 15% of sporadic cases are associated with RET gene mutations that inactivate RET receptor kinase activity. RET promotes survival and growth of neurites and provides direction to migrating neural crest cells. The incidence of Hirschsprung disease is 1 in 5000 livebirths. It has a 4:1 male to female predominance. Short segment disease is more common in males, while the rarer long segment disease predominates in females. +Shown here is dilation of bowel (megacolon) proximal to the affected region of narrowing at the lower left center in sigmoid colon. Mucosal damage and secondary infection may follow. +Hirschsprung disease results from an absence of ganglion cells in both submucosal and myenteric plexuses and can occur in either a segment of colon (short segment disease) or the entire colon (long segment disease). The aganglionic segment becomes narrowed, causing obstruction, with proximal dilation. Affected newborns may develop focal inflammation at the point of obstruction, with fever and diarrhea. Colonic perforation may occur. Infants with the disease may have alternating diarrhea and constipation, while children mainly have constipation. Treatment consists of surgical correction with resection of the aganglionic segment. +Hirschsprung disease is thought to result from mutation of susceptible genes interacting with environmental and other factors, resulting in variable penetrance. Multiple genetic mutations have been found, but about half of familial cases and 15% of sporadic cases are associated with RET gene mutations that inactivate RET receptor kinase activity. RET promotes survival and growth of neurites and provides direction to migrating neural crest cells. The incidence of Hirschsprung disease is 1 in 5000 livebirths. It has a 4:1 male to female predominance. Short segment disease is more common in males, while the rarer long segment disease predominates in females. +## 77. Pneumatosis intestinalis, microscopic {#item-77} +![](../../images/pediatric_10547635.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Pneumatosis intestinalis is a rare finding in whichgas-filled cystsappear in submucosa. It may complicate necrotizing enterocolitis, as in this case. The gas may dissect into submucosa or may be generated by bacteria. +## 78. Normal skin with hair, gross {#item-78} +![](../../images/pediatric_1ac2e25f.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The skin is soft and the hair is fine in a normal newborn, as seen here. +## 79. Accessory spleens, gross {#item-79} +![](../../images/pediatric_245be30b.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The accessory spleens seen here at the hilum of the normal-sized spleen are not uncommon and by themselves have no significance. +## 80. Postmaturity with prominent fingernails, gross {#item-80} +![](../../images/pediatric_aaa78c92.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +There are few changes indicative of postmaturity (gestation beyond 42 weeks). Here are long fingernails that can be seen with postmaturity. +## 81. Maceration, gross {#item-81} +![](../../images/pediatric_b6889ee7.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Death of the fetus in utero is accompanied by changes of maceration. Seen here is one of the earliest changes (within half a day) which isslippage of the skin. As this process advances, the skin becomes reddened. +## 82. Fetal chest with thymus, gross {#item-82} +![](../../images/pediatric_82f9137a.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The normal fetal chest at term is shown here. Thethymusis a large structure with the important job of developing the cell-mediated immune system with T-cells. Theright lung,heart,diaphragm, andliverare seen here as well. +## 83. Thymus with macrophages, low power microscopic {#item-83} +![](../../images/pediatric_b4599dd9.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Stress from a variety of illnesses in the fetus and neonate may be manifested with thymic involution. One of the earliest changes seen is an increase in cortical macrophages, typical in 1 to 2 days following the onset of illness. Note the "starry sky" appearances here from increasedmacrophages. +## 84. Subgaleal hemorrhage, gross {#item-84} +![](../../images/pediatric_1f9b56db.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The neonatal scalp is reflected at autopsy to revealdark red bloodbeneath the galea aponeurotica (dense connective tissue of scalp) and over the cranium. This is subgaleal hemorrhage and it is fairly common during the birth process. +## 85. Meconium aspiration, medium power microscopic {#item-85} +![](../../images/pediatric_284bcc85.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Meconium spillage is a complication seen at or near term, typically when there is fetal distress with loss of anal sphincter tone and passage of meconium into amniotic fluid. A clue to this occurrence is greenish staining of fetal skin or fetal surface of the placenta. The worst consequence of meconium spillage is meconium aspiration into the lungs. Fetal distress also leads to reflex gasping efforts by the baby, with the result that the meconium in the amniotic cavity is aspirated into the lungs. Rugby ball shapedballs of meconiumas well as numerous"squames"from fetal skin are seen here. +## 86. Meconium aspiration, high power microscopic {#item-86} +![](../../images/pediatric_92abbc6e.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +In this case of meconium aspiration, small roundedballs of meconiumare seen in an alveolus, along with flattened"squames"or desquamated fetal skin cells that are found in the amnionic fluid. Meconium is an irritant that leads to respiratory distress. At birth, tracheal suction and lung lavage may be useful to help remove the meconium. diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/pathology_\345\205\215\347\226\253\347\227\205\347\220\206\345\255\246_cleaned.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/pathology_\345\205\215\347\226\253\347\227\205\347\220\206\345\255\246_cleaned.txt" new file mode 100644 index 0000000..7047090 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/pathology_\345\205\215\347\226\253\347\227\205\347\220\206\345\255\246_cleaned.txt" @@ -0,0 +1,475 @@ +## 1. Type 1 Hypersensitivity: Review {#item-1} +![](../../images/immunopathology_9034bf9f.gif) + +![](../../images/atherosclerosis_d5033905.gif) +Type I hypersensitivityAnaphylaxis: Prior sensitization has resulted in an immune response initially mediated by CD4 lymphocytes (of the Th2 variety) that promote mast cell proliferation and plasma cell production of IgE. The IgE becomes bound to mast cells in places such as respiratory tract mucosa. Encountering the allergen again leads to mast cell degranulation with release of primary mediators (such as histamine, serotonin) which cause vasodilation, bronchoconstriction, etc. and release of secondary mediators (such as leukotrienes, prostaglandin) which lead to inflammatory cell infiltrates. The process of mast cell degranulation is diagrammed below:There are two forms of anaphylaxis:Systemic anaphylaxis: In some individuals, a severe reaction occurs within minutes, leading to symptomatology such as acute asthma, laryngeal edema, diarrhea, urticaria, and shock. Classic examples are penicillin allergy and bee sting allergy.Local anaphylaxis (atopy): About 10% of people have "atopy" and are easily sensitized to allergens that cause a localized reaction when inhaled or ingested. This can produce hay fever, hives, asthma, etc. Classic examples are food allergies and hay fever to ragweed pollen.Laboratory FindingsType 1 hypersensitivity reactions may be accompanied by an increase in eosinophils, as noted with differential count of peripheral white blood cells.The serum tryptase may be increased in the hour following mast cell activation.Measurement of serum total IgE and levels of specific IgE for certain antigens may be undertaken when allergy therapies are planned. Testing for total or specific IgE should be done only when the history is consistent with allergy and specific allergens are suspected as the cause.Treatment: A standard adult dose of self-injecting epinephrine is 0.3 mg of 1:1000 epinephrine, which raises blood epinephrine from 0.035 ng/mL at rest to about 10 times that amount, the same as for vigorous exercise. In children, the dose is 0.01 mg per kilogram. Injection is subcutaneous or intramuscular. The injection can be repeated 3 times at 10 minute intervals if indicated. The epinephrine can be life-saving for the acute phase of type I hypersensitivity. Additional therapies including albuterol, antihistamines, and corticosteroids may be indicated for the late phase reaction. +Type I hypersensitivity +Anaphylaxis: Prior sensitization has resulted in an immune response initially mediated by CD4 lymphocytes (of the Th2 variety) that promote mast cell proliferation and plasma cell production of IgE. The IgE becomes bound to mast cells in places such as respiratory tract mucosa. Encountering the allergen again leads to mast cell degranulation with release of primary mediators (such as histamine, serotonin) which cause vasodilation, bronchoconstriction, etc. and release of secondary mediators (such as leukotrienes, prostaglandin) which lead to inflammatory cell infiltrates. The process of mast cell degranulation is diagrammed below: +There are two forms of anaphylaxis: +Systemic anaphylaxis: In some individuals, a severe reaction occurs within minutes, leading to symptomatology such as acute asthma, laryngeal edema, diarrhea, urticaria, and shock. Classic examples are penicillin allergy and bee sting allergy. +Local anaphylaxis (atopy): About 10% of people have "atopy" and are easily sensitized to allergens that cause a localized reaction when inhaled or ingested. This can produce hay fever, hives, asthma, etc. Classic examples are food allergies and hay fever to ragweed pollen. +Laboratory Findings +Type 1 hypersensitivity reactions may be accompanied by an increase in eosinophils, as noted with differential count of peripheral white blood cells. +The serum tryptase may be increased in the hour following mast cell activation. +Measurement of serum total IgE and levels of specific IgE for certain antigens may be undertaken when allergy therapies are planned. Testing for total or specific IgE should be done only when the history is consistent with allergy and specific allergens are suspected as the cause. +Treatment: A standard adult dose of self-injecting epinephrine is 0.3 mg of 1:1000 epinephrine, which raises blood epinephrine from 0.035 ng/mL at rest to about 10 times that amount, the same as for vigorous exercise. In children, the dose is 0.01 mg per kilogram. Injection is subcutaneous or intramuscular. The injection can be repeated 3 times at 10 minute intervals if indicated. The epinephrine can be life-saving for the acute phase of type I hypersensitivity. Additional therapies including albuterol, antihistamines, and corticosteroids may be indicated for the late phase reaction. +## 2. Type 1: Anaphylaxis, localized, with hay fever, high power microscopic {#item-2} +![](../../images/immunopathology_f01d0913.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +A form of localized anaphylaxis with type I hypersensitivity occurs with "hay fever" when allergens in plant pollens contact IgE bound tomast cells, causing them to release their granules containing mediators such as histamine that promote vasodilation and edema. Beneath the nasal mucosa at the left,eosinophilshave been attracted. Theplasma cellsseen here have collected along with many small blue lymphocytes due to the chronic nature of the antigenic stimulation with upregulation of the arachidonic acid pathway. +## 3. Type 1: Anaphylaxis, systemic, with acute laryngeal edema, gross {#item-3} +![](../../images/immunopathology_5b81ed8d.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The acute laryngeal edema seen here that killed the patient was due to an anaphylactic reaction to penicillin. Such an allergy is a form of type I hypersensitivity reaction in which there is preformed IgE antibody on mast cells that quickly reacts with an antigen. The mast cells release histamine and other mediators that lead to the edema. +## 4. Type 2 Hypersensitivity: Review {#item-4} +![](../../images/immunopathology_201195e1.gif) +![](../../images/immunopathology_334fa72b.gif) +![](../../images/immunopathology_6d6be40e.gif) + +![](../../images/atherosclerosis_d5033905.gif) +Type II HypersensitivityComplement dependent reactions: Antibody is directed against antigen on cells (such as circulating red blood cells) or extracellular materials (basement membrane). The resulting Ag-Ab complexes activate complement (via the classic pathway), leading to cell lysis or extracellular tissue damage.In the above diagram, a red blood cell has antigen fixed on its surface to which antibody attaches. The attached antibody sets off the complement cascade, which ends with the formation of the "membrane attack complex" of C5-9 which causes lysis of the cell. Other complement components may be generated, such as the opsonin C3b.Diseases in this complement dependent category include:Transfusion reactions: incompatible RBC's or serum is transfused.Autoimmune hemolytic anemia: antibody is made against one's own RBC's.Erythroblastosis fetalis: maternal IgG crosses the placenta and attaches to fetal RBC's.Goodpasture's syndrome: glomerular basement membrane antibody is present.Antibody-dependent cell-mediated cytotoxicity (ADCC): Low concentrations of IgG or IgE (in the case of parasites) coat target cells. Inflammatory cells such as NK (natural killer) cells, monocytes, and granulocytes then bind to the immunoglobulin Fc receptors and lyse, but do not phagocytize, the target cells.In the diagram above, a macrophage with Fc receptors on its surface is able to recognize a target cell coated with antibody via the Fc receptor portion of the attached antibody. The macrophage can then demolish the targeted cell by elaboration of proteases.Examples of ADCC include:Transplant rejectionImmune reactions against neoplasmsImmune reactions against parasitesAntireceptor antibodies: IgG antibody is directed against receptors in target cells, resulting in complement-mediated destruction of the receptors.In the diagram above, antibody is directed against acetylcholine receptors at the motor end plate of a muscle, blocking the receptors and diminishing the muscular response. This is the mechanism for muscle weakness in myasthenia gravis.Diseases caused by this mechanism include:Myasthenia gravis: acetylcholine receptor antibody.Graves disease (thyrotoxicosis): anti-TSH receptor antibodyPernicious anemia: anti-parietal cell antibody. +Type II Hypersensitivity +Complement dependent reactions: Antibody is directed against antigen on cells (such as circulating red blood cells) or extracellular materials (basement membrane). The resulting Ag-Ab complexes activate complement (via the classic pathway), leading to cell lysis or extracellular tissue damage. +In the above diagram, a red blood cell has antigen fixed on its surface to which antibody attaches. The attached antibody sets off the complement cascade, which ends with the formation of the "membrane attack complex" of C5-9 which causes lysis of the cell. Other complement components may be generated, such as the opsonin C3b. +Diseases in this complement dependent category include: +Transfusion reactions: incompatible RBC's or serum is transfused. +Autoimmune hemolytic anemia: antibody is made against one's own RBC's. +Erythroblastosis fetalis: maternal IgG crosses the placenta and attaches to fetal RBC's. +Goodpasture's syndrome: glomerular basement membrane antibody is present. +Antibody-dependent cell-mediated cytotoxicity (ADCC): Low concentrations of IgG or IgE (in the case of parasites) coat target cells. Inflammatory cells such as NK (natural killer) cells, monocytes, and granulocytes then bind to the immunoglobulin Fc receptors and lyse, but do not phagocytize, the target cells. +In the diagram above, a macrophage with Fc receptors on its surface is able to recognize a target cell coated with antibody via the Fc receptor portion of the attached antibody. The macrophage can then demolish the targeted cell by elaboration of proteases. +Examples of ADCC include: +Immune reactions against neoplasms +Immune reactions against parasites +Antireceptor antibodies: IgG antibody is directed against receptors in target cells, resulting in complement-mediated destruction of the receptors. +In the diagram above, antibody is directed against acetylcholine receptors at the motor end plate of a muscle, blocking the receptors and diminishing the muscular response. This is the mechanism for muscle weakness in myasthenia gravis. +Diseases caused by this mechanism include: +Myasthenia gravis: acetylcholine receptor antibody. +Graves disease (thyrotoxicosis): anti-TSH receptor antibody +Pernicious anemia: anti-parietal cell antibody. +## 5. Type 2: Linear immune complex deposition in glomerulus, Goodpasture syndrome, fluorescence microscopy {#item-5} +![](../../images/immunopathology_88eff350.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is the linear pattern of immunofluorescence with antibody to IgG in a patient with Goodpasture syndrome. The even linear pattern is produced because the antibody is directed against the entire glomerular basement membrane (antiglomerular basement membrane antibody). +## 6. Type 3 Hypersensitivity: Review {#item-6} +![](../../images/immunopathology_d0613664.gif) + +![](../../images/atherosclerosis_d5033905.gif) +Type III HypersensitivityThis reaction is mediated by immune (Ag-Ab) complexes which promote tissue damage primarily through complement activation (alternate pathway). C3b as an opsonin attracts neutrophils, which then release lysosomal enzymes. C5a as a chemoattractant brings in neutrophils. Serum complement is reduced as it is used up in this process.In the diagram above, antigen-antibody complexes are circulating and becoming trapped beneath the basement membrane of a small blood vessel, setting off the complement cascade and generating components that attract PMN's to generate an ongoing inflammatory response.Immune complexes can be deposited systemically or locallySystemic immune complex disease: Ag-Ab complexes form in the circulatory system and are deposited in tissues, typically near basement membranes in places such as blood vessels, glomeruli, skin, joints, pleura, and pericardium. Larger immune complexes are quickly phagocytized by macrophages and removed, but small to intermediate complexes formed with antigen excess may escape removal leading to:GlomerulonephritisSerum sicknessVasculitisLocal immune complex disease: Also called an "Arthus" reaction, it occurs with local injection of the antigen and leads to focal vasculitis. This kind of immune reaction also plays a role in the development of hypersensitivity pneumonitis (so-called "farmer's lung"). +Type III Hypersensitivity +This reaction is mediated by immune (Ag-Ab) complexes which promote tissue damage primarily through complement activation (alternate pathway). C3b as an opsonin attracts neutrophils, which then release lysosomal enzymes. C5a as a chemoattractant brings in neutrophils. Serum complement is reduced as it is used up in this process. +In the diagram above, antigen-antibody complexes are circulating and becoming trapped beneath the basement membrane of a small blood vessel, setting off the complement cascade and generating components that attract PMN's to generate an ongoing inflammatory response. +Immune complexes can be deposited systemically or locally +Systemic immune complex disease: Ag-Ab complexes form in the circulatory system and are deposited in tissues, typically near basement membranes in places such as blood vessels, glomeruli, skin, joints, pleura, and pericardium. Larger immune complexes are quickly phagocytized by macrophages and removed, but small to intermediate complexes formed with antigen excess may escape removal leading to: +Glomerulonephritis +Local immune complex disease: Also called an "Arthus" reaction, it occurs with local injection of the antigen and leads to focal vasculitis. This kind of immune reaction also plays a role in the development of hypersensitivity pneumonitis (so-called "farmer's lung"). +## 7. Type 3: Immune complex deposits (antibody to C3), skin, patient with SLE, fluorescence microscopy {#item-7} +![](../../images/immunopathology_81460e14.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +If immunofluorescence microscopy using an antibody to complement or immunoglobulin is performed, then one can see the brightly fluorescing band along the dermal epidermal junction that indicates immune complex deposits are present. A variety of immunoglobulins can be present, usually IgG, and the immune complexes trigger the "classic" complement cascade so that components such as C3 are present. +## 8. Type 3: Immune complex deposits with lupus nephritis (antibody to IgG), fluorescence microscopy {#item-8} +![](../../images/immunopathology_831da177.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +If immunofluorescence is performed, here with antibody to IgG, then a granular pattern of immunofluorescence is seen, indicative of deposition of immune complexes in the basement membranes of the glomerular capillary loops. [Image contributed by Elizabeth Hammond, MD, University of Utah] +## 9. Type 4 Hypersensitivity: Review {#item-9} +![](../../images/immunopathology_cd3f6530.gif) + +![](../../images/atherosclerosis_d5033905.gif) +Type IV HypersensitivityThis reaction is called "delayed hypersensitivity" because it is mediated by sensitized CD4+ T lymphocytes which process antigens in association with class II HLA molecules and release lymphokines. The lymphokines promote a reaction (especially mediated through macrophages) beginning in hours but reaching a peak in 2 to 3 days.This diagram above illustrates a sequence of events in granuloma formation in response toMycobacterium tuberculosis(MTB). The key cell in the process is the epithelioid macrophage.Hypersensitivity reactions with this mode of action include:Granulomatous diseases (mycobacteria, fungi)Tuberculin skin reactionsTransplant rejectionContact dermatitisCytotoxic T lymphocyte (CTL) mediated responses: CD8+ T cells are generated and lyse specific cells. Class I HLA molecules play a role. Reactions with this mode include:Neoplastic cell lysisTransplant rejectionVirus-infected cell lysis +Type IV Hypersensitivity +This reaction is called "delayed hypersensitivity" because it is mediated by sensitized CD4+ T lymphocytes which process antigens in association with class II HLA molecules and release lymphokines. The lymphokines promote a reaction (especially mediated through macrophages) beginning in hours but reaching a peak in 2 to 3 days. +This diagram above illustrates a sequence of events in granuloma formation in response toMycobacterium tuberculosis(MTB). The key cell in the process is the epithelioid macrophage. +Granulomatous diseases (mycobacteria, fungi) +Tuberculin skin reactions +Contact dermatitis +Cytotoxic T lymphocyte (CTL) mediated responses: CD8+ T cells are generated and lyse specific cells. Class I HLA molecules play a role. Reactions with this mode include: +Neoplastic cell lysis +Virus-infected cell lysis +## 10. Type 4: Contact dermatitis, skin, gross {#item-10} +![](../../images/immunopathology_d6f88dce.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is contact dermatitis, a form of type IV hypersensitivity in which pre-sensitized lymphocytes led to this inflammatory reaction a couple of days after contact with the offending plant material. Antigens such as those in poison oak and poison ivy are most often responsible for this appearance. +## 11. Autoimmune Diseases: Review {#item-11} + +![](../../images/atherosclerosis_d5033905.gif) +Autoimmune Diseases"The fancier the plumbing, the easier it is to stop up the drain" -- The human immune system is very complex and, hence, there are numerous ways it can malfunction. There are a number of diseases that can result, and many of these have similarities. It is sometimes difficult to separate them. They are also often called "connective tissue" disorders because many of them are manifested in a variety of tissues.Hypersensitivity reactions involved in autoimmunity are primarily types II and III, though type IV reactions can also be present.Mechanisms proposed for development of autoimmunity include:Bypass of CD4+ T-cell tolerance of "self" antigens by:complex of antigen with a hapten (such as a drug or infectious agent) or infectious degradation of an antigencross-reaction with a hapten on an infectious agent that is similar to tissue proteins--classic for poststreptoccocal glomerulonephritis and rheumatic heart diseasedirect activation of B-cells via bacterial endotoxin and via Epstein-Barr virus receptors on B-cellsIdiotype bypass through ligand mimicry, as seen in antireceptor antibody mediated disease, and cross-reactivity with infectious agents:T-suppressor/helper imbalanceemergence of a sequestered antigen through tissue trauma or inflammatory destruction. Examples include: lens crystalline of eye, spermatozoa in testis, and myelin in CNSAntinuclear AntibodiesMany autoimmune diseases have serologic evidence for antibodies directed at components of "self" cell nuclei. Though these antibodies may not be the direct cause of, or evidence for, tissue injury, they are very useful for diagnosis and categorization of autoimmune diseases. The types include:ANA (antinuclear antibody): seen in many autoimmune diseases and not diagnostic of any. In general, the higher the titer, the worse the disease. There are some characteristic fluorescent staining patterns for ANA:homogenous (diffuse) - not very specific for anythingrim - may be indicative of anti-double stranded DNA, seen in SLEspeckled - indicative of antibody to extractable nuclear antigens, often seen in MCTDnucleolar - antibody to nucleolar RNA, seen often in PSScentromere - antibody to centromeric protein, seen in CREST syndromeAutoantibody PanelsThough indirect immunofluorescence is a reference method to detect autoantibides, methods using enzyme immunoassay can be utilized that are faster and less prone to interpretive variables. For general screening for a systemic autoimmune disease, the venerable antinuclear antibody (ANA) test is employed, but for more specific classification of autoimmune conditions, a panel of autoantibodies is obtained. A titer or a numeric value may be reported for each autoantibody.The autoantibodies called "extractable nuclear antigens" (ENA) are so named because they represent antigens that can be extracted from the cell nucleus with saline. Such antibodies include: SS-A, SS-B, U1-RNP, Scl-70, Jo-1, and Sm.Though no autoantibody is completely sensitive or specific for a particular autoimmune disease, some of the strongest associations include:Anti-double stranded DNA (native DNA antibody): SLEAnti-Smith: SLEanti-histone: drug-induced SLEanti SS-A and anti SS-B: Sjogren's syndromeanti DNA-topoisomerase I (Scl-70): PSSanti-histidyl-tRNA synthetase (Jo-1): polymyositisanti-RNP (ribonucleoprotein): MCTDanti-phospholipid antibody (anti-cardiolipin antibody): SLE and others +Autoimmune Diseases +"The fancier the plumbing, the easier it is to stop up the drain" -- The human immune system is very complex and, hence, there are numerous ways it can malfunction. There are a number of diseases that can result, and many of these have similarities. It is sometimes difficult to separate them. They are also often called "connective tissue" disorders because many of them are manifested in a variety of tissues. +Hypersensitivity reactions involved in autoimmunity are primarily types II and III, though type IV reactions can also be present. +Mechanisms proposed for development of autoimmunity include: +Bypass of CD4+ T-cell tolerance of "self" antigens by: +complex of antigen with a hapten (such as a drug or infectious agent) or infectious degradation of an antigen +cross-reaction with a hapten on an infectious agent that is similar to tissue proteins--classic for poststreptoccocal glomerulonephritis and rheumatic heart disease +direct activation of B-cells via bacterial endotoxin and via Epstein-Barr virus receptors on B-cells +Idiotype bypass through ligand mimicry, as seen in antireceptor antibody mediated disease, and cross-reactivity with infectious agents: +T-suppressor/helper imbalance +emergence of a sequestered antigen through tissue trauma or inflammatory destruction. Examples include: lens crystalline of eye, spermatozoa in testis, and myelin in CNS +Antinuclear Antibodies +Many autoimmune diseases have serologic evidence for antibodies directed at components of "self" cell nuclei. Though these antibodies may not be the direct cause of, or evidence for, tissue injury, they are very useful for diagnosis and categorization of autoimmune diseases. The types include: +ANA (antinuclear antibody): seen in many autoimmune diseases and not diagnostic of any. In general, the higher the titer, the worse the disease. There are some characteristic fluorescent staining patterns for ANA: +homogenous (diffuse) - not very specific for anything +rim - may be indicative of anti-double stranded DNA, seen in SLE +speckled - indicative of antibody to extractable nuclear antigens, often seen in MCTD +nucleolar - antibody to nucleolar RNA, seen often in PSS +centromere - antibody to centromeric protein, seen in CREST syndrome +Autoantibody Panels +Though indirect immunofluorescence is a reference method to detect autoantibides, methods using enzyme immunoassay can be utilized that are faster and less prone to interpretive variables. For general screening for a systemic autoimmune disease, the venerable antinuclear antibody (ANA) test is employed, but for more specific classification of autoimmune conditions, a panel of autoantibodies is obtained. A titer or a numeric value may be reported for each autoantibody. +The autoantibodies called "extractable nuclear antigens" (ENA) are so named because they represent antigens that can be extracted from the cell nucleus with saline. Such antibodies include: SS-A, SS-B, U1-RNP, Scl-70, Jo-1, and Sm. +Though no autoantibody is completely sensitive or specific for a particular autoimmune disease, some of the strongest associations include: +Anti-double stranded DNA (native DNA antibody): SLE +Anti-Smith: SLE +anti-histone: drug-induced SLE +anti SS-A and anti SS-B: Sjogren's syndrome +anti DNA-topoisomerase I (Scl-70): PSS +anti-histidyl-tRNA synthetase (Jo-1): polymyositis +anti-RNP (ribonucleoprotein): MCTD +anti-phospholipid antibody (anti-cardiolipin antibody): SLE and others +## 12. Antinuclear antibody test, homogenous +pattern, fluorescence microscopy {#item-12} +![](../../images/patternfluorescencemicroscopy{#item-12}.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Screening for autoimmune diseases is often performed with the antinuclear antibody (ANA) test in which patient serum is incubated with a tissue substrate to which any autoantibodies to nuclear antigens will bind. Then, a fluorosceinated antibody is added and the tissue is observed under fluorescence microscopy to see if staining is present. Seen here is the typical "homogenous" pattern of nuclear staining of a positive ANA. +## 13. Antinuclear antibody test, homogenous +pattern, fluorescence microscopy {#item-13} +![](../../images/patternfluorescencemicroscopy{#item-13}.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is another positive ANA in which the substrate cells are a human cell line known as Hep2. A positive ANA can be reported with a titer, which gives an indication of the strength of the immune response. The titer is simply the highest dilution of patient serum at which the test is still positive. The test is typically reported as positive at greater than 1:16 or 1:20 (depending upon the laboratory) to be positive at all. In general, the higher the titer, the more likely a serious autoimmune disease is present. Thus, a 1:40 result might not mean much, but a 1:1012 certainly should not be ignored. A negative ANA, however, does not exclude a diagnosis of an autoimmune disease. +## 14. Antinuclear antibody test, rim pattern, +fluorescence microscopy {#item-14} +![](../../images/fluorescencemicroscopy{#item-14}.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Sometimes when performing the ANA test, the substrate cells demonstrate particular patterns of staining. This is the so-called "rim" pattern that is more characteristic of systemic lupus erythematosus (SLE) than other autoimmune diseases. +## 15. Antinuclear antibody test, double stranded +DNA, fluorescence microscopy {#item-15} +![](../../images/DNAfluorescencemicroscopy{#item-15}.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +These areCrithidiaorganisms, whose sole purpose for existence is to serve as a substrate for the double stranded DNA test. Here the little critters have brightly fluorescing kinetoplasts indicative of a positive test. A positive double stranded DNA test strongly suggests a diagnosis of SLE. +## 16. Antinuclear antibody test, speckled pattern, +fluorescence microscopy {#item-16} +![](../../images/fluorescencemicroscopy{#item-16}.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is the so-called "speckled" pattern of antinuclear antibody test staining which is more characteristic of the presence of autoantibodies to extractable nuclear antigens (ENA), particularly to ribonucleoprotein. This pattern is not very specific, but may be seen with an entity called "mixed connective tissue disease" (MCTD) which is an "overlap" condition that is a mix among SLE, scleroderma, and polymyositis features, but without serious renal or pulmonary disease. The autoimmune diseases are very hard to classify, even for the experts. +## 17. Antinuclear antibody test, nucleolar pattern, +fluorescence microscopy {#item-17} +![](../../images/fluorescencemicroscopy{#item-17}.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is the so-called "nucleolar pattern" of staining in which the bright fluorescence is seen within the nucleoli of the Hep2 cells. This pattern is more suggestive of progressive systemic sclerosis (scleroderma). +## 18. Antinuclear antibody test, nucleolar pattern, +fluorescence microscopy {#item-18} +![](../../images/fluorescencemicroscopy{#item-18}.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is another nucleolar pattern of staining with the ANA test that is more reminiscent of a view from the Hubble space telescope (before the repair). +## 19. LE cell preparation, microscopic {#item-19} +![](../../images/immunopathology_89b8f26e.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is the famous "LE cell" test which has value only in demonstrating how the concept of autoantibodies work. Thepink blobsare denatured nuclei. Here are two, with one seen being phagocytozed in the center by a PMN. This test is not nearly as sensitive as the ANA which has supplanted the LE cell test. Therefore, NEVER order an LE cell test. [Image contributed by Elizabeth Hammond, MD, University of Utah] +## 20. SLE: Review {#item-20} + +![](../../images/atherosclerosis_d5033905.gif) +Systemic Lupus Erythematosus (SLE)The manifestations are protean, and there is no characteristic or pathognomonic finding. Instead, this disease is diagnosed by finding suggestive serologic and clinical findings. Findings may include:Skin rash - malar or discoidSensitivity to light (photodermatitis)Serositis - inflammation of serosal surfaces along with effusionsGlomerulonephritis - the worst problem with SLECytopenias - anemia, leukopenia, thrombocytopeniaAntinuclear antibody - rim pattern, anti double stranded-DNA and anti-Smith autoantibodies are most specific for SLEArthralgias, myalgiasVasculitis - anywhere: CNS, skin, kidney, etcDecreased serum complement - especially C1qThrombosis - in arteries or veinsGenetic factors: tends to run in families; association with HLA Dr-2 and Dr-3; more common in young women (especially African-American).Drugs can produce "drug-induced" SLE: list includes procainamide, hydralazine, isoniazid, d-penicillamine.Discoid lupus erythematosus (DLE): a benign disease with skin involvement; ANA positive in only a third (but some of these go on to SLE).Mixed Connective Tissue Disease (MCTD)A wastebasket category for patients who do not clearly fit into other categories. There are features similar to SLE, scleroderma, and polymyositis. Most patients are middle aged females. Characteristic feature is a speckled ANA pattern. +Systemic Lupus Erythematosus (SLE) +The manifestations are protean, and there is no characteristic or pathognomonic finding. Instead, this disease is diagnosed by finding suggestive serologic and clinical findings. Findings may include: +Skin rash - malar or discoid +Sensitivity to light (photodermatitis) +Serositis - inflammation of serosal surfaces along with effusions +Glomerulonephritis - the worst problem with SLE +Cytopenias - anemia, leukopenia, thrombocytopenia +Antinuclear antibody - rim pattern, anti double stranded-DNA and anti-Smith autoantibodies are most specific for SLE +Arthralgias, myalgias +Vasculitis - anywhere: CNS, skin, kidney, etc +Decreased serum complement - especially C1q +Thrombosis - in arteries or veins +Genetic factors: tends to run in families; association with HLA Dr-2 and Dr-3; more common in young women (especially African-American). +Drugs can produce "drug-induced" SLE: list includes procainamide, hydralazine, isoniazid, d-penicillamine. +Discoid lupus erythematosus (DLE): a benign disease with skin involvement; ANA positive in only a third (but some of these go on to SLE). +Mixed Connective Tissue Disease (MCTD) +A wastebasket category for patients who do not clearly fit into other categories. There are features similar to SLE, scleroderma, and polymyositis. Most patients are middle aged females. Characteristic feature is a speckled ANA pattern. +## 21. Malar ("butterfly") rash, patient with SLE, gross {#item-21} +![](../../images/immunopathology_f1b1c36a.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This young woman has a malar rash (the so-called "butterfly" rash because of the shape across the cheeks). Such a rash suggests lupus. Discoid lupus erythematosus (DLE) involves mainly just the skin and is, therefore, relatively benign compared to systemic lupus erythematosus (SLE). In either case, sunlight exposure accentuates this erythematous rash ("photosensitivity"). A small number (5 to 10%) of DLE patients go on to develop SLE (usually the DLE patients with a positive ANA). [Image contributed by Elizabeth Hammond, MD, University of Utah] +## 22. Malar ("butterfly") rash, patient with SLE, gross {#item-22} +![](../../images/immunopathology_25d2e044.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is a more subtle malar rash. Such a rash is more typical for lupus than other autoimmune diseasease, but is not entirely specific for it. [Image contributed by Elizabeth Hammond, MD, University of Utah] +## 23. Vasculitis, skin, patient with SLE, microscopic {#item-23} +![](../../images/immunopathology_3be3c217.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Histologically, the skin of a patient with SLE may demonstrate a vasculitis and dermal chronic inflammatory infiltrates, as seen here. Vasculitis with autoimmune disease (often related to deposition of antigen-antibody complexes) can occur in many different organs and can lead to the often confusing signs and symptoms of patients with rheumatic diseases. [Image contributed by Elizabeth Hammond, MD, University of Utah] +## 24. Vasculitis with marked inflammation, skin, patient with SLE, microscopic {#item-24} +![](../../images/immunopathology_ed4e91d0.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is a more severe inflammatory skin infiltrate in the upper dermis of a patient with SLE in which the basal layer of epidermis is undergoing vacuolization and dissolution, and there is purpura with RBCs extravasated into the upper dermis (which are the reasons for the rash). [Image contributed by Elizabeth Hammond, MD, University of Utah] +## 25. Immune complex deposits (antibody to IgG), skin, patient with SLE, fluorescence microscopy {#item-25} +![](../../images/immunopathology_107a2058.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is another immunofluorescence staining pattern with antibody to IgG showing evidence for immune complexes at the dermal-epidermal junction. If such a pattern is seen only in skin involved by a rash, then the pattern is more characteristic for DLE, but if this pattern appears even in skin uninvolved by a rash, then SLE may underlie this phenomenon. +## 26. Antiphospholipid syndrome with thrombosis in dermal vessel, microscopic {#item-26} +![](../../images/immunopathology_db869254.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +There isvascular thrombosisin the dermis of the skin in this patient with antiphospholipid syndrome (APS). This syndrome results from presence of autoantibodies directed against anionic phospholipids, such as cardiolipin. This syndrome can occur in patients with SLE, and the antibody interferes with coagulation assays, giving it the name "lupus anticoagulant." However, in vivo, patients have a hypercoagulable state with recurrent arterial and venous thromboses. In preganancy, APS can lead to fetal loss. +## 27. Periarteriolar fibrosis, spleen, patient with SLE, microscopic {#item-27} +![](../../images/immunopathology_f0bdccb3.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The periarteriolar fibrosis ("onion skinning") seen in the spleen in patients with SLE at autopsy is quite striking, though of no major clinical consequence. This results from vasculitis. +## 28. Lupus nephritis, kidney, microscopic {#item-28} +![](../../images/immunopathology_9a1138c6.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +One of the feared complications of the autoimmune diseases is renal failure. This is most likely to occur with SLE and the diffuse form of scleroderma. Here is a glomerulus in which the capillary loops are markedlypink and thickenedsuch that capillary lumens are hard to see. This is characteristic for lupus nephritis. +## 29. Lupus nephritis, kidney, microscopic {#item-29} +![](../../images/immunopathology_56a28bc3.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is a glomerulus with thickened pink capillary loops, the so-called"wire loops", in a patient with lupus nephritis. The surrounding renal tubules are unremarkable. +## 30. Immune complex deposits with lupus nephritis (antibody to C1q), fluorescence microscopy {#item-30} +![](../../images/immunopathology_ce025a3f.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is another granular pattern of immunofluorescence in the glomerulus, this time with antibody to C1q complement, which is more specific for SLE. [Image contributed by Elizabeth Hammond, MD, University of Utah] +## 31. Lupus nephritis, electron micrograph {#item-31} +![](../../images/immunopathology_82b5e6c0.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The thickened basement membrane (arrow) that results from immune complex deposition in the glomerular capillary loop is prominent in this electron micrograph. The dark immune deposits are located mainly in a subendothelial position. +## 32. Lupus nephritis, electron micrograph {#item-32} +![](../../images/immunopathology_ffd74f0a.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The electron dense deposits by electron microscopy at high magnification are seen here. [Image contributed by Elizabeth Hammond, MD, University of Utah] +## 33. Systemic Sclerosis: Review {#item-33} + +![](../../images/atherosclerosis_d5033905.gif) +Scleroderma (Progressive Systemic Sclerosis, PSS)Characterized by excessive fibrosis in a variety of tissues from collagen deposition by activated fibroblasts. About 75% of cases are in women, mostly middle aged. Patterns of disease include:Limited scleroderm, or CREST syndrome: the benign form of PSS, serologically suggested by the presence of anti-centromere antibodyC = Calcinosis in skin and elsewhereR = Raynaud's phenomenon, sensitivity to coldE = Esophageal dysmotility from submucosal fibrosisS = Sclerodactyly from dermal fibrosisT = TelangiectasiasDiffuse scleroderma: the worst form of PSS; Scl-70 (anti-DNA topoisomerase I) antibody shows specificity for this form. It may include all of the findings with CREST, but additionally has renal findings: arterial intimal thickening and proliferation (hyperplastic arteriolosclerosis) leading to hypertensive emergency (malignant hypertension) when systolic pressure is ≥180 and/or diastolic pressure ≥120 mmHg along with signs of acute or ongoing end-organ damage with arterial fibrinoid necrosis, thrombosis, and renal infarction. Half of diffuse PSS patients die from renal disease. The lungs in this form of scleroderma may have diffuse alveolar fibrosis leading to honeycomb fibrosisMorphea: this is skin fibrosis only +Scleroderma (Progressive Systemic Sclerosis, PSS) +Characterized by excessive fibrosis in a variety of tissues from collagen deposition by activated fibroblasts. About 75% of cases are in women, mostly middle aged. Patterns of disease include: +Limited scleroderm, or CREST syndrome: the benign form of PSS, serologically suggested by the presence of anti-centromere antibody +C = Calcinosis in skin and elsewhere +R = Raynaud's phenomenon, sensitivity to cold +E = Esophageal dysmotility from submucosal fibrosis +S = Sclerodactyly from dermal fibrosis +T = Telangiectasias +Diffuse scleroderma: the worst form of PSS; Scl-70 (anti-DNA topoisomerase I) antibody shows specificity for this form. It may include all of the findings with CREST, but additionally has renal findings: arterial intimal thickening and proliferation (hyperplastic arteriolosclerosis) leading to hypertensive emergency (malignant hypertension) when systolic pressure is ≥180 and/or diastolic pressure ≥120 mmHg along with signs of acute or ongoing end-organ damage with arterial fibrinoid necrosis, thrombosis, and renal infarction. Half of diffuse PSS patients die from renal disease. The lungs in this form of scleroderma may have diffuse alveolar fibrosis leading to honeycomb fibrosis +Morphea: this is skin fibrosis only +## 34. Sclerodactyly, skin, patient with scleroderma, gross {#item-34} +![](../../images/immunopathology_99baf18b.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is a patient with the taut and shiny skin typical of sclerodactyly. The skin becomes inelastic and it is hard to move the fingers. If sclerodactyly is seen along with calcinosis, Raynaud phenomenon, esophageal dysmotility, and telangietasias, then the best diagnosis is CREST syndrome ("limited" scleroderma). [Image contributed by Elizabeth Hammond, MD, University of Utah] +## 35. Sclerodactyly, skin, patient with scleroderma, gross {#item-35} +![](../../images/immunopathology_66f0d300.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is a closer view of the taut, shiny, inelastic skin with sclerodactyly. Note also the cheilosis at the corners of the mouth from riboflavin deficiency as a result of the malabsorbtion that can occur with scleroderma. +## 36. Sclerodactyly, skin, patient with scleroderma, low power microscopic {#item-36} +![](../../images/immunopathology_35ff623e.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +At low magnification, there is a greater amount and depth of dermal collagen, leading to the decrease in elasticity. Though scleroderma (systemic sclerosis) is an autoimmune disease, the main microscopic feature is fibrosis, and chronic inflammatory cell infiltrates are sparse, unlike SLE. +## 37. Sclerodactyly, skin, patient with scleroderma, high power microscopic {#item-37} +![](../../images/immunopathology_5f0c2a72.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +At high magnification, the dermis is expanded by dense collagenous fibrosis in a patient with systemic sclerosis. Immunofluorescence staining of the skin is not helpful with scleroderma, since immune complex deposition is not a prominent feature of this disease. +## 38. Raynaud phenomenon with skin necrosis in patient with CREST syndrome, gross {#item-38} +![](../../images/immunopathology_70c47033.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +A serious consequence of the "R" in the CREST syndrome (limited scleroderma) is seen here. The fingertips are blackened and additional portions of the hand purplish with early gangrenous necrosis from vasospasm with the Raynaud phenomenon. +## 39. Gastrointestinal fibrosis, patient with scleroderma, Trichrome stain, microscopic {#item-39} +![](../../images/immunopathology_f90c7612.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This trichrome stain of the stomach demonstrates intense blue staining in the submucosa from the collagen deposition. Such fibrosis can occur anywhere in the gastrointestinal tract, but is most common in the lower esophagus, leading to the esophageal dysmotility that is characteristic for systemic sclerosis. +## 40. Hyperplastic arteriolosclerosis in kidney, with hypertensive emergency, patient with scleroderma, microscopic {#item-40} +![](../../images/atherosclerosis_701f78a8.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This patient with hyperplastic arteriolosclerosis and a hypertensive emergency (blood pressure 300/150 mm Hg) had renal failure. The underlying condition is diffuse scleroderma. [Image contributed by Elizabeth Hammond, MD, University of Utah] +## 41. Sjogren Syndrome: Review {#item-41} + +![](../../images/atherosclerosis_d5033905.gif) +Sjogren SyndromeCharacterized by dry eyes and dry mouth as a result of lacrimal and salivary gland involvement by lymphocytic infiltration, fibrosis, and destruction mediated by CD4+ cells helping antibody production, of which anti-SS-A and anti-SS-B are the most specific. Most patients are middle to older age women. Lacrimal and salivary gland inflammation of any cause (including Sjogren's) is called Mikulicz's syndrome. +Sjogren Syndrome +Characterized by dry eyes and dry mouth as a result of lacrimal and salivary gland involvement by lymphocytic infiltration, fibrosis, and destruction mediated by CD4+ cells helping antibody production, of which anti-SS-A and anti-SS-B are the most specific. Most patients are middle to older age women. Lacrimal and salivary gland inflammation of any cause (including Sjogren's) is called Mikulicz's syndrome. +## 42. Sjogren syndrome, minor salivary gland, microscopic {#item-42} +![](../../images/immunopathology_fdc01809.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The mononuclear inflammatory infiltrates, interstitial fibrosis, and acinar atrophy of a minor salivary gland in a biopsy of lip is typical for long-standing Sjögren syndrome, an autoimmune disease that involves salivary glands (with xerostomia) and lacrimal glands (with xerophthalmia). Most patients are middle-aged women. The autoantibodies SS-A (Ro) and SS-B (La) have more specificity for Sjögren syndrome than others, though the antinuclear antibody test is positive in over half of cases. +## 43. Polymyositis-Dermatomyositis: Review {#item-43} + +![](../../images/atherosclerosis_d5033905.gif) +Polymyositis-DermatomyositisCharacterized by inflammation of skeletal muscle with weakness. Sometimes it is associated with a skin rash (hence, dermatomyositis). It is seen in ages 40-60, but also in ages 5-15, mostly in women. Some of these patients have Jo-1 antibody. Inflammation in polymyositis is mainly mediated by cytotoxic CD8 cells. In dermatomyositis, mainly antigen-antibody complexes produce a vasculitis in muscle and skin. Some adults (10-20%) develop cancer. +Polymyositis-Dermatomyositis +Characterized by inflammation of skeletal muscle with weakness. Sometimes it is associated with a skin rash (hence, dermatomyositis). It is seen in ages 40-60, but also in ages 5-15, mostly in women. Some of these patients have Jo-1 antibody. Inflammation in polymyositis is mainly mediated by cytotoxic CD8 cells. In dermatomyositis, mainly antigen-antibody complexes produce a vasculitis in muscle and skin. Some adults (10-20%) develop cancer. +## 44. Polymyositis, muscle, microscopic {#item-44} +![](../../images/immunopathology_9a4e1e49.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is another example of polymyositis. Note the degeneration of muscle fibers in the region of inflammation. Of the autoantibodies, anti-Jo1 is probably the most common with this disorder. +## 45. Disorders of T and B cell function: Review {#item-45} + +![](../../images/atherosclerosis_d5033905.gif) +X-Linked AgammaglobulinemiaMutations in the Bruton tyrosine kinase (Btk) gene with failure of pre-B cells to differentiate into functional B cellsNormal numbers of circulating T cells with low to absent B cells, 7 mg/dl but >2 standard deviations below normal) at >4 years of age. Normal numbers of T and B cells but absent IgA-secreting plasma cellsRecurrent sinopulmonary infections and possible bronchiectasis. Atopy with asthma. Gastrointestinal infections withGiardia duodenalis, with mild diarrhea. Autoimmunity possible. Systemic anaphylaxis with blood transfusion due to circulating anti-IgA antibodiesCommon Variable Immunodeficiency (CVID)Multiple abnormalities possible: selective abnormality of T-cell activation, T- and B-cell autoantibodies. Possible failure of B-cell maturation to plasma cells, excessive T-cell suppression, or defective T-helper cell function. May be linked to selective IgA deŢciencyHypogammaglobulinaemia of two or more immunoglobulin isotypes (more often IgG and IgA); recurrent sinopulmonary infections; and impaired functional antibody responses with absent isohemagglutinins, poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (pneumococcus), or both.Normal numbers of T cells are present, but NK cells are decreasedOnset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Mutations in the Bruton tyrosine kinase (Btk) gene with failure of pre-B cells to differentiate into functional B cellsNormal numbers of circulating T cells with low to absent B cells, 7 mg/dl but >2 standard deviations below normal) at >4 years of age. Normal numbers of T and B cells but absent IgA-secreting plasma cellsRecurrent sinopulmonary infections and possible bronchiectasis. Atopy with asthma. Gastrointestinal infections withGiardia duodenalis, with mild diarrhea. Autoimmunity possible. Systemic anaphylaxis with blood transfusion due to circulating anti-IgA antibodiesCommon Variable Immunodeficiency (CVID)Multiple abnormalities possible: selective abnormality of T-cell activation, T- and B-cell autoantibodies. Possible failure of B-cell maturation to plasma cells, excessive T-cell suppression, or defective T-helper cell function. May be linked to selective IgA deŢciencyHypogammaglobulinaemia of two or more immunoglobulin isotypes (more often IgG and IgA); recurrent sinopulmonary infections; and impaired functional antibody responses with absent isohemagglutinins, poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (pneumococcus), or both.Normal numbers of T cells are present, but NK cells are decreasedOnset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Normal numbers of circulating T cells with low to absent B cells, 7 mg/dl but >2 standard deviations below normal) at >4 years of age. Normal numbers of T and B cells but absent IgA-secreting plasma cellsRecurrent sinopulmonary infections and possible bronchiectasis. Atopy with asthma. Gastrointestinal infections withGiardia duodenalis, with mild diarrhea. Autoimmunity possible. Systemic anaphylaxis with blood transfusion due to circulating anti-IgA antibodiesCommon Variable Immunodeficiency (CVID)Multiple abnormalities possible: selective abnormality of T-cell activation, T- and B-cell autoantibodies. Possible failure of B-cell maturation to plasma cells, excessive T-cell suppression, or defective T-helper cell function. May be linked to selective IgA deŢciencyHypogammaglobulinaemia of two or more immunoglobulin isotypes (more often IgG and IgA); recurrent sinopulmonary infections; and impaired functional antibody responses with absent isohemagglutinins, poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (pneumococcus), or both.Normal numbers of T cells are present, but NK cells are decreasedOnset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Recurrent bacterial infections beginning in infancy when passively acquired maternal antibody diminishes. Some affected persons will eventually develop an autoimmune diseaseDiGeorge SyndromeDeletions of chromosome 22q11 with failure of thymic development and lack of functional T cells but normal levels of immunoglobulinAbnormal morphogenesis of 3rd and 4th pharyngeal pouch/arch derivatives: Thymic abnormalities, great vessel and cardiac anomalies, parathyroid hypoplasia or agenesis (with hypocalcemia), and facial anomalies. Lymph nodes have follicles but decreased numbers of T cells in paracortical and mantle zones.Severe and recurrent viral and fungal infections starting in infancySevere Combined Immunodeficiency (SCID)Half of cases are X-linked, with most involving the IL2RG gene encoding for the common gamma chain of interleukin-2, which forms a receptor for many cytokines needed for T-cell development. Half of cases have autosomal recessive mutations, including the adenosine deaminase (ADA) gene, leading to accumulation of purine metabolites toxic to T cellsMarkedly decreased circulating lymphocytes (7 mg/dl but >2 standard deviations below normal) at >4 years of age. Normal numbers of T and B cells but absent IgA-secreting plasma cellsRecurrent sinopulmonary infections and possible bronchiectasis. Atopy with asthma. Gastrointestinal infections withGiardia duodenalis, with mild diarrhea. Autoimmunity possible. Systemic anaphylaxis with blood transfusion due to circulating anti-IgA antibodiesCommon Variable Immunodeficiency (CVID)Multiple abnormalities possible: selective abnormality of T-cell activation, T- and B-cell autoantibodies. Possible failure of B-cell maturation to plasma cells, excessive T-cell suppression, or defective T-helper cell function. May be linked to selective IgA deŢciencyHypogammaglobulinaemia of two or more immunoglobulin isotypes (more often IgG and IgA); recurrent sinopulmonary infections; and impaired functional antibody responses with absent isohemagglutinins, poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (pneumococcus), or both.Normal numbers of T cells are present, but NK cells are decreasedOnset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +DiGeorge SyndromeDeletions of chromosome 22q11 with failure of thymic development and lack of functional T cells but normal levels of immunoglobulinAbnormal morphogenesis of 3rd and 4th pharyngeal pouch/arch derivatives: Thymic abnormalities, great vessel and cardiac anomalies, parathyroid hypoplasia or agenesis (with hypocalcemia), and facial anomalies. Lymph nodes have follicles but decreased numbers of T cells in paracortical and mantle zones.Severe and recurrent viral and fungal infections starting in infancySevere Combined Immunodeficiency (SCID)Half of cases are X-linked, with most involving the IL2RG gene encoding for the common gamma chain of interleukin-2, which forms a receptor for many cytokines needed for T-cell development. Half of cases have autosomal recessive mutations, including the adenosine deaminase (ADA) gene, leading to accumulation of purine metabolites toxic to T cellsMarkedly decreased circulating lymphocytes (7 mg/dl but >2 standard deviations below normal) at >4 years of age. Normal numbers of T and B cells but absent IgA-secreting plasma cellsRecurrent sinopulmonary infections and possible bronchiectasis. Atopy with asthma. Gastrointestinal infections withGiardia duodenalis, with mild diarrhea. Autoimmunity possible. Systemic anaphylaxis with blood transfusion due to circulating anti-IgA antibodiesCommon Variable Immunodeficiency (CVID)Multiple abnormalities possible: selective abnormality of T-cell activation, T- and B-cell autoantibodies. Possible failure of B-cell maturation to plasma cells, excessive T-cell suppression, or defective T-helper cell function. May be linked to selective IgA deŢciencyHypogammaglobulinaemia of two or more immunoglobulin isotypes (more often IgG and IgA); recurrent sinopulmonary infections; and impaired functional antibody responses with absent isohemagglutinins, poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (pneumococcus), or both.Normal numbers of T cells are present, but NK cells are decreasedOnset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Deletions of chromosome 22q11 with failure of thymic development and lack of functional T cells but normal levels of immunoglobulinAbnormal morphogenesis of 3rd and 4th pharyngeal pouch/arch derivatives: Thymic abnormalities, great vessel and cardiac anomalies, parathyroid hypoplasia or agenesis (with hypocalcemia), and facial anomalies. Lymph nodes have follicles but decreased numbers of T cells in paracortical and mantle zones.Severe and recurrent viral and fungal infections starting in infancySevere Combined Immunodeficiency (SCID)Half of cases are X-linked, with most involving the IL2RG gene encoding for the common gamma chain of interleukin-2, which forms a receptor for many cytokines needed for T-cell development. Half of cases have autosomal recessive mutations, including the adenosine deaminase (ADA) gene, leading to accumulation of purine metabolites toxic to T cellsMarkedly decreased circulating lymphocytes (7 mg/dl but >2 standard deviations below normal) at >4 years of age. Normal numbers of T and B cells but absent IgA-secreting plasma cellsRecurrent sinopulmonary infections and possible bronchiectasis. Atopy with asthma. Gastrointestinal infections withGiardia duodenalis, with mild diarrhea. Autoimmunity possible. Systemic anaphylaxis with blood transfusion due to circulating anti-IgA antibodiesCommon Variable Immunodeficiency (CVID)Multiple abnormalities possible: selective abnormality of T-cell activation, T- and B-cell autoantibodies. Possible failure of B-cell maturation to plasma cells, excessive T-cell suppression, or defective T-helper cell function. May be linked to selective IgA deŢciencyHypogammaglobulinaemia of two or more immunoglobulin isotypes (more often IgG and IgA); recurrent sinopulmonary infections; and impaired functional antibody responses with absent isohemagglutinins, poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (pneumococcus), or both.Normal numbers of T cells are present, but NK cells are decreasedOnset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Abnormal morphogenesis of 3rd and 4th pharyngeal pouch/arch derivatives: Thymic abnormalities, great vessel and cardiac anomalies, parathyroid hypoplasia or agenesis (with hypocalcemia), and facial anomalies. Lymph nodes have follicles but decreased numbers of T cells in paracortical and mantle zones.Severe and recurrent viral and fungal infections starting in infancySevere Combined Immunodeficiency (SCID)Half of cases are X-linked, with most involving the IL2RG gene encoding for the common gamma chain of interleukin-2, which forms a receptor for many cytokines needed for T-cell development. Half of cases have autosomal recessive mutations, including the adenosine deaminase (ADA) gene, leading to accumulation of purine metabolites toxic to T cellsMarkedly decreased circulating lymphocytes (7 mg/dl but >2 standard deviations below normal) at >4 years of age. Normal numbers of T and B cells but absent IgA-secreting plasma cellsRecurrent sinopulmonary infections and possible bronchiectasis. Atopy with asthma. Gastrointestinal infections withGiardia duodenalis, with mild diarrhea. Autoimmunity possible. Systemic anaphylaxis with blood transfusion due to circulating anti-IgA antibodiesCommon Variable Immunodeficiency (CVID)Multiple abnormalities possible: selective abnormality of T-cell activation, T- and B-cell autoantibodies. Possible failure of B-cell maturation to plasma cells, excessive T-cell suppression, or defective T-helper cell function. May be linked to selective IgA deŢciencyHypogammaglobulinaemia of two or more immunoglobulin isotypes (more often IgG and IgA); recurrent sinopulmonary infections; and impaired functional antibody responses with absent isohemagglutinins, poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (pneumococcus), or both.Normal numbers of T cells are present, but NK cells are decreasedOnset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Severe and recurrent viral and fungal infections starting in infancySevere Combined Immunodeficiency (SCID)Half of cases are X-linked, with most involving the IL2RG gene encoding for the common gamma chain of interleukin-2, which forms a receptor for many cytokines needed for T-cell development. Half of cases have autosomal recessive mutations, including the adenosine deaminase (ADA) gene, leading to accumulation of purine metabolites toxic to T cellsMarkedly decreased circulating lymphocytes (7 mg/dl but >2 standard deviations below normal) at >4 years of age. Normal numbers of T and B cells but absent IgA-secreting plasma cellsRecurrent sinopulmonary infections and possible bronchiectasis. Atopy with asthma. Gastrointestinal infections withGiardia duodenalis, with mild diarrhea. Autoimmunity possible. Systemic anaphylaxis with blood transfusion due to circulating anti-IgA antibodiesCommon Variable Immunodeficiency (CVID)Multiple abnormalities possible: selective abnormality of T-cell activation, T- and B-cell autoantibodies. Possible failure of B-cell maturation to plasma cells, excessive T-cell suppression, or defective T-helper cell function. May be linked to selective IgA deŢciencyHypogammaglobulinaemia of two or more immunoglobulin isotypes (more often IgG and IgA); recurrent sinopulmonary infections; and impaired functional antibody responses with absent isohemagglutinins, poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (pneumococcus), or both.Normal numbers of T cells are present, but NK cells are decreasedOnset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Severe Combined Immunodeficiency (SCID)Half of cases are X-linked, with most involving the IL2RG gene encoding for the common gamma chain of interleukin-2, which forms a receptor for many cytokines needed for T-cell development. Half of cases have autosomal recessive mutations, including the adenosine deaminase (ADA) gene, leading to accumulation of purine metabolites toxic to T cellsMarkedly decreased circulating lymphocytes (7 mg/dl but >2 standard deviations below normal) at >4 years of age. Normal numbers of T and B cells but absent IgA-secreting plasma cellsRecurrent sinopulmonary infections and possible bronchiectasis. Atopy with asthma. Gastrointestinal infections withGiardia duodenalis, with mild diarrhea. Autoimmunity possible. Systemic anaphylaxis with blood transfusion due to circulating anti-IgA antibodiesCommon Variable Immunodeficiency (CVID)Multiple abnormalities possible: selective abnormality of T-cell activation, T- and B-cell autoantibodies. Possible failure of B-cell maturation to plasma cells, excessive T-cell suppression, or defective T-helper cell function. May be linked to selective IgA deŢciencyHypogammaglobulinaemia of two or more immunoglobulin isotypes (more often IgG and IgA); recurrent sinopulmonary infections; and impaired functional antibody responses with absent isohemagglutinins, poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (pneumococcus), or both.Normal numbers of T cells are present, but NK cells are decreasedOnset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Half of cases are X-linked, with most involving the IL2RG gene encoding for the common gamma chain of interleukin-2, which forms a receptor for many cytokines needed for T-cell development. Half of cases have autosomal recessive mutations, including the adenosine deaminase (ADA) gene, leading to accumulation of purine metabolites toxic to T cellsMarkedly decreased circulating lymphocytes (7 mg/dl but >2 standard deviations below normal) at >4 years of age. Normal numbers of T and B cells but absent IgA-secreting plasma cellsRecurrent sinopulmonary infections and possible bronchiectasis. Atopy with asthma. Gastrointestinal infections withGiardia duodenalis, with mild diarrhea. Autoimmunity possible. Systemic anaphylaxis with blood transfusion due to circulating anti-IgA antibodiesCommon Variable Immunodeficiency (CVID)Multiple abnormalities possible: selective abnormality of T-cell activation, T- and B-cell autoantibodies. Possible failure of B-cell maturation to plasma cells, excessive T-cell suppression, or defective T-helper cell function. May be linked to selective IgA deŢciencyHypogammaglobulinaemia of two or more immunoglobulin isotypes (more often IgG and IgA); recurrent sinopulmonary infections; and impaired functional antibody responses with absent isohemagglutinins, poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (pneumococcus), or both.Normal numbers of T cells are present, but NK cells are decreasedOnset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Markedly decreased circulating lymphocytes (7 mg/dl but >2 standard deviations below normal) at >4 years of age. Normal numbers of T and B cells but absent IgA-secreting plasma cellsRecurrent sinopulmonary infections and possible bronchiectasis. Atopy with asthma. Gastrointestinal infections withGiardia duodenalis, with mild diarrhea. Autoimmunity possible. Systemic anaphylaxis with blood transfusion due to circulating anti-IgA antibodiesCommon Variable Immunodeficiency (CVID)Multiple abnormalities possible: selective abnormality of T-cell activation, T- and B-cell autoantibodies. Possible failure of B-cell maturation to plasma cells, excessive T-cell suppression, or defective T-helper cell function. May be linked to selective IgA deŢciencyHypogammaglobulinaemia of two or more immunoglobulin isotypes (more often IgG and IgA); recurrent sinopulmonary infections; and impaired functional antibody responses with absent isohemagglutinins, poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (pneumococcus), or both.Normal numbers of T cells are present, but NK cells are decreasedOnset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Increased susceptibility to virtually all infectious organisms. Infants develop Candida skin rashes and thrush, persistent diarrhea, severe respiratory tract infections with Pneumocystis jiroveci and Pseudomonas soon after birth, and diarrhea with failure to thrive after 3 months of age. Severe viral infections can occurSelective IgA DeficiencyStem cell defect involving alterations in the transmembrane activator and calcium modulator cyclophilin ligand interactor gene, with failure in final differentiation of IgA-secreting B cells into plasma cells or decreased survival of plasma cellsLack of both circulating IgA (7 mg/dl but >2 standard deviations below normal) at >4 years of age. Normal numbers of T and B cells but absent IgA-secreting plasma cellsRecurrent sinopulmonary infections and possible bronchiectasis. Atopy with asthma. Gastrointestinal infections withGiardia duodenalis, with mild diarrhea. Autoimmunity possible. Systemic anaphylaxis with blood transfusion due to circulating anti-IgA antibodiesCommon Variable Immunodeficiency (CVID)Multiple abnormalities possible: selective abnormality of T-cell activation, T- and B-cell autoantibodies. Possible failure of B-cell maturation to plasma cells, excessive T-cell suppression, or defective T-helper cell function. May be linked to selective IgA deŢciencyHypogammaglobulinaemia of two or more immunoglobulin isotypes (more often IgG and IgA); recurrent sinopulmonary infections; and impaired functional antibody responses with absent isohemagglutinins, poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (pneumococcus), or both.Normal numbers of T cells are present, but NK cells are decreasedOnset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Selective IgA DeficiencyStem cell defect involving alterations in the transmembrane activator and calcium modulator cyclophilin ligand interactor gene, with failure in final differentiation of IgA-secreting B cells into plasma cells or decreased survival of plasma cellsLack of both circulating IgA (7 mg/dl but >2 standard deviations below normal) at >4 years of age. Normal numbers of T and B cells but absent IgA-secreting plasma cellsRecurrent sinopulmonary infections and possible bronchiectasis. Atopy with asthma. Gastrointestinal infections withGiardia duodenalis, with mild diarrhea. Autoimmunity possible. Systemic anaphylaxis with blood transfusion due to circulating anti-IgA antibodiesCommon Variable Immunodeficiency (CVID)Multiple abnormalities possible: selective abnormality of T-cell activation, T- and B-cell autoantibodies. Possible failure of B-cell maturation to plasma cells, excessive T-cell suppression, or defective T-helper cell function. May be linked to selective IgA deŢciencyHypogammaglobulinaemia of two or more immunoglobulin isotypes (more often IgG and IgA); recurrent sinopulmonary infections; and impaired functional antibody responses with absent isohemagglutinins, poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (pneumococcus), or both.Normal numbers of T cells are present, but NK cells are decreasedOnset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Stem cell defect involving alterations in the transmembrane activator and calcium modulator cyclophilin ligand interactor gene, with failure in final differentiation of IgA-secreting B cells into plasma cells or decreased survival of plasma cellsLack of both circulating IgA (7 mg/dl but >2 standard deviations below normal) at >4 years of age. Normal numbers of T and B cells but absent IgA-secreting plasma cellsRecurrent sinopulmonary infections and possible bronchiectasis. Atopy with asthma. Gastrointestinal infections withGiardia duodenalis, with mild diarrhea. Autoimmunity possible. Systemic anaphylaxis with blood transfusion due to circulating anti-IgA antibodiesCommon Variable Immunodeficiency (CVID)Multiple abnormalities possible: selective abnormality of T-cell activation, T- and B-cell autoantibodies. Possible failure of B-cell maturation to plasma cells, excessive T-cell suppression, or defective T-helper cell function. May be linked to selective IgA deŢciencyHypogammaglobulinaemia of two or more immunoglobulin isotypes (more often IgG and IgA); recurrent sinopulmonary infections; and impaired functional antibody responses with absent isohemagglutinins, poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (pneumococcus), or both.Normal numbers of T cells are present, but NK cells are decreasedOnset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Lack of both circulating IgA (7 mg/dl but >2 standard deviations below normal) at >4 years of age. Normal numbers of T and B cells but absent IgA-secreting plasma cellsRecurrent sinopulmonary infections and possible bronchiectasis. Atopy with asthma. Gastrointestinal infections withGiardia duodenalis, with mild diarrhea. Autoimmunity possible. Systemic anaphylaxis with blood transfusion due to circulating anti-IgA antibodiesCommon Variable Immunodeficiency (CVID)Multiple abnormalities possible: selective abnormality of T-cell activation, T- and B-cell autoantibodies. Possible failure of B-cell maturation to plasma cells, excessive T-cell suppression, or defective T-helper cell function. May be linked to selective IgA deŢciencyHypogammaglobulinaemia of two or more immunoglobulin isotypes (more often IgG and IgA); recurrent sinopulmonary infections; and impaired functional antibody responses with absent isohemagglutinins, poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (pneumococcus), or both.Normal numbers of T cells are present, but NK cells are decreasedOnset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Recurrent sinopulmonary infections and possible bronchiectasis. Atopy with asthma. Gastrointestinal infections withGiardia duodenalis, with mild diarrhea. Autoimmunity possible. Systemic anaphylaxis with blood transfusion due to circulating anti-IgA antibodiesCommon Variable Immunodeficiency (CVID)Multiple abnormalities possible: selective abnormality of T-cell activation, T- and B-cell autoantibodies. Possible failure of B-cell maturation to plasma cells, excessive T-cell suppression, or defective T-helper cell function. May be linked to selective IgA deŢciencyHypogammaglobulinaemia of two or more immunoglobulin isotypes (more often IgG and IgA); recurrent sinopulmonary infections; and impaired functional antibody responses with absent isohemagglutinins, poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (pneumococcus), or both.Normal numbers of T cells are present, but NK cells are decreasedOnset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Common Variable Immunodeficiency (CVID)Multiple abnormalities possible: selective abnormality of T-cell activation, T- and B-cell autoantibodies. Possible failure of B-cell maturation to plasma cells, excessive T-cell suppression, or defective T-helper cell function. May be linked to selective IgA deŢciencyHypogammaglobulinaemia of two or more immunoglobulin isotypes (more often IgG and IgA); recurrent sinopulmonary infections; and impaired functional antibody responses with absent isohemagglutinins, poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (pneumococcus), or both.Normal numbers of T cells are present, but NK cells are decreasedOnset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Multiple abnormalities possible: selective abnormality of T-cell activation, T- and B-cell autoantibodies. Possible failure of B-cell maturation to plasma cells, excessive T-cell suppression, or defective T-helper cell function. May be linked to selective IgA deŢciencyHypogammaglobulinaemia of two or more immunoglobulin isotypes (more often IgG and IgA); recurrent sinopulmonary infections; and impaired functional antibody responses with absent isohemagglutinins, poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (pneumococcus), or both.Normal numbers of T cells are present, but NK cells are decreasedOnset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Hypogammaglobulinaemia of two or more immunoglobulin isotypes (more often IgG and IgA); recurrent sinopulmonary infections; and impaired functional antibody responses with absent isohemagglutinins, poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (pneumococcus), or both.Normal numbers of T cells are present, but NK cells are decreasedOnset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Onset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Hyper IgM Syndrome (HIGM)Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropeniaIncreased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Increased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levelsOnset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +Onset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations. +## 46. Disorders of neutrophil function: Review {#item-46} + +![](../../images/atherosclerosis_d5033905.gif) +Chronic Granulomatous Disease (CGD)Mutations in genes coding for phox proteins in the NADPH oxidative killing pathway; X-linked mutation in 60% of cases and more severe than the autosomal recessive forms.Normal numbers of neutrophils but decreased killing of microorganisms ingested by phagocytes, mainly granulocytes; defect in flow cytometry respiratory burst assayBeginning in childhood lymphadenitis, liver abscesses, osteomyelitis, pneumonia, or skin infections with granulomatous inflammation from recurrent infections. Causative agents are catalase positive bacteria including Staphylococcus aureus, Serratia marcescens, Salmonella species, and Burkholderia cepacia, along with fungal Aspergillus. Autoimmunity possible.Chediak-Higashi Syndrome (CHS)Mutations in the CHS1/LYST gene encoding a protein that regulates lysosome-related organelle size and movementAffected cells have enlarged cytoplasmic vesicles including lysosomes, melanosomes (with variable albinism), platelet dense granules (with bleeding), and cytolytic granules; abnormal fusion of lysosomes forms giant granules in peripheral blood granulocytesRecurrent severe bacterial infections and progressive neurologic problems including weakness, ataxia, sensory deficits, and neurodegeneration. Risk for aggressive lymphoproliferative disorder with NK and cytotoxic T cells infiltrating major organsLeukocyte Adhesion Deficiency (type 1)Autosomal recessive mutations in the CD18 gene, encoding the common beta chain of cellular integrins that aid in binding of leukocytes to endothelium prior to diapedesisMarked peripheral blood neutrophilia but absence of suppurative inflammation and poor wound healing in areas of tissue necrosis and ulceration caused by Staphylococcus aureus and gram-negative enteric bacteria, sometimes fungiRecurrent subcutaneous and mucosal infections, septicemia, poor wound healing +Mutations in genes coding for phox proteins in the NADPH oxidative killing pathway; X-linked mutation in 60% of cases and more severe than the autosomal recessive forms.Normal numbers of neutrophils but decreased killing of microorganisms ingested by phagocytes, mainly granulocytes; defect in flow cytometry respiratory burst assayBeginning in childhood lymphadenitis, liver abscesses, osteomyelitis, pneumonia, or skin infections with granulomatous inflammation from recurrent infections. Causative agents are catalase positive bacteria including Staphylococcus aureus, Serratia marcescens, Salmonella species, and Burkholderia cepacia, along with fungal Aspergillus. Autoimmunity possible.Chediak-Higashi Syndrome (CHS)Mutations in the CHS1/LYST gene encoding a protein that regulates lysosome-related organelle size and movementAffected cells have enlarged cytoplasmic vesicles including lysosomes, melanosomes (with variable albinism), platelet dense granules (with bleeding), and cytolytic granules; abnormal fusion of lysosomes forms giant granules in peripheral blood granulocytesRecurrent severe bacterial infections and progressive neurologic problems including weakness, ataxia, sensory deficits, and neurodegeneration. Risk for aggressive lymphoproliferative disorder with NK and cytotoxic T cells infiltrating major organsLeukocyte Adhesion Deficiency (type 1)Autosomal recessive mutations in the CD18 gene, encoding the common beta chain of cellular integrins that aid in binding of leukocytes to endothelium prior to diapedesisMarked peripheral blood neutrophilia but absence of suppurative inflammation and poor wound healing in areas of tissue necrosis and ulceration caused by Staphylococcus aureus and gram-negative enteric bacteria, sometimes fungiRecurrent subcutaneous and mucosal infections, septicemia, poor wound healing +Normal numbers of neutrophils but decreased killing of microorganisms ingested by phagocytes, mainly granulocytes; defect in flow cytometry respiratory burst assayBeginning in childhood lymphadenitis, liver abscesses, osteomyelitis, pneumonia, or skin infections with granulomatous inflammation from recurrent infections. Causative agents are catalase positive bacteria including Staphylococcus aureus, Serratia marcescens, Salmonella species, and Burkholderia cepacia, along with fungal Aspergillus. Autoimmunity possible.Chediak-Higashi Syndrome (CHS)Mutations in the CHS1/LYST gene encoding a protein that regulates lysosome-related organelle size and movementAffected cells have enlarged cytoplasmic vesicles including lysosomes, melanosomes (with variable albinism), platelet dense granules (with bleeding), and cytolytic granules; abnormal fusion of lysosomes forms giant granules in peripheral blood granulocytesRecurrent severe bacterial infections and progressive neurologic problems including weakness, ataxia, sensory deficits, and neurodegeneration. Risk for aggressive lymphoproliferative disorder with NK and cytotoxic T cells infiltrating major organsLeukocyte Adhesion Deficiency (type 1)Autosomal recessive mutations in the CD18 gene, encoding the common beta chain of cellular integrins that aid in binding of leukocytes to endothelium prior to diapedesisMarked peripheral blood neutrophilia but absence of suppurative inflammation and poor wound healing in areas of tissue necrosis and ulceration caused by Staphylococcus aureus and gram-negative enteric bacteria, sometimes fungiRecurrent subcutaneous and mucosal infections, septicemia, poor wound healing +Beginning in childhood lymphadenitis, liver abscesses, osteomyelitis, pneumonia, or skin infections with granulomatous inflammation from recurrent infections. Causative agents are catalase positive bacteria including Staphylococcus aureus, Serratia marcescens, Salmonella species, and Burkholderia cepacia, along with fungal Aspergillus. Autoimmunity possible.Chediak-Higashi Syndrome (CHS)Mutations in the CHS1/LYST gene encoding a protein that regulates lysosome-related organelle size and movementAffected cells have enlarged cytoplasmic vesicles including lysosomes, melanosomes (with variable albinism), platelet dense granules (with bleeding), and cytolytic granules; abnormal fusion of lysosomes forms giant granules in peripheral blood granulocytesRecurrent severe bacterial infections and progressive neurologic problems including weakness, ataxia, sensory deficits, and neurodegeneration. Risk for aggressive lymphoproliferative disorder with NK and cytotoxic T cells infiltrating major organsLeukocyte Adhesion Deficiency (type 1)Autosomal recessive mutations in the CD18 gene, encoding the common beta chain of cellular integrins that aid in binding of leukocytes to endothelium prior to diapedesisMarked peripheral blood neutrophilia but absence of suppurative inflammation and poor wound healing in areas of tissue necrosis and ulceration caused by Staphylococcus aureus and gram-negative enteric bacteria, sometimes fungiRecurrent subcutaneous and mucosal infections, septicemia, poor wound healing +Chediak-Higashi Syndrome (CHS)Mutations in the CHS1/LYST gene encoding a protein that regulates lysosome-related organelle size and movementAffected cells have enlarged cytoplasmic vesicles including lysosomes, melanosomes (with variable albinism), platelet dense granules (with bleeding), and cytolytic granules; abnormal fusion of lysosomes forms giant granules in peripheral blood granulocytesRecurrent severe bacterial infections and progressive neurologic problems including weakness, ataxia, sensory deficits, and neurodegeneration. Risk for aggressive lymphoproliferative disorder with NK and cytotoxic T cells infiltrating major organsLeukocyte Adhesion Deficiency (type 1)Autosomal recessive mutations in the CD18 gene, encoding the common beta chain of cellular integrins that aid in binding of leukocytes to endothelium prior to diapedesisMarked peripheral blood neutrophilia but absence of suppurative inflammation and poor wound healing in areas of tissue necrosis and ulceration caused by Staphylococcus aureus and gram-negative enteric bacteria, sometimes fungiRecurrent subcutaneous and mucosal infections, septicemia, poor wound healing +Mutations in the CHS1/LYST gene encoding a protein that regulates lysosome-related organelle size and movementAffected cells have enlarged cytoplasmic vesicles including lysosomes, melanosomes (with variable albinism), platelet dense granules (with bleeding), and cytolytic granules; abnormal fusion of lysosomes forms giant granules in peripheral blood granulocytesRecurrent severe bacterial infections and progressive neurologic problems including weakness, ataxia, sensory deficits, and neurodegeneration. Risk for aggressive lymphoproliferative disorder with NK and cytotoxic T cells infiltrating major organsLeukocyte Adhesion Deficiency (type 1)Autosomal recessive mutations in the CD18 gene, encoding the common beta chain of cellular integrins that aid in binding of leukocytes to endothelium prior to diapedesisMarked peripheral blood neutrophilia but absence of suppurative inflammation and poor wound healing in areas of tissue necrosis and ulceration caused by Staphylococcus aureus and gram-negative enteric bacteria, sometimes fungiRecurrent subcutaneous and mucosal infections, septicemia, poor wound healing +Affected cells have enlarged cytoplasmic vesicles including lysosomes, melanosomes (with variable albinism), platelet dense granules (with bleeding), and cytolytic granules; abnormal fusion of lysosomes forms giant granules in peripheral blood granulocytesRecurrent severe bacterial infections and progressive neurologic problems including weakness, ataxia, sensory deficits, and neurodegeneration. Risk for aggressive lymphoproliferative disorder with NK and cytotoxic T cells infiltrating major organsLeukocyte Adhesion Deficiency (type 1)Autosomal recessive mutations in the CD18 gene, encoding the common beta chain of cellular integrins that aid in binding of leukocytes to endothelium prior to diapedesisMarked peripheral blood neutrophilia but absence of suppurative inflammation and poor wound healing in areas of tissue necrosis and ulceration caused by Staphylococcus aureus and gram-negative enteric bacteria, sometimes fungiRecurrent subcutaneous and mucosal infections, septicemia, poor wound healing +Recurrent severe bacterial infections and progressive neurologic problems including weakness, ataxia, sensory deficits, and neurodegeneration. Risk for aggressive lymphoproliferative disorder with NK and cytotoxic T cells infiltrating major organsLeukocyte Adhesion Deficiency (type 1)Autosomal recessive mutations in the CD18 gene, encoding the common beta chain of cellular integrins that aid in binding of leukocytes to endothelium prior to diapedesisMarked peripheral blood neutrophilia but absence of suppurative inflammation and poor wound healing in areas of tissue necrosis and ulceration caused by Staphylococcus aureus and gram-negative enteric bacteria, sometimes fungiRecurrent subcutaneous and mucosal infections, septicemia, poor wound healing +Leukocyte Adhesion Deficiency (type 1)Autosomal recessive mutations in the CD18 gene, encoding the common beta chain of cellular integrins that aid in binding of leukocytes to endothelium prior to diapedesisMarked peripheral blood neutrophilia but absence of suppurative inflammation and poor wound healing in areas of tissue necrosis and ulceration caused by Staphylococcus aureus and gram-negative enteric bacteria, sometimes fungiRecurrent subcutaneous and mucosal infections, septicemia, poor wound healing +Autosomal recessive mutations in the CD18 gene, encoding the common beta chain of cellular integrins that aid in binding of leukocytes to endothelium prior to diapedesisMarked peripheral blood neutrophilia but absence of suppurative inflammation and poor wound healing in areas of tissue necrosis and ulceration caused by Staphylococcus aureus and gram-negative enteric bacteria, sometimes fungiRecurrent subcutaneous and mucosal infections, septicemia, poor wound healing +Marked peripheral blood neutrophilia but absence of suppurative inflammation and poor wound healing in areas of tissue necrosis and ulceration caused by Staphylococcus aureus and gram-negative enteric bacteria, sometimes fungiRecurrent subcutaneous and mucosal infections, septicemia, poor wound healing +Recurrent subcutaneous and mucosal infections, septicemia, poor wound healing +## 47. Transplant Rejection: Review {#item-47} + +![](../../images/atherosclerosis_d5033905.gif) +TRANSPLANT REJECTIONImmunologic MechanismsThe HLA system is a key factor in most reactions. Reactions are mediated by either T lymphocytes or by antibody. The major types of hypersensitivity reactions involved are types II and IV.The ABO system, best characterized as the major blood group antigens, is also important because these antigens are expresed on all cells except those in the central nervous system. Thus, matching for ABO compatibility is important for transplantation.T-cell mediated reactions: Can be either CD4+ cells generating delayed hypersensitivity reactions after recognizing foreign HLA class II (DR) antigens or cytotoxic CD8+ cells recognizing foreign HLA class I (A,B, or C) antigens. The donor tissue or donor lymphocytes within the transplanted tissue carry the offending HLA antigens.Antibody mediated reactions: These can be mediated through complement-mediated cytotoxicity, antibody-dependent cytotoxicity (ADCC), or immune complexes.Organ System PathologyRenal transplants: three classic modes of rejection are described. HLA matching for both class I and class II antigens improves survival:Hyperacute rejection: previous sensitization through transfusion, pregnancy, or infections (through HLA cross-reacting bacterial or viral antigens) leads to preformed antibody that causes immediate (minutes to hours) vascular injury via ADCC.Acute rejection: Cellular infiltrates with both CD4+ and CD8+ cells are present. Occurence is sometimes within days, but usually within months (and sometimes years later when immunosuppressive therapy is discontinued). Humoral immunity is also involved in acute rejection, and necrotizing vasculitis occurs; intimal proliferation results. Ag-Ab complexes play a role.Chronic rejection: There is intimal fibrosis with vascular thickening, leading to ischemic changes. Mononuclear infiltrates with prominent plasma cells are present. Both T-cell and humoral mechanisms are involved.Liver transplants: HLA is less important than simple matching of organ size (since most of these are done in children). There are two modes of rejection:Acute rejection: seen within two months, there are mixed inflammatory portal and central vein infiltrates.chronic rejection: at some later time, with continued inflammation, portal fibrosis, arteriolar thickening, and bile ductular necrosis occurs.Heart transplants: HLA is less important than simple matching of organ size. Immunosuppressive therapy is carefully monitored in relationship to signs of rejection seen on endomyocardial biopsy. There are two modes of rejection:Acute cellular rejection: there are lymphocytic infiltrates and possible myocardial fiber necrosis.Acute vascular rejection: immunoglobulin deposition occurs in small arteries and produces a vasculitis.Bone marrow transplants: HLA matching is important. A distinct problem is graft versus host disease (GVHD) which results from the donor lymphocytes attacking the recipient tissues having the offending HLA antigens. Chemotherapy agents used to prepare the patient for marrow transplantation may result in hepatic veno-occlusive disease in the weeks following transplantation. +TRANSPLANT REJECTION +Immunologic Mechanisms +The HLA system is a key factor in most reactions. Reactions are mediated by either T lymphocytes or by antibody. The major types of hypersensitivity reactions involved are types II and IV. +The ABO system, best characterized as the major blood group antigens, is also important because these antigens are expresed on all cells except those in the central nervous system. Thus, matching for ABO compatibility is important for transplantation. +T-cell mediated reactions: Can be either CD4+ cells generating delayed hypersensitivity reactions after recognizing foreign HLA class II (DR) antigens or cytotoxic CD8+ cells recognizing foreign HLA class I (A,B, or C) antigens. The donor tissue or donor lymphocytes within the transplanted tissue carry the offending HLA antigens. +Antibody mediated reactions: These can be mediated through complement-mediated cytotoxicity, antibody-dependent cytotoxicity (ADCC), or immune complexes. +Organ System Pathology +Renal transplants: three classic modes of rejection are described. HLA matching for both class I and class II antigens improves survival: +Hyperacute rejection: previous sensitization through transfusion, pregnancy, or infections (through HLA cross-reacting bacterial or viral antigens) leads to preformed antibody that causes immediate (minutes to hours) vascular injury via ADCC. +Acute rejection: Cellular infiltrates with both CD4+ and CD8+ cells are present. Occurence is sometimes within days, but usually within months (and sometimes years later when immunosuppressive therapy is discontinued). Humoral immunity is also involved in acute rejection, and necrotizing vasculitis occurs; intimal proliferation results. Ag-Ab complexes play a role. +Chronic rejection: There is intimal fibrosis with vascular thickening, leading to ischemic changes. Mononuclear infiltrates with prominent plasma cells are present. Both T-cell and humoral mechanisms are involved. +Liver transplants: HLA is less important than simple matching of organ size (since most of these are done in children). There are two modes of rejection: +Acute rejection: seen within two months, there are mixed inflammatory portal and central vein infiltrates. +chronic rejection: at some later time, with continued inflammation, portal fibrosis, arteriolar thickening, and bile ductular necrosis occurs. +Heart transplants: HLA is less important than simple matching of organ size. Immunosuppressive therapy is carefully monitored in relationship to signs of rejection seen on endomyocardial biopsy. There are two modes of rejection: +Acute cellular rejection: there are lymphocytic infiltrates and possible myocardial fiber necrosis. +Acute vascular rejection: immunoglobulin deposition occurs in small arteries and produces a vasculitis. +Bone marrow transplants: HLA matching is important. A distinct problem is graft versus host disease (GVHD) which results from the donor lymphocytes attacking the recipient tissues having the offending HLA antigens. Chemotherapy agents used to prepare the patient for marrow transplantation may result in hepatic veno-occlusive disease in the weeks following transplantation. +## 48. Chronic vascular rejection following renal transplantation, low power microscopic {#item-48} +![](../../images/immunopathology_a98801dd.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Immunologic disease can also complicate solid organ transplantation. Here is a renal biopsy that demonstrates marked interstitial fibrosis in a patient with chronic vascular rejection. +## 49. Chronic vascular rejection following renal transplantation, high power microscopic {#item-49} +![](../../images/immunopathology_dbf6169d.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +At high magnification, the renal arteries with chronic vascular rejection are markedly thickened and fibrotic. There is interstitial fibrosis and chronic inflammation. Such chronic rejection usually occurs slowly over several months to years following transplantation. This form of rejection, unlike acute cellular rejection, is difficult to treat. +## 50. Acute cellular tubulointerstitial rejection following renal transplantation, medium power microscopic {#item-50} +![](../../images/immunopathology_1496ffed.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is a form of acute renal transplant rejection known as acute cellular tubulointerstitial rejection because most of the inflammation is in the interstitium. The glomerulus seen here is normal, but the tubules are infiltrated by many lymphocytes at the upper right. +## 51. Acute cellular tubulointerstitial rejection following renal transplantation, high power microscopic {#item-51} +![](../../images/immunopathology_f919bf26.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +At high magnification, the lymphocytes and plasma cells are seen around a renal tubule in a renal transplant patient with acute cellular rejection. This type of rejection can occur at any time following transplantation when immunosuppression is diminished. This is treated by administering cyclosporine and other immunosuppressive agents. +## 52. Acute cellular tubulointerstitial rejection following renal transplantation, immune deposits, fluorescence microscopy {#item-52} +![](../../images/immunopathology_853b90e3.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The immunofluorescence pattern with acute tubulointerstitial renal transplant rejection is shown here, in which immune deposits occur between glomeruli in the interstitium. Both type II and type IV immune hypersensitivity reactions contribute to this rejection reaction. +## 53. Acute vascular rejection following heart transplantation, microscopic {#item-53} +![](../../images/immunopathology_81ee58a8.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is acute vascular rejection in a heart transplant. The inflammatory reaction consists mostly of lymphocytes and is seen mainly around small arteries, a vasculitis. Such a reaction can occur when the dose of immunosuppressive drugs is decreased in the months following transplantation. Increasing immunosuppresive therapy in these patients is not as effective as for acute cellular rejection. +## 54. Acute vascular rejection following heart transplantation, immune deposits, fluorescence microscopy {#item-54} +![](../../images/immunopathology_6584ff69.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +By immunofluorescence, antibody to IgG is seen highlighting the vascular walls in this heart with acute vascular rejection. [Image contributed by Elizabeth Hammond, MD, University of Utah] +## 55. Acute cellular rejection following heart transplantation, T-cells stained with CD-3 by immunohistochemical, low power microscopic {#item-55} +![](../../images/immunopathology_4c1dea1a.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +By immunohistochemical staining with antibody to CD3, the T-lymphocytes in the myocardium involved in this acute cellular rejection phenomenon in a heart transplant recipient can be identified here. +## 56. Skin rash with graft versus host disease, gross {#item-56} +![](../../images/cellular_injury_0d75872c.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Besides the icterus (yellow color, or jaundice) in this skin there is a fine scaling rash in this patient following bone marrow transplantation with a 5 out of 6 antigen match. This is an example of graft versus host disease (GVHD) in which donor lymphocytes attack host tissues. +## 57. Graft versus host disease, skin, microscopic {#item-57} +![](../../images/immunopathology_a05943bf.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Microscopically, graft versus host disease (GVHD) is one of the best examples of a process called "apoptosis" or single cell necrosis. There is vacuolization and dissolution of epidermal cells along the basal layer, along with lymphocytes. At the arrow is a rounded pink apoptotic body. +## 58. Graft versus host disease, liver, cholestasis, microscopic {#item-58} +![](../../images/cellular_injury_4a771043.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Graft versus host disease (GVHD) also leads to marked cholestasis in the liver, seen here as large collections of yellow-green bile pigment within the bile canaliculi. +## 59. Graft versus host disease, liver, cholestasis, microscopic {#item-59} +![](../../images/immunopathology_4fcaee6a.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The graft versus host disease (GVHD) here is affecting the liver, and marked by yellow-brown collections of bile within the canaliculi, as well as chronic inflammatory cells within the liver parenchyma. +## 60. Amyloid deposition, myocardium, microscopic {#item-60} +![](../../images/immunopathology_a04bc3b0.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is a peculiar disease known as amyloidosis. Amyloidosis is characterized by slow deposition over years of increasing amounts of an amorphous proteinaceous material in one or more tissues. Seen here in the heart between the darker red myofibers are pale pink amyloid deposits. +## 61. Amyloid deposition, adrenal, Congo red stain, microscopic {#item-61} +![](../../images/immunopathology_0378cc7d.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +When stained with Congo red and observed under polarized light, amyloid has a characteristic"apple green" birefringenceas seen here in deposits around small arteries and within the cortex of the adrenal gland of a patient with multiple myeloma and excessive light chain production (AL amyloid). +## 62. Amyloid deposition, electron micrograph {#item-62} +![](../../images/immunopathology_4557b628.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +By electron microscopy, amyloid is seen to be composed of a "beta-pleated sheet" of fibrils, seen here as irregular grey material. When the amyloid protein is made up of immunoglobulin light chains, then it is "AL amyloid" and when it is derived from serum amyloid-associated protein, then it is "AA amyloid." In terms of the effect upon the organs, "amyloid is amyloid". +## 63. Amyloid deposition, fluorescence microscopy {#item-63} +![](../../images/immunopathology_94e40b63.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is the immunofluorescent appearance of the myocardium with antibody to lambda light chain. Thus, this is "AL amyloid". [Image contributed by Elizabeth Hammond, MD, University of Utah] diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/pathology_\345\212\250\350\204\211\347\262\245\346\240\267\347\241\254\345\214\226\344\270\216\350\241\200\346\240\223\345\275\242\346\210\220_cleaned.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/pathology_\345\212\250\350\204\211\347\262\245\346\240\267\347\241\254\345\214\226\344\270\216\350\241\200\346\240\223\345\275\242\346\210\220_cleaned.txt" new file mode 100644 index 0000000..e72c92b --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/pathology_\345\212\250\350\204\211\347\262\245\346\240\267\347\241\254\345\214\226\344\270\216\350\241\200\346\240\223\345\275\242\346\210\220_cleaned.txt" @@ -0,0 +1,261 @@ +## 1. Normal coronary artery, microscopic {#item-1} +![](../../images/atherosclerosis_c8673a14.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Shown here is the low power microscopic appearance of a normal coronary artery with no atherosclerosis and awidely patent lumenthat can carry as much blood as the myocardium requires. There is no impediment to blood flow. +## 2. Atherosclerosis, mechanisms for development, diagram {#item-2} +![](../../images/atherosclerosis_2763185d.gif) + +![](../../images/atherosclerosis_d5033905.gif) +The risk factors for atherosclerosis are diagrammed here in relation to the mechanisms that favor development of arterial atheroma formation. Atherosclerosis is a potentially reversible process. The process of reversal can be summarized as follows: eat fewer total calories and exercise more. +## 3. Mild coronary atherosclerosis, microscopic {#item-3} +![](../../images/atherosclerosis_70d10449.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is mild coronary atherosclerosis. A few scatteredyellow lipid plaquesare seen on the intimal surface of the opened coronary artery traversing the epicardial surface of a heart. The degree of atherosclerosis here is not significant enough to cause disease, but could be the harbinger of worse atherosclerosis to come. +## 4. Severe calcific coronary atherosclerosis, microscopic {#item-4} +![](../../images/atherosclerosis_f44b223c.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The degree of atherosclerosis is much greater in this coronary artery, and thelumenis narrowed by half. A small area ofcalcificationis seen in the plaque at the right. +## 5. Coronary atherosclerosis, cross sections, gross {#item-5} +![](../../images/atherosclerosis_e7c46186.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +These cross sections of the anterior interventricular (left anterior descending) coronary artery demonstrate more pronounced atherosclerosis with narrowing at the left, which is the proximal portion of this artery. Atherosclerosis is generally worse at the beginning of an artery where turbulence of vascular flow with ongoing endothelial stress and injury is greater. +## 6. Coronary atherosclerosis, plaque with thrombus, microscopic {#item-6} +![](../../images/atherosclerosis_07785207.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is an atheromatous plaque in a coronary artery that shows endothelial denudation with disruption and overlyingthrombusformation at the right. The arterialmediais at the left. Note thecholesterol cleftsand thefoam cellsas part of this atheromatous process. +## 7. Coronary atherosclerosis with thrombosis, microscopic {#item-7} +![](../../images/atherosclerosis_878e7a6a.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is occlusive coronary atherosclerosis. The coronary at the left is narrowed by 60 to 70%. The coronary at the right is even worse with evidence for previous thrombosis with organization of the thrombus and recanalization such that there are three small lumens remaining, one of which contains additional recentthrombus. +## 8. Severe coronary atherosclerosis, gross {#item-8} +![](../../images/atherosclerosis_36041249.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is the gross appearance of severe coronary atherosclerosis, which involves virtually 100% of the surface of this coronary artery. There is extensive calcification, especially at the right where the lumen isnarrowed. +## 9. Coronary atherosclerosis with hemorrhage into plaque, gross {#item-9} +![](../../images/atherosclerosis_88ea8944.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is a coronary artery with atherosclerotic plaques. There is recentinto the plaque. This is one of the complications of atherosclerosis. Such hemorrhage could acutely narrow the lumen and produce an acute coronary syndrome with ischemia and/or infarction of the myocardium. +## 10. Coronary thrombosis, gross {#item-10} +![](../../images/atherosclerosis_ce278ea2.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is the anterior surface of the heart with the anterior interventricular (left anterior descending) coronary artery opened longitudinally. This is coronary thrombosis, one of the complications of atherosclerosis. The occlusivedark red thrombusis seen within the lumen of the coronary artery. This produces an acute coronary syndrome. +## 11. Coronary thrombosis, gross {#item-11} +![](../../images/atherosclerosis_409d3191.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is a closer view of the gross appearnace of a coronary thrombosis. Thethrombusoccludes the lumen and produces ischemia and/or infarction of the myocardium. Atherosclerosis is an ongoing process that takes years to decades for clinically apparent problems to appear. +## 12. Coronary thrombosis, microscopic {#item-12} +![](../../images/atherosclerosis_7224585f.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +A coronarythrombosisis seen microscopically occluding the remaining small lumen of this coronary artery. Such an acute coronary thrombosis is often the antecedent to acute myocardial infarction. +## 13. Acute myocardial infarction, gross {#item-13} +![](../../images/atherosclerosis_38e49445.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The interventricular septum of the heart has been sectioned to reveal an extensive acute myocardial infarction. The dead muscle istan-yellowwith a surroundinghyperemic border. +## 14. Acute myocardial infarction, gross {#item-14} +![](../../images/atherosclerosis_ccd348b9.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This cross section through the heart reveals a large myocardial infarction involving the anterior left ventricular wall and septum. The infarct is beginning to heal, but still has anecrotic center. The ejection fraction from the left ventricle would be significantly reduced. +## 15. Remote myocardial infarction, gross {#item-15} +![](../../images/atherosclerosis_d75ab448.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The tan to white areas of myocardial scarring seen from the endocardial surface here represent a remote healed myocardial infarction. This healed infarct is most prominent over theseptumbut also involves theleft ventricle. +## 16. Left ventricular aneurysm, gross {#item-16} +![](../../images/atherosclerosis_8b759a68.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +There has been a previous extensive transmural myocardial infarction involving the free wall of the left ventricle. Note that the thickness of the myocardial wall isnormalsuperiorly, but inferiorly is only athin fibrous wall. The thinned area represents a ventricular aneurysm that has developed as a consequence of the healed infarct. Such an aneurysm represents non-contractile tissue that reduces stroke volume and strains the remaining myocardium. The stasis of blood in the aneurysm predisposes to mural thrombosis. +## 17. Aorta, lipid streaks, gross {#item-17} +![](../../images/atherosclerosis_35a924bf.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The pale yellowlipid streaksin the aorta are the earliest lesion of atherosclerosis. Almost everyone has them, and by themselves they do not produce disease. They are precursor lesions to more severe atherosclerosis if risk factors for atheroma formation continue. +## 18. Aorta, lipid streaks, gross {#item-18} +![](../../images/atherosclerosis_4f4b011a.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Put down that extra slice of pizza and look carefully at this aorta. The white arrow denotes the most prominent fatty streak in this image, but there are other fatty streaks scattered over the aortic surface. Fatty streaks are the earliest lesions seen with atherosclerosis in arteries. Increased total cholesterol and decreased HDL cholesterol contribute to this process. +## 19. Aortas with mild, moderate, and severe atherosclerosis, gross {#item-19} +![](../../images/atherosclerosis_6112de07.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Three aortas are shown to demonstrate mild, moderate, and severe atherosclerosis from bottom to top. +## 20. Aorta, atheromatous plaque, medium power microscopic {#item-20} +![](../../images/atherosclerosis_d12e065c.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Microscopically, the aortic atheromatous plaque is thicker than the remainingmediaat the right. The plaque contains amorphous pink material with slit-like "cholesterol clefts" of lipid material. There is overlyingrecent hemorrhageat the left. Thrombus may form on top of such a plaque. +## 21. Aorta, atheromatous plaque, high power microscopic {#item-21} +![](../../images/atherosclerosis_f6be4cac.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +At higher magnification, manyfoam cells(macrophages full of lipid material) and acholesterol cleftare seen in this atheromatous plaque. +## 22. Aorta, atheromatous plaque, high power microscopic {#item-22} +![](../../images/atherosclerosis_85c920a2.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Thecholesterol cleftscomposed of lipid, along with a few scatteredfoam cellsderived from macrophages and a few lymphocytes are seen at high magnification in this atheromatous plaque. +## 23. Aorta, atherosclerotic aneurysm, gross {#item-23} +![](../../images/atherosclerosis_a4af5b0b.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Atherosclerosis may weaken the wall of the aorta such that it bulges out to form ananeurysm. An atherosclerotic aortic aneurysm typically occurs in the abdominal portion below the renal arteries, as shown here, but aneurysms can form in the more proximal aorta as well as in branches of the aorta. Aortic aneurysms that get bigger than 5 to 7 cm in diameter are more prone to rupture. +## 24. Atherosclerotic peripheral vascular disease, CT angiography {#item-24} +![](../../images/atherosclerosis_46d93585.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Atherosclerosis may involve peripheral arteries, particularly the leg, starting from the iliac arteries and extending to femoral, popliteal, and lower leg arteries. Shown here with CT angiography is anocclusion of the right popliteal artery. There is runoff into acollateral arterial branch. Complications include reduced exercise tolerance, pain, and ischemic changes that can culminate in gangrenous necrosis. +The ankle-branchial index (ABI) can document peripheral vascular disease and is measured with a manual blood pressure (BP) cuff and a Doppler ultrasound device. With DU the systolic arterial occlusion pressure is measured, first at the level of the brachial artery in the arm, then at the level of the ankle. ABI is the ratio of ankle occlusion pressure to brachial artery occlusion pressure. The ABI should normally be 1.0. An ABI below 0.85 is consistent with PAD.Another measure of peripheral vascular disease that performed along with ABI is pulse-volume recording (PVR) of volume changes that occur with arterial blood flow into the leg. PVR is performed by placing multiple pressure cuffs along the thigh, calf, ankle, and great toes. The cuffs are inflated to 40-60 mm Hg. Changes in the volume in the leg correlate with changes in pressure in the cuff that are recorded via a transducer over time. +The ankle-branchial index (ABI) can document peripheral vascular disease and is measured with a manual blood pressure (BP) cuff and a Doppler ultrasound device. With DU the systolic arterial occlusion pressure is measured, first at the level of the brachial artery in the arm, then at the level of the ankle. ABI is the ratio of ankle occlusion pressure to brachial artery occlusion pressure. The ABI should normally be 1.0. An ABI below 0.85 is consistent with PAD. +Another measure of peripheral vascular disease that performed along with ABI is pulse-volume recording (PVR) of volume changes that occur with arterial blood flow into the leg. PVR is performed by placing multiple pressure cuffs along the thigh, calf, ankle, and great toes. The cuffs are inflated to 40-60 mm Hg. Changes in the volume in the leg correlate with changes in pressure in the cuff that are recorded via a transducer over time. +## 25. Renal hyperplastic arteriolosclerosis, microscopic {#item-25} +![](../../images/atherosclerosis_701f78a8.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is a different kind of arteriosclerosis. This is hyperplastic arteriolosclerosis, which most often appears in the kidney in patients with hypertensive emergency (malignant hypertension) when systolic pressure is ≥180 and/or diastolic pressure ≥120 mmHg along with signs of acute or ongoing end-organ damage. Thearteriolar wallis markedly thickened and thelumenis narrowed. +Arteriosclerosis, or "hardening of the arteries" is a generic term that includes atherosclerosis, arteriolosclerosis, and medial calcific sclerosis. +## 26. Renal arterial fibrinoid necrosis with hypertensive emergency, microscopic {#item-26} +![](../../images/atherosclerosis_4feca92e.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Sometimes the small arteries and arterioles can be damaged so severely in a hypertensive emergency that they demonstratenecrosis with a pink fibrin-like qualitythat gives this process its name--fibrinoid necrosis. +## 27. Renal hyaline arteriolosclerosis with diabetes mellitus, microscopic {#item-27} +![](../../images/atherosclerosis_00d81abf.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is hyaline arteriolosclerosis, which can be seen in patients with diabetes mellitus and with hypertension. This glomerulus stained with PAS showsnodular depositsof amorphous material (nodular glomerulosclerosis). Adjacent to this glomerulus is athickened arteriolewith narrowed lumen from hyaline arteriolosclerosis. +## 28. Monckeberg's medial calcific arteriosclerosis, microscopic {#item-28} +![](../../images/atherosclerosis_da1be293.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is Monckeberg's medial calcific sclerosis, which is the most insignificant form of arteriosclerosis (both atherosclerosis and arteriolosclerosis are definitely significant). Note thepurplish blue calcificationsin the media; note that the lumen is unaffected by this process. Thus, there are usually no real clinical consequences. Remember this process when calcified muscular arteries show up on a radiograph of the pelvic region in an older person. +## 29. GIF animation of pulmonary thromboembolus, diagram {#item-29} +![](../../images/atherosclerosis_10085134.gif) + +![](../../images/atherosclerosis_d5033905.gif) +A pulmonary thromboembolus travels from a large vein in the leg up the inferior vena cava, through the right side of the heart, and to the main pulmonary arteries as they branch. Such thrombi embolize most often from large veins in the legs and pelvis where thrombi may form with stasis and/or inflammation. +## 30. Pulmonary thromboembolus, gross {#item-30} +![](../../images/atherosclerosis_6bd53102.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The main pulmonary trunk and pulmonary arteries to therightand to theleftlung are seen here opened to reveal a large "saddle" pulmonarythromboembolus. Patients with such an embolus will have a high mortality rate. +## 31. Pulmonary thromboembolus, gross {#item-31} +![](../../images/atherosclerosis_d67c4f8c.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is another large pulmonarythromboembolusseen in cross section of this lung. The typical source for such thromboemboli is from large veins in the legs and pelvis.Pulmonary emboli can be classified by size as small, medium, and large. Small ones may be clinically inapparent. Medium-sized ones may not kill the patient, but may lead to pulmonary infarction. Large ones can be life-threatening. Recurrent pulmonary embolization can reduce pulmonary vascular flow and cause pulmonary hypertension. +Here is another large pulmonarythromboembolusseen in cross section of this lung. The typical source for such thromboemboli is from large veins in the legs and pelvis. +Pulmonary emboli can be classified by size as small, medium, and large. Small ones may be clinically inapparent. Medium-sized ones may not kill the patient, but may lead to pulmonary infarction. Large ones can be life-threatening. Recurrent pulmonary embolization can reduce pulmonary vascular flow and cause pulmonary hypertension. +## 32. Pulmonary thromboembolus, gross {#item-32} +![](../../images/atherosclerosis_53798112.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This pulmonarythromboembolusis occluding the main pulmonary artery. Persons who are immobilized for weeks are at greatest risk. The patient can experience sudden onset of shortness of breath. Death may occur within minutes. +## 33. Pulmonary thromboembolus, microscopic {#item-33} +![](../../images/atherosclerosis_c68f89d6.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is the microscopic appearance of a pulmonary embolus (PE) in a major pulmonary artery branch. The layering of the RBC's and the lighter pink fibrin enmeshing leukocytes and platelets occurred in the vein in which the thrombus originally formed. +## 34. Pulmonary thromboembolus, microscopic {#item-34} +![](../../images/atherosclerosis_11f86bb6.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This pulmonary embolus is adherent to thepulmonary arterial wall. If the patient survives, the thromboembolus will organize and, for the most part, be removed. +## 35. Recent thrombus with lines of Zahn, microscopic {#item-35} +![](../../images/atherosclerosis_362b477c.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +These are "lines of Zahn" which are the alternating pale pink bands of platelets with fibrin and red bands of RBC's forming a true thrombus. +## 36. Hemorrhagic pulmonary infarction, gross {#item-36} +![](../../images/atherosclerosis_c196e16a.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Occlusion of main pulmonary arteries can kill the patient suddenly. Occlusion of small pulmonary arteries has no major immediate effect. Occlusion of a medium-sized branch of pulmonary artery can lead to a pulmonaryinfarctionin a person with compromised cardiac or respiratory status. A pulmonary infarct is hemorrhagic because of the dual blood supply: some blood still flows from the non-occluded bronchial arteries which mainly supply blood to interstitium, but do not prevent the infarction. +## 37. Ischemic infarction, bowel, gross {#item-37} +![](../../images/atherosclerosis_f862d15c.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Hemorrhagic infarction may be seen in places where some collateral flow can occur, as in the bowel, shown here at autopsy with marked dark red ischemic small bowel. Ordinarily, it is difficult to infarct the small or large bowel, because of an extensive anastomosing blood supply. Typically, severe compromise of at least 2 of the 3 major arterial supplies (celiac trunk, superior mesenteric, inferior mesenteric) is required for infarction to occur. Such arterial compromise is most likely to occur with severe atherosclerosis (often with diabetes mellitus) and with vasculitis (as with classic polyarteritis nodosa). Of course, cardiac failure with severe hypotension can produce a similar result. +## 38. Ischemic infarction, brain, gross {#item-38} +![](../../images/atherosclerosis_7a71918b.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Infarction of the brain can result from thrombosis, though most cases occur following embolization, involving cerebral arteries, often the circle of Willis. Cerebral infarction typically results in liquefactive necrosis, as shown here with beginning cystic resolution of the infarct. +## 39. Ischemic infarction, myocardium, gross {#item-39} +![](../../images/atherosclerosis_ccd348b9.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Infarction of many internal organs leads to a "pale" infarct from loss of hte blood supply, resulting in coagulative necrosis. Shown here is a myocardial infarction from occlusion of a major coronary artery, here the anterior interventricular (left anterior descending) artery. +## 40. Ischemic infarction, spleen, gross {#item-40} +![](../../images/atherosclerosis_b46a5d74.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Infarction of many internal organs leads to a "pale" infarct with a wedge-shaped gross appearance (conical in 3 dimensions) from occlusion of a branching blood supply. Here aresplenic infarctsin a patient with infective endocarditis. Portions of the vegetations have embolized to the spleen. These infarcts are typical of ischemic infarcts: they are based on the capsule, pale, and wedge-shaped. The remaining splenic parenchyma appears dark red. +## 41. Platelet, electron micrograph {#item-41} +![](../../images/atherosclerosis_1a467782.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +![](../../images/atherosclerosis_0c203cb0.jpg) +Here is an actual electron micrograph of a platelet. Note that this platelet bears a striking resemblance to a chocolate chip cookie (for comparison, chocolate chip cookies are shown below). The chocolate chips are the alpha and dense granules that contain a variety of mediators such as ADP. When activated, platelets release their granules to promote coagulation, change shape, and become sticky to aggregate and plug small vascular holes. +## 42. Hypercoagulable states, table {#item-42} + +![](../../images/atherosclerosis_d5033905.gif) +Antiphospholipid syndromeThere are circulating antibodies that bind plasma proteins with an affinity for phospholipid surfaces, and this can cause thrombosis and in women stillbirth. This syndrome is most often acquired in adulthood, either from an underlying disease or as an idiopathic condition. The two subsets of this syndrome, as defined by laboratory testing, are: lupus anticoagulant (which may or may not be seen with SLE), and anti-cardiolipin antibodyFactor V Leiden mutationThis is the most common inherited form of hypercoagulability. The mutation, which leads to activated protein C resistance, is present in 5% of Caucasians but is rare in persons of African and Asian ancestry. Heterozygotes have a mild risk for thrombosis, but the rare homozygotes have a marked risk. A point mutation leads to impaired inactivation of factor V by activated protein C. Recurrent venous thrombosis can occur, starting even in young persons, and in women stillbirth.Elevated factor VIIIThis condition is as common as factor V Leiden mutation. There may be genetic and environmental factors causing it. Oral contraceptive use increases factor VIII levels. The result is deep venous thrombosis.Malignant neoplasmsNeoplastic cells may elaborate a factor, such as a thromboplastin-like substance, that can increase the risk for thrombosis. This is one form of paraneoplastic syndrome, with the name Trousseau's syndrome. There can be venous (more likely) or arterial thrombosis.Protein C, Protein S, antithrombin III deficienciesThese conditions are autosomal dominant and lead to recurrent venous thrombosis, even starting in young persons. Thrombosis is often spontaneous, without other precipitating events. They can be detected by laboratory testing for the respective coagulation factorSticky platelet syndromeThis is an autosomal dominant disorder that can lead to both arterial and venous thrombosis. Stillbirth may occur in women. Stress is a precipitating event.HomocystinemiaPersons with elevated plasma homocysteine levels not only have increased problems with atherosclerosis, but also arterial and venous thrombosis. Stillbirth may occur in women.Prothrombin mutationThe prothrombin G20210A mutation increases the level and activity of prothrombin that mildly increases the risk for arterial and venous thrombosis. The mutation occurs more often in persons of southern European ancestry.Plasminogen abnormalitiesPlasminogen, which has an anticoagulant effect, can be deficient. The features resemble protein C or S deficiency. Also, tissue plasminogen activator can be deficient. Plasminogen activator inhibitor can be increased.Congenital dysfibrinogenemiaThis rare autosomal dominant disorder may cause either thrombosis or hemorrhage. +There are circulating antibodies that bind plasma proteins with an affinity for phospholipid surfaces, and this can cause thrombosis and in women stillbirth. This syndrome is most often acquired in adulthood, either from an underlying disease or as an idiopathic condition. The two subsets of this syndrome, as defined by laboratory testing, are: lupus anticoagulant (which may or may not be seen with SLE), and anti-cardiolipin antibodyFactor V Leiden mutationThis is the most common inherited form of hypercoagulability. The mutation, which leads to activated protein C resistance, is present in 5% of Caucasians but is rare in persons of African and Asian ancestry. Heterozygotes have a mild risk for thrombosis, but the rare homozygotes have a marked risk. A point mutation leads to impaired inactivation of factor V by activated protein C. Recurrent venous thrombosis can occur, starting even in young persons, and in women stillbirth.Elevated factor VIIIThis condition is as common as factor V Leiden mutation. There may be genetic and environmental factors causing it. Oral contraceptive use increases factor VIII levels. The result is deep venous thrombosis.Malignant neoplasmsNeoplastic cells may elaborate a factor, such as a thromboplastin-like substance, that can increase the risk for thrombosis. This is one form of paraneoplastic syndrome, with the name Trousseau's syndrome. There can be venous (more likely) or arterial thrombosis.Protein C, Protein S, antithrombin III deficienciesThese conditions are autosomal dominant and lead to recurrent venous thrombosis, even starting in young persons. Thrombosis is often spontaneous, without other precipitating events. They can be detected by laboratory testing for the respective coagulation factorSticky platelet syndromeThis is an autosomal dominant disorder that can lead to both arterial and venous thrombosis. Stillbirth may occur in women. Stress is a precipitating event.HomocystinemiaPersons with elevated plasma homocysteine levels not only have increased problems with atherosclerosis, but also arterial and venous thrombosis. Stillbirth may occur in women.Prothrombin mutationThe prothrombin G20210A mutation increases the level and activity of prothrombin that mildly increases the risk for arterial and venous thrombosis. The mutation occurs more often in persons of southern European ancestry.Plasminogen abnormalitiesPlasminogen, which has an anticoagulant effect, can be deficient. The features resemble protein C or S deficiency. Also, tissue plasminogen activator can be deficient. Plasminogen activator inhibitor can be increased.Congenital dysfibrinogenemiaThis rare autosomal dominant disorder may cause either thrombosis or hemorrhage. +Factor V Leiden mutationThis is the most common inherited form of hypercoagulability. The mutation, which leads to activated protein C resistance, is present in 5% of Caucasians but is rare in persons of African and Asian ancestry. Heterozygotes have a mild risk for thrombosis, but the rare homozygotes have a marked risk. A point mutation leads to impaired inactivation of factor V by activated protein C. Recurrent venous thrombosis can occur, starting even in young persons, and in women stillbirth.Elevated factor VIIIThis condition is as common as factor V Leiden mutation. There may be genetic and environmental factors causing it. Oral contraceptive use increases factor VIII levels. The result is deep venous thrombosis.Malignant neoplasmsNeoplastic cells may elaborate a factor, such as a thromboplastin-like substance, that can increase the risk for thrombosis. This is one form of paraneoplastic syndrome, with the name Trousseau's syndrome. There can be venous (more likely) or arterial thrombosis.Protein C, Protein S, antithrombin III deficienciesThese conditions are autosomal dominant and lead to recurrent venous thrombosis, even starting in young persons. Thrombosis is often spontaneous, without other precipitating events. They can be detected by laboratory testing for the respective coagulation factorSticky platelet syndromeThis is an autosomal dominant disorder that can lead to both arterial and venous thrombosis. Stillbirth may occur in women. Stress is a precipitating event.HomocystinemiaPersons with elevated plasma homocysteine levels not only have increased problems with atherosclerosis, but also arterial and venous thrombosis. Stillbirth may occur in women.Prothrombin mutationThe prothrombin G20210A mutation increases the level and activity of prothrombin that mildly increases the risk for arterial and venous thrombosis. The mutation occurs more often in persons of southern European ancestry.Plasminogen abnormalitiesPlasminogen, which has an anticoagulant effect, can be deficient. The features resemble protein C or S deficiency. Also, tissue plasminogen activator can be deficient. Plasminogen activator inhibitor can be increased.Congenital dysfibrinogenemiaThis rare autosomal dominant disorder may cause either thrombosis or hemorrhage. +This is the most common inherited form of hypercoagulability. The mutation, which leads to activated protein C resistance, is present in 5% of Caucasians but is rare in persons of African and Asian ancestry. Heterozygotes have a mild risk for thrombosis, but the rare homozygotes have a marked risk. A point mutation leads to impaired inactivation of factor V by activated protein C. Recurrent venous thrombosis can occur, starting even in young persons, and in women stillbirth.Elevated factor VIIIThis condition is as common as factor V Leiden mutation. There may be genetic and environmental factors causing it. Oral contraceptive use increases factor VIII levels. The result is deep venous thrombosis.Malignant neoplasmsNeoplastic cells may elaborate a factor, such as a thromboplastin-like substance, that can increase the risk for thrombosis. This is one form of paraneoplastic syndrome, with the name Trousseau's syndrome. There can be venous (more likely) or arterial thrombosis.Protein C, Protein S, antithrombin III deficienciesThese conditions are autosomal dominant and lead to recurrent venous thrombosis, even starting in young persons. Thrombosis is often spontaneous, without other precipitating events. They can be detected by laboratory testing for the respective coagulation factorSticky platelet syndromeThis is an autosomal dominant disorder that can lead to both arterial and venous thrombosis. Stillbirth may occur in women. Stress is a precipitating event.HomocystinemiaPersons with elevated plasma homocysteine levels not only have increased problems with atherosclerosis, but also arterial and venous thrombosis. Stillbirth may occur in women.Prothrombin mutationThe prothrombin G20210A mutation increases the level and activity of prothrombin that mildly increases the risk for arterial and venous thrombosis. The mutation occurs more often in persons of southern European ancestry.Plasminogen abnormalitiesPlasminogen, which has an anticoagulant effect, can be deficient. The features resemble protein C or S deficiency. Also, tissue plasminogen activator can be deficient. Plasminogen activator inhibitor can be increased.Congenital dysfibrinogenemiaThis rare autosomal dominant disorder may cause either thrombosis or hemorrhage. +Elevated factor VIIIThis condition is as common as factor V Leiden mutation. There may be genetic and environmental factors causing it. Oral contraceptive use increases factor VIII levels. The result is deep venous thrombosis.Malignant neoplasmsNeoplastic cells may elaborate a factor, such as a thromboplastin-like substance, that can increase the risk for thrombosis. This is one form of paraneoplastic syndrome, with the name Trousseau's syndrome. There can be venous (more likely) or arterial thrombosis.Protein C, Protein S, antithrombin III deficienciesThese conditions are autosomal dominant and lead to recurrent venous thrombosis, even starting in young persons. Thrombosis is often spontaneous, without other precipitating events. They can be detected by laboratory testing for the respective coagulation factorSticky platelet syndromeThis is an autosomal dominant disorder that can lead to both arterial and venous thrombosis. Stillbirth may occur in women. Stress is a precipitating event.HomocystinemiaPersons with elevated plasma homocysteine levels not only have increased problems with atherosclerosis, but also arterial and venous thrombosis. Stillbirth may occur in women.Prothrombin mutationThe prothrombin G20210A mutation increases the level and activity of prothrombin that mildly increases the risk for arterial and venous thrombosis. The mutation occurs more often in persons of southern European ancestry.Plasminogen abnormalitiesPlasminogen, which has an anticoagulant effect, can be deficient. The features resemble protein C or S deficiency. Also, tissue plasminogen activator can be deficient. Plasminogen activator inhibitor can be increased.Congenital dysfibrinogenemiaThis rare autosomal dominant disorder may cause either thrombosis or hemorrhage. +This condition is as common as factor V Leiden mutation. There may be genetic and environmental factors causing it. Oral contraceptive use increases factor VIII levels. The result is deep venous thrombosis.Malignant neoplasmsNeoplastic cells may elaborate a factor, such as a thromboplastin-like substance, that can increase the risk for thrombosis. This is one form of paraneoplastic syndrome, with the name Trousseau's syndrome. There can be venous (more likely) or arterial thrombosis.Protein C, Protein S, antithrombin III deficienciesThese conditions are autosomal dominant and lead to recurrent venous thrombosis, even starting in young persons. Thrombosis is often spontaneous, without other precipitating events. They can be detected by laboratory testing for the respective coagulation factorSticky platelet syndromeThis is an autosomal dominant disorder that can lead to both arterial and venous thrombosis. Stillbirth may occur in women. Stress is a precipitating event.HomocystinemiaPersons with elevated plasma homocysteine levels not only have increased problems with atherosclerosis, but also arterial and venous thrombosis. Stillbirth may occur in women.Prothrombin mutationThe prothrombin G20210A mutation increases the level and activity of prothrombin that mildly increases the risk for arterial and venous thrombosis. The mutation occurs more often in persons of southern European ancestry.Plasminogen abnormalitiesPlasminogen, which has an anticoagulant effect, can be deficient. The features resemble protein C or S deficiency. Also, tissue plasminogen activator can be deficient. Plasminogen activator inhibitor can be increased.Congenital dysfibrinogenemiaThis rare autosomal dominant disorder may cause either thrombosis or hemorrhage. +Malignant neoplasmsNeoplastic cells may elaborate a factor, such as a thromboplastin-like substance, that can increase the risk for thrombosis. This is one form of paraneoplastic syndrome, with the name Trousseau's syndrome. There can be venous (more likely) or arterial thrombosis.Protein C, Protein S, antithrombin III deficienciesThese conditions are autosomal dominant and lead to recurrent venous thrombosis, even starting in young persons. Thrombosis is often spontaneous, without other precipitating events. They can be detected by laboratory testing for the respective coagulation factorSticky platelet syndromeThis is an autosomal dominant disorder that can lead to both arterial and venous thrombosis. Stillbirth may occur in women. Stress is a precipitating event.HomocystinemiaPersons with elevated plasma homocysteine levels not only have increased problems with atherosclerosis, but also arterial and venous thrombosis. Stillbirth may occur in women.Prothrombin mutationThe prothrombin G20210A mutation increases the level and activity of prothrombin that mildly increases the risk for arterial and venous thrombosis. The mutation occurs more often in persons of southern European ancestry.Plasminogen abnormalitiesPlasminogen, which has an anticoagulant effect, can be deficient. The features resemble protein C or S deficiency. Also, tissue plasminogen activator can be deficient. Plasminogen activator inhibitor can be increased.Congenital dysfibrinogenemiaThis rare autosomal dominant disorder may cause either thrombosis or hemorrhage. +Neoplastic cells may elaborate a factor, such as a thromboplastin-like substance, that can increase the risk for thrombosis. This is one form of paraneoplastic syndrome, with the name Trousseau's syndrome. There can be venous (more likely) or arterial thrombosis.Protein C, Protein S, antithrombin III deficienciesThese conditions are autosomal dominant and lead to recurrent venous thrombosis, even starting in young persons. Thrombosis is often spontaneous, without other precipitating events. They can be detected by laboratory testing for the respective coagulation factorSticky platelet syndromeThis is an autosomal dominant disorder that can lead to both arterial and venous thrombosis. Stillbirth may occur in women. Stress is a precipitating event.HomocystinemiaPersons with elevated plasma homocysteine levels not only have increased problems with atherosclerosis, but also arterial and venous thrombosis. Stillbirth may occur in women.Prothrombin mutationThe prothrombin G20210A mutation increases the level and activity of prothrombin that mildly increases the risk for arterial and venous thrombosis. The mutation occurs more often in persons of southern European ancestry.Plasminogen abnormalitiesPlasminogen, which has an anticoagulant effect, can be deficient. The features resemble protein C or S deficiency. Also, tissue plasminogen activator can be deficient. Plasminogen activator inhibitor can be increased.Congenital dysfibrinogenemiaThis rare autosomal dominant disorder may cause either thrombosis or hemorrhage. +Protein C, Protein S, antithrombin III deficienciesThese conditions are autosomal dominant and lead to recurrent venous thrombosis, even starting in young persons. Thrombosis is often spontaneous, without other precipitating events. They can be detected by laboratory testing for the respective coagulation factorSticky platelet syndromeThis is an autosomal dominant disorder that can lead to both arterial and venous thrombosis. Stillbirth may occur in women. Stress is a precipitating event.HomocystinemiaPersons with elevated plasma homocysteine levels not only have increased problems with atherosclerosis, but also arterial and venous thrombosis. Stillbirth may occur in women.Prothrombin mutationThe prothrombin G20210A mutation increases the level and activity of prothrombin that mildly increases the risk for arterial and venous thrombosis. The mutation occurs more often in persons of southern European ancestry.Plasminogen abnormalitiesPlasminogen, which has an anticoagulant effect, can be deficient. The features resemble protein C or S deficiency. Also, tissue plasminogen activator can be deficient. Plasminogen activator inhibitor can be increased.Congenital dysfibrinogenemiaThis rare autosomal dominant disorder may cause either thrombosis or hemorrhage. +These conditions are autosomal dominant and lead to recurrent venous thrombosis, even starting in young persons. Thrombosis is often spontaneous, without other precipitating events. They can be detected by laboratory testing for the respective coagulation factorSticky platelet syndromeThis is an autosomal dominant disorder that can lead to both arterial and venous thrombosis. Stillbirth may occur in women. Stress is a precipitating event.HomocystinemiaPersons with elevated plasma homocysteine levels not only have increased problems with atherosclerosis, but also arterial and venous thrombosis. Stillbirth may occur in women.Prothrombin mutationThe prothrombin G20210A mutation increases the level and activity of prothrombin that mildly increases the risk for arterial and venous thrombosis. The mutation occurs more often in persons of southern European ancestry.Plasminogen abnormalitiesPlasminogen, which has an anticoagulant effect, can be deficient. The features resemble protein C or S deficiency. Also, tissue plasminogen activator can be deficient. Plasminogen activator inhibitor can be increased.Congenital dysfibrinogenemiaThis rare autosomal dominant disorder may cause either thrombosis or hemorrhage. +Sticky platelet syndromeThis is an autosomal dominant disorder that can lead to both arterial and venous thrombosis. Stillbirth may occur in women. Stress is a precipitating event.HomocystinemiaPersons with elevated plasma homocysteine levels not only have increased problems with atherosclerosis, but also arterial and venous thrombosis. Stillbirth may occur in women.Prothrombin mutationThe prothrombin G20210A mutation increases the level and activity of prothrombin that mildly increases the risk for arterial and venous thrombosis. The mutation occurs more often in persons of southern European ancestry.Plasminogen abnormalitiesPlasminogen, which has an anticoagulant effect, can be deficient. The features resemble protein C or S deficiency. Also, tissue plasminogen activator can be deficient. Plasminogen activator inhibitor can be increased.Congenital dysfibrinogenemiaThis rare autosomal dominant disorder may cause either thrombosis or hemorrhage. +This is an autosomal dominant disorder that can lead to both arterial and venous thrombosis. Stillbirth may occur in women. Stress is a precipitating event.HomocystinemiaPersons with elevated plasma homocysteine levels not only have increased problems with atherosclerosis, but also arterial and venous thrombosis. Stillbirth may occur in women.Prothrombin mutationThe prothrombin G20210A mutation increases the level and activity of prothrombin that mildly increases the risk for arterial and venous thrombosis. The mutation occurs more often in persons of southern European ancestry.Plasminogen abnormalitiesPlasminogen, which has an anticoagulant effect, can be deficient. The features resemble protein C or S deficiency. Also, tissue plasminogen activator can be deficient. Plasminogen activator inhibitor can be increased.Congenital dysfibrinogenemiaThis rare autosomal dominant disorder may cause either thrombosis or hemorrhage. +HomocystinemiaPersons with elevated plasma homocysteine levels not only have increased problems with atherosclerosis, but also arterial and venous thrombosis. Stillbirth may occur in women.Prothrombin mutationThe prothrombin G20210A mutation increases the level and activity of prothrombin that mildly increases the risk for arterial and venous thrombosis. The mutation occurs more often in persons of southern European ancestry.Plasminogen abnormalitiesPlasminogen, which has an anticoagulant effect, can be deficient. The features resemble protein C or S deficiency. Also, tissue plasminogen activator can be deficient. Plasminogen activator inhibitor can be increased.Congenital dysfibrinogenemiaThis rare autosomal dominant disorder may cause either thrombosis or hemorrhage. +Persons with elevated plasma homocysteine levels not only have increased problems with atherosclerosis, but also arterial and venous thrombosis. Stillbirth may occur in women.Prothrombin mutationThe prothrombin G20210A mutation increases the level and activity of prothrombin that mildly increases the risk for arterial and venous thrombosis. The mutation occurs more often in persons of southern European ancestry.Plasminogen abnormalitiesPlasminogen, which has an anticoagulant effect, can be deficient. The features resemble protein C or S deficiency. Also, tissue plasminogen activator can be deficient. Plasminogen activator inhibitor can be increased.Congenital dysfibrinogenemiaThis rare autosomal dominant disorder may cause either thrombosis or hemorrhage. +Prothrombin mutationThe prothrombin G20210A mutation increases the level and activity of prothrombin that mildly increases the risk for arterial and venous thrombosis. The mutation occurs more often in persons of southern European ancestry.Plasminogen abnormalitiesPlasminogen, which has an anticoagulant effect, can be deficient. The features resemble protein C or S deficiency. Also, tissue plasminogen activator can be deficient. Plasminogen activator inhibitor can be increased.Congenital dysfibrinogenemiaThis rare autosomal dominant disorder may cause either thrombosis or hemorrhage. +The prothrombin G20210A mutation increases the level and activity of prothrombin that mildly increases the risk for arterial and venous thrombosis. The mutation occurs more often in persons of southern European ancestry.Plasminogen abnormalitiesPlasminogen, which has an anticoagulant effect, can be deficient. The features resemble protein C or S deficiency. Also, tissue plasminogen activator can be deficient. Plasminogen activator inhibitor can be increased.Congenital dysfibrinogenemiaThis rare autosomal dominant disorder may cause either thrombosis or hemorrhage. +Plasminogen abnormalitiesPlasminogen, which has an anticoagulant effect, can be deficient. The features resemble protein C or S deficiency. Also, tissue plasminogen activator can be deficient. Plasminogen activator inhibitor can be increased.Congenital dysfibrinogenemiaThis rare autosomal dominant disorder may cause either thrombosis or hemorrhage. +Plasminogen, which has an anticoagulant effect, can be deficient. The features resemble protein C or S deficiency. Also, tissue plasminogen activator can be deficient. Plasminogen activator inhibitor can be increased.Congenital dysfibrinogenemiaThis rare autosomal dominant disorder may cause either thrombosis or hemorrhage. +Congenital dysfibrinogenemiaThis rare autosomal dominant disorder may cause either thrombosis or hemorrhage. +This rare autosomal dominant disorder may cause either thrombosis or hemorrhage. +## 43. Petechial hemorrhages, epicardium, gross {#item-43} +![](../../images/atherosclerosis_f68d5088.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here are petechial hemorrhages seen on the epicardium of the heart. Petechiae (pinpoint hemorrhages) represent bleeding from small vessels and are classically found when a coagulopathy is due to a low platelet count. They can also appear following sudden hypoxia. +## 44. Ecchymoses, skin of arm, gross {#item-44} +![](../../images/atherosclerosis_f39aea13.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The blotchy areas of hemorrhage in the skin are called ecchymoses (singular ecchymosis). Ecchymoses are larger than petechiae. In between in size are hemorrhages called purpura. The terms ecchymosis and purpura are often used interchangeably. They can appear with coagulation disorders. In the setting of normal tissues subjected to sufficient blunt trauma to rupture small blood vessels and produce soft tissue bleeding, the process would be called contusion. +## 45. Hematoma, toenail, gross {#item-45} +![](../../images/atherosclerosis_1b3b3d5f.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +A localized collection of blood outside the vascular system within tissues is known as a hematoma. Here is a small hematoma under the toenail following trauma, which has a bluish appearance from the deoxygenated blood within it. +## 46. Disseminated intravascular coagulopathy (DIC), fibrin thrombus in lung, high power microscopic {#item-46} +![](../../images/atherosclerosis_34dcef3b.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Click on the fibrin thrombus in the section of lung above: +Disseminated intravascular coagulation (DIC) is a consequence of widespread activation of the coagulation system through endothelial injury and/or release of thromboplastic substances into the circulation. DIC can be seen with severe infections, trauma, neoplasia, and obstetric complications, among others. Small fibrin thrombi can form in small arteries of brain, heart, lungs, kidneys, and other organs to produce ischemic tissue damage. +## 47. Disseminated intravascular coagulopathy (DIC), fibrin thrombi with fibrin stain, glomerulus, high power microscopic {#item-47} +![](../../images/atherosclerosis_40ceb58e.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Small fibrin thrombifrom widespread activation of the coagulation system with disseminated intravascular coagulopathy (DIC) can be seen in capillary loops in this glomerulus, highlighted by a fibrin stain. Laboratory findings with DIC include decreased platelets, diminished fibrinogen, prolonged prothrombin time, elevated partial thromboplastin time, and elevated D-dimer. Consumption of coagulation factors with generation of fibrin split products, along with platelet consumption, leads to these findings. diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/pathology_\346\204\237\346\237\223_cleaned.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/pathology_\346\204\237\346\237\223_cleaned.txt" new file mode 100644 index 0000000..c63e0cb --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/pathology_\346\204\237\346\237\223_cleaned.txt" @@ -0,0 +1,426 @@ +## 1. Go to the tutorial on tuberculosis. {#item-1} + +Pathology of Tuberculosis +General FeaturesMycobacterium tuberculosisis the organism that is the causative agent for tuberculosis (TB, or MTB). There are other "atypical" mycobacteria such asM. kansasiithat may produced a similar clincal and pathologic appearance of disease.M. avium-intracellularecomplex (MAI, or MAC) seen in immunocompromised hosts (particularly in persons with AIDS) is not primarily a pulmonary infection in terms of its organ distribution (mostly in organs of the mononuclear phagocyte system).Tuberculosis has affected mankind throughout history and remains a world-wide problem. Social determinants of health play a role in spread of MTB as well as risk for morbidity and mortality. War, famine, homelessness, and a lack of medical care all contribute to the spread with prevalence of tuberculosis, particularly among disadvantaged persons. Since MTB is easily transmissible between persons, then the increase in MTB in any segment of the population represents a threat to all segments of the population. This means that it is important to institute and maintain appropriate public health measures, including screening, vaccination (where deemed of value), and treatment. A laxity of public health measures will contribute to an increase in cases. Failure of adequate treatment promotes the development of resistant strains of tuberculosis.The World Health Organization's End MTB Strategy strives to eliminate the global MTB epidemic by 2035, educing MTB deaths by 95% (compared with 2015 baseline). Achieving this target is contingent on the introduction of new, more effective tools to prevent, diagnose, and treat MTB. There are still 1.5 million deaths worldwide from tuberculosis each year (10 million new infections per year, and nearly half a million with drug resistance), but since illness and death do not appear acute, and affect mainly persons of lower socioeconomic status, then the risk for many people is deemed low. https://www.who.int/teams/global-tuberculosis-programme/the-end-tb-strategyPatterns of InfectionMycobacteria have mycolic acids in their outer cell wall which makes them resistant to quick immune destruction. Mycobacteria typically produce an adaptive immune response with an inflammatory reaction characterized as granulomatous inflammation, which can continue for weeks to months to years, depending upon the host response. A robust TH1 adaptive cell-mediated immune response is more effective than a TH2 response. In persons who are healthy, infection may be subclinical and inapparent, detected only by testing for evidence of an immune response.There are two major patterns of disease with MTB:Primary tuberculosis: seen as an initial infection, typical for infection in children. The initial focus of infection is a small subpleural granuloma accompanied by granulomatous hilar lymph node infection. Together, these make up the Ghon complex. In most cases, these granulomas resolve and there is no further spread of the infection.Secondary tuberculosis: seen mostly in adults as a reactivation of previous infection (or reinfection), particularly when health status declines. The granulomatous inflammation is much more florid and widespread. Typically, the upper lung lobes are most affected, and cavitation can occur.When resistance to infection is particularly poor, a "miliary" pattern of spread can occur in which there are a myriad of small millet seed (1-3 mm) sized granulomas, either in lung or in other organs.Dissemination of tuberculosis outside of lungs can lead to the appearance of a number of uncommon findings with characteristic patterns:Skeletal Tuberculosis:Tuberculous osteomyelitis involves mainly the thoracic and lumbar vertebrae (known as Pott disease) followed by knee and hip. There is extensive necrosis and bony destruction with compressed fractures (with kyphosis) and extension to soft tissues, including psoas "cold" abscess.Genital Tract Tuberculosis:Tuberculous salpingitis and endometritis result from dissemination of tuberculosis to the fallopian tube that leads to granulomatous salpingitis, which can drain into the endometrial cavity and cause a granulomatous endometritis with irregular menstrual bleeding and infertility. In the male, tuberculosis involves prostate and epididymis most often with non-tender induration and infertility.Urinary Tract Tuberculosis:A "sterile pyuria" with WBC's present in urine but a negative routine bacterial culture may suggest the diagnosis of renal tuberculosis. Progressive destruction of renal parenchyma occurs if not treated. Drainage to the ureters can lead to inflammation with ureteral stricture.CNS Tuberculosis:A meningeal pattern of spread can occur, and the cerebrospinal fluid typically shows a high protein, low glucose, and lymphocytosis. The base of the brain is often involved, so that various cranial nerve signs may be present. Rarely, a solitary granuloma, or "tuberculoma", may form and manifest with seizures or mass effect.Gastrointestinal Tuberculosis:This is uncommon today because routine pasteurization of milk has eliminatedMycobacterium bovisinfections. However,M. tuberculosisorganisms coughed up in sputum may be swallowed into the GI tract. The classic lesions are circumferential ulcerations with stricture of the small intestine. There is a predilection for ileocecal involvement because of the abundant lymphoid tissue and slower rate of passage of lumenal contents.Adrenal Tuberculosis:Spread of tuberculosis to adrenals is usually bilateral, so that both adrenals are markedly enlarged. Destruction of cortex leads to Addison disease.Scrofula:Tuberculous lymphadenitis of the cervical nodes may produce a mass of firm, matted nodes just under the mandible. There can be chronic draining fistulous tracts to overlying skin. This complication may appear in children, andMycobacterium scrofulaceummay be cultured.Cardiac Tuberculosis:The pericardium is the usual site for tuberculous infection of heart. The result is a granulomatous pericarditis that can be hemorrhagic. If extensive and chronic, there can be fibrosis with calcification, leading to a constrictive pericarditis.The following images illustrate gross pathologic findings with tuberculosis:Ghon complex in lung, gross.Ghon complex in lung, closer view, gross.Cavitary tuberculosis in lung, gross.Cavitary tuberculosis in lung, closer view, gross.Cavitary tuberculosis in lung, florid, gross.Miliary tuberculosis in lung, gross.Miliary tuberculosis in lung, closer view, gross.Microscopic FindingsThe inflammation with MTB infection is granulomatous, with epithelioid macrophages and Langhans giant cells along with lymphocytes, plasma cells, maybe a few neutrophils (PMN's), and fibroblasts with collagen. Ongoing inflammation is characteristic caseous necrosis in the center of granulomas. The inflammatory response is mediated by a type IV hypersensitivity reaction. This can be utilized as a basis for diagnosis by a MTB skin test. An acid fast stain (Ziehl-Neelsen or Kinyoun's acid fast stains) will show the organisms as slender red rods. An auramine stain of the organisms as viewed under fluorescence microscopy will be easier to screen and more organisms will be apparent. The most common specimen screened is sputum, but the histologic stains can also be performed on tissues or other body fluids. Culture of sputum or tissues or other body fluids can be done to determine drug sensitivities.Granulomas in lung, low power microscopic.Granuloma with caseous necrosis, high power microscopic.Granuloma with epithelioid macrophages and a Langhans giant cell, high power microscopic.Granulomatous endometritis, high power microscopic.Ziehl-Neelsen acid fast stain, microscopic, AFB stain.Auramine stain, M. tuberculosis, fluorescence microscopy.DiagnosisSkin testing for tuberculosis is useful in countries where the incidence of tuberculosis is low, and the health care system works well to detect and treat new cases. In countries where BCG vaccination has been widely used, the MTB skin test is not useful, because persons vaccinated with BCG will have a positive skin test.The MTB skin test is based upon the type IV hypersensitivity reaction to a previous MTB infection producing sensitized lymphocytes that can react to another encounter with antigens from MTB organisms. For the MTB skin test, a measured amount (the intermediate strength of 5 tuberculin units, used in North America) of tuberculin purified protein derivative (PPD) is injected intracutaneously to form a small wheal, typically on the forearm. In 48 to 72 hours, a positive reaction is marked by an area of red induration that can be measured by gentle palpation (redness from itching and scratching doesn't count). Reactions over 10 mm in size are considered positive in non-immunocompromised persons.Repeated testing of infected persons may increase the size of the reaction (induration), but repeated MTB skin testing will not lead to a positive test in a person not infected by MTB. Anergy (absence of PPD reactivity in persons infected with MTB) can occur in immunocompromised persons, or it may even occur in persons newly infected with MTB still mounting an immune response, or in persons with miliary MTB.A blood test for suspected MTB infection consists of an interferon-gamma release assay (IGRA) that measures the interferon-gamma released from sensitized T lymphocytes after in vitro stimulation with antigens specific forM. tuberculosis. Though there may be some cross-reactivity withM. kansasii, there is minimal reactivity following BCG vaccination, so the antigens are more specific for MTB.A decision to give antimicrobial therapy depends upon the clinical scenario. Treatment may be guided by obtaining specimens for mycobacterial culture, with laboratory results that may come weeks later, indicating the mycobacterial species present and the possible antibiotic resistance pattern.A chest radiograph may be obtained to assess evidence for pulmonary disease suggesting active mycobacterial infection.Injecting PPD intracutaneously, gross.A properly placed MTB skin test, gross.A positive MTB skin test, gross. +General Features +Mycobacterium tuberculosisis the organism that is the causative agent for tuberculosis (TB, or MTB). There are other "atypical" mycobacteria such asM. kansasiithat may produced a similar clincal and pathologic appearance of disease.M. avium-intracellularecomplex (MAI, or MAC) seen in immunocompromised hosts (particularly in persons with AIDS) is not primarily a pulmonary infection in terms of its organ distribution (mostly in organs of the mononuclear phagocyte system). +Tuberculosis has affected mankind throughout history and remains a world-wide problem. Social determinants of health play a role in spread of MTB as well as risk for morbidity and mortality. War, famine, homelessness, and a lack of medical care all contribute to the spread with prevalence of tuberculosis, particularly among disadvantaged persons. Since MTB is easily transmissible between persons, then the increase in MTB in any segment of the population represents a threat to all segments of the population. This means that it is important to institute and maintain appropriate public health measures, including screening, vaccination (where deemed of value), and treatment. A laxity of public health measures will contribute to an increase in cases. Failure of adequate treatment promotes the development of resistant strains of tuberculosis. +The World Health Organization's End MTB Strategy strives to eliminate the global MTB epidemic by 2035, educing MTB deaths by 95% (compared with 2015 baseline). Achieving this target is contingent on the introduction of new, more effective tools to prevent, diagnose, and treat MTB. There are still 1.5 million deaths worldwide from tuberculosis each year (10 million new infections per year, and nearly half a million with drug resistance), but since illness and death do not appear acute, and affect mainly persons of lower socioeconomic status, then the risk for many people is deemed low. https://www.who.int/teams/global-tuberculosis-programme/the-end-tb-strategy +Patterns of Infection +Mycobacteria have mycolic acids in their outer cell wall which makes them resistant to quick immune destruction. Mycobacteria typically produce an adaptive immune response with an inflammatory reaction characterized as granulomatous inflammation, which can continue for weeks to months to years, depending upon the host response. A robust TH1 adaptive cell-mediated immune response is more effective than a TH2 response. In persons who are healthy, infection may be subclinical and inapparent, detected only by testing for evidence of an immune response. +There are two major patterns of disease with MTB: +Primary tuberculosis: seen as an initial infection, typical for infection in children. The initial focus of infection is a small subpleural granuloma accompanied by granulomatous hilar lymph node infection. Together, these make up the Ghon complex. In most cases, these granulomas resolve and there is no further spread of the infection. +Secondary tuberculosis: seen mostly in adults as a reactivation of previous infection (or reinfection), particularly when health status declines. The granulomatous inflammation is much more florid and widespread. Typically, the upper lung lobes are most affected, and cavitation can occur. +When resistance to infection is particularly poor, a "miliary" pattern of spread can occur in which there are a myriad of small millet seed (1-3 mm) sized granulomas, either in lung or in other organs. +Dissemination of tuberculosis outside of lungs can lead to the appearance of a number of uncommon findings with characteristic patterns: +Skeletal Tuberculosis:Tuberculous osteomyelitis involves mainly the thoracic and lumbar vertebrae (known as Pott disease) followed by knee and hip. There is extensive necrosis and bony destruction with compressed fractures (with kyphosis) and extension to soft tissues, including psoas "cold" abscess. +Genital Tract Tuberculosis:Tuberculous salpingitis and endometritis result from dissemination of tuberculosis to the fallopian tube that leads to granulomatous salpingitis, which can drain into the endometrial cavity and cause a granulomatous endometritis with irregular menstrual bleeding and infertility. In the male, tuberculosis involves prostate and epididymis most often with non-tender induration and infertility. +Urinary Tract Tuberculosis:A "sterile pyuria" with WBC's present in urine but a negative routine bacterial culture may suggest the diagnosis of renal tuberculosis. Progressive destruction of renal parenchyma occurs if not treated. Drainage to the ureters can lead to inflammation with ureteral stricture. +CNS Tuberculosis:A meningeal pattern of spread can occur, and the cerebrospinal fluid typically shows a high protein, low glucose, and lymphocytosis. The base of the brain is often involved, so that various cranial nerve signs may be present. Rarely, a solitary granuloma, or "tuberculoma", may form and manifest with seizures or mass effect. +Gastrointestinal Tuberculosis:This is uncommon today because routine pasteurization of milk has eliminatedMycobacterium bovisinfections. However,M. tuberculosisorganisms coughed up in sputum may be swallowed into the GI tract. The classic lesions are circumferential ulcerations with stricture of the small intestine. There is a predilection for ileocecal involvement because of the abundant lymphoid tissue and slower rate of passage of lumenal contents. +Adrenal Tuberculosis:Spread of tuberculosis to adrenals is usually bilateral, so that both adrenals are markedly enlarged. Destruction of cortex leads to Addison disease. +Scrofula:Tuberculous lymphadenitis of the cervical nodes may produce a mass of firm, matted nodes just under the mandible. There can be chronic draining fistulous tracts to overlying skin. This complication may appear in children, andMycobacterium scrofulaceummay be cultured. +Cardiac Tuberculosis:The pericardium is the usual site for tuberculous infection of heart. The result is a granulomatous pericarditis that can be hemorrhagic. If extensive and chronic, there can be fibrosis with calcification, leading to a constrictive pericarditis. +The following images illustrate gross pathologic findings with tuberculosis: +Ghon complex in lung, gross. +Ghon complex in lung, closer view, gross. +Cavitary tuberculosis in lung, gross. +Cavitary tuberculosis in lung, closer view, gross. +Cavitary tuberculosis in lung, florid, gross. +Miliary tuberculosis in lung, gross. +Miliary tuberculosis in lung, closer view, gross. +Microscopic Findings +The inflammation with MTB infection is granulomatous, with epithelioid macrophages and Langhans giant cells along with lymphocytes, plasma cells, maybe a few neutrophils (PMN's), and fibroblasts with collagen. Ongoing inflammation is characteristic caseous necrosis in the center of granulomas. The inflammatory response is mediated by a type IV hypersensitivity reaction. This can be utilized as a basis for diagnosis by a MTB skin test. An acid fast stain (Ziehl-Neelsen or Kinyoun's acid fast stains) will show the organisms as slender red rods. An auramine stain of the organisms as viewed under fluorescence microscopy will be easier to screen and more organisms will be apparent. The most common specimen screened is sputum, but the histologic stains can also be performed on tissues or other body fluids. Culture of sputum or tissues or other body fluids can be done to determine drug sensitivities. +Granulomas in lung, low power microscopic. +Granuloma with caseous necrosis, high power microscopic. +Granuloma with epithelioid macrophages and a Langhans giant cell, high power microscopic. +Granulomatous endometritis, high power microscopic. +Ziehl-Neelsen acid fast stain, microscopic, AFB stain. +Auramine stain, M. tuberculosis, fluorescence microscopy. +Skin testing for tuberculosis is useful in countries where the incidence of tuberculosis is low, and the health care system works well to detect and treat new cases. In countries where BCG vaccination has been widely used, the MTB skin test is not useful, because persons vaccinated with BCG will have a positive skin test. +The MTB skin test is based upon the type IV hypersensitivity reaction to a previous MTB infection producing sensitized lymphocytes that can react to another encounter with antigens from MTB organisms. For the MTB skin test, a measured amount (the intermediate strength of 5 tuberculin units, used in North America) of tuberculin purified protein derivative (PPD) is injected intracutaneously to form a small wheal, typically on the forearm. In 48 to 72 hours, a positive reaction is marked by an area of red induration that can be measured by gentle palpation (redness from itching and scratching doesn't count). Reactions over 10 mm in size are considered positive in non-immunocompromised persons. +Repeated testing of infected persons may increase the size of the reaction (induration), but repeated MTB skin testing will not lead to a positive test in a person not infected by MTB. Anergy (absence of PPD reactivity in persons infected with MTB) can occur in immunocompromised persons, or it may even occur in persons newly infected with MTB still mounting an immune response, or in persons with miliary MTB. +A blood test for suspected MTB infection consists of an interferon-gamma release assay (IGRA) that measures the interferon-gamma released from sensitized T lymphocytes after in vitro stimulation with antigens specific forM. tuberculosis. Though there may be some cross-reactivity withM. kansasii, there is minimal reactivity following BCG vaccination, so the antigens are more specific for MTB. +A decision to give antimicrobial therapy depends upon the clinical scenario. Treatment may be guided by obtaining specimens for mycobacterial culture, with laboratory results that may come weeks later, indicating the mycobacterial species present and the possible antibiotic resistance pattern. +A chest radiograph may be obtained to assess evidence for pulmonary disease suggesting active mycobacterial infection. +Injecting PPD intracutaneously, gross. +A properly placed MTB skin test, gross. +A positive MTB skin test, gross. +## 2. Go to the tutorial on acquired immunodeficiency syndrome (AIDS). {#item-2} + +![](../../images/infection_ad967610.jpg) + +Textbook of AIDS PathologyAvailable is the newest (April 15, 2025) 36th edition of the electronic textbook "Pathology of HIV/AIDS" that is approximately 4.3 MB (including text, tables, graphics, and references). It is in PDF and can be viewed with a reader for such files.The textbook, now in its 36th edition, includes a general discussion of the pathophysiology of HIV infection, organ system pathology of AIDS, and descriptions of the opportunistic infections and neoplasms associated with AIDS, and a general discussion of issues, including safety and education, related to the HIV/AIDS pandemic.This textbook is dedicated to persons living with HIV/AIDS past, present, and future who provide the knowledge, to researchers who utilize the knowledge, to health care workers who apply the knowledge, and to public officials who do their best to promote the health of their citizens with the knowledge of the biology, pathophysiology, treatment, and prevention of HIV/AIDS.Go to the textbook, Pathology of AIDSHuman Immunodeficiency VirusA tutorial about HIV and AIDS is available:Go to the HIV tutorial.Prevention of HIV InfectionIf everyone with a risk factor for HIV infection underwent prompt HIV testing, and if everyone identified as positive for HIV received ongoing antiretroviral therapy, then viremia could be suppressed to undetectable levels so that infectivity to others would be very low. Condom usage combined with antiretroviral therapy can reduce HIV transmission by over 99%. Decreasing infectivity to near 0 by this strategy would markedly reduce the number of new infections. Infected persons could live a near normal lifespan on antiretroviral therapy.Biology of HIV and AIDSHuman immunodeficiency virus (HIV) is the causative agent for AIDS. The most common type is known as HIV-1 and is the infectious agent that has led to the worldwide AIDS epidemic. There is also an HIV-2 that is much less common and less virulent, but eventually produces clinical findings similar to HIV-1. The HIV-1 type itself has a number of subtypes (A through H and O) which have differing geographic distributions but all produce AIDS similarly. HIV is a retrovirus that contains only RNA.The testing algorithm for diagnosis of HIV infection employs sensitive and specific assays, as follows [Tsoi BW, Parker M, Fine SM, et al. HIV Testing [Internet]. Baltimore (MD): Johns Hopkins University; 2022 May. Figure 2, HIV Laboratory Testing Algorithm [a] Available from: https://www.ncbi.nlm.nih.gov/books/NBK581840/figure/figure-2/ (Accessed February 21, 2025)]:HIV is a sexually transmitted disease. Infection is aided by Langerhans cells in mucosal epithelial surfaces which can become infected. Infection is also aided by the presence of other sexually transmitted diseases that can produce mucosal ulceration and inflammation. The CD4+ T-lymphocytes have surface receptors to which HIV can attach to promote entry into the cell. The infection extends to lymphoid tissues which contain follicular dendritic cells that can become infected and provide a reservoir for continuing infection of CD4+ T-lymphocytes. HIV can also be spread via blood or blood products, most commonly with shared contaminated needles used by persons engaging in intravenous drug use. Mothers who are HIV infected can pass the virus on to their fetuses in utero or to infants via breast milk.When HIV infects a cell, it must use its reverse transcriptase enzyme to transcribe its RNA to host cell proviral DNA. It is this proviral DNA that directs the cell to produce additional HIV virions which are released.The genome of HIV contains only three major genes: env, gag, and pol. These genes direct the formation of the basic components of HIV. The env gene directs production of an envelope precursor protein gp160 which undergoes proteolytic cleavage to the outer envelope glycoprotein gp120, which is responsible for tropism to CD4+ receptors, and transmembrane glycoprotein gp41, which catalyzes fusion of HIV to the target cell's membrane. The gag gene directs formation of the proteins of the matrix p17, the "core" capsid p24, and the nucleocapsid p7. The pol gene directs synthesis of important enzymes including reverse transcriptase p51 and p66, integrase p32, and protease p11.In addition to the CD4 receptor, a coreceptor known as a chemokine is needed for HIV infection. Chemokines are cell surface fusion-mediating molecules. Such coreceptors include CXCR4 and CCR5. Their presence on cells can aid binding of the HIV envelope glycoprotein gp120, promoting infection. Initial binding of HIV to the CD4 receptor is mediated by conformational changes in the gp120 subunit, but such conformational changes are not sufficient of fusion. The chemokine receptors produce a conformational change in the gp41 subunit which allows fusion of HIV. The differences in chemokine coreceptors that are present on a cell also explains how different strains of HIV may infect cells selectively. There are strains of HIV known as T-tropic strains which selectively interact with the CXCR4 chemokine coreceptor to infect lymphocytes. The M-tropic strains of HIV interact with the CCR5 chemokine coreceptor to infect macrophages. Dual tropic HIV stains have been identified. The presence of a CCR5 mutation may explain the phenomenon of resistance to HIV infection in some cases. Over time, mutations in HIV may increase the ability of the virus to infect cells via these routes. Infection with cytomegalovirus may serve to enhance HIV infection via this mechanism, because CMV encodes a chemokine receptor similar to human chemokine receptors.Human immunodeficiency virus, electron micrograph.Human immunodeficiency virus, electron micrograph.Human immunodeficiency virus, electron micrograph.Human immunodeficiency virus, structural components, diagram.Human immunodeficiency virus, life cycle, diagram.Human immunodeficiency virus within lymphoid tissues, diagram.Human immunodeficiency virus, process of infection, diagram.Human immunodeficiency virus, schematic diagram of genome.Human immunodeficiency virus (HIV) subtypes and simian immunodeficiency virus (SIV) phylogeny, diagram.Life cycle of HIV, with the points of pharmacologic agent effectiveness, diagram.Schematic diagram of CD4 receptor and chemokine coreceptor.Acquired Immunodeficiency Syndrome (AIDS)When the CD4 lymphocyte count drops below 200/microliter, then the stage of clinical AIDS has been reached. This is the point at which the characteristic opportunistic infections and neoplasms of AIDS appear. Listed below are some of the more common complications seen with AIDS with images that illustrate gross and microscopic pathologic findings.The organ involvement of infections with AIDS represents the typical appearance of opportunistic infections in the immunocompromised host--that of an overwhelming infection--that makes treatment more difficult. The strategies employed in AIDS patients to meet this challenge consist of (1) preserving immune function as long as possible with antiretroviral therapies, (2) using prophylactic pharmacologic therapies to prevent infections (such asPneumocystis jirovecipneumonia), and (3) diagnosing and treating acute infections as soon as possible.Pneumocystis jiroveciPneumocystis jiroveci(formerly carinii) is the most frequent opportunistic infection seen with AIDS. It commonly produces a pulmonary infection but rarely disseminates outside of lung. The most frequent clinical findings in patients with pneumonia are acute onset of fever, non-productive cough, and dyspnea. Chest radiograph may show perihilar infiltrates. Diagnosis is made histologically by finding the organisms in cytologic (bronchoalveolar lavage) or biopsy (transbronchial biopsy) material from lung, typically via bronchoscopy. The cysts ofP jirovecistain brown to black with the Gomori methenamine silver stain. With Giemsa or Dif-Quik stain on cytologic smears, the dot-like intracystic bodies are seen.Pneumocystis jiroveci, appearance of organisms, diagram.Pneumocystis jirovecipneumonia, gross.Pneumocystis jirovecipneumonia with cavitary change, gross.Pneumocystis jirovecipneumonia, low power microscopic.Pneumocystis jirovecipneumonia, medium power microscopic, GMS stain.Pneumocystis jirovecipneumonia, high power microscopic, GMS stain.Pneumocystis jirovecipneumonia, microscopic, bronchoalveolar lavage, cytologic smear, Giemsa stain.Pneumocystis jirovecipneumonia, microscopic, bronchoalveolar lavage, cytologic smear, Giemsa stain.Pneumocystis jirovecipneumonia, microscopic, bronchoalveolar lavage, cytologic smear, Pap stain.Pneumocystis jirovecipneumonia, lung, microscopic, immunohistochemical stain.Pneumocystis jiroveci, disseminated, gross.Pneumocystis jiroveci, disseminated, spleen, CT scan.Pneumocystis jiroveci, exudate with calcification, medium power microscopic.Pneumocystis jirovecipneumonia, interstitial fibrosis, medium power microscopic.CytomegalovirusCytomegalovirus (CMV) is the most frequent disseminated opportunistic infection seen with AIDS. It causes the most serious disease as a pneumonia in the lung, but it can also cause serious disease in the brain and gastrointestinal tract. It is also a common cause for retinitis and blindness in persons with AIDS. CMV is identified by the presence of very large cytomegalic cells with enlarged nuclei that contain a violaceous intranuclear inclusion surrounded by a clear halo. Sometimes, basophilic stippling is present in the cytoplasm.Cytomegalovirus, appearance of organisms, diagram.Cytomegalovirus, ulcers in cecum, gross.Cytomegalovirus pneumonia, microscopic.Cytomegalovirus pneumonia, microscopic.Cytomegalovirus pneumonia, microscopic.Cytomegalovirus adrenalitis, microscopic.Cytomegalovirus, liver, microscopic.Cytomegalovirus pneumonitis, immunohistochemical stain, medium and high power microscopic.MycobacteriaMycobacterial infections are frequently seen with AIDS.Mycobacterium tuberculosishas been increasing in frequency since the start of the AIDS epidemic. The appearance of M tuberculosis with AIDS is similar to that of non-AIDS patients, with granulomatous pulmonary disease, though the infection may be more extensive or may be disseminated to other organs.Mycobacterium aviumcomplex (MAC) infection is more unique to AIDS and is characterized by involvement mostly of the organs of the mononuclear phagocyte system (lymph node, spleen, liver, marrow). MAC infections are less likely to produce visible granulomas, and the lesions often consist of clusters of macrophages filled with numerous mycobacteria. Definitive diagnosis of mycobacterial disease is made by culture.Mycobacterium tuberculosis, lung, gross.Mycobacterium tuberculosis, lung, AFB stain, microscopic.Mycobacterium aviumcomplex (MAC), spleen with miliary granulomas, gross.Mycobacterium aviumcomplex (MAC), mesenteric lymph nodes, gross.Mycobacterium aviumcomplex (MAC), diagram.Mycobacterium aviumcomplex (MAC), macrophages filled with mycobacteria, spleen, AFB stain, microscopic.Fungal InfectionsThere are many types of fungi that can complicate the course of AIDS. One of the most frequent (though uncommonly life-threatening) isCandida. Oral candidiasis is often seen with HIV infection and may presage the progression to AIDS.Candidacan occasionally produce invasive infections in esophagus, upper respiratory tract, and lung.Infections with the pathogenic fungiCryptococcus neoformans,Histoplasma capsulatum, andCoccidioides immitisare more serious infections that are often widely disseminated.C neoformansoften produces pneumonia and meningitis.Candida albicans, lung, gross.Candida albicans, diagram.Candida albicans, invasive in bronchus, H&E stain, microscopic.Candida albicans, invasive in esophagus, PAS stain, microscopic.Candida albicans, invasive in esophagus, GMS stain, microscopic.Cryptococcus neoformans, diagram.Cryptococcus neoformans(with capsules), H&E stain, microscopic.Cryptococcus neoformans(without capsules), meninges, GMS stain, microscopic.Cryptococcus neoformans, India ink preparation of cerebrospinal fluid, microscopic.Histoplasma capsulatum, diagram.Histoplasma capsulatum, granulomas in liver, gross.Histoplasma capsulatum, liver, H and E stain, microscopic.Histoplasma capsulatum, liver, PAS stain, microscopic.Coccidioides immitis, diagram.Coccidioides immitis, lung, H&E stain, microscopic.Coccidioides immitis, liver, H&E stain, microscopic.ToxoplasmosisToxoplasma gondiiis a protozoan parasite that most often leads to infection of the brain with AIDS. The lesions are usually multiple and have the appearance of abscesses. Less commonly,T gondiiinfection is disseminated to other organs.Toxoplasma gondii, organizing cerebral abscess, gross.Toxoplasma gondii, diagram.Toxoplasma gondii, pseudocysts, microglial nodule, microscopic.Toxoplasma gondii, myocardium, microscopic.Toxoplasma gondii, lung, immunohistochemical stain, microscopic.Herpes simplexHerpes simplex virus infection with AIDS is most likely to involve the gastrointestinal tract, mainly the esophagus and the perianal region. Herpes zoster infection of the skin can also occur prior to the onset of clinical AIDS. Herpes infections are rarely life-threatening.Herpes simplex virus, diagram.Herpes simplex virus, esophagus, microscopic.Herpes simplex virus, esophagus, microscopic.Gastrointestinal Protozoal InfectionsCryptosporidium, Microsporidium, and Isospora are all capable of producing a voluminous watery diarrhea in patients with AIDS. Diagnosis can be made by examination of stool specimens and/or intestinal biopsy.Gastrointestinal protozoa, diagram.Cryptosporidiosis, small intestine, H and E stain, microscopic.Cryptosporidiosis, stool specimen, AFB stain,microscopic.Cryptosporidia, electron micrograph.Isospora belli, stool specimen, AFB stain, microscopic.Malignant NeoplasmsKaposi's sarcoma (KS) produces reddish purple patches, plaques, or nodules over the skin and can be diagnosed with skin biopsy. Visceral organ involvement eventually occurs in 3/4 of patients with KS.Malignant lymphomas seen with AIDS are typically of a high grade and extranodal, often in the brain. They are very aggressive and respond poorly to therapy.Kaposi's sarcoma, skin, gross.Kaposi's sarcoma, skin, patch stage, microscopic.Kaposi's sarcoma, skin, nodule, microscopic.Kaposi's sarcoma, skin, extravasation of RBC's, microscopic.Kaposi's sarcoma, skin, hemosiderin and hyaline globules, microscopic.Kaposi's sarcoma, skin, hyaline globules, PAS stain, microscopic.Kaposi's sarcoma, oral cavity, immunohistochemical with antibody to CD34, microscopic.Kaposi's sarcoma, stomach, gross.Kaposi's sarcoma, liver, gross.Malignant lymphoma, lymph node, gross.Malignant lymphoma, small intestine, gross.Malignant lymphoma, liver, gross.Malignant lymphoma, small intestine, high power microscopic.Malignant lymphoma, brain, low power microscopic.Malignant lymphoma, brain, high power microscopic.MiscellaneousLymphoid interstitial pneumonitis (LIP) is a condition involving the lung that can be seen in AIDS in children. By chest radiograph, bilateral reticulonodular interstitial pulmonary infiltrates are seen. The earliest pathologic finding is a hyperplasia of bronchial associated lymphoid tissue with aggregates of lymphocytes and plasma cells in a bronchovascular distribution. Later lesions demonstrate diffuse lung round cell infiltrates, and lymphoid aggregates can be present.Lymphoid interstitial pneumonitis (LIP) of lung, low power microscopic.Lymphoid interstitial pneumonitis (LIP) of lung, low power microscopic.Lymphoid interstitial pneumonitis (LIP) of lung, medium power microscopic.Lymphoid interstitial pneumonitis (LIP) of lung, high power microscopic.Progressive multifocal leukoencephalopathy (PML), gross.Progressive multifocal leukoencephalopathy (PML), Luxol fast blue stain, low power microscopic.Progressive multifocal leukoencephalopathy (PML), high power microscopic.Progressive multifocal leukoencephalopathy (PML) JC viral particles in nucleus, electron micrograph.HIV lymphadenopathy, early phase with follicular hyperplasia, medium power microscopic. +Textbook of AIDS Pathology +Available is the newest (April 15, 2025) 36th edition of the electronic textbook "Pathology of HIV/AIDS" that is approximately 4.3 MB (including text, tables, graphics, and references). It is in PDF and can be viewed with a reader for such files. +The textbook, now in its 36th edition, includes a general discussion of the pathophysiology of HIV infection, organ system pathology of AIDS, and descriptions of the opportunistic infections and neoplasms associated with AIDS, and a general discussion of issues, including safety and education, related to the HIV/AIDS pandemic. +This textbook is dedicated to persons living with HIV/AIDS past, present, and future who provide the knowledge, to researchers who utilize the knowledge, to health care workers who apply the knowledge, and to public officials who do their best to promote the health of their citizens with the knowledge of the biology, pathophysiology, treatment, and prevention of HIV/AIDS. +Go to the textbook, Pathology of AIDS +Human Immunodeficiency Virus +A tutorial about HIV and AIDS is available: +Go to the HIV tutorial. +Prevention of HIV Infection +If everyone with a risk factor for HIV infection underwent prompt HIV testing, and if everyone identified as positive for HIV received ongoing antiretroviral therapy, then viremia could be suppressed to undetectable levels so that infectivity to others would be very low. Condom usage combined with antiretroviral therapy can reduce HIV transmission by over 99%. Decreasing infectivity to near 0 by this strategy would markedly reduce the number of new infections. Infected persons could live a near normal lifespan on antiretroviral therapy. +Biology of HIV and AIDS +Human immunodeficiency virus (HIV) is the causative agent for AIDS. The most common type is known as HIV-1 and is the infectious agent that has led to the worldwide AIDS epidemic. There is also an HIV-2 that is much less common and less virulent, but eventually produces clinical findings similar to HIV-1. The HIV-1 type itself has a number of subtypes (A through H and O) which have differing geographic distributions but all produce AIDS similarly. HIV is a retrovirus that contains only RNA. +The testing algorithm for diagnosis of HIV infection employs sensitive and specific assays, as follows [Tsoi BW, Parker M, Fine SM, et al. HIV Testing [Internet]. Baltimore (MD): Johns Hopkins University; 2022 May. Figure 2, HIV Laboratory Testing Algorithm [a] Available from: https://www.ncbi.nlm.nih.gov/books/NBK581840/figure/figure-2/ (Accessed February 21, 2025)]: +HIV is a sexually transmitted disease. Infection is aided by Langerhans cells in mucosal epithelial surfaces which can become infected. Infection is also aided by the presence of other sexually transmitted diseases that can produce mucosal ulceration and inflammation. The CD4+ T-lymphocytes have surface receptors to which HIV can attach to promote entry into the cell. The infection extends to lymphoid tissues which contain follicular dendritic cells that can become infected and provide a reservoir for continuing infection of CD4+ T-lymphocytes. HIV can also be spread via blood or blood products, most commonly with shared contaminated needles used by persons engaging in intravenous drug use. Mothers who are HIV infected can pass the virus on to their fetuses in utero or to infants via breast milk. +When HIV infects a cell, it must use its reverse transcriptase enzyme to transcribe its RNA to host cell proviral DNA. It is this proviral DNA that directs the cell to produce additional HIV virions which are released. +The genome of HIV contains only three major genes: env, gag, and pol. These genes direct the formation of the basic components of HIV. The env gene directs production of an envelope precursor protein gp160 which undergoes proteolytic cleavage to the outer envelope glycoprotein gp120, which is responsible for tropism to CD4+ receptors, and transmembrane glycoprotein gp41, which catalyzes fusion of HIV to the target cell's membrane. The gag gene directs formation of the proteins of the matrix p17, the "core" capsid p24, and the nucleocapsid p7. The pol gene directs synthesis of important enzymes including reverse transcriptase p51 and p66, integrase p32, and protease p11. +In addition to the CD4 receptor, a coreceptor known as a chemokine is needed for HIV infection. Chemokines are cell surface fusion-mediating molecules. Such coreceptors include CXCR4 and CCR5. Their presence on cells can aid binding of the HIV envelope glycoprotein gp120, promoting infection. Initial binding of HIV to the CD4 receptor is mediated by conformational changes in the gp120 subunit, but such conformational changes are not sufficient of fusion. The chemokine receptors produce a conformational change in the gp41 subunit which allows fusion of HIV. The differences in chemokine coreceptors that are present on a cell also explains how different strains of HIV may infect cells selectively. There are strains of HIV known as T-tropic strains which selectively interact with the CXCR4 chemokine coreceptor to infect lymphocytes. The M-tropic strains of HIV interact with the CCR5 chemokine coreceptor to infect macrophages. Dual tropic HIV stains have been identified. The presence of a CCR5 mutation may explain the phenomenon of resistance to HIV infection in some cases. Over time, mutations in HIV may increase the ability of the virus to infect cells via these routes. Infection with cytomegalovirus may serve to enhance HIV infection via this mechanism, because CMV encodes a chemokine receptor similar to human chemokine receptors. +Human immunodeficiency virus, electron micrograph. +Human immunodeficiency virus, structural components, diagram. +Human immunodeficiency virus, life cycle, diagram. +Human immunodeficiency virus within lymphoid tissues, diagram. +Human immunodeficiency virus, process of infection, diagram. +Human immunodeficiency virus, schematic diagram of genome. +Human immunodeficiency virus (HIV) subtypes and simian immunodeficiency virus (SIV) phylogeny, diagram. +Life cycle of HIV, with the points of pharmacologic agent effectiveness, diagram. +Schematic diagram of CD4 receptor and chemokine coreceptor. +Acquired Immunodeficiency Syndrome (AIDS) +When the CD4 lymphocyte count drops below 200/microliter, then the stage of clinical AIDS has been reached. This is the point at which the characteristic opportunistic infections and neoplasms of AIDS appear. Listed below are some of the more common complications seen with AIDS with images that illustrate gross and microscopic pathologic findings. +The organ involvement of infections with AIDS represents the typical appearance of opportunistic infections in the immunocompromised host--that of an overwhelming infection--that makes treatment more difficult. The strategies employed in AIDS patients to meet this challenge consist of (1) preserving immune function as long as possible with antiretroviral therapies, (2) using prophylactic pharmacologic therapies to prevent infections (such asPneumocystis jirovecipneumonia), and (3) diagnosing and treating acute infections as soon as possible. +Pneumocystis jiroveci +Pneumocystis jiroveci(formerly carinii) is the most frequent opportunistic infection seen with AIDS. It commonly produces a pulmonary infection but rarely disseminates outside of lung. The most frequent clinical findings in patients with pneumonia are acute onset of fever, non-productive cough, and dyspnea. Chest radiograph may show perihilar infiltrates. Diagnosis is made histologically by finding the organisms in cytologic (bronchoalveolar lavage) or biopsy (transbronchial biopsy) material from lung, typically via bronchoscopy. The cysts ofP jirovecistain brown to black with the Gomori methenamine silver stain. With Giemsa or Dif-Quik stain on cytologic smears, the dot-like intracystic bodies are seen. +Pneumocystis jiroveci, appearance of organisms, diagram. +Pneumocystis jirovecipneumonia, gross. +Pneumocystis jirovecipneumonia with cavitary change, gross. +Pneumocystis jirovecipneumonia, low power microscopic. +Pneumocystis jirovecipneumonia, medium power microscopic, GMS stain. +Pneumocystis jirovecipneumonia, high power microscopic, GMS stain. +Pneumocystis jirovecipneumonia, microscopic, bronchoalveolar lavage, cytologic smear, Giemsa stain. +Pneumocystis jirovecipneumonia, microscopic, bronchoalveolar lavage, cytologic smear, Pap stain. +Pneumocystis jirovecipneumonia, lung, microscopic, immunohistochemical stain. +Pneumocystis jiroveci, disseminated, gross. +Pneumocystis jiroveci, disseminated, spleen, CT scan. +Pneumocystis jiroveci, exudate with calcification, medium power microscopic. +Pneumocystis jirovecipneumonia, interstitial fibrosis, medium power microscopic. +Cytomegalovirus +Cytomegalovirus (CMV) is the most frequent disseminated opportunistic infection seen with AIDS. It causes the most serious disease as a pneumonia in the lung, but it can also cause serious disease in the brain and gastrointestinal tract. It is also a common cause for retinitis and blindness in persons with AIDS. CMV is identified by the presence of very large cytomegalic cells with enlarged nuclei that contain a violaceous intranuclear inclusion surrounded by a clear halo. Sometimes, basophilic stippling is present in the cytoplasm. +Cytomegalovirus, appearance of organisms, diagram. +Cytomegalovirus, ulcers in cecum, gross. +Cytomegalovirus pneumonia, microscopic. +Cytomegalovirus adrenalitis, microscopic. +Cytomegalovirus, liver, microscopic. +Cytomegalovirus pneumonitis, immunohistochemical stain, medium and high power microscopic. +Mycobacterial infections are frequently seen with AIDS.Mycobacterium tuberculosishas been increasing in frequency since the start of the AIDS epidemic. The appearance of M tuberculosis with AIDS is similar to that of non-AIDS patients, with granulomatous pulmonary disease, though the infection may be more extensive or may be disseminated to other organs.Mycobacterium aviumcomplex (MAC) infection is more unique to AIDS and is characterized by involvement mostly of the organs of the mononuclear phagocyte system (lymph node, spleen, liver, marrow). MAC infections are less likely to produce visible granulomas, and the lesions often consist of clusters of macrophages filled with numerous mycobacteria. Definitive diagnosis of mycobacterial disease is made by culture. +Mycobacterium tuberculosis, lung, gross. +Mycobacterium tuberculosis, lung, AFB stain, microscopic. +Mycobacterium aviumcomplex (MAC), spleen with miliary granulomas, gross. +Mycobacterium aviumcomplex (MAC), mesenteric lymph nodes, gross. +Mycobacterium aviumcomplex (MAC), diagram. +Mycobacterium aviumcomplex (MAC), macrophages filled with mycobacteria, spleen, AFB stain, microscopic. +Fungal Infections +There are many types of fungi that can complicate the course of AIDS. One of the most frequent (though uncommonly life-threatening) isCandida. Oral candidiasis is often seen with HIV infection and may presage the progression to AIDS.Candidacan occasionally produce invasive infections in esophagus, upper respiratory tract, and lung. +Infections with the pathogenic fungiCryptococcus neoformans,Histoplasma capsulatum, andCoccidioides immitisare more serious infections that are often widely disseminated.C neoformansoften produces pneumonia and meningitis. +Candida albicans, lung, gross. +Candida albicans, diagram. +Candida albicans, invasive in bronchus, H&E stain, microscopic. +Candida albicans, invasive in esophagus, PAS stain, microscopic. +Candida albicans, invasive in esophagus, GMS stain, microscopic. +Cryptococcus neoformans, diagram. +Cryptococcus neoformans(with capsules), H&E stain, microscopic. +Cryptococcus neoformans(without capsules), meninges, GMS stain, microscopic. +Cryptococcus neoformans, India ink preparation of cerebrospinal fluid, microscopic. +Histoplasma capsulatum, diagram. +Histoplasma capsulatum, granulomas in liver, gross. +Histoplasma capsulatum, liver, H and E stain, microscopic. +Histoplasma capsulatum, liver, PAS stain, microscopic. +Coccidioides immitis, diagram. +Coccidioides immitis, lung, H&E stain, microscopic. +Coccidioides immitis, liver, H&E stain, microscopic. +Toxoplasma gondiiis a protozoan parasite that most often leads to infection of the brain with AIDS. The lesions are usually multiple and have the appearance of abscesses. Less commonly,T gondiiinfection is disseminated to other organs. +Toxoplasma gondii, organizing cerebral abscess, gross. +Toxoplasma gondii, diagram. +Toxoplasma gondii, pseudocysts, microglial nodule, microscopic. +Toxoplasma gondii, myocardium, microscopic. +Toxoplasma gondii, lung, immunohistochemical stain, microscopic. +Herpes simplex virus infection with AIDS is most likely to involve the gastrointestinal tract, mainly the esophagus and the perianal region. Herpes zoster infection of the skin can also occur prior to the onset of clinical AIDS. Herpes infections are rarely life-threatening. +Herpes simplex virus, diagram. +Herpes simplex virus, esophagus, microscopic. +Gastrointestinal Protozoal Infections +Cryptosporidium, Microsporidium, and Isospora are all capable of producing a voluminous watery diarrhea in patients with AIDS. Diagnosis can be made by examination of stool specimens and/or intestinal biopsy. +Gastrointestinal protozoa, diagram. +Cryptosporidiosis, small intestine, H and E stain, microscopic. +Cryptosporidiosis, stool specimen, AFB stain,microscopic. +Cryptosporidia, electron micrograph. +Isospora belli, stool specimen, AFB stain, microscopic. +Malignant Neoplasms +Kaposi's sarcoma (KS) produces reddish purple patches, plaques, or nodules over the skin and can be diagnosed with skin biopsy. Visceral organ involvement eventually occurs in 3/4 of patients with KS.Malignant lymphomas seen with AIDS are typically of a high grade and extranodal, often in the brain. They are very aggressive and respond poorly to therapy.Kaposi's sarcoma, skin, gross.Kaposi's sarcoma, skin, patch stage, microscopic.Kaposi's sarcoma, skin, nodule, microscopic.Kaposi's sarcoma, skin, extravasation of RBC's, microscopic.Kaposi's sarcoma, skin, hemosiderin and hyaline globules, microscopic.Kaposi's sarcoma, skin, hyaline globules, PAS stain, microscopic.Kaposi's sarcoma, oral cavity, immunohistochemical with antibody to CD34, microscopic.Kaposi's sarcoma, stomach, gross.Kaposi's sarcoma, liver, gross.Malignant lymphoma, lymph node, gross.Malignant lymphoma, small intestine, gross.Malignant lymphoma, liver, gross.Malignant lymphoma, small intestine, high power microscopic.Malignant lymphoma, brain, low power microscopic.Malignant lymphoma, brain, high power microscopic.MiscellaneousLymphoid interstitial pneumonitis (LIP) is a condition involving the lung that can be seen in AIDS in children. By chest radiograph, bilateral reticulonodular interstitial pulmonary infiltrates are seen. The earliest pathologic finding is a hyperplasia of bronchial associated lymphoid tissue with aggregates of lymphocytes and plasma cells in a bronchovascular distribution. Later lesions demonstrate diffuse lung round cell infiltrates, and lymphoid aggregates can be present.Lymphoid interstitial pneumonitis (LIP) of lung, low power microscopic.Lymphoid interstitial pneumonitis (LIP) of lung, low power microscopic.Lymphoid interstitial pneumonitis (LIP) of lung, medium power microscopic.Lymphoid interstitial pneumonitis (LIP) of lung, high power microscopic.Progressive multifocal leukoencephalopathy (PML), gross.Progressive multifocal leukoencephalopathy (PML), Luxol fast blue stain, low power microscopic.Progressive multifocal leukoencephalopathy (PML), high power microscopic.Progressive multifocal leukoencephalopathy (PML) JC viral particles in nucleus, electron micrograph.HIV lymphadenopathy, early phase with follicular hyperplasia, medium power microscopic. +Malignant lymphomas seen with AIDS are typically of a high grade and extranodal, often in the brain. They are very aggressive and respond poorly to therapy. +Kaposi's sarcoma, skin, gross. +Kaposi's sarcoma, skin, patch stage, microscopic. +Kaposi's sarcoma, skin, nodule, microscopic. +Kaposi's sarcoma, skin, extravasation of RBC's, microscopic. +Kaposi's sarcoma, skin, hemosiderin and hyaline globules, microscopic. +Kaposi's sarcoma, skin, hyaline globules, PAS stain, microscopic. +Kaposi's sarcoma, oral cavity, immunohistochemical with antibody to CD34, microscopic. +Kaposi's sarcoma, stomach, gross. +Kaposi's sarcoma, liver, gross. +Malignant lymphoma, lymph node, gross. +Malignant lymphoma, small intestine, gross. +Malignant lymphoma, liver, gross. +Malignant lymphoma, small intestine, high power microscopic. +Malignant lymphoma, brain, low power microscopic. +Malignant lymphoma, brain, high power microscopic. +Lymphoid interstitial pneumonitis (LIP) is a condition involving the lung that can be seen in AIDS in children. By chest radiograph, bilateral reticulonodular interstitial pulmonary infiltrates are seen. The earliest pathologic finding is a hyperplasia of bronchial associated lymphoid tissue with aggregates of lymphocytes and plasma cells in a bronchovascular distribution. Later lesions demonstrate diffuse lung round cell infiltrates, and lymphoid aggregates can be present. +Lymphoid interstitial pneumonitis (LIP) of lung, low power microscopic. +Lymphoid interstitial pneumonitis (LIP) of lung, medium power microscopic. +Lymphoid interstitial pneumonitis (LIP) of lung, high power microscopic. +Progressive multifocal leukoencephalopathy (PML), gross. +Progressive multifocal leukoencephalopathy (PML), Luxol fast blue stain, low power microscopic. +Progressive multifocal leukoencephalopathy (PML), high power microscopic. +Progressive multifocal leukoencephalopathy (PML) JC viral particles in nucleus, electron micrograph. +HIV lymphadenopathy, early phase with follicular hyperplasia, medium power microscopic. +## 3. Pneumocystis carinii (jirovecii)pneumonia, gross {#item-3} +![](../../images/infection_51188582.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This lung is as solid as liver because ofPneumocystis jiroveci (carinii)pneumonia (PCP). There is diffuse consolidation of all lung lobes. PCP is typical of immunocompromised patients, particularly those with HIV/AIDS.Pneumocystis jirovecihas DNA similar to fungi, but clinically produces disease similar to a unicellular parasite. +## 4. Pneumocystis carinii (jirovecii)pneumonia, gross {#item-4} +![](../../images/infection_ab184c04.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Upon closer view, the cut surface of the lung withPneumocystis jiroveci (carinii)pneumonia (PCP) has a salmon pink appearance due to the diffuse nature of the infectious process. Fever, nonproductive cough, and dyspnea are the usual presenting findings. +## 5. Pneumocystis carinii (jirovecii)pneumonia, medium power microscopic {#item-5} +![](../../images/infection_68ca678e.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Microscopically, every alveolus is filled with granular pink exudate in this case ofPneumocystis carinii (jirovecii)pneumonia (PCP). This reduces oxygen exchange and leads to the dyspnea and cough characteristic for PCP. +## 6. Pneumocystis carinii (jirovecii)pneumonia, high power microscopic {#item-6} +![](../../images/infection_a76a3065.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +At higher magnification, the granular pink exudate ofPneumocystis carinii (jirovecii)pneumonia is seen. The exudate consists of edema fluid, protein,Pneumocystisorganisms, and dead macrophages. One can see why gas exchange is severely compromised. +## 7. Pneumocystis carinii (jirovecii)pneumonia, Gomori methenamine silver stain, high power microscopic {#item-7} +![](../../images/infection_cd98bff4.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +![](../../images/infection_2e0d77ca.gif) +The best way to make the diagnosis ofPneumocystis jiroveci (carinii)pneumonia is to perform a Gomori methenamine silver (GMS) stain on the lung tissue or bronchoalveolar lavage (BAL) fluid. The cyst wall is stained, and the organisms appear as crushed ping-pong balls, or crescent shapes, or folded spheres, or flattened beach balls, or deflated tennis balls. A diagram of this appearance is shown below. +## 8. Candida, microscopic {#item-8} +![](../../images/infection_a3d714a5.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Budding cells with pseudohyphae seen here are characteristic forCandidainfection. Mouse over the box below to view an animation of budding. +## 9. Candida, PAS stain, microscopic {#item-9} +![](../../images/infection_12dc94b8.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +![](../../images/infection_36d9e916.gif) +With a PAS stain, the budding cells and pseudohyphae (short filaments that are not true hyphae) ofCandidastain bright red. This organism favors moist, warm surfaces, but is usually limited to the epithelium. A diagrammatic representation of this organism is shown below. +## 10. Candida, Gomori methenamine silver stain, microscopic {#item-10} +![](../../images/infection_fb133f8c.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is a GMS stain ofCandidawith the organisms staining black. The various species are morphologically similar and vary somewhat in virulence. +## 11. Oral candidiasis, gross {#item-11} +![](../../images/infection_c2a6b350.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Oral candidiasis is common in immunocompromised hosts, such as those with HIV infection. There is coating of the tongue seen here, more on the lateral aspects. This is called "oral thrush". +## 12. Oral candidiasis, PAS stain, microscopic {#item-12} +![](../../images/infection_d1ea8924.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +A PAS stain reveals the purple-coloured budding cells and pseudohyphae ofCandidaon the surface of the tongue. Candidiasis tends to be limited to epithelial surfaces and is uncommonly invasive to underlying tissues or a systemic infection. +## 13. Aspergillus fungal abscess, lung, gross {#item-13} +![](../../images/infection_0eea29b9.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is a fungal abscess of the lung. Note the yellow tan material in the abscess. It is very firm material, because it is composed of fungal hyphae. This one is due toAspergillus.Aspergillusorganisms have a habit of colonizing previously formed cavities in lung, such as those resulting fromMycobacterium tuberculosisinfection. +## 14. Aspergillus fungal abscess, lung, gross {#item-14} +![](../../images/infection_b87f38b5.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This isAspergillusinfection of the lung. Note how the infection crosses the pleura between the lobes. Note that asmall pulmonary arteryto the left of the yellow-brown fungal abscess is thrombosed and surrounded by hemorrhage.Aspergillusfungal hyphae like to invade vessels and surrounding tissues. +## 15. Aspergillus fungus ball, bronchus of lung, low power microscopic {#item-15} +![](../../images/infection_7368833e.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is anAspergillusfungus ball within a dilated bronchus. This organism may colonize abnormal lung damaged from prior disease, such as tuberculosis cavities or bronchiectasis. There are multiple species ofAspergillusand they have similar morphologic appearance on microscopy. +## 16. Aspergillus fungus ball, lung, high power microscopic {#item-16} +![](../../images/infection_1602e542.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +![](../../images/infection_96424b78.gif) +At higher magnification,Aspergillushyphae are seen to branch. A diagrammatic representation of this organism is shown below, compared withMucorwith broader, non-septate hyphae. +## 17. Aspergillus fungus ball, lung, high power microscopic {#item-17} +![](../../images/infection_3b12312c.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here are branchingAspergillushyphae. Mouseover the box below for an animation of the fungal growth of hyphae. +## 18. Mucormycosis, high power microscopic {#item-18} +![](../../images/infection_2cce983c.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The broad, non-septate hyphae seen here are characteristic forMucor. There are several species of zygomycetes, all of which are collectively referred to as the cause for mucormycosis. As in this case, the setting of infection was the nasopharynx in a patient with diabetes mellitus. Ketoacidosis potentiates the growth of this organism in tissues. +## 19. Cryptococcus neoformans, lung, microscopic {#item-19} +![](../../images/infection_ab7fa090.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This isCryptococcus neoformansinfection of the lung. There are numerous organisms that have a large mucoid capsule, giving the appearance of a clear zone around a faint round nucleus. Mouseover the box below to view a cryptococcal organism with central nucleus and large mucoid capsule. +## 20. Cryptococcus neoformans, meninges, Gomori methenamine silver stain, microscopic {#item-20} +![](../../images/infection_afead8b4.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +![](../../images/infection_08411292.gif) +This is aCryptococcus neoformansmeningitis stained with GMS to reveal the nuclei. In this AIDS patient, the organisms didn't even bother to make a capsule. The budding cells ofCryptococcushave a narrow base. A diagrammatic representation of this organism is shown below. +## 21. Cryptococcus neoformans, cerebrospinal fluid, India ink preparation, microscopic {#item-21} +![](../../images/infection_c747c6b4.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is an India ink preparation of cerebrospinal fluid in a patient withCryptococcus neoformansmeningitis. Note the clear zone of the capsule around the central nucleus of the organisms. Microscopically, this appearance can be challenging to distinguish from leukocytes. Serologic testing for cryptococcal antigen is a test with high sensitivity. +## 22. Coccidioides immitis, high power microscopic {#item-22} +![](../../images/infection_b243d2ca.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +![](../../images/infection_5d7eb268.gif) +These large spherules with a thick wall and filled with endospores are characteristic forCoccidioides immitisgrowing in tissues. "Cocci" is endemic to the desert southwest of the U.S. and other dry areas. Note how the spherule at the left is bursting to expel its endospores, which grow and continue the infection. A diagrammatic representation of this organism is shown below. +## 23. Coccidioides immitis, high power microscopic {#item-23} +![](../../images/infection_1dd13a64.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This pulmonary infection is due to coccidioidomycosis, as evidenced by the two large spherules filled with endospores. Shown here is the yeast phase with infection. In the environment,Coccidioidesgrows in the mold phase as alternating arthrospores. +## 24. Histoplasma capsulatumgranulomas, liver, gross {#item-24} +![](../../images/infection_4b1dd8d3.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Many fungal infections can produce a granulomatous pattern of inflammation in tissues. In immunocompromised hosts, the immune response is often poor, so granulomas are poorly formed, if at all. This portion of liver demonstrates somepinpoint yellow-tan granulomasin a patient with disseminated histoplasmosis. +## 25. Histoplasma capsulatum, microscopic {#item-25} +![](../../images/infection_b35f2d5c.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +![](../../images/infection_111de51e.gif) +This is infection withHistoplasma capsulatum. Note how each macrophage is filled with numeroussmall organisms. The organisms have a clear zone around a central blue nucleus which gives the cell membrane the appearance of a capsule. Hence, the name of the organism. A diagrammatic representation of this organism is shown below. +## 26. Histoplasma capsulatum, PAS stain, microscopic {#item-26} +![](../../images/infection_bc641e2a.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +A PAS stain highlightsHistoplasma capsulatuminfection in the liver. +## 27. Toxoplasma gondiipseudocyst, myocardium, high power microscopic {#item-27} +![](../../images/infection_8fa0dfb7.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is aToxoplasma gondiipseudocyst in the myocardium of a patient with AIDS. Toxo is an opportunistic infection of immunocompromised adults. It may also be a congenital infection. +## 28. Toxoplasma gondiiabscess, cerebrum, gross {#item-28} +![](../../images/infection_a748e288.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is aToxoplasma gondiiabscess in the brain, which would appear as a ring-enhancing lesion on radiologic imaging with a CT scan. +## 29. Toxoplasma gondiipseudocyst, cerebrum, high power microscopic {#item-29} +![](../../images/infection_8d32f10c.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +A brain biopsy reveals cysts ofToxoplasma gondiiin a microglial nodule with a variety of inflammatory cell types in a patient with AIDS. +## 30. Cryptosporidosis, small intestine, microscopic {#item-30} +![](../../images/infection_50e1781f.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +![](../../images/infection_eb57bc37.gif) +Thelittle blue organismslined up along the brush border of the small intestinal epithelium areCryptosporidium parvumorganisms causing the disease cryptosporidiosis. This infection may cause a mild diarrhea in immunocompetent persons but more severe illness in immunocompromised hosts. A diagrammatic representation of this organism is shown below. +## 31. Cryptosporidiosis, cysts in stool specimen, AFB stain, microscopic {#item-31} +![](../../images/infection_ac8d9bf6.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Cryptosporidium parvuminfection is best diagnosed by stool exam. ThreecystsofCryptosporidium parvumappear here in stool with acid fast stain. +## 32. Plasmodium vivax(malaria parasites), blood smear, microscopic {#item-32} +![](../../images/infection_f12f58e0.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This peripheral blood smear comes from a patient with malaria. This infection happens to be withPlasmodium vivax. At the arrow is a RBC with a malarial parasite in the shape of a ring. Three other RBC's in this smear are also infected with a ring trophozoite. The rarely seen sexual phase of this organism, thegametocyte, is shown. Speciation ofPlasmodiumcan be done, albeit with difficulty, by identification of subtle morphologic variations in the appearance of these parasites. +## 33. Ascaris lumbricoides, gross {#item-33} +![](../../images/infection_4d93e835.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is a ball ofAscaris lumbricoidesworms removed from the colon of an adult. This is a heavy infection. Though these worms are disgusting, they produce minimal disease in most infected persons. +## 34. Trichuris trichiuria(whipworm) infection, colon, gross {#item-34} +![](../../images/infection_0256a54d.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This colonic mucosal surface is erythematous because of the enormous infestation byTrichuris trichiuriaorganisms (whipworms). A heavy infestation of these helminths can lead to colitis with hemorrhage. +## 35. Microfilaria in blood smear (Wuchereria bancrofti), microscopic {#item-35} +![](../../images/infection_b4072422.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here are microfilaria. These tiny worms circulate in the bloodstream. There are several species with slightly different clinical characteristics, but they are spread by mosquitos. These microfilaria happen to beWuchereria bancrofti. +## 36. Mycobacterium tuberculosis, lung, AFB stain, microscopic {#item-36} +![](../../images/infection_1f5859cf.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is an acid fast stain ofMycobacterium tuberculosis(MTB). Note the red rods--hence the terminology for MTB in histologic sections or smears: acid fast bacilli.Mycobacteriahave a cell wall with lipids including fatty acids, specifically mycolic acid, making them resistant to phagocytic destruction, and acid fast. +## 37. Mycobacterium tuberculosis, lung, auramine stain, fluorescence microscopy {#item-37} +![](../../images/infection_d36c46e0.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Mycobacteria can also be stained with auramine and viewed with fluorescence microscopy, in which acid fast bacilli now appear as glowing yellow rods. This method is easier to use to screen for mycobacteria and is the method routinely used in sputum specimens sent to the laboratory. +## 38. Mycobacterium avium-complex, miliary granulomas in spleen, gross {#item-38} +![](../../images/infection_c649c0ce.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This spleen shows a miliary pattern of granulomatous inflammation, with numerous small tan granulomas. This suggests a poor immune response. This patient had AIDS. The infection turned out to beMycobacterium avium-intracellulare (MAI), also known asMycobacterium avium-complex (MAC). This organism is unlikely to produce infection in immunocompetent patients. +## 39. Mycobacterium avium-complex, mesenteric lymph nodes, gross {#item-39} +![](../../images/infection_9f2bb3ff.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Theenlarged lymph nodesin this mesentery, best seen at the left, have cut surfaces that appear yellow-tan. These nodes are filled with sheets ofMycobacterium avium-complex (MAC) organisms, and the immune response is so poor in this AIDS patient that there is no focal, localized granuloma formation. +## 40. Mycobacterium avium-complex, AFB stain, microscopic {#item-40} +![](../../images/infection_fb8e9e71.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Microscopically,Mycobacterium avium-complex (MAC) infection is marked by numerous acid fast organisms growing within macrophages. Lots of bright red rods are seen, particularly in macrophages, in this acid fast stain of lymph node. The mycobacterial organisms are naturally resistant to phagocytic destruction, and an immunocompromised state diminishes the TH1 cell mediated immune response that would increase the granulomatous response with macrophage killing of the organisms. +## 41. Herpes simplex virus, skin, high power microscopic {#item-41} +![](../../images/infection_f6799a2b.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is a microscopic section from the edge of one of a group of small round clear vesicles on the skin, just above the lip. Notice the mauve to pink homogenous intranuclear inclusions in the epithelial cells of the epidermis. This is typical for Herpes simplex virus (HSV) infection. The most common sites for Herpes simplex virus infections (either primary or reactivation) are skin and mucus membranes. HSV type I is seen most often in oral cavity, while HSV type II is more commonly a sexually transmitted disease. +## 42. Herpes simplex virus, esophagus, high power microscopic {#item-42} +![](../../images/infection_4468f140.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The esophageal squamous epithelium here is from a sharply demarcated "punched out" ulcer from herpes simplex virus infection. Note the mauve to pink intranuclear inclusions. Often, multinucleated cells are seen. Such gastrointestinal infections are most common in immunocompromised hosts. +## 43. Herpes simplex virus, cerebrum, electron micrograph {#item-43} +![](../../images/infection_0feac21a.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +By electron microscopy, viral particles of any herpesvirus appear as arrays and scattered single particles as shown here in a nucleus of a neuron from the cerebrum from a patient with herpes simplex encephalitis. Herpesviruses are large encapsulated viruses that contain double-stranded DNA in the nucleocapsid surrounded by the viral envelope. +## 44. Cytomegalovirus, lung, microscopic {#item-44} +![](../../images/infection_02ed80c4.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is cytomegalovirus (CMV) infection in the lung. Note thevery large cellsthat have large violet intranuclear inclusions with a small clear halo. Basophilic stippling can sometimes be seen in the cytoplasm. Over 50% of persons have antibody to CMV, indicating past subclinical infection, but disease producing infection is most likely to occur with immune compromise. +## 45. Cytomegalovirus, adrenal, microscopic {#item-45} +![](../../images/infection_cd527df1.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Manycytomegalovirus inclusionsare seen in this adrenal, which has necrosis and hemorrhage as well at the right. CMV is usually seen in immunocompromised hosts and can be widespread in many organs. +## 46. Cytomegalovirus, kidney, microscopic {#item-46} +![](../../images/infection_09173092.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is a congenital cytomegalovirus infection in a fetus. A CMV positive mother may pass the virus transplacentally, but only a small number of such infections produce severe disease in the fetus. Note thelarge CMV inclusionsin the renal tubular epithelium. +## 47. Parvovirus inclusions, spleen, microscopic {#item-47} +![](../../images/infection_401cb453.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Thepink intranuclear inclusionsin the erythroid precursors seen here are characteristic for parvovirus infection. Parvovirus, or "fifth disease" is a self-limited infection that can produce a "slapped cheek" appearance of a rash in children, and often goes unnoticed in adults. However, pregnant mothers can pass the virus to the fetus, and a severe anemia with fetal hydrops and intrauterine demise can result. +## 48. Respiratory syncytial virus, lung, microscopic {#item-48} +![](../../images/infection_0c1da128.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Scattered giant cells with a scant mononuclear interstitial infiltrate are seen here in the lung. The pink, roundedintracytoplasmic inclusionin the giant cell of the inset at the upper right is typically seen with respiratory syncytial virus (RSV), a common cause for pneumonia in infants and children under 2 years of age. +## 49. Sarcoptes scabiei(scabies mite), microscopic {#item-49} +![](../../images/infection_962a91f1.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is a scabies mite. The official name isSarcoptes scabiei. These little critters burrow in the epidermis, usually on the hands but sometimes elsewhere, and produce itching along the linear burrows. These lesions are often excoriated because of the itching. +## 50. Head lice, gross {#item-50} +![](../../images/infection_687d0f5f.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Small tan sesame seed-sized lice are seen scattered amongst the hairs of the head. Head lice are relatively common, particularly among children, and can cause itching, sometimes to the point of excoriation with risk for secondary infection. The lice and their eggs can easily be passed from one person to another with close contact or from sharing combs, towels, etc. +## 51. Lice, microscopic {#item-51} +![](../../images/infection_9778e7fb.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Lice are arthropods of the class Insecta which generally inhabit hair and bite the human host for a blood meal. At the left is the head louse (Pediculus humanis capitis) and at the right is the crab (pubic) louse (Phthirus pubis). diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/pathology_\346\263\225\345\214\273\347\227\205\347\220\206\345\255\246_cleaned.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/pathology_\346\263\225\345\214\273\347\227\205\347\220\206\345\255\246_cleaned.txt" new file mode 100644 index 0000000..cb8c487 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/corpus/pathology_\346\263\225\345\214\273\347\227\205\347\220\206\345\255\246_cleaned.txt" @@ -0,0 +1,537 @@ +## 1. Go to the tutorial on firearm injuries. {#item-1} + +Firearms Tutorial +IntroductionNo matter which side you take on the sale and use of firearms, you will encounter the results of firearms injuries in health care settings. This tutorial is designed to give you a working knowledge of the types of firearms, the types of ammunition used, the nature of injuries that can be produced in the body, and the investigative techniques employed in law enforcement aided by the forensic pathologist in assessing firearms injuries.Sections of the TutorialStatistics, Gun Control Issues, and SafetyHistory of FirearmsTerminologyAnatomy of FirearmsBallisticsPatterns of Tissue InjuryCriminalistics Laboratory MethodsExamination of Gunshot ResidueOther Issues and InjuriesReferences +No matter which side you take on the sale and use of firearms, you will encounter the results of firearms injuries in health care settings. This tutorial is designed to give you a working knowledge of the types of firearms, the types of ammunition used, the nature of injuries that can be produced in the body, and the investigative techniques employed in law enforcement aided by the forensic pathologist in assessing firearms injuries. +Sections of the Tutorial +Statistics, Gun Control Issues, and Safety +History of Firearms +Anatomy of Firearms +Patterns of Tissue Injury +Criminalistics Laboratory Methods +Examination of Gunshot Residue +Other Issues and Injuries +## 2. Go to the tutorial on drug abuse pathology. {#item-2} + +Pathology of Drug Abuse +Tobacco and SmokingSmoking tobacco leads to the greatest number of problems of any drug in use in the world today. Smoking contributes to more than 7 million deaths each year worldwide. These deaths are mainly the result of increased numbers of lung cancers as well as increased numbers of cases of atherosclerotic heart disease and emphysema of the lung. Smoking increases the risk for cancers of the bladder, pancreas, kidney, and cervix. There is an increased risk for gastritis and gastric ulceration in persons who smoke. Cataracts of the crystalline lens of the eye occur with increased frequency in smokers. (GBD, 2017)Women who are pregnant and who smoke put their fetuses at increased risk for spontaneous abortion, ectopic pregnancy, placental abruption, placenta praevia, premature labor, and preterm birth, stillbirth,low birth weight, and small for gestational age (SGA) compared to women who do not smoke during pregnancy. Prenatal maternal smoking is also associated with risk of sudden unexplained death in infancy. (Gould et al, 2020)Normal lung, gross.Small cell anaplastic (oat cell) carcinoma of lung, gross.Squamous cell carcinoma of lung, gross.Emphysema, centrilobular type, gross.Emphysema, representing a modern version of "The Masque of the Red Death" in Edgar Allen Poe's short story.Composite photograph with a narrowed coronary artery at the left and a markedly narrowed coronary artery at the right, microscopic.Pelvis of kidney, urothelial carcinoma, gross.Acute gastric ulcerations, gross.Hyaline membrane disease in the lung of a premature neonate, microscopic.VapingElectronic cigarettes (e-cigarettes) produce an inhaled vapor. The major chemical component of the vapor is nicotine, but additional toxic constituents include metals, volatile organic compounds (VOCs such as benzene and toluene), nitrosamines, and Vitamin E acetate (VEA). Thus, the substitution of vaping for traditional cigarette smoking does not eliminate health hazards, but only trade one set of problems for another set. Nicotine by itself is highly addictive and promotes continued usage, leading to more exposure to the additional toxic compounds inhaled with the nicotine. Adolescent brains are more susceptible to this addiction. Persons using e-cigarettes are more likely to also use traditional tobacco products, compounding health risks. (Walley et al, 2019)E-cigarette use is linked to poisoning, immediate inhalation toxicity, and lung injury. Environmental effects include waste, fires, and generation of indoor airborne particulate matter. The nicotine e-cigarettes can cause dependence in non-smokers, and young non-smokers who use e-cigarettes are more likely than non-users to initiate smoking and to become regular smokers. (Banks et al, 2023)Short-term health risks of e-cigarettes include increased airway resistance and increased exhaled carbon monoxide (CO). CO binds to hemoglobin tightly to displace oxygen. Airway resistance reduces optimal lung function. (Stockley et al, 2018)Radiologic imaging studies document a variety of lung injury patterns associated with vaping. Patterns include hypersensitivity pneumonitis, diffuse alveolar hemorrhage, diffuse alveolar damage, acute eosinophilic pneumonia, giant cell interstitial pneumonia, and lipid pneumonia. These injuries can acutely lead to diminished lung function. A more long-term pattern of injury is organizing pneumonia with fibroblast proliferation and collagen deposition - features of scar tissue formation that reduces lung capacity. (Henry et al, 2019)Pathologic findings with vaping confirm the imaging patterns. Acute lung injury patterns include diffuse alveolar damage and organizing pneumonia. Microscopic pathologic findings include bronchiolitis, mucosal edema, sloughing of the bronchiolar epithelium, eosinophils, and peribronchiolar organization following accumulation of macrophages. There can be fibrinous exudates and type 2 pneumocyte hyperplasia. More severe injury can lead to diffuse alveolar damage with formation of hyaline membranes. There can be progression to chronic inflammation and fibroblast plugs in bronchioles. Clinical features associated with these pathologic alterations include fever, night sweats, weight loss, dyspnea, cough, nausea, and vomiting. (Butt et al, 2019) (Mukhopadhyay et al, 2020)EVALI (e-cigarette or vaping product use associated lung injury) describes the acute respiratory illness related to toxic effects of substances inhaled in vaping. Findings include shortness of breath, cough, chest pain, and fever, along with hypoxia and tachycardia. The inhaled compounds can produce toxic effects upon cells in the respiratory tract and induce neutrophilic inflammation. Thus, EVALI can mimic infectious diseases of the lungs, and should be considered in persons with recent e-cigarette use. (Krishnasamy et al, 2020) (Park et al, 2022)Alcohol AbuseThe abuse of alcohol (ethanol) contributes to many deaths per year worldwide. It can also be a cause for drug overdose leading to death from ingestion of a large amount of alcohol, and second only to opioid overdose in number of drug-related deaths. Almost 1 in 5 visits to an emergency department involve prior use of alcohol. (https://www.niaaa.nih.gov/alcohols-effects-health/alcohol-topics/alcohol-facts-and-statistics/alcohol-related-emergencies-and-deaths-united-states)Chronic alcohol use leads to liver disease that can be manifested initially as fatty change (steatosis). Excessive alcohol ingestion over many years can lead to micronodular cirrhosis. A cirrhotic liver leads to portal hypertension and the complication of bleeding esophageal varices with massive, life-threatening gastrointestinal hemorrhage. There is also an increased risk for hepatocellular carcinoma arising in a cirrhotic liver. Acute excessive alcohol consumption can lead to alcoholic hepatitis. Laboratory testing of a blood specimen for evidence of ethanol ingestion includes phosphatidylethanol for recent (within 2 weeks) and carbohydrate-deficient transferrin for chronic use. (Patel and Flamm, 2023)In the brain, alcohol use disorder predisposing to poor dietary intake lacking nutrients can lead to thiamine deficiency with neurotoxicity and development of Wernicke–Korsakoff syndrome (WKS), with components of Wernicke encephalopathy and Korsakoff’s psychosis, with higher mental function affected by confusion and confabulation. Acute Wernicke encephalopathy is a potentially reversible condition characterized by confusion, oculomotor disturbances, and ataxia. Continued alcohol use leads to permanent brain damage. (Nutt et al, 2021)Abrupt cessation of alcohol ingestion in persons who are chronic alcohol users predisposes to alcohol withdrawal Symptoms, and signs within 8 to 24 hours include transient visual, auditory or tactile hallucinations. There can be progression to withdrawal-related seizures which, if not treated may progress to life-threatening delirium tremens. (Day and Daly, 2022)Alcohol use during pregnancy can lead to fetal alcohol spectrum disorders, also termed the fetal alcohol syndrome (FAS). The risk increases with the time and amount of exposure, but there is no completely safe level of maternal alcohol consumption. This syndrome is estimated to occur in 1 in 100 live births, but the actual incidence is probably higher. Whenever a pregnant woman stops drinking, she reduces the risk of having a baby with FAS. Damage to the fetus from FAS cannot be reversed. Later in development, affected children have increased behavioral problems and learning disabilities. There are no specific, distinctive morphologic findings, so it is challenging to diagnose. The most common deformity with FAS is moderate to severe growth retardation. The three most distinctive features are a thin upper lip, smooth philtrum, and short palpebral fissures. (Popova et al, 2023)Additional FAS anomalies include microcephaly, long and narrow forehead, hypotelorism, maxillary and mandibular hypoplasia, narrow palpebal fissures, thin elongated philtrum and vermillion border of the upper lip, temporomandibular joint disorders, and dental malocclusion. Ocular problems include microphthalmia, coloboma, nystagmus, strabismus, and ptosis. The physical anomalies tend to become less apparent as the child ages. (Mukherjee et al, 2006)Normal liver, gross.Fatty change of liver, microscopic.Micronodular cirrhosis of liver, gross.Micronodular cirrhosis of liver, microscopic.Hepatocellular carcinoma, liver with micronodular cirrhosis, gross.Esophageal varices, gross.Wernicke's disease, hemorrhages in the mammillary bodies, gross.OpiatesOpiates by themselves have minimal pathologic tissue effects. Higher doses of more powerful opiates can lead to respiratory depression and death. Persons who really need the pain relief that opiate medications can offer do not become addicted, but unfortunately tolerance may develop over time, requiring higher doses to maintain analgesia. The major problems with opiate abuse are the psychosocial consequences, the infections from route of administration (injection), and possible overdose with death. (Torres-Lockhart et al, 2022)An opioid epidemic in the 21st century has been driven by increasing demand and increasing supply, particularly of synthetic opioid compounds. The prescription opiate most often abused is fentanyl, which has great affinity for the mu opioid receptor, and is 80 to 100 times more potent than morphine, producing an intense, temporary euphoria. (Liu et al, 2018) An overdose is treated with naloxone, and the synthetic opioids require higher doses of naloxone. (Walker, 2023) In the U.S. in 2022, of over 100,000 deaths from drug overdose, about 80% were due to opiates, mainly synthetic opioids. (https://blogs.cdc.gov/nchs/2023/05/18/7365/)Psychosocial problems related to behavioral issues from drug dependence. Drug-seeking behaviors result in lack of concern for oneself or others. If the route of administration is intravenous, without attention to sterile technique, there is increased risk for infection. Withdrawl from chronic opiate usage typically results in marked physiologic and psychologic disturbances such as pupillary dilation, tachycardia, yawning, lacrimation, rhinorrhea, piloerection, abdominal cramping, nausea, vomiting, diarrhea, muscle or bone pain, irritability, restlessness, anxiety, and insomnia. (Torres-Lockhart et al, 2022)Oxycodone, best known by the trade name OxyContin®, is a controlled release form of opioid analgesic prescribed to treat moderate to severe pain of constant and prolonged duration. Persons abusing this medication risk addiction and death, particularly if oxycodone is used in association with other drugs. Abusers may progress to usage by intravenous injection and to usage of other opiates or drugs of abuse. (Hays, 2004)Intravenous Drug AbuseMany drugs can be injected intravenously. The drugs themselves may have the major effect of impairment of mental function, but the route of administration can have serious complications. Injection of drugs with needles that are not sterile leads to the potential for a wide variety of infections. Such infections include: human immunodeficiency virus (the causative agent for AIDS), viral hepatitis (particularly hepatitis B and C), and bacterial infections. (Marks et al, 2022)Persons with a history of intravenous drug abuse also are more likely to have tuberculosis of the lungs. The drug heroin can produce a nephropathy in the kidney that resembles focal segmental glomerulosclerosis. In addition, a "talc granulomatosis" can occur because many injected drugs have been adulterated with an inert substance (such as talcum powder) to "cut" or dilute the amount of drug. (Milroy and Parai, 2011)Normal aortic valve compared with infective endocarditis, gross.Surface of the brain with acute meningitis, gross.Viral hepatitis of the liver, gross.Viral hepatitis of the liver, microscopic.Macronodular cirrhosis of the liver, gross.Mycobacterium tuberculosis, lung, cavitary disease, gross.Glomerulus of kidney demonstrating focal scarring with heroin nephropathy, microscopic.Talc granulomatosis of the liver, gross.Talc granulomatosis of the lungs, polarized light, microscopic.CocaineCocaine can exert a variety of effects. The major acute effects producing pathologic conditions result from the increased circulating catecholamine levels with cocaine use. These increased catecholamines can produce vasoconstriction. The lesions can include acute hemorrhages and infarction in the brain. Cerebral infarction can occur within 3 hours of cocaine use even in young persons. Subarachnoid haemorrhage is often associated with rupture of a berry aneurysm. Intraparenchymal haemorrhage can occur in the basal ganglia and thalamus. (Milroy and Parai, 2011)Ischemic changes in the heart from small artery narrowing and sclerosis lead to contraction band necrosis of the myocardium and possible sudden death. With chronic usage, the myocardium develops interstitial fibrosis, and the heart becomes enlarged. Atheroma formation in artereis as well as arterial dissection can occur. (Milroy and Parai, 2011) Combining cocaine use with ethanol use can compound the myocardial damage. (Awtry and Philippides, 2010)Pregnant mothers who use cocaine can affect their fetuses from abnormalities of placental function leading to low birth weight babies or an increased risk for placental abruption. Maternal cocaine use increases the risk for spontaneous abortion. (Kuczkowski, 2007)Persons with cocaine intoxication (not necessarily related to the drug level) may develop a state of iatrogenic psychosis (cocaine psychosis) with "excited delerium" in which they are markedly agitated and combative and develop hyperthermia, often of a severe degree (to 106 F). Organ damage can accompany this state of excited delerium and may include rhabdomyolysis of muscle, hepatotoxicity, and renal failure. Disseminated intravascular coagulation (DIC), hypotension, and sudden death are additional complications. (Devlin and Henry, 2008)Massive intracerebral hemorrhage associated with cocaine use, gross.Cerebral infarction, gross.Heart with myocardial contraction band necrosis, microscopic.Heart with peripheral coronary artery sclerosis, microscopic.Abruptio placenta with large recent blood clot compressing the parenchyma, gross.MethamphetamineMethampetamine is a stimulant drug with inotropic effects upon the cardiovascular system. Methamphetamine is metabolized to amphetamine, which is also a stimulant. Methamphetamine and amphetamine have similar effects to cocaine on the cardiovascular system. The heart may have such stress placed upon it that there are ischemic changes to the myocardial fibers. Chronic use leads to hypertrophy, interstitial fibrosis and microvascular disease. The myocardial effects are made worse by concomitant ethanol use. (Milroy and Parai, 2011)Heart with ischemic changes, microscopic.Amphetamines also damage both the serotonergic and dopaminergic systems of the central nervous system. Alterations of the dopaminergic system may persist even after years of abstinence from use of methamphetamine and may be associated with deficits in motor and cognitive performance. (Gouzoulis-Mayfrank and Daumann, 2009)CNS toxicity of methamphetamine may be the result of both hyperthermia as well as direct effects upon individual cells. A dose-related increase in body temperature occurs with acute ingestion of methamphetamine. This can potentiate acute effects of methamphetamine upon the blood-brain barrier and upon neurons, leading to edema. (Kiyatkin and Sharma, 2009)Methamphetamine and cocaine use can cause tooth decay that mainly affects the facial (outward) smooth and interproximal regions of teeth. The xerostomia patients experience may promote consumption of soft drinks with sugar. (Milroy and Parai, 2011)GHBGamma-hydroxybutyrate (GHB) is a metabolite of the neurotransmitter gamma aminobutyric acid (GABA) and also functions as a neurotransmitter by affecting the dopaminergic system. GHB may also potentiate the effects of endogenous or exogenous opiates. GHB was introduced into the U.S. in 1990 as a purported stimulant to muscle growth during sleep, but it was soon banned because of problems with overdose and adverse reactions. Moreover, GHB is no longer used as an anesthetic agent because of the risks. However, Gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are readily available as industrial solvents and when consumed are metabolized to GHB. The effects of GHB are primarily on the brain. GHB gained reputation as a euphoric and sexual performance enhancing agent. Its effects can be potentiated by alcohol and by benzodiazepines. The ingestion of GHB results in drowsiness and dizziness with the feeling of a "high" within 10 to 20 minutes and lasting up to 4 hours. There are a multitude of dose dependent adverse effects that can occur within 15 minutes to an hour, including: headache, nausea, vomiting, hallucinations, loss of peripheral vision, and nystagmus. These findings generally subside in 2 hours to 4 days. More severe acute toxicity includes respiratory depression, bradycardia, seizures, and reduced level of consciousness to deep coma. It is difficult to predict how much GHB will produce an overdose. Withdrawl from GHB can have an onset in 12 hours and last up to 12 days. In rare instances, deaths have occurred from these adverse effects. (Timby et al, 2000) (Tay et al, 2022)EcstasyThe methylene-dioxy derivatives of amphetamine and methamphetamine are "designer drugs" that generically are termed "ecstasy" and include 3,4-methylenedioxy-methamphetamine, also known as "Adam," 3,4-methylenedioxy-ethylamphetamine (MDEA), also known as "Eve," and N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB), also known as "Methyl-J" or "Eden." A "designer drug" is a compound that is chemically altered from the form of a controlled substance in order to produce special effects and to bypass legal regulations. MDMA and similar compounds are "entactogens" that act upon serotonergic pathways in the brain to give users a feeling of euphoria, energy, and a desire to socialize. These immediate effects last approximately 3 to 6 hours. (Fineschi et al, 1999) (Christophersen, 2000)The adverse effects of ecstasy use may include hyperthermia, liver toxicity, and neuropsychiatric effects. Severe dehydration leading to excessive fluid intake and water intoxication. Cardiovascular effects are similar to methamphetamine. There can be memory deficits, confusion, depression, and sleep problems even weeks after taking this drug. (Milroy and Parai, 2011)MDMA experimentally causes selective and persistent lesions of central serotonergic nerve terminals. MDMA users can have residual alterations of serotonergic transmission, and though at least partial recovery may occur after long-term abstinence, functional sequelae may persist even after longer periods of abstinence. Long term use may be accompanied by long-lasting brain damage and memory impairment. (Carter et al, 2000) (McQuire, 2000) (Gouzoulis-Mayfrank and Daumann, 2009)A syndrome including hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, hepatic failure, and renal failure has been reported with MDMA use, findings similar to the excited delirium of cocaine use. In addition persons using MDMA may develop acute fulminant hepatitis with liver failure, and possible death, that can occur days to weeks following drug use. (Scully et al, 2001)Cannabinoids (marijuana)Some of the most widely used psychoactive agents include derivatives from the hemp plantCannabis, typically containing the active compound delta-9-tetrahydrocannabinol (THC). The most common form is marijuana. Hashish is stronger, with more active drug. Throughout much of human history for the past 4000 years, preparations ofCannabiscontained small amounts of THC, less than 1%. In the latter part of the 20th century,Cannabisplants with higher THC concentrations and processing of the plants to yield more potent products with greater amounts of THC became widely employed. (Hall and Degenhardt, 2009)The plant products are typically smoked and the drug absorbed into the blood via respiratory tract. The drug acts through cannabinoid receptors in brain and elsewhere in the body. These receptors normally interact with short acting and less potent endogenous compounds (endocannabinoids) that affect brain function. THC induces mild euphoria, relaxation, and perceptual alterations for up to 2 hours following usage. The lifetime risk for THC dependence is about 9% and nearly double that for persons beginning regular use in adolescence. Only tobacco (32%) and alcohol (15%) dependence are more common. (Hall and Degenhardt, 2009)During adolescence, the brain undergoes modification of neurons with proliferation, migration, differentiation, and pruning of synapses that promote brain development for adulthood. Cannabinoids alter those processes and increase the risk for subsequent development of psychoses, including schizophrenia. (Malone et al, 2010) Adolescent users ofCannabisare less likely to complete schooling and more likely to become unemployed than nonusers. (Hall and Degenhardt, 2009)Acute adverse reactions to THC include anxiety, panic, and psychosis, more often in persons with no prior use of the drug. Impairments in attention, perception, and motor coordination affect ability to perform critical tasks such as operating a motor vehicle, increasing the risk for accidents. SinceCannabisis smoked, there are irritant effects upon the respiratory tract. There is risk for airway inflammation and for emphysema. (Murtha et al, 2022) There is risk for chronic bronchitis and lung cancer. Effects upon the cardiovascular system increase the risk for myocardial infarction in adults. (Hall and Degenhardt, 2009) A high-fat diet and ethanol use upregulate hepatic cannabinoid receptors so that THC may promote development of fatty liver. (Purohit et al, 2010)Some regularCannabisusers develop severe nausea with vomiting (cannabinoid hyperemesis) and the urge to bathe frequently in warm water for relief of these symptoms. Either the effects of the THC upon cannabinoid receptors near the thermoregulatory center of the hypothalamus, or upon cannabinoid receptors in splanchnic vasculature may play a role. The warm water exposure redirects blood flow to peripheral vasculature. (Patterson et al, 2010)Synthetic Cannabinoids (spice drugs)The so-called 'spice drugs' are synthetic cannabinoid compounds that can bind to brain cannibinoid receptors CB1 and CB2. Their structural chemistry is not like the tetrahydrocannabinol (THC) found in the cannabis of marijuana. Binding to the CB1 receptor produces strong but short-lived psychoactive effects and potential complications due to unknown pharmacologic effects and toxicity. They are 2 to 100 times more potent than THC because both parent drug and metabolites are potent THC receptor agonists, while marijuana is a partial agonist. (Liu et al, 2018) (Roque-Bravo et al, 2023)Adverse cardiovascular and pulmonary reactions reported include tachycardia, hypertension, chest pain, arrhythmias, tachypnea, cough, and dyspnea. Mental status changes include altered consciousness, hallucinations, racing thoughts, and seizures. Psychosis, withdrawal, and death have been reported with usage of these compounds. Users of these drugs are at risk due to their variability as well as their potency. As is the case with drugs of abuse in general, there is no safety factor of quality control in production or packaging, so the amount one is getting is unpredictable. (Roque-Bravo et al, 2023)Initially, synthetic cannabinoids were mainly JWH compounds (after the initials of the scientist who synthesized them) with predominantly sympathomimetic effects. Subsequently, compounds of the XLR-11 and CID families have appeared that produce CNS depressant effects and bradycardia. They are also full cannabinoid receptor agonists. The synthetic cannabinoids may not be detected by routine urine drug screening methods. (Sud et al, 2018)Synthetic Cathinones, or PABS ("bath salts")The synthetic cathinones are one form of "designer drug" with modified chemical structures from a natural form and designed to mimic or amplify the effect of a natural source psychostimulant. These compounds are typically sold as "bath salts" (PABS) but have nothing to do with bathing. Instead are psychoactive "uppers" that are synthetic forms of cathinones. Cathinone is a naturally occurring beta-ketone amphetamine analogue found in the leaves of theCatha edulisplant, indigenous to eastern Africa and the Arabian Peninsula, which is chewed as "khat" for a mild stimulant effect. (Daziani et al, 2023)Derivative synthetic cathinones being used as drugs of abuse include butylone, dimethylcathinone, ethcathinone, ethylone, 3- and 4-fluoromethcathinone, mephedrone, methedrone, methylenedioxypyrovalerone (MDPV), methylone, and pyrovalerone. They mainly contain methylenedioxypyrovalerone (MDPV), which is structurally related to pyrovalerone and pyrrolidinophenone compounds that inhibit norepinephrine-dopamine reuptake. Therefore, they cause central nervous system stimulation and sympathetic stimulation. They are marketed as aphrodisiacs and stimulants. (Prosser and Nelson, 2012)They are absorbed quickly through mucosal surfaces (nasal, oral, gastric, rectal). Only a few milligrams produce a high, but the quantities marketed may be 100 times that amount, increasing the risk for overdose. Their effects peak at 90 minutes following ingestion and last for 3 or 4 hours before the user "crashes". Long-term users of PABS may develop tolerance, and abstinence can lead to withdrawal and intense craving. (Ross et al, 2011)The toxicity from PABS may include extreme sympathetic stimulation with tachycardia, hypertension, shortness of breath, blurred vision, dry mouth, and hyperthermia. There can be markedly altered mental status with severe panic attacks, agitation, paranoia, hallucinations, and violent behavior such as self-mutilation, suicide attempts, and homicidal activity. Seizures may occur. Rhabdomyolysis can develop. Deaths have been reported, most often from alpha-pyrrolidinopentiophenone ("flakka"). The toxicity profile includes the worst effects of other drugs of abuse including lysergic acid diethylamide (LSD), phencyclidine (PCP), methylenedioxymethamphetamine ("ecstasy"), cocaine, and methamphetamine. Routine drug screens do not detect PABS. (Ross et al, 2011; Liu et al, 2018)Mitragynine ("kratom")The kratom plant grows in Southeast Asia and from it can be extracted the psychoactive alkyloid mitragynine, and in small quantities 7-hydromitragynine, which is more potent. At low doses it produces a stimulant effect. At high doses it has a sedative effect as an agonist at the mu opioid receptor. (Liu et al, 2018)Anabolic-Androgenic SteroidsThe use of anabolic-androgenic steroids (AAS) has increased substantially over the past 4 decades. These drugs are used mainly for their effect of increasing muscle mass for the desired goal of increasing athletic performance and enhancing physical appearance. However, such drugs do not increase the level of skill in performance and cardiovascular function--the major enhancers to most sports-related activities. (Sjöqvist et al, 2008) (Thirumalai and Anawalt, 2023)Both oral and injectable compounds are used, more often the latter. Users may cycle on and off usage to avoid complications, but prolonged usage brings many adverse effects. In men these include: testicular atrophy, decreased testosterone production, gynecomastia, decreased sex drive, infertility, baldness, hypertension, heart disease, and tendon injuries. In women, the adverse effects reported include: decreased breast size, fluid retention, hypertension, and sleep disorders. Physical changes such as testicular atrophy and gynecomastia in men, or breast atrophy in women, are often not reversible even after stopping the drugs. Adolescents taking AAS may have diminished bone growth and shorter stature. AAS may produce cholestatic jaundice; they reduce the level of HDL cholesterol to promote atherogenesis and heart disease. (Sjöqvist et al, 2008) (Thirumalai and Anawalt, 2023)The major psychiatric effects of AAS use include changes in mood, worse with greater usage. While using the drugs increased aggression and mania can occur. Off the drugs depression occurs. The combination resembles bipolar disorder, a disabling mental health disorder. Such adverse effects could significantly impact athletic performance negatively and decrease sexual function. In short, AAS can prevent the very things that they are supposed to enhance. (Thirumalai and Anawalt, 2023)The most serious complication of AAS use is an increased risk for heart disease and sudden death. Anabolic steroids decrease HDL cholesterol and increase cardiac size. Myocardial fibrosis can occur, similar to cardiomyopathy. Hypertension induced by AAS further increases heart size. These effects may persist even after use of AAS has been stopped, increasing the risk for morbidity and mortality. Anabolic steroids have been shown to enhance the coronary artery response to catecholamines released during periods of stress, and this may play a role in the sudden cardiac deaths reported with their use. Contraction band necrosis, indicative of ischemia, has been observed in such deaths. (Fineschi et al, 2001)The use of growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin at high, non-physiologic amounts, as anabolic hormonal substances has no significant effect upon increasing muscle mass. Instead, such compounds over time lead to disease states: acromegaly with disfiguring soft tissue changes, diabetes mellitus, hypertension, heart disease, and nerve damage. (García-Arnés and García-Casares, 2023)Improper methods of injection with lack of sterile technique increase the risk for transmissible infections, including viral hepatitis B, viral hepatitis C, and human immunodeficiency virus (HIV). (Thirumalai and Anawalt, 2023)Heart with hypertrophy, gross.Heart with myocardial contraction band necrosis, trichrome stain, microscopic.Testicular atrophy, gross.Testicular atrophy, microscopic.Gynecomastia, gross.Blood DopingIncreasing the amount of circulating red blood cells with their oxygen-carrying hemoglobin is a physiologic adaptation to living at a higher altitude with less atmospheric oxygen. Increasing hemoglobin by 10% will increase oxygen utilization (VO2max) by 5 to 10% for sports where endurance is essential. The quick method is blood transfusion. Such practices are banned in competitive sports, and there are continuing attempts by athletes to mask such practices while methods for detection continue to evolve. (García-Arnés and García-Casares, 2023)Why do sudden deaths occur in athletes who use human recombinant eryrthropoietin ("epo") but very infrequently in patients with anemia who really need it? The drug has predictable results in anemic patients, and raises red cell mass, but not typically above normal. In healthy persons, particularly athletes who do not need more erythropoietin, there are unpredictable results, including an increase in the number of red blood cells (RBCs) into a polycythemic range with increase in blood viscosity to the point of thrombosis (clotting). That could lead to stroke, myocardial infarction, retinal artery occlusion (blindness), and pulmonary thromboembolism. There is also another rare but frightening complication: the development of antibodies, not only to the human recombinant form but also naturally occurring erythropoietin, leading to a condition called "pure red cell aplasia" with transfusion dependence for life. How is the recombinant form detected? The recombinant products include glycan isoforms that differ from natural erythropoietin, and those can be detected in a urine sample. (John et al, 2012) (García-Arnés and García-Casares, 2023)Laboratory TestingTesting for the presence of drugs can be performed on body fluids, principally urine and blood. Urine is easier to obtain, and it is likely to contain both drugs and their metabolites, but detection is qualitativem, since quantification is modified by fluid intake. Blood is obtained when quantification is needed, as for blood ethanol.Screening can include immunoassays that require less equipment and skill in interpretation, but may have cross-reactivity with related drugs that may not be classified as drugs of abuse (e.g., codeine in cough medicines can cross react with opiate drugs of abuse).Confirmation of screening test results, or primary detection of compounds not easily detected by other means, is done by mass spectroscopy (MS). 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Acute methamphetamine intoxication brain hyperthermia, blood-brain barrier, brain edema, and morphological cell abnormalities. Int Rev Neurobiol. 2009;88:65-100.Krishnasamy VP, Hallowell BD, Ko JY, et al. Update: Characteristics of a Nationwide Outbreak of E-cigarette, or Vaping, Product Use–Associated Lung Injury — United States, August 2019–January 2020. MMWR Morb Mortal Wkly Rep 2020;69:90–94. DOI: http://dx.doi.org/10.15585/mmwr.mm6903e2.Kuczkowski KM. The effects of drug abuse on pregnancy. Curr Opin Obstet Gynecol. 2007;19:578-585.Liu L, Wheeler SE, Venkataramanan R, Rymer JA, Pizon AF, Lynch MJ, Tamama K. Newly emerging drugs of abuse and their detection methods: an ACLPS critical review. Am J Clin Pathol. 2018;149(2):105-116.Malone DT, Hill MN, Rubino T. Adolescent cannabis use and psychosis: epidemiology and neurodevelopmental models. Br J Pharmacol. 2010;160:511-522.Marks LR, Nolan NS, Liang SY, Durkin MJ, Weimer MB. Infectious Complications of Injection Drug Use. 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Clin Liver Dis. 2023 Feb;27(1):157-172. doi: 10.1016/j.cld.2022.08.005.Patterson DA, Smith E, Monahan M, Medvecz A, Hagerty B, Krijger L, Chauhan A, Walsh M. Cannabinoid hyperemesis and compulsive bathing: a case series and paradoxical pathophysiological explanation. J Am Board Fam Med. 2010;23:790-793.Popova S, Charness ME, Burd L, Crawford A, Hoyme HE, Mukherjee RAS, Riley EP, Elliott EJ. Fetal alcohol spectrum disorders. Nat Rev Dis Primers. 2023 Feb 23;9(1):11. doi: 10.1038/s41572-023-00420-x.Prosser JM, Nelson LS. The toxicology of bath salts: a review of synthetic cathinones. J Med Toxicol. 2012 Mar;8(1):33-42.Purohit V, Rapaka R, Shurtleff D. Role of cannabinoids in the development of fatty liver (steatosis). AAPS J. 2010;12:233-237.Roque-Bravo R, Silva RS, Malheiro RF, Carmo H, Carvalho F, da Silva DD, Silva JP. Synthetic Cannabinoids: A Pharmacological and Toxicological Overview. Annu Rev Pharmacol Toxicol. 2023 Jan 20;63:187-209. doi: 10.1146/annurev-pharmtox-031122-113758.Ross EA, Watson M. Goldberger B. "Bath salts" intoxication. N Engl J Med 2011; 365:967-968.Salihu HM, Wilson RE. Epidemiology of prenatal smoking and perinatal outcomes. Early Hum Dev. 2007;83:713-720.Scully RE, Mark EJ, McNeely WF, et al. Case 6-2001: Case records of the Massachusetts General Hospital. New Engl J Med. 2001;344:591-599.Sjöqvist F, Garle M, Rane A. Use of doping agents, particularly anabolic steroids, in sports and society. Lancet. 2008;371:1872-1882.Stockley J, Sapey E, Gompertz S, Edgar R, Cooper B. Pilot data of the short-term effects of e-cigarrette vaping on lung function. European Respiratory Journal. 2018, 52 (suppl 62) PA2420; DOI: 10.1183/13993003.congress-2018.PA2420.Sud P, Gordon M, Tortora L, Stripp M, Borg D, Berman A. Retrospective Chart Review of Synthetic Cannabinoid Intoxication with Toxicologic Analysis. West J Emerg Med. 2018 May;19(3):567-572.Tay E, Lo WKW, Murnion B. Current Insights on the Impact of Gamma-Hydroxybutyrate (GHB) Abuse. Subst Abuse Rehabil. 2022 Feb 9;13:13-23. doi: 10.2147/SAR.S315720.Timby N, Eriksson A, Bostrom K. Gamma-hydroxybutyrate associated deaths. Am J Med. 2000;108:518-519.Torres-Lockhart KE, Lu TY, Weimer MB, Stein MR, Cunningham CO. Clinical Management of Opioid Withdrawal. Addiction. 2022 Sep;117(9):2540-2550. doi: 10.1111/add.15818.Walter K. Fentanyl Overdose. JAMA. 2023 Jan 10;329(2):184. doi: 10.1001/jama.2022.22462.Walley SC, Wilson KM, Winickoff JP, Groner J. A public health crisis: electronic cigarettes, vape, and JUUL. Pediatrics. 2019;143(6). pii: e20182741. doi: 10.1542/peds.2018-2741. +Tobacco and Smoking +Smoking tobacco leads to the greatest number of problems of any drug in use in the world today. Smoking contributes to more than 7 million deaths each year worldwide. These deaths are mainly the result of increased numbers of lung cancers as well as increased numbers of cases of atherosclerotic heart disease and emphysema of the lung. Smoking increases the risk for cancers of the bladder, pancreas, kidney, and cervix. There is an increased risk for gastritis and gastric ulceration in persons who smoke. Cataracts of the crystalline lens of the eye occur with increased frequency in smokers. (GBD, 2017) +Women who are pregnant and who smoke put their fetuses at increased risk for spontaneous abortion, ectopic pregnancy, placental abruption, placenta praevia, premature labor, and preterm birth, stillbirth,low birth weight, and small for gestational age (SGA) compared to women who do not smoke during pregnancy. Prenatal maternal smoking is also associated with risk of sudden unexplained death in infancy. (Gould et al, 2020) +Normal lung, gross. +Small cell anaplastic (oat cell) carcinoma of lung, gross. +Squamous cell carcinoma of lung, gross. +Emphysema, centrilobular type, gross. +Emphysema, representing a modern version of "The Masque of the Red Death" in Edgar Allen Poe's short story. +Composite photograph with a narrowed coronary artery at the left and a markedly narrowed coronary artery at the right, microscopic. +Pelvis of kidney, urothelial carcinoma, gross. +Acute gastric ulcerations, gross. +Hyaline membrane disease in the lung of a premature neonate, microscopic. +Electronic cigarettes (e-cigarettes) produce an inhaled vapor. The major chemical component of the vapor is nicotine, but additional toxic constituents include metals, volatile organic compounds (VOCs such as benzene and toluene), nitrosamines, and Vitamin E acetate (VEA). Thus, the substitution of vaping for traditional cigarette smoking does not eliminate health hazards, but only trade one set of problems for another set. Nicotine by itself is highly addictive and promotes continued usage, leading to more exposure to the additional toxic compounds inhaled with the nicotine. Adolescent brains are more susceptible to this addiction. Persons using e-cigarettes are more likely to also use traditional tobacco products, compounding health risks. (Walley et al, 2019)E-cigarette use is linked to poisoning, immediate inhalation toxicity, and lung injury. Environmental effects include waste, fires, and generation of indoor airborne particulate matter. The nicotine e-cigarettes can cause dependence in non-smokers, and young non-smokers who use e-cigarettes are more likely than non-users to initiate smoking and to become regular smokers. (Banks et al, 2023)Short-term health risks of e-cigarettes include increased airway resistance and increased exhaled carbon monoxide (CO). CO binds to hemoglobin tightly to displace oxygen. Airway resistance reduces optimal lung function. (Stockley et al, 2018)Radiologic imaging studies document a variety of lung injury patterns associated with vaping. Patterns include hypersensitivity pneumonitis, diffuse alveolar hemorrhage, diffuse alveolar damage, acute eosinophilic pneumonia, giant cell interstitial pneumonia, and lipid pneumonia. These injuries can acutely lead to diminished lung function. A more long-term pattern of injury is organizing pneumonia with fibroblast proliferation and collagen deposition - features of scar tissue formation that reduces lung capacity. (Henry et al, 2019)Pathologic findings with vaping confirm the imaging patterns. Acute lung injury patterns include diffuse alveolar damage and organizing pneumonia. Microscopic pathologic findings include bronchiolitis, mucosal edema, sloughing of the bronchiolar epithelium, eosinophils, and peribronchiolar organization following accumulation of macrophages. There can be fibrinous exudates and type 2 pneumocyte hyperplasia. More severe injury can lead to diffuse alveolar damage with formation of hyaline membranes. There can be progression to chronic inflammation and fibroblast plugs in bronchioles. Clinical features associated with these pathologic alterations include fever, night sweats, weight loss, dyspnea, cough, nausea, and vomiting. (Butt et al, 2019) (Mukhopadhyay et al, 2020)EVALI (e-cigarette or vaping product use associated lung injury) describes the acute respiratory illness related to toxic effects of substances inhaled in vaping. Findings include shortness of breath, cough, chest pain, and fever, along with hypoxia and tachycardia. The inhaled compounds can produce toxic effects upon cells in the respiratory tract and induce neutrophilic inflammation. Thus, EVALI can mimic infectious diseases of the lungs, and should be considered in persons with recent e-cigarette use. (Krishnasamy et al, 2020) (Park et al, 2022)Alcohol AbuseThe abuse of alcohol (ethanol) contributes to many deaths per year worldwide. It can also be a cause for drug overdose leading to death from ingestion of a large amount of alcohol, and second only to opioid overdose in number of drug-related deaths. Almost 1 in 5 visits to an emergency department involve prior use of alcohol. (https://www.niaaa.nih.gov/alcohols-effects-health/alcohol-topics/alcohol-facts-and-statistics/alcohol-related-emergencies-and-deaths-united-states)Chronic alcohol use leads to liver disease that can be manifested initially as fatty change (steatosis). Excessive alcohol ingestion over many years can lead to micronodular cirrhosis. A cirrhotic liver leads to portal hypertension and the complication of bleeding esophageal varices with massive, life-threatening gastrointestinal hemorrhage. There is also an increased risk for hepatocellular carcinoma arising in a cirrhotic liver. Acute excessive alcohol consumption can lead to alcoholic hepatitis. Laboratory testing of a blood specimen for evidence of ethanol ingestion includes phosphatidylethanol for recent (within 2 weeks) and carbohydrate-deficient transferrin for chronic use. (Patel and Flamm, 2023)In the brain, alcohol use disorder predisposing to poor dietary intake lacking nutrients can lead to thiamine deficiency with neurotoxicity and development of Wernicke–Korsakoff syndrome (WKS), with components of Wernicke encephalopathy and Korsakoff’s psychosis, with higher mental function affected by confusion and confabulation. Acute Wernicke encephalopathy is a potentially reversible condition characterized by confusion, oculomotor disturbances, and ataxia. Continued alcohol use leads to permanent brain damage. (Nutt et al, 2021)Abrupt cessation of alcohol ingestion in persons who are chronic alcohol users predisposes to alcohol withdrawal Symptoms, and signs within 8 to 24 hours include transient visual, auditory or tactile hallucinations. There can be progression to withdrawal-related seizures which, if not treated may progress to life-threatening delirium tremens. (Day and Daly, 2022)Alcohol use during pregnancy can lead to fetal alcohol spectrum disorders, also termed the fetal alcohol syndrome (FAS). The risk increases with the time and amount of exposure, but there is no completely safe level of maternal alcohol consumption. This syndrome is estimated to occur in 1 in 100 live births, but the actual incidence is probably higher. Whenever a pregnant woman stops drinking, she reduces the risk of having a baby with FAS. Damage to the fetus from FAS cannot be reversed. Later in development, affected children have increased behavioral problems and learning disabilities. There are no specific, distinctive morphologic findings, so it is challenging to diagnose. The most common deformity with FAS is moderate to severe growth retardation. The three most distinctive features are a thin upper lip, smooth philtrum, and short palpebral fissures. (Popova et al, 2023)Additional FAS anomalies include microcephaly, long and narrow forehead, hypotelorism, maxillary and mandibular hypoplasia, narrow palpebal fissures, thin elongated philtrum and vermillion border of the upper lip, temporomandibular joint disorders, and dental malocclusion. Ocular problems include microphthalmia, coloboma, nystagmus, strabismus, and ptosis. The physical anomalies tend to become less apparent as the child ages. (Mukherjee et al, 2006)Normal liver, gross.Fatty change of liver, microscopic.Micronodular cirrhosis of liver, gross.Micronodular cirrhosis of liver, microscopic.Hepatocellular carcinoma, liver with micronodular cirrhosis, gross.Esophageal varices, gross.Wernicke's disease, hemorrhages in the mammillary bodies, gross.OpiatesOpiates by themselves have minimal pathologic tissue effects. Higher doses of more powerful opiates can lead to respiratory depression and death. Persons who really need the pain relief that opiate medications can offer do not become addicted, but unfortunately tolerance may develop over time, requiring higher doses to maintain analgesia. The major problems with opiate abuse are the psychosocial consequences, the infections from route of administration (injection), and possible overdose with death. (Torres-Lockhart et al, 2022)An opioid epidemic in the 21st century has been driven by increasing demand and increasing supply, particularly of synthetic opioid compounds. The prescription opiate most often abused is fentanyl, which has great affinity for the mu opioid receptor, and is 80 to 100 times more potent than morphine, producing an intense, temporary euphoria. (Liu et al, 2018) An overdose is treated with naloxone, and the synthetic opioids require higher doses of naloxone. (Walker, 2023) In the U.S. in 2022, of over 100,000 deaths from drug overdose, about 80% were due to opiates, mainly synthetic opioids. (https://blogs.cdc.gov/nchs/2023/05/18/7365/)Psychosocial problems related to behavioral issues from drug dependence. Drug-seeking behaviors result in lack of concern for oneself or others. If the route of administration is intravenous, without attention to sterile technique, there is increased risk for infection. Withdrawl from chronic opiate usage typically results in marked physiologic and psychologic disturbances such as pupillary dilation, tachycardia, yawning, lacrimation, rhinorrhea, piloerection, abdominal cramping, nausea, vomiting, diarrhea, muscle or bone pain, irritability, restlessness, anxiety, and insomnia. (Torres-Lockhart et al, 2022)Oxycodone, best known by the trade name OxyContin®, is a controlled release form of opioid analgesic prescribed to treat moderate to severe pain of constant and prolonged duration. Persons abusing this medication risk addiction and death, particularly if oxycodone is used in association with other drugs. Abusers may progress to usage by intravenous injection and to usage of other opiates or drugs of abuse. (Hays, 2004)Intravenous Drug AbuseMany drugs can be injected intravenously. The drugs themselves may have the major effect of impairment of mental function, but the route of administration can have serious complications. Injection of drugs with needles that are not sterile leads to the potential for a wide variety of infections. Such infections include: human immunodeficiency virus (the causative agent for AIDS), viral hepatitis (particularly hepatitis B and C), and bacterial infections. (Marks et al, 2022)Persons with a history of intravenous drug abuse also are more likely to have tuberculosis of the lungs. The drug heroin can produce a nephropathy in the kidney that resembles focal segmental glomerulosclerosis. In addition, a "talc granulomatosis" can occur because many injected drugs have been adulterated with an inert substance (such as talcum powder) to "cut" or dilute the amount of drug. (Milroy and Parai, 2011)Normal aortic valve compared with infective endocarditis, gross.Surface of the brain with acute meningitis, gross.Viral hepatitis of the liver, gross.Viral hepatitis of the liver, microscopic.Macronodular cirrhosis of the liver, gross.Mycobacterium tuberculosis, lung, cavitary disease, gross.Glomerulus of kidney demonstrating focal scarring with heroin nephropathy, microscopic.Talc granulomatosis of the liver, gross.Talc granulomatosis of the lungs, polarized light, microscopic.CocaineCocaine can exert a variety of effects. The major acute effects producing pathologic conditions result from the increased circulating catecholamine levels with cocaine use. These increased catecholamines can produce vasoconstriction. The lesions can include acute hemorrhages and infarction in the brain. Cerebral infarction can occur within 3 hours of cocaine use even in young persons. Subarachnoid haemorrhage is often associated with rupture of a berry aneurysm. Intraparenchymal haemorrhage can occur in the basal ganglia and thalamus. (Milroy and Parai, 2011)Ischemic changes in the heart from small artery narrowing and sclerosis lead to contraction band necrosis of the myocardium and possible sudden death. With chronic usage, the myocardium develops interstitial fibrosis, and the heart becomes enlarged. Atheroma formation in artereis as well as arterial dissection can occur. (Milroy and Parai, 2011) Combining cocaine use with ethanol use can compound the myocardial damage. (Awtry and Philippides, 2010)Pregnant mothers who use cocaine can affect their fetuses from abnormalities of placental function leading to low birth weight babies or an increased risk for placental abruption. Maternal cocaine use increases the risk for spontaneous abortion. (Kuczkowski, 2007)Persons with cocaine intoxication (not necessarily related to the drug level) may develop a state of iatrogenic psychosis (cocaine psychosis) with "excited delerium" in which they are markedly agitated and combative and develop hyperthermia, often of a severe degree (to 106 F). Organ damage can accompany this state of excited delerium and may include rhabdomyolysis of muscle, hepatotoxicity, and renal failure. Disseminated intravascular coagulation (DIC), hypotension, and sudden death are additional complications. (Devlin and Henry, 2008)Massive intracerebral hemorrhage associated with cocaine use, gross.Cerebral infarction, gross.Heart with myocardial contraction band necrosis, microscopic.Heart with peripheral coronary artery sclerosis, microscopic.Abruptio placenta with large recent blood clot compressing the parenchyma, gross.MethamphetamineMethampetamine is a stimulant drug with inotropic effects upon the cardiovascular system. Methamphetamine is metabolized to amphetamine, which is also a stimulant. Methamphetamine and amphetamine have similar effects to cocaine on the cardiovascular system. The heart may have such stress placed upon it that there are ischemic changes to the myocardial fibers. Chronic use leads to hypertrophy, interstitial fibrosis and microvascular disease. The myocardial effects are made worse by concomitant ethanol use. (Milroy and Parai, 2011)Heart with ischemic changes, microscopic.Amphetamines also damage both the serotonergic and dopaminergic systems of the central nervous system. Alterations of the dopaminergic system may persist even after years of abstinence from use of methamphetamine and may be associated with deficits in motor and cognitive performance. (Gouzoulis-Mayfrank and Daumann, 2009)CNS toxicity of methamphetamine may be the result of both hyperthermia as well as direct effects upon individual cells. A dose-related increase in body temperature occurs with acute ingestion of methamphetamine. This can potentiate acute effects of methamphetamine upon the blood-brain barrier and upon neurons, leading to edema. (Kiyatkin and Sharma, 2009)Methamphetamine and cocaine use can cause tooth decay that mainly affects the facial (outward) smooth and interproximal regions of teeth. The xerostomia patients experience may promote consumption of soft drinks with sugar. (Milroy and Parai, 2011)GHBGamma-hydroxybutyrate (GHB) is a metabolite of the neurotransmitter gamma aminobutyric acid (GABA) and also functions as a neurotransmitter by affecting the dopaminergic system. GHB may also potentiate the effects of endogenous or exogenous opiates. GHB was introduced into the U.S. in 1990 as a purported stimulant to muscle growth during sleep, but it was soon banned because of problems with overdose and adverse reactions. Moreover, GHB is no longer used as an anesthetic agent because of the risks. However, Gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are readily available as industrial solvents and when consumed are metabolized to GHB. The effects of GHB are primarily on the brain. GHB gained reputation as a euphoric and sexual performance enhancing agent. Its effects can be potentiated by alcohol and by benzodiazepines. The ingestion of GHB results in drowsiness and dizziness with the feeling of a "high" within 10 to 20 minutes and lasting up to 4 hours. There are a multitude of dose dependent adverse effects that can occur within 15 minutes to an hour, including: headache, nausea, vomiting, hallucinations, loss of peripheral vision, and nystagmus. These findings generally subside in 2 hours to 4 days. More severe acute toxicity includes respiratory depression, bradycardia, seizures, and reduced level of consciousness to deep coma. It is difficult to predict how much GHB will produce an overdose. Withdrawl from GHB can have an onset in 12 hours and last up to 12 days. In rare instances, deaths have occurred from these adverse effects. (Timby et al, 2000) (Tay et al, 2022)EcstasyThe methylene-dioxy derivatives of amphetamine and methamphetamine are "designer drugs" that generically are termed "ecstasy" and include 3,4-methylenedioxy-methamphetamine, also known as "Adam," 3,4-methylenedioxy-ethylamphetamine (MDEA), also known as "Eve," and N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB), also known as "Methyl-J" or "Eden." A "designer drug" is a compound that is chemically altered from the form of a controlled substance in order to produce special effects and to bypass legal regulations. MDMA and similar compounds are "entactogens" that act upon serotonergic pathways in the brain to give users a feeling of euphoria, energy, and a desire to socialize. These immediate effects last approximately 3 to 6 hours. (Fineschi et al, 1999) (Christophersen, 2000)The adverse effects of ecstasy use may include hyperthermia, liver toxicity, and neuropsychiatric effects. Severe dehydration leading to excessive fluid intake and water intoxication. Cardiovascular effects are similar to methamphetamine. There can be memory deficits, confusion, depression, and sleep problems even weeks after taking this drug. (Milroy and Parai, 2011)MDMA experimentally causes selective and persistent lesions of central serotonergic nerve terminals. MDMA users can have residual alterations of serotonergic transmission, and though at least partial recovery may occur after long-term abstinence, functional sequelae may persist even after longer periods of abstinence. Long term use may be accompanied by long-lasting brain damage and memory impairment. (Carter et al, 2000) (McQuire, 2000) (Gouzoulis-Mayfrank and Daumann, 2009)A syndrome including hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, hepatic failure, and renal failure has been reported with MDMA use, findings similar to the excited delirium of cocaine use. In addition persons using MDMA may develop acute fulminant hepatitis with liver failure, and possible death, that can occur days to weeks following drug use. (Scully et al, 2001)Cannabinoids (marijuana)Some of the most widely used psychoactive agents include derivatives from the hemp plantCannabis, typically containing the active compound delta-9-tetrahydrocannabinol (THC). The most common form is marijuana. Hashish is stronger, with more active drug. Throughout much of human history for the past 4000 years, preparations ofCannabiscontained small amounts of THC, less than 1%. In the latter part of the 20th century,Cannabisplants with higher THC concentrations and processing of the plants to yield more potent products with greater amounts of THC became widely employed. (Hall and Degenhardt, 2009)The plant products are typically smoked and the drug absorbed into the blood via respiratory tract. The drug acts through cannabinoid receptors in brain and elsewhere in the body. These receptors normally interact with short acting and less potent endogenous compounds (endocannabinoids) that affect brain function. THC induces mild euphoria, relaxation, and perceptual alterations for up to 2 hours following usage. The lifetime risk for THC dependence is about 9% and nearly double that for persons beginning regular use in adolescence. Only tobacco (32%) and alcohol (15%) dependence are more common. (Hall and Degenhardt, 2009)During adolescence, the brain undergoes modification of neurons with proliferation, migration, differentiation, and pruning of synapses that promote brain development for adulthood. Cannabinoids alter those processes and increase the risk for subsequent development of psychoses, including schizophrenia. (Malone et al, 2010) Adolescent users ofCannabisare less likely to complete schooling and more likely to become unemployed than nonusers. (Hall and Degenhardt, 2009)Acute adverse reactions to THC include anxiety, panic, and psychosis, more often in persons with no prior use of the drug. Impairments in attention, perception, and motor coordination affect ability to perform critical tasks such as operating a motor vehicle, increasing the risk for accidents. SinceCannabisis smoked, there are irritant effects upon the respiratory tract. There is risk for airway inflammation and for emphysema. (Murtha et al, 2022) There is risk for chronic bronchitis and lung cancer. Effects upon the cardiovascular system increase the risk for myocardial infarction in adults. (Hall and Degenhardt, 2009) A high-fat diet and ethanol use upregulate hepatic cannabinoid receptors so that THC may promote development of fatty liver. (Purohit et al, 2010)Some regularCannabisusers develop severe nausea with vomiting (cannabinoid hyperemesis) and the urge to bathe frequently in warm water for relief of these symptoms. Either the effects of the THC upon cannabinoid receptors near the thermoregulatory center of the hypothalamus, or upon cannabinoid receptors in splanchnic vasculature may play a role. The warm water exposure redirects blood flow to peripheral vasculature. (Patterson et al, 2010)Synthetic Cannabinoids (spice drugs)The so-called 'spice drugs' are synthetic cannabinoid compounds that can bind to brain cannibinoid receptors CB1 and CB2. Their structural chemistry is not like the tetrahydrocannabinol (THC) found in the cannabis of marijuana. Binding to the CB1 receptor produces strong but short-lived psychoactive effects and potential complications due to unknown pharmacologic effects and toxicity. They are 2 to 100 times more potent than THC because both parent drug and metabolites are potent THC receptor agonists, while marijuana is a partial agonist. (Liu et al, 2018) (Roque-Bravo et al, 2023)Adverse cardiovascular and pulmonary reactions reported include tachycardia, hypertension, chest pain, arrhythmias, tachypnea, cough, and dyspnea. Mental status changes include altered consciousness, hallucinations, racing thoughts, and seizures. Psychosis, withdrawal, and death have been reported with usage of these compounds. Users of these drugs are at risk due to their variability as well as their potency. As is the case with drugs of abuse in general, there is no safety factor of quality control in production or packaging, so the amount one is getting is unpredictable. (Roque-Bravo et al, 2023)Initially, synthetic cannabinoids were mainly JWH compounds (after the initials of the scientist who synthesized them) with predominantly sympathomimetic effects. Subsequently, compounds of the XLR-11 and CID families have appeared that produce CNS depressant effects and bradycardia. They are also full cannabinoid receptor agonists. The synthetic cannabinoids may not be detected by routine urine drug screening methods. (Sud et al, 2018)Synthetic Cathinones, or PABS ("bath salts")The synthetic cathinones are one form of "designer drug" with modified chemical structures from a natural form and designed to mimic or amplify the effect of a natural source psychostimulant. These compounds are typically sold as "bath salts" (PABS) but have nothing to do with bathing. Instead are psychoactive "uppers" that are synthetic forms of cathinones. Cathinone is a naturally occurring beta-ketone amphetamine analogue found in the leaves of theCatha edulisplant, indigenous to eastern Africa and the Arabian Peninsula, which is chewed as "khat" for a mild stimulant effect. (Daziani et al, 2023)Derivative synthetic cathinones being used as drugs of abuse include butylone, dimethylcathinone, ethcathinone, ethylone, 3- and 4-fluoromethcathinone, mephedrone, methedrone, methylenedioxypyrovalerone (MDPV), methylone, and pyrovalerone. They mainly contain methylenedioxypyrovalerone (MDPV), which is structurally related to pyrovalerone and pyrrolidinophenone compounds that inhibit norepinephrine-dopamine reuptake. Therefore, they cause central nervous system stimulation and sympathetic stimulation. They are marketed as aphrodisiacs and stimulants. (Prosser and Nelson, 2012)They are absorbed quickly through mucosal surfaces (nasal, oral, gastric, rectal). Only a few milligrams produce a high, but the quantities marketed may be 100 times that amount, increasing the risk for overdose. Their effects peak at 90 minutes following ingestion and last for 3 or 4 hours before the user "crashes". Long-term users of PABS may develop tolerance, and abstinence can lead to withdrawal and intense craving. (Ross et al, 2011)The toxicity from PABS may include extreme sympathetic stimulation with tachycardia, hypertension, shortness of breath, blurred vision, dry mouth, and hyperthermia. There can be markedly altered mental status with severe panic attacks, agitation, paranoia, hallucinations, and violent behavior such as self-mutilation, suicide attempts, and homicidal activity. Seizures may occur. Rhabdomyolysis can develop. Deaths have been reported, most often from alpha-pyrrolidinopentiophenone ("flakka"). The toxicity profile includes the worst effects of other drugs of abuse including lysergic acid diethylamide (LSD), phencyclidine (PCP), methylenedioxymethamphetamine ("ecstasy"), cocaine, and methamphetamine. Routine drug screens do not detect PABS. (Ross et al, 2011; Liu et al, 2018)Mitragynine ("kratom")The kratom plant grows in Southeast Asia and from it can be extracted the psychoactive alkyloid mitragynine, and in small quantities 7-hydromitragynine, which is more potent. At low doses it produces a stimulant effect. At high doses it has a sedative effect as an agonist at the mu opioid receptor. (Liu et al, 2018)Anabolic-Androgenic SteroidsThe use of anabolic-androgenic steroids (AAS) has increased substantially over the past 4 decades. These drugs are used mainly for their effect of increasing muscle mass for the desired goal of increasing athletic performance and enhancing physical appearance. However, such drugs do not increase the level of skill in performance and cardiovascular function--the major enhancers to most sports-related activities. (Sjöqvist et al, 2008) (Thirumalai and Anawalt, 2023)Both oral and injectable compounds are used, more often the latter. Users may cycle on and off usage to avoid complications, but prolonged usage brings many adverse effects. In men these include: testicular atrophy, decreased testosterone production, gynecomastia, decreased sex drive, infertility, baldness, hypertension, heart disease, and tendon injuries. In women, the adverse effects reported include: decreased breast size, fluid retention, hypertension, and sleep disorders. Physical changes such as testicular atrophy and gynecomastia in men, or breast atrophy in women, are often not reversible even after stopping the drugs. Adolescents taking AAS may have diminished bone growth and shorter stature. AAS may produce cholestatic jaundice; they reduce the level of HDL cholesterol to promote atherogenesis and heart disease. (Sjöqvist et al, 2008) (Thirumalai and Anawalt, 2023)The major psychiatric effects of AAS use include changes in mood, worse with greater usage. While using the drugs increased aggression and mania can occur. Off the drugs depression occurs. The combination resembles bipolar disorder, a disabling mental health disorder. Such adverse effects could significantly impact athletic performance negatively and decrease sexual function. In short, AAS can prevent the very things that they are supposed to enhance. (Thirumalai and Anawalt, 2023)The most serious complication of AAS use is an increased risk for heart disease and sudden death. Anabolic steroids decrease HDL cholesterol and increase cardiac size. Myocardial fibrosis can occur, similar to cardiomyopathy. Hypertension induced by AAS further increases heart size. These effects may persist even after use of AAS has been stopped, increasing the risk for morbidity and mortality. Anabolic steroids have been shown to enhance the coronary artery response to catecholamines released during periods of stress, and this may play a role in the sudden cardiac deaths reported with their use. Contraction band necrosis, indicative of ischemia, has been observed in such deaths. (Fineschi et al, 2001)The use of growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin at high, non-physiologic amounts, as anabolic hormonal substances has no significant effect upon increasing muscle mass. Instead, such compounds over time lead to disease states: acromegaly with disfiguring soft tissue changes, diabetes mellitus, hypertension, heart disease, and nerve damage. (García-Arnés and García-Casares, 2023)Improper methods of injection with lack of sterile technique increase the risk for transmissible infections, including viral hepatitis B, viral hepatitis C, and human immunodeficiency virus (HIV). (Thirumalai and Anawalt, 2023)Heart with hypertrophy, gross.Heart with myocardial contraction band necrosis, trichrome stain, microscopic.Testicular atrophy, gross.Testicular atrophy, microscopic.Gynecomastia, gross.Blood DopingIncreasing the amount of circulating red blood cells with their oxygen-carrying hemoglobin is a physiologic adaptation to living at a higher altitude with less atmospheric oxygen. Increasing hemoglobin by 10% will increase oxygen utilization (VO2max) by 5 to 10% for sports where endurance is essential. The quick method is blood transfusion. Such practices are banned in competitive sports, and there are continuing attempts by athletes to mask such practices while methods for detection continue to evolve. (García-Arnés and García-Casares, 2023)Why do sudden deaths occur in athletes who use human recombinant eryrthropoietin ("epo") but very infrequently in patients with anemia who really need it? The drug has predictable results in anemic patients, and raises red cell mass, but not typically above normal. In healthy persons, particularly athletes who do not need more erythropoietin, there are unpredictable results, including an increase in the number of red blood cells (RBCs) into a polycythemic range with increase in blood viscosity to the point of thrombosis (clotting). That could lead to stroke, myocardial infarction, retinal artery occlusion (blindness), and pulmonary thromboembolism. There is also another rare but frightening complication: the development of antibodies, not only to the human recombinant form but also naturally occurring erythropoietin, leading to a condition called "pure red cell aplasia" with transfusion dependence for life. How is the recombinant form detected? The recombinant products include glycan isoforms that differ from natural erythropoietin, and those can be detected in a urine sample. (John et al, 2012) (García-Arnés and García-Casares, 2023)Laboratory TestingTesting for the presence of drugs can be performed on body fluids, principally urine and blood. Urine is easier to obtain, and it is likely to contain both drugs and their metabolites, but detection is qualitativem, since quantification is modified by fluid intake. Blood is obtained when quantification is needed, as for blood ethanol.Screening can include immunoassays that require less equipment and skill in interpretation, but may have cross-reactivity with related drugs that may not be classified as drugs of abuse (e.g., codeine in cough medicines can cross react with opiate drugs of abuse).Confirmation of screening test results, or primary detection of compounds not easily detected by other means, is done by mass spectroscopy (MS). The first step is chromatography for separation of the drug compounds in a gas phase (gas chromatography (GC) or liquid phase (liquid chromatography, or LC). the next step is mass spectroscopic analysis of the separated compounds. Thus, the method can be GC-MS or LC-MS. (Liu et al, 2018)ReferencesAwtry EH, Philippides GJ. Alcoholic and cocaine-associated cardiomyopathies. Prog Cardiovasc Dis. 2010;52:289-299.Banks E, Yazidjoglou A, Brown S, et al. Electronic cigarettes and health outcomes: umbrella and systematic review of the global evidence. Med J Aust. 2023 Apr 3;218(6):267-275. doi: 10.5694/mja2.51890.Bedene A, Dahan A, Rosendaal FR, van Dorp ELA. Opioid epidemic: lessons learned and updated recommendations for misuse involving prescription versus non-prescription opioids. Expert Rev Clin Pharmacol. 2022 Sep;15(9):1081-1094. doi: 10.1080/17512433.2022.2114898.Butt YM, Smith ML, Tazelaar HD, et al.Pathology of Vaping-Associated Lung Injury. 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West J Emerg Med. 2018 May;19(3):567-572.Tay E, Lo WKW, Murnion B. Current Insights on the Impact of Gamma-Hydroxybutyrate (GHB) Abuse. Subst Abuse Rehabil. 2022 Feb 9;13:13-23. doi: 10.2147/SAR.S315720.Timby N, Eriksson A, Bostrom K. Gamma-hydroxybutyrate associated deaths. Am J Med. 2000;108:518-519.Torres-Lockhart KE, Lu TY, Weimer MB, Stein MR, Cunningham CO. Clinical Management of Opioid Withdrawal. Addiction. 2022 Sep;117(9):2540-2550. doi: 10.1111/add.15818.Walter K. Fentanyl Overdose. JAMA. 2023 Jan 10;329(2):184. doi: 10.1001/jama.2022.22462.Walley SC, Wilson KM, Winickoff JP, Groner J. A public health crisis: electronic cigarettes, vape, and JUUL. Pediatrics. 2019;143(6). pii: e20182741. doi: 10.1542/peds.2018-2741. +E-cigarette use is linked to poisoning, immediate inhalation toxicity, and lung injury. Environmental effects include waste, fires, and generation of indoor airborne particulate matter. The nicotine e-cigarettes can cause dependence in non-smokers, and young non-smokers who use e-cigarettes are more likely than non-users to initiate smoking and to become regular smokers. (Banks et al, 2023)Short-term health risks of e-cigarettes include increased airway resistance and increased exhaled carbon monoxide (CO). CO binds to hemoglobin tightly to displace oxygen. Airway resistance reduces optimal lung function. (Stockley et al, 2018)Radiologic imaging studies document a variety of lung injury patterns associated with vaping. Patterns include hypersensitivity pneumonitis, diffuse alveolar hemorrhage, diffuse alveolar damage, acute eosinophilic pneumonia, giant cell interstitial pneumonia, and lipid pneumonia. These injuries can acutely lead to diminished lung function. A more long-term pattern of injury is organizing pneumonia with fibroblast proliferation and collagen deposition - features of scar tissue formation that reduces lung capacity. (Henry et al, 2019)Pathologic findings with vaping confirm the imaging patterns. Acute lung injury patterns include diffuse alveolar damage and organizing pneumonia. Microscopic pathologic findings include bronchiolitis, mucosal edema, sloughing of the bronchiolar epithelium, eosinophils, and peribronchiolar organization following accumulation of macrophages. There can be fibrinous exudates and type 2 pneumocyte hyperplasia. More severe injury can lead to diffuse alveolar damage with formation of hyaline membranes. There can be progression to chronic inflammation and fibroblast plugs in bronchioles. Clinical features associated with these pathologic alterations include fever, night sweats, weight loss, dyspnea, cough, nausea, and vomiting. (Butt et al, 2019) (Mukhopadhyay et al, 2020)EVALI (e-cigarette or vaping product use associated lung injury) describes the acute respiratory illness related to toxic effects of substances inhaled in vaping. Findings include shortness of breath, cough, chest pain, and fever, along with hypoxia and tachycardia. The inhaled compounds can produce toxic effects upon cells in the respiratory tract and induce neutrophilic inflammation. Thus, EVALI can mimic infectious diseases of the lungs, and should be considered in persons with recent e-cigarette use. (Krishnasamy et al, 2020) (Park et al, 2022)Alcohol AbuseThe abuse of alcohol (ethanol) contributes to many deaths per year worldwide. It can also be a cause for drug overdose leading to death from ingestion of a large amount of alcohol, and second only to opioid overdose in number of drug-related deaths. Almost 1 in 5 visits to an emergency department involve prior use of alcohol. (https://www.niaaa.nih.gov/alcohols-effects-health/alcohol-topics/alcohol-facts-and-statistics/alcohol-related-emergencies-and-deaths-united-states)Chronic alcohol use leads to liver disease that can be manifested initially as fatty change (steatosis). Excessive alcohol ingestion over many years can lead to micronodular cirrhosis. A cirrhotic liver leads to portal hypertension and the complication of bleeding esophageal varices with massive, life-threatening gastrointestinal hemorrhage. There is also an increased risk for hepatocellular carcinoma arising in a cirrhotic liver. Acute excessive alcohol consumption can lead to alcoholic hepatitis. Laboratory testing of a blood specimen for evidence of ethanol ingestion includes phosphatidylethanol for recent (within 2 weeks) and carbohydrate-deficient transferrin for chronic use. (Patel and Flamm, 2023)In the brain, alcohol use disorder predisposing to poor dietary intake lacking nutrients can lead to thiamine deficiency with neurotoxicity and development of Wernicke–Korsakoff syndrome (WKS), with components of Wernicke encephalopathy and Korsakoff’s psychosis, with higher mental function affected by confusion and confabulation. Acute Wernicke encephalopathy is a potentially reversible condition characterized by confusion, oculomotor disturbances, and ataxia. Continued alcohol use leads to permanent brain damage. (Nutt et al, 2021)Abrupt cessation of alcohol ingestion in persons who are chronic alcohol users predisposes to alcohol withdrawal Symptoms, and signs within 8 to 24 hours include transient visual, auditory or tactile hallucinations. There can be progression to withdrawal-related seizures which, if not treated may progress to life-threatening delirium tremens. (Day and Daly, 2022)Alcohol use during pregnancy can lead to fetal alcohol spectrum disorders, also termed the fetal alcohol syndrome (FAS). The risk increases with the time and amount of exposure, but there is no completely safe level of maternal alcohol consumption. This syndrome is estimated to occur in 1 in 100 live births, but the actual incidence is probably higher. Whenever a pregnant woman stops drinking, she reduces the risk of having a baby with FAS. Damage to the fetus from FAS cannot be reversed. Later in development, affected children have increased behavioral problems and learning disabilities. There are no specific, distinctive morphologic findings, so it is challenging to diagnose. The most common deformity with FAS is moderate to severe growth retardation. The three most distinctive features are a thin upper lip, smooth philtrum, and short palpebral fissures. (Popova et al, 2023)Additional FAS anomalies include microcephaly, long and narrow forehead, hypotelorism, maxillary and mandibular hypoplasia, narrow palpebal fissures, thin elongated philtrum and vermillion border of the upper lip, temporomandibular joint disorders, and dental malocclusion. Ocular problems include microphthalmia, coloboma, nystagmus, strabismus, and ptosis. The physical anomalies tend to become less apparent as the child ages. (Mukherjee et al, 2006)Normal liver, gross.Fatty change of liver, microscopic.Micronodular cirrhosis of liver, gross.Micronodular cirrhosis of liver, microscopic.Hepatocellular carcinoma, liver with micronodular cirrhosis, gross.Esophageal varices, gross.Wernicke's disease, hemorrhages in the mammillary bodies, gross.OpiatesOpiates by themselves have minimal pathologic tissue effects. Higher doses of more powerful opiates can lead to respiratory depression and death. Persons who really need the pain relief that opiate medications can offer do not become addicted, but unfortunately tolerance may develop over time, requiring higher doses to maintain analgesia. The major problems with opiate abuse are the psychosocial consequences, the infections from route of administration (injection), and possible overdose with death. (Torres-Lockhart et al, 2022)An opioid epidemic in the 21st century has been driven by increasing demand and increasing supply, particularly of synthetic opioid compounds. The prescription opiate most often abused is fentanyl, which has great affinity for the mu opioid receptor, and is 80 to 100 times more potent than morphine, producing an intense, temporary euphoria. (Liu et al, 2018) An overdose is treated with naloxone, and the synthetic opioids require higher doses of naloxone. (Walker, 2023) In the U.S. in 2022, of over 100,000 deaths from drug overdose, about 80% were due to opiates, mainly synthetic opioids. (https://blogs.cdc.gov/nchs/2023/05/18/7365/)Psychosocial problems related to behavioral issues from drug dependence. Drug-seeking behaviors result in lack of concern for oneself or others. If the route of administration is intravenous, without attention to sterile technique, there is increased risk for infection. Withdrawl from chronic opiate usage typically results in marked physiologic and psychologic disturbances such as pupillary dilation, tachycardia, yawning, lacrimation, rhinorrhea, piloerection, abdominal cramping, nausea, vomiting, diarrhea, muscle or bone pain, irritability, restlessness, anxiety, and insomnia. (Torres-Lockhart et al, 2022)Oxycodone, best known by the trade name OxyContin®, is a controlled release form of opioid analgesic prescribed to treat moderate to severe pain of constant and prolonged duration. Persons abusing this medication risk addiction and death, particularly if oxycodone is used in association with other drugs. Abusers may progress to usage by intravenous injection and to usage of other opiates or drugs of abuse. (Hays, 2004)Intravenous Drug AbuseMany drugs can be injected intravenously. The drugs themselves may have the major effect of impairment of mental function, but the route of administration can have serious complications. Injection of drugs with needles that are not sterile leads to the potential for a wide variety of infections. Such infections include: human immunodeficiency virus (the causative agent for AIDS), viral hepatitis (particularly hepatitis B and C), and bacterial infections. (Marks et al, 2022)Persons with a history of intravenous drug abuse also are more likely to have tuberculosis of the lungs. The drug heroin can produce a nephropathy in the kidney that resembles focal segmental glomerulosclerosis. In addition, a "talc granulomatosis" can occur because many injected drugs have been adulterated with an inert substance (such as talcum powder) to "cut" or dilute the amount of drug. (Milroy and Parai, 2011)Normal aortic valve compared with infective endocarditis, gross.Surface of the brain with acute meningitis, gross.Viral hepatitis of the liver, gross.Viral hepatitis of the liver, microscopic.Macronodular cirrhosis of the liver, gross.Mycobacterium tuberculosis, lung, cavitary disease, gross.Glomerulus of kidney demonstrating focal scarring with heroin nephropathy, microscopic.Talc granulomatosis of the liver, gross.Talc granulomatosis of the lungs, polarized light, microscopic.CocaineCocaine can exert a variety of effects. The major acute effects producing pathologic conditions result from the increased circulating catecholamine levels with cocaine use. These increased catecholamines can produce vasoconstriction. The lesions can include acute hemorrhages and infarction in the brain. Cerebral infarction can occur within 3 hours of cocaine use even in young persons. Subarachnoid haemorrhage is often associated with rupture of a berry aneurysm. Intraparenchymal haemorrhage can occur in the basal ganglia and thalamus. (Milroy and Parai, 2011)Ischemic changes in the heart from small artery narrowing and sclerosis lead to contraction band necrosis of the myocardium and possible sudden death. With chronic usage, the myocardium develops interstitial fibrosis, and the heart becomes enlarged. Atheroma formation in artereis as well as arterial dissection can occur. (Milroy and Parai, 2011) Combining cocaine use with ethanol use can compound the myocardial damage. (Awtry and Philippides, 2010)Pregnant mothers who use cocaine can affect their fetuses from abnormalities of placental function leading to low birth weight babies or an increased risk for placental abruption. Maternal cocaine use increases the risk for spontaneous abortion. (Kuczkowski, 2007)Persons with cocaine intoxication (not necessarily related to the drug level) may develop a state of iatrogenic psychosis (cocaine psychosis) with "excited delerium" in which they are markedly agitated and combative and develop hyperthermia, often of a severe degree (to 106 F). Organ damage can accompany this state of excited delerium and may include rhabdomyolysis of muscle, hepatotoxicity, and renal failure. Disseminated intravascular coagulation (DIC), hypotension, and sudden death are additional complications. (Devlin and Henry, 2008)Massive intracerebral hemorrhage associated with cocaine use, gross.Cerebral infarction, gross.Heart with myocardial contraction band necrosis, microscopic.Heart with peripheral coronary artery sclerosis, microscopic.Abruptio placenta with large recent blood clot compressing the parenchyma, gross.MethamphetamineMethampetamine is a stimulant drug with inotropic effects upon the cardiovascular system. Methamphetamine is metabolized to amphetamine, which is also a stimulant. Methamphetamine and amphetamine have similar effects to cocaine on the cardiovascular system. The heart may have such stress placed upon it that there are ischemic changes to the myocardial fibers. Chronic use leads to hypertrophy, interstitial fibrosis and microvascular disease. The myocardial effects are made worse by concomitant ethanol use. (Milroy and Parai, 2011)Heart with ischemic changes, microscopic.Amphetamines also damage both the serotonergic and dopaminergic systems of the central nervous system. Alterations of the dopaminergic system may persist even after years of abstinence from use of methamphetamine and may be associated with deficits in motor and cognitive performance. (Gouzoulis-Mayfrank and Daumann, 2009)CNS toxicity of methamphetamine may be the result of both hyperthermia as well as direct effects upon individual cells. A dose-related increase in body temperature occurs with acute ingestion of methamphetamine. This can potentiate acute effects of methamphetamine upon the blood-brain barrier and upon neurons, leading to edema. (Kiyatkin and Sharma, 2009)Methamphetamine and cocaine use can cause tooth decay that mainly affects the facial (outward) smooth and interproximal regions of teeth. The xerostomia patients experience may promote consumption of soft drinks with sugar. (Milroy and Parai, 2011)GHBGamma-hydroxybutyrate (GHB) is a metabolite of the neurotransmitter gamma aminobutyric acid (GABA) and also functions as a neurotransmitter by affecting the dopaminergic system. GHB may also potentiate the effects of endogenous or exogenous opiates. GHB was introduced into the U.S. in 1990 as a purported stimulant to muscle growth during sleep, but it was soon banned because of problems with overdose and adverse reactions. Moreover, GHB is no longer used as an anesthetic agent because of the risks. However, Gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are readily available as industrial solvents and when consumed are metabolized to GHB. The effects of GHB are primarily on the brain. GHB gained reputation as a euphoric and sexual performance enhancing agent. Its effects can be potentiated by alcohol and by benzodiazepines. The ingestion of GHB results in drowsiness and dizziness with the feeling of a "high" within 10 to 20 minutes and lasting up to 4 hours. There are a multitude of dose dependent adverse effects that can occur within 15 minutes to an hour, including: headache, nausea, vomiting, hallucinations, loss of peripheral vision, and nystagmus. These findings generally subside in 2 hours to 4 days. More severe acute toxicity includes respiratory depression, bradycardia, seizures, and reduced level of consciousness to deep coma. It is difficult to predict how much GHB will produce an overdose. Withdrawl from GHB can have an onset in 12 hours and last up to 12 days. In rare instances, deaths have occurred from these adverse effects. (Timby et al, 2000) (Tay et al, 2022)EcstasyThe methylene-dioxy derivatives of amphetamine and methamphetamine are "designer drugs" that generically are termed "ecstasy" and include 3,4-methylenedioxy-methamphetamine, also known as "Adam," 3,4-methylenedioxy-ethylamphetamine (MDEA), also known as "Eve," and N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB), also known as "Methyl-J" or "Eden." A "designer drug" is a compound that is chemically altered from the form of a controlled substance in order to produce special effects and to bypass legal regulations. MDMA and similar compounds are "entactogens" that act upon serotonergic pathways in the brain to give users a feeling of euphoria, energy, and a desire to socialize. These immediate effects last approximately 3 to 6 hours. (Fineschi et al, 1999) (Christophersen, 2000)The adverse effects of ecstasy use may include hyperthermia, liver toxicity, and neuropsychiatric effects. Severe dehydration leading to excessive fluid intake and water intoxication. Cardiovascular effects are similar to methamphetamine. There can be memory deficits, confusion, depression, and sleep problems even weeks after taking this drug. (Milroy and Parai, 2011)MDMA experimentally causes selective and persistent lesions of central serotonergic nerve terminals. MDMA users can have residual alterations of serotonergic transmission, and though at least partial recovery may occur after long-term abstinence, functional sequelae may persist even after longer periods of abstinence. Long term use may be accompanied by long-lasting brain damage and memory impairment. (Carter et al, 2000) (McQuire, 2000) (Gouzoulis-Mayfrank and Daumann, 2009)A syndrome including hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, hepatic failure, and renal failure has been reported with MDMA use, findings similar to the excited delirium of cocaine use. In addition persons using MDMA may develop acute fulminant hepatitis with liver failure, and possible death, that can occur days to weeks following drug use. (Scully et al, 2001)Cannabinoids (marijuana)Some of the most widely used psychoactive agents include derivatives from the hemp plantCannabis, typically containing the active compound delta-9-tetrahydrocannabinol (THC). The most common form is marijuana. Hashish is stronger, with more active drug. Throughout much of human history for the past 4000 years, preparations ofCannabiscontained small amounts of THC, less than 1%. In the latter part of the 20th century,Cannabisplants with higher THC concentrations and processing of the plants to yield more potent products with greater amounts of THC became widely employed. (Hall and Degenhardt, 2009)The plant products are typically smoked and the drug absorbed into the blood via respiratory tract. The drug acts through cannabinoid receptors in brain and elsewhere in the body. These receptors normally interact with short acting and less potent endogenous compounds (endocannabinoids) that affect brain function. THC induces mild euphoria, relaxation, and perceptual alterations for up to 2 hours following usage. The lifetime risk for THC dependence is about 9% and nearly double that for persons beginning regular use in adolescence. Only tobacco (32%) and alcohol (15%) dependence are more common. (Hall and Degenhardt, 2009)During adolescence, the brain undergoes modification of neurons with proliferation, migration, differentiation, and pruning of synapses that promote brain development for adulthood. Cannabinoids alter those processes and increase the risk for subsequent development of psychoses, including schizophrenia. (Malone et al, 2010) Adolescent users ofCannabisare less likely to complete schooling and more likely to become unemployed than nonusers. (Hall and Degenhardt, 2009)Acute adverse reactions to THC include anxiety, panic, and psychosis, more often in persons with no prior use of the drug. Impairments in attention, perception, and motor coordination affect ability to perform critical tasks such as operating a motor vehicle, increasing the risk for accidents. SinceCannabisis smoked, there are irritant effects upon the respiratory tract. There is risk for airway inflammation and for emphysema. (Murtha et al, 2022) There is risk for chronic bronchitis and lung cancer. Effects upon the cardiovascular system increase the risk for myocardial infarction in adults. (Hall and Degenhardt, 2009) A high-fat diet and ethanol use upregulate hepatic cannabinoid receptors so that THC may promote development of fatty liver. (Purohit et al, 2010)Some regularCannabisusers develop severe nausea with vomiting (cannabinoid hyperemesis) and the urge to bathe frequently in warm water for relief of these symptoms. Either the effects of the THC upon cannabinoid receptors near the thermoregulatory center of the hypothalamus, or upon cannabinoid receptors in splanchnic vasculature may play a role. The warm water exposure redirects blood flow to peripheral vasculature. (Patterson et al, 2010)Synthetic Cannabinoids (spice drugs)The so-called 'spice drugs' are synthetic cannabinoid compounds that can bind to brain cannibinoid receptors CB1 and CB2. Their structural chemistry is not like the tetrahydrocannabinol (THC) found in the cannabis of marijuana. Binding to the CB1 receptor produces strong but short-lived psychoactive effects and potential complications due to unknown pharmacologic effects and toxicity. They are 2 to 100 times more potent than THC because both parent drug and metabolites are potent THC receptor agonists, while marijuana is a partial agonist. (Liu et al, 2018) (Roque-Bravo et al, 2023)Adverse cardiovascular and pulmonary reactions reported include tachycardia, hypertension, chest pain, arrhythmias, tachypnea, cough, and dyspnea. Mental status changes include altered consciousness, hallucinations, racing thoughts, and seizures. Psychosis, withdrawal, and death have been reported with usage of these compounds. Users of these drugs are at risk due to their variability as well as their potency. As is the case with drugs of abuse in general, there is no safety factor of quality control in production or packaging, so the amount one is getting is unpredictable. (Roque-Bravo et al, 2023)Initially, synthetic cannabinoids were mainly JWH compounds (after the initials of the scientist who synthesized them) with predominantly sympathomimetic effects. Subsequently, compounds of the XLR-11 and CID families have appeared that produce CNS depressant effects and bradycardia. They are also full cannabinoid receptor agonists. The synthetic cannabinoids may not be detected by routine urine drug screening methods. (Sud et al, 2018)Synthetic Cathinones, or PABS ("bath salts")The synthetic cathinones are one form of "designer drug" with modified chemical structures from a natural form and designed to mimic or amplify the effect of a natural source psychostimulant. These compounds are typically sold as "bath salts" (PABS) but have nothing to do with bathing. Instead are psychoactive "uppers" that are synthetic forms of cathinones. Cathinone is a naturally occurring beta-ketone amphetamine analogue found in the leaves of theCatha edulisplant, indigenous to eastern Africa and the Arabian Peninsula, which is chewed as "khat" for a mild stimulant effect. (Daziani et al, 2023)Derivative synthetic cathinones being used as drugs of abuse include butylone, dimethylcathinone, ethcathinone, ethylone, 3- and 4-fluoromethcathinone, mephedrone, methedrone, methylenedioxypyrovalerone (MDPV), methylone, and pyrovalerone. They mainly contain methylenedioxypyrovalerone (MDPV), which is structurally related to pyrovalerone and pyrrolidinophenone compounds that inhibit norepinephrine-dopamine reuptake. Therefore, they cause central nervous system stimulation and sympathetic stimulation. They are marketed as aphrodisiacs and stimulants. (Prosser and Nelson, 2012)They are absorbed quickly through mucosal surfaces (nasal, oral, gastric, rectal). Only a few milligrams produce a high, but the quantities marketed may be 100 times that amount, increasing the risk for overdose. Their effects peak at 90 minutes following ingestion and last for 3 or 4 hours before the user "crashes". Long-term users of PABS may develop tolerance, and abstinence can lead to withdrawal and intense craving. (Ross et al, 2011)The toxicity from PABS may include extreme sympathetic stimulation with tachycardia, hypertension, shortness of breath, blurred vision, dry mouth, and hyperthermia. There can be markedly altered mental status with severe panic attacks, agitation, paranoia, hallucinations, and violent behavior such as self-mutilation, suicide attempts, and homicidal activity. Seizures may occur. Rhabdomyolysis can develop. Deaths have been reported, most often from alpha-pyrrolidinopentiophenone ("flakka"). The toxicity profile includes the worst effects of other drugs of abuse including lysergic acid diethylamide (LSD), phencyclidine (PCP), methylenedioxymethamphetamine ("ecstasy"), cocaine, and methamphetamine. Routine drug screens do not detect PABS. (Ross et al, 2011; Liu et al, 2018)Mitragynine ("kratom")The kratom plant grows in Southeast Asia and from it can be extracted the psychoactive alkyloid mitragynine, and in small quantities 7-hydromitragynine, which is more potent. At low doses it produces a stimulant effect. At high doses it has a sedative effect as an agonist at the mu opioid receptor. (Liu et al, 2018)Anabolic-Androgenic SteroidsThe use of anabolic-androgenic steroids (AAS) has increased substantially over the past 4 decades. These drugs are used mainly for their effect of increasing muscle mass for the desired goal of increasing athletic performance and enhancing physical appearance. However, such drugs do not increase the level of skill in performance and cardiovascular function--the major enhancers to most sports-related activities. (Sjöqvist et al, 2008) (Thirumalai and Anawalt, 2023)Both oral and injectable compounds are used, more often the latter. Users may cycle on and off usage to avoid complications, but prolonged usage brings many adverse effects. In men these include: testicular atrophy, decreased testosterone production, gynecomastia, decreased sex drive, infertility, baldness, hypertension, heart disease, and tendon injuries. In women, the adverse effects reported include: decreased breast size, fluid retention, hypertension, and sleep disorders. Physical changes such as testicular atrophy and gynecomastia in men, or breast atrophy in women, are often not reversible even after stopping the drugs. Adolescents taking AAS may have diminished bone growth and shorter stature. AAS may produce cholestatic jaundice; they reduce the level of HDL cholesterol to promote atherogenesis and heart disease. (Sjöqvist et al, 2008) (Thirumalai and Anawalt, 2023)The major psychiatric effects of AAS use include changes in mood, worse with greater usage. While using the drugs increased aggression and mania can occur. Off the drugs depression occurs. The combination resembles bipolar disorder, a disabling mental health disorder. Such adverse effects could significantly impact athletic performance negatively and decrease sexual function. In short, AAS can prevent the very things that they are supposed to enhance. (Thirumalai and Anawalt, 2023)The most serious complication of AAS use is an increased risk for heart disease and sudden death. Anabolic steroids decrease HDL cholesterol and increase cardiac size. Myocardial fibrosis can occur, similar to cardiomyopathy. Hypertension induced by AAS further increases heart size. These effects may persist even after use of AAS has been stopped, increasing the risk for morbidity and mortality. Anabolic steroids have been shown to enhance the coronary artery response to catecholamines released during periods of stress, and this may play a role in the sudden cardiac deaths reported with their use. Contraction band necrosis, indicative of ischemia, has been observed in such deaths. (Fineschi et al, 2001)The use of growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin at high, non-physiologic amounts, as anabolic hormonal substances has no significant effect upon increasing muscle mass. Instead, such compounds over time lead to disease states: acromegaly with disfiguring soft tissue changes, diabetes mellitus, hypertension, heart disease, and nerve damage. (García-Arnés and García-Casares, 2023)Improper methods of injection with lack of sterile technique increase the risk for transmissible infections, including viral hepatitis B, viral hepatitis C, and human immunodeficiency virus (HIV). (Thirumalai and Anawalt, 2023)Heart with hypertrophy, gross.Heart with myocardial contraction band necrosis, trichrome stain, microscopic.Testicular atrophy, gross.Testicular atrophy, microscopic.Gynecomastia, gross.Blood DopingIncreasing the amount of circulating red blood cells with their oxygen-carrying hemoglobin is a physiologic adaptation to living at a higher altitude with less atmospheric oxygen. Increasing hemoglobin by 10% will increase oxygen utilization (VO2max) by 5 to 10% for sports where endurance is essential. The quick method is blood transfusion. Such practices are banned in competitive sports, and there are continuing attempts by athletes to mask such practices while methods for detection continue to evolve. (García-Arnés and García-Casares, 2023)Why do sudden deaths occur in athletes who use human recombinant eryrthropoietin ("epo") but very infrequently in patients with anemia who really need it? The drug has predictable results in anemic patients, and raises red cell mass, but not typically above normal. In healthy persons, particularly athletes who do not need more erythropoietin, there are unpredictable results, including an increase in the number of red blood cells (RBCs) into a polycythemic range with increase in blood viscosity to the point of thrombosis (clotting). That could lead to stroke, myocardial infarction, retinal artery occlusion (blindness), and pulmonary thromboembolism. There is also another rare but frightening complication: the development of antibodies, not only to the human recombinant form but also naturally occurring erythropoietin, leading to a condition called "pure red cell aplasia" with transfusion dependence for life. How is the recombinant form detected? The recombinant products include glycan isoforms that differ from natural erythropoietin, and those can be detected in a urine sample. (John et al, 2012) (García-Arnés and García-Casares, 2023)Laboratory TestingTesting for the presence of drugs can be performed on body fluids, principally urine and blood. Urine is easier to obtain, and it is likely to contain both drugs and their metabolites, but detection is qualitativem, since quantification is modified by fluid intake. Blood is obtained when quantification is needed, as for blood ethanol.Screening can include immunoassays that require less equipment and skill in interpretation, but may have cross-reactivity with related drugs that may not be classified as drugs of abuse (e.g., codeine in cough medicines can cross react with opiate drugs of abuse).Confirmation of screening test results, or primary detection of compounds not easily detected by other means, is done by mass spectroscopy (MS). The first step is chromatography for separation of the drug compounds in a gas phase (gas chromatography (GC) or liquid phase (liquid chromatography, or LC). the next step is mass spectroscopic analysis of the separated compounds. Thus, the method can be GC-MS or LC-MS. (Liu et al, 2018)ReferencesAwtry EH, Philippides GJ. Alcoholic and cocaine-associated cardiomyopathies. Prog Cardiovasc Dis. 2010;52:289-299.Banks E, Yazidjoglou A, Brown S, et al. Electronic cigarettes and health outcomes: umbrella and systematic review of the global evidence. Med J Aust. 2023 Apr 3;218(6):267-275. doi: 10.5694/mja2.51890.Bedene A, Dahan A, Rosendaal FR, van Dorp ELA. Opioid epidemic: lessons learned and updated recommendations for misuse involving prescription versus non-prescription opioids. Expert Rev Clin Pharmacol. 2022 Sep;15(9):1081-1094. doi: 10.1080/17512433.2022.2114898.Butt YM, Smith ML, Tazelaar HD, et al.Pathology of Vaping-Associated Lung Injury. 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(Stockley et al, 2018) +Radiologic imaging studies document a variety of lung injury patterns associated with vaping. Patterns include hypersensitivity pneumonitis, diffuse alveolar hemorrhage, diffuse alveolar damage, acute eosinophilic pneumonia, giant cell interstitial pneumonia, and lipid pneumonia. These injuries can acutely lead to diminished lung function. A more long-term pattern of injury is organizing pneumonia with fibroblast proliferation and collagen deposition - features of scar tissue formation that reduces lung capacity. (Henry et al, 2019) +Pathologic findings with vaping confirm the imaging patterns. Acute lung injury patterns include diffuse alveolar damage and organizing pneumonia. Microscopic pathologic findings include bronchiolitis, mucosal edema, sloughing of the bronchiolar epithelium, eosinophils, and peribronchiolar organization following accumulation of macrophages. There can be fibrinous exudates and type 2 pneumocyte hyperplasia. More severe injury can lead to diffuse alveolar damage with formation of hyaline membranes. There can be progression to chronic inflammation and fibroblast plugs in bronchioles. Clinical features associated with these pathologic alterations include fever, night sweats, weight loss, dyspnea, cough, nausea, and vomiting. (Butt et al, 2019) (Mukhopadhyay et al, 2020) +EVALI (e-cigarette or vaping product use associated lung injury) describes the acute respiratory illness related to toxic effects of substances inhaled in vaping. Findings include shortness of breath, cough, chest pain, and fever, along with hypoxia and tachycardia. The inhaled compounds can produce toxic effects upon cells in the respiratory tract and induce neutrophilic inflammation. Thus, EVALI can mimic infectious diseases of the lungs, and should be considered in persons with recent e-cigarette use. (Krishnasamy et al, 2020) (Park et al, 2022) +The abuse of alcohol (ethanol) contributes to many deaths per year worldwide. It can also be a cause for drug overdose leading to death from ingestion of a large amount of alcohol, and second only to opioid overdose in number of drug-related deaths. Almost 1 in 5 visits to an emergency department involve prior use of alcohol. (https://www.niaaa.nih.gov/alcohols-effects-health/alcohol-topics/alcohol-facts-and-statistics/alcohol-related-emergencies-and-deaths-united-states) +Chronic alcohol use leads to liver disease that can be manifested initially as fatty change (steatosis). Excessive alcohol ingestion over many years can lead to micronodular cirrhosis. A cirrhotic liver leads to portal hypertension and the complication of bleeding esophageal varices with massive, life-threatening gastrointestinal hemorrhage. There is also an increased risk for hepatocellular carcinoma arising in a cirrhotic liver. Acute excessive alcohol consumption can lead to alcoholic hepatitis. Laboratory testing of a blood specimen for evidence of ethanol ingestion includes phosphatidylethanol for recent (within 2 weeks) and carbohydrate-deficient transferrin for chronic use. (Patel and Flamm, 2023) +In the brain, alcohol use disorder predisposing to poor dietary intake lacking nutrients can lead to thiamine deficiency with neurotoxicity and development of Wernicke–Korsakoff syndrome (WKS), with components of Wernicke encephalopathy and Korsakoff’s psychosis, with higher mental function affected by confusion and confabulation. Acute Wernicke encephalopathy is a potentially reversible condition characterized by confusion, oculomotor disturbances, and ataxia. Continued alcohol use leads to permanent brain damage. (Nutt et al, 2021) +Abrupt cessation of alcohol ingestion in persons who are chronic alcohol users predisposes to alcohol withdrawal Symptoms, and signs within 8 to 24 hours include transient visual, auditory or tactile hallucinations. There can be progression to withdrawal-related seizures which, if not treated may progress to life-threatening delirium tremens. (Day and Daly, 2022) +Alcohol use during pregnancy can lead to fetal alcohol spectrum disorders, also termed the fetal alcohol syndrome (FAS). The risk increases with the time and amount of exposure, but there is no completely safe level of maternal alcohol consumption. This syndrome is estimated to occur in 1 in 100 live births, but the actual incidence is probably higher. Whenever a pregnant woman stops drinking, she reduces the risk of having a baby with FAS. Damage to the fetus from FAS cannot be reversed. Later in development, affected children have increased behavioral problems and learning disabilities. There are no specific, distinctive morphologic findings, so it is challenging to diagnose. The most common deformity with FAS is moderate to severe growth retardation. The three most distinctive features are a thin upper lip, smooth philtrum, and short palpebral fissures. (Popova et al, 2023)Additional FAS anomalies include microcephaly, long and narrow forehead, hypotelorism, maxillary and mandibular hypoplasia, narrow palpebal fissures, thin elongated philtrum and vermillion border of the upper lip, temporomandibular joint disorders, and dental malocclusion. Ocular problems include microphthalmia, coloboma, nystagmus, strabismus, and ptosis. The physical anomalies tend to become less apparent as the child ages. (Mukherjee et al, 2006)Normal liver, gross.Fatty change of liver, microscopic.Micronodular cirrhosis of liver, gross.Micronodular cirrhosis of liver, microscopic.Hepatocellular carcinoma, liver with micronodular cirrhosis, gross.Esophageal varices, gross.Wernicke's disease, hemorrhages in the mammillary bodies, gross.OpiatesOpiates by themselves have minimal pathologic tissue effects. Higher doses of more powerful opiates can lead to respiratory depression and death. Persons who really need the pain relief that opiate medications can offer do not become addicted, but unfortunately tolerance may develop over time, requiring higher doses to maintain analgesia. The major problems with opiate abuse are the psychosocial consequences, the infections from route of administration (injection), and possible overdose with death. (Torres-Lockhart et al, 2022)An opioid epidemic in the 21st century has been driven by increasing demand and increasing supply, particularly of synthetic opioid compounds. The prescription opiate most often abused is fentanyl, which has great affinity for the mu opioid receptor, and is 80 to 100 times more potent than morphine, producing an intense, temporary euphoria. (Liu et al, 2018) An overdose is treated with naloxone, and the synthetic opioids require higher doses of naloxone. (Walker, 2023) In the U.S. in 2022, of over 100,000 deaths from drug overdose, about 80% were due to opiates, mainly synthetic opioids. (https://blogs.cdc.gov/nchs/2023/05/18/7365/)Psychosocial problems related to behavioral issues from drug dependence. Drug-seeking behaviors result in lack of concern for oneself or others. If the route of administration is intravenous, without attention to sterile technique, there is increased risk for infection. Withdrawl from chronic opiate usage typically results in marked physiologic and psychologic disturbances such as pupillary dilation, tachycardia, yawning, lacrimation, rhinorrhea, piloerection, abdominal cramping, nausea, vomiting, diarrhea, muscle or bone pain, irritability, restlessness, anxiety, and insomnia. (Torres-Lockhart et al, 2022)Oxycodone, best known by the trade name OxyContin®, is a controlled release form of opioid analgesic prescribed to treat moderate to severe pain of constant and prolonged duration. Persons abusing this medication risk addiction and death, particularly if oxycodone is used in association with other drugs. Abusers may progress to usage by intravenous injection and to usage of other opiates or drugs of abuse. (Hays, 2004)Intravenous Drug AbuseMany drugs can be injected intravenously. The drugs themselves may have the major effect of impairment of mental function, but the route of administration can have serious complications. Injection of drugs with needles that are not sterile leads to the potential for a wide variety of infections. Such infections include: human immunodeficiency virus (the causative agent for AIDS), viral hepatitis (particularly hepatitis B and C), and bacterial infections. (Marks et al, 2022)Persons with a history of intravenous drug abuse also are more likely to have tuberculosis of the lungs. The drug heroin can produce a nephropathy in the kidney that resembles focal segmental glomerulosclerosis. In addition, a "talc granulomatosis" can occur because many injected drugs have been adulterated with an inert substance (such as talcum powder) to "cut" or dilute the amount of drug. (Milroy and Parai, 2011)Normal aortic valve compared with infective endocarditis, gross.Surface of the brain with acute meningitis, gross.Viral hepatitis of the liver, gross.Viral hepatitis of the liver, microscopic.Macronodular cirrhosis of the liver, gross.Mycobacterium tuberculosis, lung, cavitary disease, gross.Glomerulus of kidney demonstrating focal scarring with heroin nephropathy, microscopic.Talc granulomatosis of the liver, gross.Talc granulomatosis of the lungs, polarized light, microscopic.CocaineCocaine can exert a variety of effects. The major acute effects producing pathologic conditions result from the increased circulating catecholamine levels with cocaine use. These increased catecholamines can produce vasoconstriction. The lesions can include acute hemorrhages and infarction in the brain. Cerebral infarction can occur within 3 hours of cocaine use even in young persons. Subarachnoid haemorrhage is often associated with rupture of a berry aneurysm. Intraparenchymal haemorrhage can occur in the basal ganglia and thalamus. (Milroy and Parai, 2011)Ischemic changes in the heart from small artery narrowing and sclerosis lead to contraction band necrosis of the myocardium and possible sudden death. With chronic usage, the myocardium develops interstitial fibrosis, and the heart becomes enlarged. Atheroma formation in artereis as well as arterial dissection can occur. (Milroy and Parai, 2011) Combining cocaine use with ethanol use can compound the myocardial damage. (Awtry and Philippides, 2010)Pregnant mothers who use cocaine can affect their fetuses from abnormalities of placental function leading to low birth weight babies or an increased risk for placental abruption. Maternal cocaine use increases the risk for spontaneous abortion. (Kuczkowski, 2007)Persons with cocaine intoxication (not necessarily related to the drug level) may develop a state of iatrogenic psychosis (cocaine psychosis) with "excited delerium" in which they are markedly agitated and combative and develop hyperthermia, often of a severe degree (to 106 F). Organ damage can accompany this state of excited delerium and may include rhabdomyolysis of muscle, hepatotoxicity, and renal failure. Disseminated intravascular coagulation (DIC), hypotension, and sudden death are additional complications. (Devlin and Henry, 2008)Massive intracerebral hemorrhage associated with cocaine use, gross.Cerebral infarction, gross.Heart with myocardial contraction band necrosis, microscopic.Heart with peripheral coronary artery sclerosis, microscopic.Abruptio placenta with large recent blood clot compressing the parenchyma, gross.MethamphetamineMethampetamine is a stimulant drug with inotropic effects upon the cardiovascular system. Methamphetamine is metabolized to amphetamine, which is also a stimulant. Methamphetamine and amphetamine have similar effects to cocaine on the cardiovascular system. The heart may have such stress placed upon it that there are ischemic changes to the myocardial fibers. Chronic use leads to hypertrophy, interstitial fibrosis and microvascular disease. The myocardial effects are made worse by concomitant ethanol use. (Milroy and Parai, 2011)Heart with ischemic changes, microscopic.Amphetamines also damage both the serotonergic and dopaminergic systems of the central nervous system. Alterations of the dopaminergic system may persist even after years of abstinence from use of methamphetamine and may be associated with deficits in motor and cognitive performance. (Gouzoulis-Mayfrank and Daumann, 2009)CNS toxicity of methamphetamine may be the result of both hyperthermia as well as direct effects upon individual cells. A dose-related increase in body temperature occurs with acute ingestion of methamphetamine. This can potentiate acute effects of methamphetamine upon the blood-brain barrier and upon neurons, leading to edema. (Kiyatkin and Sharma, 2009)Methamphetamine and cocaine use can cause tooth decay that mainly affects the facial (outward) smooth and interproximal regions of teeth. The xerostomia patients experience may promote consumption of soft drinks with sugar. (Milroy and Parai, 2011)GHBGamma-hydroxybutyrate (GHB) is a metabolite of the neurotransmitter gamma aminobutyric acid (GABA) and also functions as a neurotransmitter by affecting the dopaminergic system. GHB may also potentiate the effects of endogenous or exogenous opiates. GHB was introduced into the U.S. in 1990 as a purported stimulant to muscle growth during sleep, but it was soon banned because of problems with overdose and adverse reactions. Moreover, GHB is no longer used as an anesthetic agent because of the risks. However, Gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are readily available as industrial solvents and when consumed are metabolized to GHB. The effects of GHB are primarily on the brain. GHB gained reputation as a euphoric and sexual performance enhancing agent. Its effects can be potentiated by alcohol and by benzodiazepines. The ingestion of GHB results in drowsiness and dizziness with the feeling of a "high" within 10 to 20 minutes and lasting up to 4 hours. There are a multitude of dose dependent adverse effects that can occur within 15 minutes to an hour, including: headache, nausea, vomiting, hallucinations, loss of peripheral vision, and nystagmus. These findings generally subside in 2 hours to 4 days. More severe acute toxicity includes respiratory depression, bradycardia, seizures, and reduced level of consciousness to deep coma. It is difficult to predict how much GHB will produce an overdose. Withdrawl from GHB can have an onset in 12 hours and last up to 12 days. In rare instances, deaths have occurred from these adverse effects. (Timby et al, 2000) (Tay et al, 2022)EcstasyThe methylene-dioxy derivatives of amphetamine and methamphetamine are "designer drugs" that generically are termed "ecstasy" and include 3,4-methylenedioxy-methamphetamine, also known as "Adam," 3,4-methylenedioxy-ethylamphetamine (MDEA), also known as "Eve," and N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB), also known as "Methyl-J" or "Eden." A "designer drug" is a compound that is chemically altered from the form of a controlled substance in order to produce special effects and to bypass legal regulations. MDMA and similar compounds are "entactogens" that act upon serotonergic pathways in the brain to give users a feeling of euphoria, energy, and a desire to socialize. These immediate effects last approximately 3 to 6 hours. (Fineschi et al, 1999) (Christophersen, 2000)The adverse effects of ecstasy use may include hyperthermia, liver toxicity, and neuropsychiatric effects. Severe dehydration leading to excessive fluid intake and water intoxication. Cardiovascular effects are similar to methamphetamine. There can be memory deficits, confusion, depression, and sleep problems even weeks after taking this drug. (Milroy and Parai, 2011)MDMA experimentally causes selective and persistent lesions of central serotonergic nerve terminals. MDMA users can have residual alterations of serotonergic transmission, and though at least partial recovery may occur after long-term abstinence, functional sequelae may persist even after longer periods of abstinence. Long term use may be accompanied by long-lasting brain damage and memory impairment. (Carter et al, 2000) (McQuire, 2000) (Gouzoulis-Mayfrank and Daumann, 2009)A syndrome including hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, hepatic failure, and renal failure has been reported with MDMA use, findings similar to the excited delirium of cocaine use. In addition persons using MDMA may develop acute fulminant hepatitis with liver failure, and possible death, that can occur days to weeks following drug use. (Scully et al, 2001)Cannabinoids (marijuana)Some of the most widely used psychoactive agents include derivatives from the hemp plantCannabis, typically containing the active compound delta-9-tetrahydrocannabinol (THC). The most common form is marijuana. Hashish is stronger, with more active drug. Throughout much of human history for the past 4000 years, preparations ofCannabiscontained small amounts of THC, less than 1%. In the latter part of the 20th century,Cannabisplants with higher THC concentrations and processing of the plants to yield more potent products with greater amounts of THC became widely employed. (Hall and Degenhardt, 2009)The plant products are typically smoked and the drug absorbed into the blood via respiratory tract. The drug acts through cannabinoid receptors in brain and elsewhere in the body. These receptors normally interact with short acting and less potent endogenous compounds (endocannabinoids) that affect brain function. THC induces mild euphoria, relaxation, and perceptual alterations for up to 2 hours following usage. The lifetime risk for THC dependence is about 9% and nearly double that for persons beginning regular use in adolescence. Only tobacco (32%) and alcohol (15%) dependence are more common. (Hall and Degenhardt, 2009)During adolescence, the brain undergoes modification of neurons with proliferation, migration, differentiation, and pruning of synapses that promote brain development for adulthood. Cannabinoids alter those processes and increase the risk for subsequent development of psychoses, including schizophrenia. (Malone et al, 2010) Adolescent users ofCannabisare less likely to complete schooling and more likely to become unemployed than nonusers. (Hall and Degenhardt, 2009)Acute adverse reactions to THC include anxiety, panic, and psychosis, more often in persons with no prior use of the drug. Impairments in attention, perception, and motor coordination affect ability to perform critical tasks such as operating a motor vehicle, increasing the risk for accidents. SinceCannabisis smoked, there are irritant effects upon the respiratory tract. There is risk for airway inflammation and for emphysema. (Murtha et al, 2022) There is risk for chronic bronchitis and lung cancer. Effects upon the cardiovascular system increase the risk for myocardial infarction in adults. (Hall and Degenhardt, 2009) A high-fat diet and ethanol use upregulate hepatic cannabinoid receptors so that THC may promote development of fatty liver. (Purohit et al, 2010)Some regularCannabisusers develop severe nausea with vomiting (cannabinoid hyperemesis) and the urge to bathe frequently in warm water for relief of these symptoms. Either the effects of the THC upon cannabinoid receptors near the thermoregulatory center of the hypothalamus, or upon cannabinoid receptors in splanchnic vasculature may play a role. The warm water exposure redirects blood flow to peripheral vasculature. (Patterson et al, 2010)Synthetic Cannabinoids (spice drugs)The so-called 'spice drugs' are synthetic cannabinoid compounds that can bind to brain cannibinoid receptors CB1 and CB2. Their structural chemistry is not like the tetrahydrocannabinol (THC) found in the cannabis of marijuana. Binding to the CB1 receptor produces strong but short-lived psychoactive effects and potential complications due to unknown pharmacologic effects and toxicity. They are 2 to 100 times more potent than THC because both parent drug and metabolites are potent THC receptor agonists, while marijuana is a partial agonist. (Liu et al, 2018) (Roque-Bravo et al, 2023)Adverse cardiovascular and pulmonary reactions reported include tachycardia, hypertension, chest pain, arrhythmias, tachypnea, cough, and dyspnea. Mental status changes include altered consciousness, hallucinations, racing thoughts, and seizures. Psychosis, withdrawal, and death have been reported with usage of these compounds. Users of these drugs are at risk due to their variability as well as their potency. As is the case with drugs of abuse in general, there is no safety factor of quality control in production or packaging, so the amount one is getting is unpredictable. (Roque-Bravo et al, 2023)Initially, synthetic cannabinoids were mainly JWH compounds (after the initials of the scientist who synthesized them) with predominantly sympathomimetic effects. Subsequently, compounds of the XLR-11 and CID families have appeared that produce CNS depressant effects and bradycardia. They are also full cannabinoid receptor agonists. The synthetic cannabinoids may not be detected by routine urine drug screening methods. (Sud et al, 2018)Synthetic Cathinones, or PABS ("bath salts")The synthetic cathinones are one form of "designer drug" with modified chemical structures from a natural form and designed to mimic or amplify the effect of a natural source psychostimulant. These compounds are typically sold as "bath salts" (PABS) but have nothing to do with bathing. Instead are psychoactive "uppers" that are synthetic forms of cathinones. Cathinone is a naturally occurring beta-ketone amphetamine analogue found in the leaves of theCatha edulisplant, indigenous to eastern Africa and the Arabian Peninsula, which is chewed as "khat" for a mild stimulant effect. (Daziani et al, 2023)Derivative synthetic cathinones being used as drugs of abuse include butylone, dimethylcathinone, ethcathinone, ethylone, 3- and 4-fluoromethcathinone, mephedrone, methedrone, methylenedioxypyrovalerone (MDPV), methylone, and pyrovalerone. They mainly contain methylenedioxypyrovalerone (MDPV), which is structurally related to pyrovalerone and pyrrolidinophenone compounds that inhibit norepinephrine-dopamine reuptake. Therefore, they cause central nervous system stimulation and sympathetic stimulation. They are marketed as aphrodisiacs and stimulants. (Prosser and Nelson, 2012)They are absorbed quickly through mucosal surfaces (nasal, oral, gastric, rectal). Only a few milligrams produce a high, but the quantities marketed may be 100 times that amount, increasing the risk for overdose. Their effects peak at 90 minutes following ingestion and last for 3 or 4 hours before the user "crashes". Long-term users of PABS may develop tolerance, and abstinence can lead to withdrawal and intense craving. (Ross et al, 2011)The toxicity from PABS may include extreme sympathetic stimulation with tachycardia, hypertension, shortness of breath, blurred vision, dry mouth, and hyperthermia. There can be markedly altered mental status with severe panic attacks, agitation, paranoia, hallucinations, and violent behavior such as self-mutilation, suicide attempts, and homicidal activity. Seizures may occur. Rhabdomyolysis can develop. Deaths have been reported, most often from alpha-pyrrolidinopentiophenone ("flakka"). The toxicity profile includes the worst effects of other drugs of abuse including lysergic acid diethylamide (LSD), phencyclidine (PCP), methylenedioxymethamphetamine ("ecstasy"), cocaine, and methamphetamine. Routine drug screens do not detect PABS. (Ross et al, 2011; Liu et al, 2018)Mitragynine ("kratom")The kratom plant grows in Southeast Asia and from it can be extracted the psychoactive alkyloid mitragynine, and in small quantities 7-hydromitragynine, which is more potent. At low doses it produces a stimulant effect. At high doses it has a sedative effect as an agonist at the mu opioid receptor. (Liu et al, 2018)Anabolic-Androgenic SteroidsThe use of anabolic-androgenic steroids (AAS) has increased substantially over the past 4 decades. These drugs are used mainly for their effect of increasing muscle mass for the desired goal of increasing athletic performance and enhancing physical appearance. However, such drugs do not increase the level of skill in performance and cardiovascular function--the major enhancers to most sports-related activities. (Sjöqvist et al, 2008) (Thirumalai and Anawalt, 2023)Both oral and injectable compounds are used, more often the latter. Users may cycle on and off usage to avoid complications, but prolonged usage brings many adverse effects. In men these include: testicular atrophy, decreased testosterone production, gynecomastia, decreased sex drive, infertility, baldness, hypertension, heart disease, and tendon injuries. In women, the adverse effects reported include: decreased breast size, fluid retention, hypertension, and sleep disorders. Physical changes such as testicular atrophy and gynecomastia in men, or breast atrophy in women, are often not reversible even after stopping the drugs. Adolescents taking AAS may have diminished bone growth and shorter stature. AAS may produce cholestatic jaundice; they reduce the level of HDL cholesterol to promote atherogenesis and heart disease. (Sjöqvist et al, 2008) (Thirumalai and Anawalt, 2023)The major psychiatric effects of AAS use include changes in mood, worse with greater usage. While using the drugs increased aggression and mania can occur. Off the drugs depression occurs. The combination resembles bipolar disorder, a disabling mental health disorder. Such adverse effects could significantly impact athletic performance negatively and decrease sexual function. In short, AAS can prevent the very things that they are supposed to enhance. (Thirumalai and Anawalt, 2023)The most serious complication of AAS use is an increased risk for heart disease and sudden death. Anabolic steroids decrease HDL cholesterol and increase cardiac size. Myocardial fibrosis can occur, similar to cardiomyopathy. Hypertension induced by AAS further increases heart size. These effects may persist even after use of AAS has been stopped, increasing the risk for morbidity and mortality. Anabolic steroids have been shown to enhance the coronary artery response to catecholamines released during periods of stress, and this may play a role in the sudden cardiac deaths reported with their use. Contraction band necrosis, indicative of ischemia, has been observed in such deaths. (Fineschi et al, 2001)The use of growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin at high, non-physiologic amounts, as anabolic hormonal substances has no significant effect upon increasing muscle mass. Instead, such compounds over time lead to disease states: acromegaly with disfiguring soft tissue changes, diabetes mellitus, hypertension, heart disease, and nerve damage. (García-Arnés and García-Casares, 2023)Improper methods of injection with lack of sterile technique increase the risk for transmissible infections, including viral hepatitis B, viral hepatitis C, and human immunodeficiency virus (HIV). (Thirumalai and Anawalt, 2023)Heart with hypertrophy, gross.Heart with myocardial contraction band necrosis, trichrome stain, microscopic.Testicular atrophy, gross.Testicular atrophy, microscopic.Gynecomastia, gross.Blood DopingIncreasing the amount of circulating red blood cells with their oxygen-carrying hemoglobin is a physiologic adaptation to living at a higher altitude with less atmospheric oxygen. Increasing hemoglobin by 10% will increase oxygen utilization (VO2max) by 5 to 10% for sports where endurance is essential. The quick method is blood transfusion. Such practices are banned in competitive sports, and there are continuing attempts by athletes to mask such practices while methods for detection continue to evolve. (García-Arnés and García-Casares, 2023)Why do sudden deaths occur in athletes who use human recombinant eryrthropoietin ("epo") but very infrequently in patients with anemia who really need it? The drug has predictable results in anemic patients, and raises red cell mass, but not typically above normal. In healthy persons, particularly athletes who do not need more erythropoietin, there are unpredictable results, including an increase in the number of red blood cells (RBCs) into a polycythemic range with increase in blood viscosity to the point of thrombosis (clotting). That could lead to stroke, myocardial infarction, retinal artery occlusion (blindness), and pulmonary thromboembolism. There is also another rare but frightening complication: the development of antibodies, not only to the human recombinant form but also naturally occurring erythropoietin, leading to a condition called "pure red cell aplasia" with transfusion dependence for life. How is the recombinant form detected? The recombinant products include glycan isoforms that differ from natural erythropoietin, and those can be detected in a urine sample. (John et al, 2012) (García-Arnés and García-Casares, 2023)Laboratory TestingTesting for the presence of drugs can be performed on body fluids, principally urine and blood. Urine is easier to obtain, and it is likely to contain both drugs and their metabolites, but detection is qualitativem, since quantification is modified by fluid intake. Blood is obtained when quantification is needed, as for blood ethanol.Screening can include immunoassays that require less equipment and skill in interpretation, but may have cross-reactivity with related drugs that may not be classified as drugs of abuse (e.g., codeine in cough medicines can cross react with opiate drugs of abuse).Confirmation of screening test results, or primary detection of compounds not easily detected by other means, is done by mass spectroscopy (MS). 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Pediatrics. 2019;143(6). pii: e20182741. doi: 10.1542/peds.2018-2741. +Additional FAS anomalies include microcephaly, long and narrow forehead, hypotelorism, maxillary and mandibular hypoplasia, narrow palpebal fissures, thin elongated philtrum and vermillion border of the upper lip, temporomandibular joint disorders, and dental malocclusion. Ocular problems include microphthalmia, coloboma, nystagmus, strabismus, and ptosis. The physical anomalies tend to become less apparent as the child ages. (Mukherjee et al, 2006) +Normal liver, gross. +Fatty change of liver, microscopic. +Micronodular cirrhosis of liver, gross. +Micronodular cirrhosis of liver, microscopic. +Hepatocellular carcinoma, liver with micronodular cirrhosis, gross. +Esophageal varices, gross. +Wernicke's disease, hemorrhages in the mammillary bodies, gross. +Opiates by themselves have minimal pathologic tissue effects. Higher doses of more powerful opiates can lead to respiratory depression and death. Persons who really need the pain relief that opiate medications can offer do not become addicted, but unfortunately tolerance may develop over time, requiring higher doses to maintain analgesia. The major problems with opiate abuse are the psychosocial consequences, the infections from route of administration (injection), and possible overdose with death. (Torres-Lockhart et al, 2022) +An opioid epidemic in the 21st century has been driven by increasing demand and increasing supply, particularly of synthetic opioid compounds. The prescription opiate most often abused is fentanyl, which has great affinity for the mu opioid receptor, and is 80 to 100 times more potent than morphine, producing an intense, temporary euphoria. (Liu et al, 2018) An overdose is treated with naloxone, and the synthetic opioids require higher doses of naloxone. (Walker, 2023) In the U.S. in 2022, of over 100,000 deaths from drug overdose, about 80% were due to opiates, mainly synthetic opioids. (https://blogs.cdc.gov/nchs/2023/05/18/7365/) +Psychosocial problems related to behavioral issues from drug dependence. Drug-seeking behaviors result in lack of concern for oneself or others. If the route of administration is intravenous, without attention to sterile technique, there is increased risk for infection. Withdrawl from chronic opiate usage typically results in marked physiologic and psychologic disturbances such as pupillary dilation, tachycardia, yawning, lacrimation, rhinorrhea, piloerection, abdominal cramping, nausea, vomiting, diarrhea, muscle or bone pain, irritability, restlessness, anxiety, and insomnia. (Torres-Lockhart et al, 2022) +Oxycodone, best known by the trade name OxyContin®, is a controlled release form of opioid analgesic prescribed to treat moderate to severe pain of constant and prolonged duration. Persons abusing this medication risk addiction and death, particularly if oxycodone is used in association with other drugs. Abusers may progress to usage by intravenous injection and to usage of other opiates or drugs of abuse. (Hays, 2004) +Intravenous Drug Abuse +Many drugs can be injected intravenously. The drugs themselves may have the major effect of impairment of mental function, but the route of administration can have serious complications. Injection of drugs with needles that are not sterile leads to the potential for a wide variety of infections. Such infections include: human immunodeficiency virus (the causative agent for AIDS), viral hepatitis (particularly hepatitis B and C), and bacterial infections. (Marks et al, 2022) +Persons with a history of intravenous drug abuse also are more likely to have tuberculosis of the lungs. The drug heroin can produce a nephropathy in the kidney that resembles focal segmental glomerulosclerosis. In addition, a "talc granulomatosis" can occur because many injected drugs have been adulterated with an inert substance (such as talcum powder) to "cut" or dilute the amount of drug. (Milroy and Parai, 2011) +Normal aortic valve compared with infective endocarditis, gross. +Surface of the brain with acute meningitis, gross. +Viral hepatitis of the liver, gross. +Viral hepatitis of the liver, microscopic. +Macronodular cirrhosis of the liver, gross. +Mycobacterium tuberculosis, lung, cavitary disease, gross. +Glomerulus of kidney demonstrating focal scarring with heroin nephropathy, microscopic. +Talc granulomatosis of the liver, gross. +Talc granulomatosis of the lungs, polarized light, microscopic. +Cocaine can exert a variety of effects. The major acute effects producing pathologic conditions result from the increased circulating catecholamine levels with cocaine use. These increased catecholamines can produce vasoconstriction. The lesions can include acute hemorrhages and infarction in the brain. Cerebral infarction can occur within 3 hours of cocaine use even in young persons. Subarachnoid haemorrhage is often associated with rupture of a berry aneurysm. Intraparenchymal haemorrhage can occur in the basal ganglia and thalamus. (Milroy and Parai, 2011) +Ischemic changes in the heart from small artery narrowing and sclerosis lead to contraction band necrosis of the myocardium and possible sudden death. With chronic usage, the myocardium develops interstitial fibrosis, and the heart becomes enlarged. Atheroma formation in artereis as well as arterial dissection can occur. (Milroy and Parai, 2011) Combining cocaine use with ethanol use can compound the myocardial damage. (Awtry and Philippides, 2010) +Pregnant mothers who use cocaine can affect their fetuses from abnormalities of placental function leading to low birth weight babies or an increased risk for placental abruption. Maternal cocaine use increases the risk for spontaneous abortion. (Kuczkowski, 2007) +Persons with cocaine intoxication (not necessarily related to the drug level) may develop a state of iatrogenic psychosis (cocaine psychosis) with "excited delerium" in which they are markedly agitated and combative and develop hyperthermia, often of a severe degree (to 106 F). Organ damage can accompany this state of excited delerium and may include rhabdomyolysis of muscle, hepatotoxicity, and renal failure. Disseminated intravascular coagulation (DIC), hypotension, and sudden death are additional complications. (Devlin and Henry, 2008) +Massive intracerebral hemorrhage associated with cocaine use, gross. +Cerebral infarction, gross. +Heart with myocardial contraction band necrosis, microscopic. +Heart with peripheral coronary artery sclerosis, microscopic. +Abruptio placenta with large recent blood clot compressing the parenchyma, gross. +Methamphetamine +Methampetamine is a stimulant drug with inotropic effects upon the cardiovascular system. Methamphetamine is metabolized to amphetamine, which is also a stimulant. Methamphetamine and amphetamine have similar effects to cocaine on the cardiovascular system. The heart may have such stress placed upon it that there are ischemic changes to the myocardial fibers. Chronic use leads to hypertrophy, interstitial fibrosis and microvascular disease. The myocardial effects are made worse by concomitant ethanol use. (Milroy and Parai, 2011) +Heart with ischemic changes, microscopic. +Amphetamines also damage both the serotonergic and dopaminergic systems of the central nervous system. Alterations of the dopaminergic system may persist even after years of abstinence from use of methamphetamine and may be associated with deficits in motor and cognitive performance. (Gouzoulis-Mayfrank and Daumann, 2009) +CNS toxicity of methamphetamine may be the result of both hyperthermia as well as direct effects upon individual cells. A dose-related increase in body temperature occurs with acute ingestion of methamphetamine. This can potentiate acute effects of methamphetamine upon the blood-brain barrier and upon neurons, leading to edema. (Kiyatkin and Sharma, 2009) +Methamphetamine and cocaine use can cause tooth decay that mainly affects the facial (outward) smooth and interproximal regions of teeth. The xerostomia patients experience may promote consumption of soft drinks with sugar. (Milroy and Parai, 2011) +Gamma-hydroxybutyrate (GHB) is a metabolite of the neurotransmitter gamma aminobutyric acid (GABA) and also functions as a neurotransmitter by affecting the dopaminergic system. GHB may also potentiate the effects of endogenous or exogenous opiates. GHB was introduced into the U.S. in 1990 as a purported stimulant to muscle growth during sleep, but it was soon banned because of problems with overdose and adverse reactions. Moreover, GHB is no longer used as an anesthetic agent because of the risks. However, Gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are readily available as industrial solvents and when consumed are metabolized to GHB. The effects of GHB are primarily on the brain. GHB gained reputation as a euphoric and sexual performance enhancing agent. Its effects can be potentiated by alcohol and by benzodiazepines. The ingestion of GHB results in drowsiness and dizziness with the feeling of a "high" within 10 to 20 minutes and lasting up to 4 hours. There are a multitude of dose dependent adverse effects that can occur within 15 minutes to an hour, including: headache, nausea, vomiting, hallucinations, loss of peripheral vision, and nystagmus. These findings generally subside in 2 hours to 4 days. More severe acute toxicity includes respiratory depression, bradycardia, seizures, and reduced level of consciousness to deep coma. It is difficult to predict how much GHB will produce an overdose. Withdrawl from GHB can have an onset in 12 hours and last up to 12 days. In rare instances, deaths have occurred from these adverse effects. (Timby et al, 2000) (Tay et al, 2022) +The methylene-dioxy derivatives of amphetamine and methamphetamine are "designer drugs" that generically are termed "ecstasy" and include 3,4-methylenedioxy-methamphetamine, also known as "Adam," 3,4-methylenedioxy-ethylamphetamine (MDEA), also known as "Eve," and N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB), also known as "Methyl-J" or "Eden." A "designer drug" is a compound that is chemically altered from the form of a controlled substance in order to produce special effects and to bypass legal regulations. MDMA and similar compounds are "entactogens" that act upon serotonergic pathways in the brain to give users a feeling of euphoria, energy, and a desire to socialize. These immediate effects last approximately 3 to 6 hours. (Fineschi et al, 1999) (Christophersen, 2000) +The adverse effects of ecstasy use may include hyperthermia, liver toxicity, and neuropsychiatric effects. Severe dehydration leading to excessive fluid intake and water intoxication. Cardiovascular effects are similar to methamphetamine. There can be memory deficits, confusion, depression, and sleep problems even weeks after taking this drug. (Milroy and Parai, 2011) +MDMA experimentally causes selective and persistent lesions of central serotonergic nerve terminals. MDMA users can have residual alterations of serotonergic transmission, and though at least partial recovery may occur after long-term abstinence, functional sequelae may persist even after longer periods of abstinence. Long term use may be accompanied by long-lasting brain damage and memory impairment. (Carter et al, 2000) (McQuire, 2000) (Gouzoulis-Mayfrank and Daumann, 2009) +A syndrome including hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, hepatic failure, and renal failure has been reported with MDMA use, findings similar to the excited delirium of cocaine use. In addition persons using MDMA may develop acute fulminant hepatitis with liver failure, and possible death, that can occur days to weeks following drug use. (Scully et al, 2001) +Cannabinoids (marijuana) +Some of the most widely used psychoactive agents include derivatives from the hemp plantCannabis, typically containing the active compound delta-9-tetrahydrocannabinol (THC). The most common form is marijuana. Hashish is stronger, with more active drug. Throughout much of human history for the past 4000 years, preparations ofCannabiscontained small amounts of THC, less than 1%. In the latter part of the 20th century,Cannabisplants with higher THC concentrations and processing of the plants to yield more potent products with greater amounts of THC became widely employed. (Hall and Degenhardt, 2009) +The plant products are typically smoked and the drug absorbed into the blood via respiratory tract. The drug acts through cannabinoid receptors in brain and elsewhere in the body. These receptors normally interact with short acting and less potent endogenous compounds (endocannabinoids) that affect brain function. THC induces mild euphoria, relaxation, and perceptual alterations for up to 2 hours following usage. The lifetime risk for THC dependence is about 9% and nearly double that for persons beginning regular use in adolescence. Only tobacco (32%) and alcohol (15%) dependence are more common. (Hall and Degenhardt, 2009) +During adolescence, the brain undergoes modification of neurons with proliferation, migration, differentiation, and pruning of synapses that promote brain development for adulthood. Cannabinoids alter those processes and increase the risk for subsequent development of psychoses, including schizophrenia. (Malone et al, 2010) Adolescent users ofCannabisare less likely to complete schooling and more likely to become unemployed than nonusers. (Hall and Degenhardt, 2009) +Acute adverse reactions to THC include anxiety, panic, and psychosis, more often in persons with no prior use of the drug. Impairments in attention, perception, and motor coordination affect ability to perform critical tasks such as operating a motor vehicle, increasing the risk for accidents. SinceCannabisis smoked, there are irritant effects upon the respiratory tract. There is risk for airway inflammation and for emphysema. (Murtha et al, 2022) There is risk for chronic bronchitis and lung cancer. Effects upon the cardiovascular system increase the risk for myocardial infarction in adults. (Hall and Degenhardt, 2009) A high-fat diet and ethanol use upregulate hepatic cannabinoid receptors so that THC may promote development of fatty liver. (Purohit et al, 2010) +Some regularCannabisusers develop severe nausea with vomiting (cannabinoid hyperemesis) and the urge to bathe frequently in warm water for relief of these symptoms. Either the effects of the THC upon cannabinoid receptors near the thermoregulatory center of the hypothalamus, or upon cannabinoid receptors in splanchnic vasculature may play a role. The warm water exposure redirects blood flow to peripheral vasculature. (Patterson et al, 2010) +Synthetic Cannabinoids (spice drugs) +The so-called 'spice drugs' are synthetic cannabinoid compounds that can bind to brain cannibinoid receptors CB1 and CB2. Their structural chemistry is not like the tetrahydrocannabinol (THC) found in the cannabis of marijuana. Binding to the CB1 receptor produces strong but short-lived psychoactive effects and potential complications due to unknown pharmacologic effects and toxicity. They are 2 to 100 times more potent than THC because both parent drug and metabolites are potent THC receptor agonists, while marijuana is a partial agonist. (Liu et al, 2018) (Roque-Bravo et al, 2023) +Adverse cardiovascular and pulmonary reactions reported include tachycardia, hypertension, chest pain, arrhythmias, tachypnea, cough, and dyspnea. Mental status changes include altered consciousness, hallucinations, racing thoughts, and seizures. Psychosis, withdrawal, and death have been reported with usage of these compounds. Users of these drugs are at risk due to their variability as well as their potency. As is the case with drugs of abuse in general, there is no safety factor of quality control in production or packaging, so the amount one is getting is unpredictable. (Roque-Bravo et al, 2023)Initially, synthetic cannabinoids were mainly JWH compounds (after the initials of the scientist who synthesized them) with predominantly sympathomimetic effects. Subsequently, compounds of the XLR-11 and CID families have appeared that produce CNS depressant effects and bradycardia. They are also full cannabinoid receptor agonists. The synthetic cannabinoids may not be detected by routine urine drug screening methods. (Sud et al, 2018)Synthetic Cathinones, or PABS ("bath salts")The synthetic cathinones are one form of "designer drug" with modified chemical structures from a natural form and designed to mimic or amplify the effect of a natural source psychostimulant. These compounds are typically sold as "bath salts" (PABS) but have nothing to do with bathing. Instead are psychoactive "uppers" that are synthetic forms of cathinones. Cathinone is a naturally occurring beta-ketone amphetamine analogue found in the leaves of theCatha edulisplant, indigenous to eastern Africa and the Arabian Peninsula, which is chewed as "khat" for a mild stimulant effect. (Daziani et al, 2023)Derivative synthetic cathinones being used as drugs of abuse include butylone, dimethylcathinone, ethcathinone, ethylone, 3- and 4-fluoromethcathinone, mephedrone, methedrone, methylenedioxypyrovalerone (MDPV), methylone, and pyrovalerone. They mainly contain methylenedioxypyrovalerone (MDPV), which is structurally related to pyrovalerone and pyrrolidinophenone compounds that inhibit norepinephrine-dopamine reuptake. Therefore, they cause central nervous system stimulation and sympathetic stimulation. They are marketed as aphrodisiacs and stimulants. (Prosser and Nelson, 2012)They are absorbed quickly through mucosal surfaces (nasal, oral, gastric, rectal). Only a few milligrams produce a high, but the quantities marketed may be 100 times that amount, increasing the risk for overdose. Their effects peak at 90 minutes following ingestion and last for 3 or 4 hours before the user "crashes". Long-term users of PABS may develop tolerance, and abstinence can lead to withdrawal and intense craving. (Ross et al, 2011)The toxicity from PABS may include extreme sympathetic stimulation with tachycardia, hypertension, shortness of breath, blurred vision, dry mouth, and hyperthermia. There can be markedly altered mental status with severe panic attacks, agitation, paranoia, hallucinations, and violent behavior such as self-mutilation, suicide attempts, and homicidal activity. Seizures may occur. Rhabdomyolysis can develop. Deaths have been reported, most often from alpha-pyrrolidinopentiophenone ("flakka"). The toxicity profile includes the worst effects of other drugs of abuse including lysergic acid diethylamide (LSD), phencyclidine (PCP), methylenedioxymethamphetamine ("ecstasy"), cocaine, and methamphetamine. Routine drug screens do not detect PABS. (Ross et al, 2011; Liu et al, 2018)Mitragynine ("kratom")The kratom plant grows in Southeast Asia and from it can be extracted the psychoactive alkyloid mitragynine, and in small quantities 7-hydromitragynine, which is more potent. At low doses it produces a stimulant effect. At high doses it has a sedative effect as an agonist at the mu opioid receptor. (Liu et al, 2018)Anabolic-Androgenic SteroidsThe use of anabolic-androgenic steroids (AAS) has increased substantially over the past 4 decades. These drugs are used mainly for their effect of increasing muscle mass for the desired goal of increasing athletic performance and enhancing physical appearance. However, such drugs do not increase the level of skill in performance and cardiovascular function--the major enhancers to most sports-related activities. (Sjöqvist et al, 2008) (Thirumalai and Anawalt, 2023)Both oral and injectable compounds are used, more often the latter. Users may cycle on and off usage to avoid complications, but prolonged usage brings many adverse effects. In men these include: testicular atrophy, decreased testosterone production, gynecomastia, decreased sex drive, infertility, baldness, hypertension, heart disease, and tendon injuries. In women, the adverse effects reported include: decreased breast size, fluid retention, hypertension, and sleep disorders. Physical changes such as testicular atrophy and gynecomastia in men, or breast atrophy in women, are often not reversible even after stopping the drugs. Adolescents taking AAS may have diminished bone growth and shorter stature. AAS may produce cholestatic jaundice; they reduce the level of HDL cholesterol to promote atherogenesis and heart disease. (Sjöqvist et al, 2008) (Thirumalai and Anawalt, 2023)The major psychiatric effects of AAS use include changes in mood, worse with greater usage. While using the drugs increased aggression and mania can occur. Off the drugs depression occurs. The combination resembles bipolar disorder, a disabling mental health disorder. Such adverse effects could significantly impact athletic performance negatively and decrease sexual function. In short, AAS can prevent the very things that they are supposed to enhance. (Thirumalai and Anawalt, 2023)The most serious complication of AAS use is an increased risk for heart disease and sudden death. Anabolic steroids decrease HDL cholesterol and increase cardiac size. Myocardial fibrosis can occur, similar to cardiomyopathy. Hypertension induced by AAS further increases heart size. These effects may persist even after use of AAS has been stopped, increasing the risk for morbidity and mortality. Anabolic steroids have been shown to enhance the coronary artery response to catecholamines released during periods of stress, and this may play a role in the sudden cardiac deaths reported with their use. Contraction band necrosis, indicative of ischemia, has been observed in such deaths. (Fineschi et al, 2001)The use of growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin at high, non-physiologic amounts, as anabolic hormonal substances has no significant effect upon increasing muscle mass. Instead, such compounds over time lead to disease states: acromegaly with disfiguring soft tissue changes, diabetes mellitus, hypertension, heart disease, and nerve damage. (García-Arnés and García-Casares, 2023)Improper methods of injection with lack of sterile technique increase the risk for transmissible infections, including viral hepatitis B, viral hepatitis C, and human immunodeficiency virus (HIV). (Thirumalai and Anawalt, 2023)Heart with hypertrophy, gross.Heart with myocardial contraction band necrosis, trichrome stain, microscopic.Testicular atrophy, gross.Testicular atrophy, microscopic.Gynecomastia, gross.Blood DopingIncreasing the amount of circulating red blood cells with their oxygen-carrying hemoglobin is a physiologic adaptation to living at a higher altitude with less atmospheric oxygen. Increasing hemoglobin by 10% will increase oxygen utilization (VO2max) by 5 to 10% for sports where endurance is essential. The quick method is blood transfusion. Such practices are banned in competitive sports, and there are continuing attempts by athletes to mask such practices while methods for detection continue to evolve. (García-Arnés and García-Casares, 2023)Why do sudden deaths occur in athletes who use human recombinant eryrthropoietin ("epo") but very infrequently in patients with anemia who really need it? The drug has predictable results in anemic patients, and raises red cell mass, but not typically above normal. In healthy persons, particularly athletes who do not need more erythropoietin, there are unpredictable results, including an increase in the number of red blood cells (RBCs) into a polycythemic range with increase in blood viscosity to the point of thrombosis (clotting). That could lead to stroke, myocardial infarction, retinal artery occlusion (blindness), and pulmonary thromboembolism. There is also another rare but frightening complication: the development of antibodies, not only to the human recombinant form but also naturally occurring erythropoietin, leading to a condition called "pure red cell aplasia" with transfusion dependence for life. How is the recombinant form detected? The recombinant products include glycan isoforms that differ from natural erythropoietin, and those can be detected in a urine sample. (John et al, 2012) (García-Arnés and García-Casares, 2023)Laboratory TestingTesting for the presence of drugs can be performed on body fluids, principally urine and blood. Urine is easier to obtain, and it is likely to contain both drugs and their metabolites, but detection is qualitativem, since quantification is modified by fluid intake. Blood is obtained when quantification is needed, as for blood ethanol.Screening can include immunoassays that require less equipment and skill in interpretation, but may have cross-reactivity with related drugs that may not be classified as drugs of abuse (e.g., codeine in cough medicines can cross react with opiate drugs of abuse).Confirmation of screening test results, or primary detection of compounds not easily detected by other means, is done by mass spectroscopy (MS). 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Clin Liver Dis. 2023 Feb;27(1):157-172. doi: 10.1016/j.cld.2022.08.005.Patterson DA, Smith E, Monahan M, Medvecz A, Hagerty B, Krijger L, Chauhan A, Walsh M. Cannabinoid hyperemesis and compulsive bathing: a case series and paradoxical pathophysiological explanation. J Am Board Fam Med. 2010;23:790-793.Popova S, Charness ME, Burd L, Crawford A, Hoyme HE, Mukherjee RAS, Riley EP, Elliott EJ. Fetal alcohol spectrum disorders. Nat Rev Dis Primers. 2023 Feb 23;9(1):11. doi: 10.1038/s41572-023-00420-x.Prosser JM, Nelson LS. The toxicology of bath salts: a review of synthetic cathinones. J Med Toxicol. 2012 Mar;8(1):33-42.Purohit V, Rapaka R, Shurtleff D. Role of cannabinoids in the development of fatty liver (steatosis). AAPS J. 2010;12:233-237.Roque-Bravo R, Silva RS, Malheiro RF, Carmo H, Carvalho F, da Silva DD, Silva JP. Synthetic Cannabinoids: A Pharmacological and Toxicological Overview. Annu Rev Pharmacol Toxicol. 2023 Jan 20;63:187-209. doi: 10.1146/annurev-pharmtox-031122-113758.Ross EA, Watson M. Goldberger B. "Bath salts" intoxication. N Engl J Med 2011; 365:967-968.Salihu HM, Wilson RE. Epidemiology of prenatal smoking and perinatal outcomes. Early Hum Dev. 2007;83:713-720.Scully RE, Mark EJ, McNeely WF, et al. Case 6-2001: Case records of the Massachusetts General Hospital. New Engl J Med. 2001;344:591-599.Sjöqvist F, Garle M, Rane A. Use of doping agents, particularly anabolic steroids, in sports and society. Lancet. 2008;371:1872-1882.Stockley J, Sapey E, Gompertz S, Edgar R, Cooper B. Pilot data of the short-term effects of e-cigarrette vaping on lung function. European Respiratory Journal. 2018, 52 (suppl 62) PA2420; DOI: 10.1183/13993003.congress-2018.PA2420.Sud P, Gordon M, Tortora L, Stripp M, Borg D, Berman A. Retrospective Chart Review of Synthetic Cannabinoid Intoxication with Toxicologic Analysis. West J Emerg Med. 2018 May;19(3):567-572.Tay E, Lo WKW, Murnion B. Current Insights on the Impact of Gamma-Hydroxybutyrate (GHB) Abuse. Subst Abuse Rehabil. 2022 Feb 9;13:13-23. doi: 10.2147/SAR.S315720.Timby N, Eriksson A, Bostrom K. Gamma-hydroxybutyrate associated deaths. Am J Med. 2000;108:518-519.Torres-Lockhart KE, Lu TY, Weimer MB, Stein MR, Cunningham CO. Clinical Management of Opioid Withdrawal. Addiction. 2022 Sep;117(9):2540-2550. doi: 10.1111/add.15818.Walter K. Fentanyl Overdose. JAMA. 2023 Jan 10;329(2):184. doi: 10.1001/jama.2022.22462.Walley SC, Wilson KM, Winickoff JP, Groner J. A public health crisis: electronic cigarettes, vape, and JUUL. Pediatrics. 2019;143(6). pii: e20182741. doi: 10.1542/peds.2018-2741. +Initially, synthetic cannabinoids were mainly JWH compounds (after the initials of the scientist who synthesized them) with predominantly sympathomimetic effects. Subsequently, compounds of the XLR-11 and CID families have appeared that produce CNS depressant effects and bradycardia. They are also full cannabinoid receptor agonists. The synthetic cannabinoids may not be detected by routine urine drug screening methods. (Sud et al, 2018) +Synthetic Cathinones, or PABS ("bath salts") +The synthetic cathinones are one form of "designer drug" with modified chemical structures from a natural form and designed to mimic or amplify the effect of a natural source psychostimulant. These compounds are typically sold as "bath salts" (PABS) but have nothing to do with bathing. Instead are psychoactive "uppers" that are synthetic forms of cathinones. Cathinone is a naturally occurring beta-ketone amphetamine analogue found in the leaves of theCatha edulisplant, indigenous to eastern Africa and the Arabian Peninsula, which is chewed as "khat" for a mild stimulant effect. (Daziani et al, 2023) +Derivative synthetic cathinones being used as drugs of abuse include butylone, dimethylcathinone, ethcathinone, ethylone, 3- and 4-fluoromethcathinone, mephedrone, methedrone, methylenedioxypyrovalerone (MDPV), methylone, and pyrovalerone. They mainly contain methylenedioxypyrovalerone (MDPV), which is structurally related to pyrovalerone and pyrrolidinophenone compounds that inhibit norepinephrine-dopamine reuptake. Therefore, they cause central nervous system stimulation and sympathetic stimulation. They are marketed as aphrodisiacs and stimulants. (Prosser and Nelson, 2012) +They are absorbed quickly through mucosal surfaces (nasal, oral, gastric, rectal). Only a few milligrams produce a high, but the quantities marketed may be 100 times that amount, increasing the risk for overdose. Their effects peak at 90 minutes following ingestion and last for 3 or 4 hours before the user "crashes". Long-term users of PABS may develop tolerance, and abstinence can lead to withdrawal and intense craving. (Ross et al, 2011) +The toxicity from PABS may include extreme sympathetic stimulation with tachycardia, hypertension, shortness of breath, blurred vision, dry mouth, and hyperthermia. There can be markedly altered mental status with severe panic attacks, agitation, paranoia, hallucinations, and violent behavior such as self-mutilation, suicide attempts, and homicidal activity. Seizures may occur. Rhabdomyolysis can develop. Deaths have been reported, most often from alpha-pyrrolidinopentiophenone ("flakka"). The toxicity profile includes the worst effects of other drugs of abuse including lysergic acid diethylamide (LSD), phencyclidine (PCP), methylenedioxymethamphetamine ("ecstasy"), cocaine, and methamphetamine. Routine drug screens do not detect PABS. (Ross et al, 2011; Liu et al, 2018) +Mitragynine ("kratom") +The kratom plant grows in Southeast Asia and from it can be extracted the psychoactive alkyloid mitragynine, and in small quantities 7-hydromitragynine, which is more potent. At low doses it produces a stimulant effect. At high doses it has a sedative effect as an agonist at the mu opioid receptor. (Liu et al, 2018) +Anabolic-Androgenic Steroids +The use of anabolic-androgenic steroids (AAS) has increased substantially over the past 4 decades. These drugs are used mainly for their effect of increasing muscle mass for the desired goal of increasing athletic performance and enhancing physical appearance. However, such drugs do not increase the level of skill in performance and cardiovascular function--the major enhancers to most sports-related activities. (Sjöqvist et al, 2008) (Thirumalai and Anawalt, 2023) +Both oral and injectable compounds are used, more often the latter. Users may cycle on and off usage to avoid complications, but prolonged usage brings many adverse effects. In men these include: testicular atrophy, decreased testosterone production, gynecomastia, decreased sex drive, infertility, baldness, hypertension, heart disease, and tendon injuries. In women, the adverse effects reported include: decreased breast size, fluid retention, hypertension, and sleep disorders. Physical changes such as testicular atrophy and gynecomastia in men, or breast atrophy in women, are often not reversible even after stopping the drugs. Adolescents taking AAS may have diminished bone growth and shorter stature. AAS may produce cholestatic jaundice; they reduce the level of HDL cholesterol to promote atherogenesis and heart disease. (Sjöqvist et al, 2008) (Thirumalai and Anawalt, 2023) +The major psychiatric effects of AAS use include changes in mood, worse with greater usage. While using the drugs increased aggression and mania can occur. Off the drugs depression occurs. The combination resembles bipolar disorder, a disabling mental health disorder. Such adverse effects could significantly impact athletic performance negatively and decrease sexual function. In short, AAS can prevent the very things that they are supposed to enhance. (Thirumalai and Anawalt, 2023) +The most serious complication of AAS use is an increased risk for heart disease and sudden death. Anabolic steroids decrease HDL cholesterol and increase cardiac size. Myocardial fibrosis can occur, similar to cardiomyopathy. Hypertension induced by AAS further increases heart size. These effects may persist even after use of AAS has been stopped, increasing the risk for morbidity and mortality. Anabolic steroids have been shown to enhance the coronary artery response to catecholamines released during periods of stress, and this may play a role in the sudden cardiac deaths reported with their use. Contraction band necrosis, indicative of ischemia, has been observed in such deaths. (Fineschi et al, 2001) +The use of growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin at high, non-physiologic amounts, as anabolic hormonal substances has no significant effect upon increasing muscle mass. Instead, such compounds over time lead to disease states: acromegaly with disfiguring soft tissue changes, diabetes mellitus, hypertension, heart disease, and nerve damage. (García-Arnés and García-Casares, 2023)Improper methods of injection with lack of sterile technique increase the risk for transmissible infections, including viral hepatitis B, viral hepatitis C, and human immunodeficiency virus (HIV). (Thirumalai and Anawalt, 2023)Heart with hypertrophy, gross.Heart with myocardial contraction band necrosis, trichrome stain, microscopic.Testicular atrophy, gross.Testicular atrophy, microscopic.Gynecomastia, gross.Blood DopingIncreasing the amount of circulating red blood cells with their oxygen-carrying hemoglobin is a physiologic adaptation to living at a higher altitude with less atmospheric oxygen. Increasing hemoglobin by 10% will increase oxygen utilization (VO2max) by 5 to 10% for sports where endurance is essential. The quick method is blood transfusion. Such practices are banned in competitive sports, and there are continuing attempts by athletes to mask such practices while methods for detection continue to evolve. (García-Arnés and García-Casares, 2023)Why do sudden deaths occur in athletes who use human recombinant eryrthropoietin ("epo") but very infrequently in patients with anemia who really need it? The drug has predictable results in anemic patients, and raises red cell mass, but not typically above normal. In healthy persons, particularly athletes who do not need more erythropoietin, there are unpredictable results, including an increase in the number of red blood cells (RBCs) into a polycythemic range with increase in blood viscosity to the point of thrombosis (clotting). That could lead to stroke, myocardial infarction, retinal artery occlusion (blindness), and pulmonary thromboembolism. There is also another rare but frightening complication: the development of antibodies, not only to the human recombinant form but also naturally occurring erythropoietin, leading to a condition called "pure red cell aplasia" with transfusion dependence for life. How is the recombinant form detected? The recombinant products include glycan isoforms that differ from natural erythropoietin, and those can be detected in a urine sample. (John et al, 2012) (García-Arnés and García-Casares, 2023)Laboratory TestingTesting for the presence of drugs can be performed on body fluids, principally urine and blood. Urine is easier to obtain, and it is likely to contain both drugs and their metabolites, but detection is qualitativem, since quantification is modified by fluid intake. Blood is obtained when quantification is needed, as for blood ethanol.Screening can include immunoassays that require less equipment and skill in interpretation, but may have cross-reactivity with related drugs that may not be classified as drugs of abuse (e.g., codeine in cough medicines can cross react with opiate drugs of abuse).Confirmation of screening test results, or primary detection of compounds not easily detected by other means, is done by mass spectroscopy (MS). The first step is chromatography for separation of the drug compounds in a gas phase (gas chromatography (GC) or liquid phase (liquid chromatography, or LC). the next step is mass spectroscopic analysis of the separated compounds. Thus, the method can be GC-MS or LC-MS. (Liu et al, 2018)ReferencesAwtry EH, Philippides GJ. Alcoholic and cocaine-associated cardiomyopathies. Prog Cardiovasc Dis. 2010;52:289-299.Banks E, Yazidjoglou A, Brown S, et al. Electronic cigarettes and health outcomes: umbrella and systematic review of the global evidence. Med J Aust. 2023 Apr 3;218(6):267-275. doi: 10.5694/mja2.51890.Bedene A, Dahan A, Rosendaal FR, van Dorp ELA. Opioid epidemic: lessons learned and updated recommendations for misuse involving prescription versus non-prescription opioids. Expert Rev Clin Pharmacol. 2022 Sep;15(9):1081-1094. doi: 10.1080/17512433.2022.2114898.Butt YM, Smith ML, Tazelaar HD, et al.Pathology of Vaping-Associated Lung Injury. N Engl J Med. 2019 Oct 2. doi:10.1056/NEJMc1913069.Carter N, Rutty GN, Milroy CM, Forrest AR. Deaths associated with MBDB misuse. Int J Legal Med. 2000;113:168-170.Christophersen AS. Amphetamine designer drugs - an overview and epidemiology. Toxicol Lett. 2000;112-113:127-131.Day E, Daly C. Clinical management of the alcohol withdrawal syndrome. Addiction. 2022 Mar;117(3):804-814. doi: 10.1111/add.15647.Daziani G, Lo Faro AF, Montana V, et al. Synthetic Cathinones and Neurotoxicity Risks: A Systematic Review. Int J Mol Sci. 2023 Mar 25;24(7):6230. doi: 10.3390/ijms24076230.Devlin RJ, Henry JA. Clinical review: Major consequences of illicit drug consumption. Crit Care. 2008;12:202.Fineschi V, Baroldi G, Monciotti F, Reattelli LP, Turillazzi E. Anabolic steroid abuse and cardiac sudden death. Arch Pathol Lab Med. 2001;125:253-255.Fineschi V, Centini F, Mazzeo E, Turillazzi E. Adam (MDMA) and Eve (MDEA) misuse: an immunohistochemical study on three fatal cases. Forensic Sci Int. 1999;104:65-74.García-Arnés JA, García-Casares N. Doping and sports endocrinology: growth hormone, IGF-1, insulin, and erythropoietin. Rev Clin Esp (Barc). 2023 Mar;223(3):181-187. doi: 10.1016/j.rceng.2023.01.005.GBD 2017 Risk Factor Collaborators. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018 Nov 10;392(10159):1923-1994. doi: 10.1016/S0140-6736(18)32225-6.Nutt D, Hayes A, Fonville L, Zafar R, Palmer EOC, Paterson L, Lingford-Hughes A. Alcohol and the Brain. Nutrients. 2021 Nov 4;13(11):3938. doi: 10.3390/nu13113938.Gould GS, Havard A, Lim LL, The Psanz Smoking In Pregnancy Expert Group, Kumar R. Exposure to Tobacco, Environmental Tobacco Smoke and Nicotine in Pregnancy: A Pragmatic Overview of Reviews of Maternal and Child Outcomes, Effectiveness of Interventions and Barriers and Facilitators to Quitting. Int J Environ Res Public Health. 2020 Mar 19;17(6):2034. doi: 10.3390/ijerph17062034.Gouzoulis-Mayfrank E, Daumann J. Neurotoxicity of drugs of abuse--the case of methylenedioxyamphetamines (MDMA, ecstasy), and amphetamines. Dialogues Clin Neurosci. 2009;11:305-317.Hall W, Degenhardt L. Adverse health effects of non-medical cannabis use. Lancet. 2009;374:1383-1391.Hays LR. A profile of OxyContin addiction. J Addict Dis. 2004;23:1-9.John MJ, Jaison V, Jain K, Kakkar N, Jacob JJ. Erythropoietin use and abuse. Indian J Endocrinol Metab. 2012;16:220-227.Henry TS, Kligerman SJ, Raptis CA, Mann H, Sechrist JW, Kanne JP. Imaging Findings of Vaping-Associated Lung Injury. AJR Am J Roentgenol. 2019 Oct 8:1-8. doi: 10.2214/AJR.19.22251.Kiyatkin EA, Sharma HS. Acute methamphetamine intoxication brain hyperthermia, blood-brain barrier, brain edema, and morphological cell abnormalities. Int Rev Neurobiol. 2009;88:65-100.Krishnasamy VP, Hallowell BD, Ko JY, et al. Update: Characteristics of a Nationwide Outbreak of E-cigarette, or Vaping, Product Use–Associated Lung Injury — United States, August 2019–January 2020. MMWR Morb Mortal Wkly Rep 2020;69:90–94. DOI: http://dx.doi.org/10.15585/mmwr.mm6903e2.Kuczkowski KM. The effects of drug abuse on pregnancy. Curr Opin Obstet Gynecol. 2007;19:578-585.Liu L, Wheeler SE, Venkataramanan R, Rymer JA, Pizon AF, Lynch MJ, Tamama K. Newly emerging drugs of abuse and their detection methods: an ACLPS critical review. Am J Clin Pathol. 2018;149(2):105-116.Malone DT, Hill MN, Rubino T. Adolescent cannabis use and psychosis: epidemiology and neurodevelopmental models. Br J Pharmacol. 2010;160:511-522.Marks LR, Nolan NS, Liang SY, Durkin MJ, Weimer MB. Infectious Complications of Injection Drug Use. Med Clin North Am. 2022 Jan;106(1):187-200. doi: 10.1016/j.mcna.2021.08.006.McGuire P. Long term psychiatric and cognitive effects of MDMA use. Toxicol Lett. 2000;112-113:153-156.Milroy CM, Parai JL. The histopathology of drugs of abuse. Histopathology. 2011 Oct;59(4):579-93. doi: 10.1111/j.1365-2559.2010.03728.x.Mukherjee RA, Hollins S, Turk J. Fetal alcohol spectrum disorder: an overview. J R Soc Med. 2006;99:298-302.Mukhopadhyay S, Mehrad M, Dammert P, et al. Lung Biopsy Findings in Severe Pulmonary Illness Associated With E-Cigarette Use (Vaping). Am J Clin Pathol. 2020;153(1):30-39.Murtha L, Sathiadoss P, Salameh JP, Mcinnes MDF, Revah G. Chest CT Findings in Marijuana Smokers. Radiology. 2022 Nov 15:212611. doi: 10.1148/radiol.212611.Park JA, Crotty Alexander LE, Christiani DC. Vaping and Lung Inflammation and Injury. Annu Rev Physiol. 2022 Feb 10;84:611-629. doi: 10.1146/annurev-physiol-061121-040014.Patel PV, Flamm SL. Alcohol-Related Liver Disease Including New Developments. Clin Liver Dis. 2023 Feb;27(1):157-172. doi: 10.1016/j.cld.2022.08.005.Patterson DA, Smith E, Monahan M, Medvecz A, Hagerty B, Krijger L, Chauhan A, Walsh M. Cannabinoid hyperemesis and compulsive bathing: a case series and paradoxical pathophysiological explanation. J Am Board Fam Med. 2010;23:790-793.Popova S, Charness ME, Burd L, Crawford A, Hoyme HE, Mukherjee RAS, Riley EP, Elliott EJ. Fetal alcohol spectrum disorders. Nat Rev Dis Primers. 2023 Feb 23;9(1):11. doi: 10.1038/s41572-023-00420-x.Prosser JM, Nelson LS. The toxicology of bath salts: a review of synthetic cathinones. J Med Toxicol. 2012 Mar;8(1):33-42.Purohit V, Rapaka R, Shurtleff D. Role of cannabinoids in the development of fatty liver (steatosis). AAPS J. 2010;12:233-237.Roque-Bravo R, Silva RS, Malheiro RF, Carmo H, Carvalho F, da Silva DD, Silva JP. Synthetic Cannabinoids: A Pharmacological and Toxicological Overview. Annu Rev Pharmacol Toxicol. 2023 Jan 20;63:187-209. doi: 10.1146/annurev-pharmtox-031122-113758.Ross EA, Watson M. Goldberger B. "Bath salts" intoxication. N Engl J Med 2011; 365:967-968.Salihu HM, Wilson RE. Epidemiology of prenatal smoking and perinatal outcomes. Early Hum Dev. 2007;83:713-720.Scully RE, Mark EJ, McNeely WF, et al. Case 6-2001: Case records of the Massachusetts General Hospital. New Engl J Med. 2001;344:591-599.Sjöqvist F, Garle M, Rane A. Use of doping agents, particularly anabolic steroids, in sports and society. Lancet. 2008;371:1872-1882.Stockley J, Sapey E, Gompertz S, Edgar R, Cooper B. Pilot data of the short-term effects of e-cigarrette vaping on lung function. European Respiratory Journal. 2018, 52 (suppl 62) PA2420; DOI: 10.1183/13993003.congress-2018.PA2420.Sud P, Gordon M, Tortora L, Stripp M, Borg D, Berman A. Retrospective Chart Review of Synthetic Cannabinoid Intoxication with Toxicologic Analysis. West J Emerg Med. 2018 May;19(3):567-572.Tay E, Lo WKW, Murnion B. Current Insights on the Impact of Gamma-Hydroxybutyrate (GHB) Abuse. Subst Abuse Rehabil. 2022 Feb 9;13:13-23. doi: 10.2147/SAR.S315720.Timby N, Eriksson A, Bostrom K. Gamma-hydroxybutyrate associated deaths. Am J Med. 2000;108:518-519.Torres-Lockhart KE, Lu TY, Weimer MB, Stein MR, Cunningham CO. Clinical Management of Opioid Withdrawal. Addiction. 2022 Sep;117(9):2540-2550. doi: 10.1111/add.15818.Walter K. Fentanyl Overdose. JAMA. 2023 Jan 10;329(2):184. doi: 10.1001/jama.2022.22462.Walley SC, Wilson KM, Winickoff JP, Groner J. A public health crisis: electronic cigarettes, vape, and JUUL. Pediatrics. 2019;143(6). pii: e20182741. doi: 10.1542/peds.2018-2741. +Improper methods of injection with lack of sterile technique increase the risk for transmissible infections, including viral hepatitis B, viral hepatitis C, and human immunodeficiency virus (HIV). (Thirumalai and Anawalt, 2023)Heart with hypertrophy, gross.Heart with myocardial contraction band necrosis, trichrome stain, microscopic.Testicular atrophy, gross.Testicular atrophy, microscopic.Gynecomastia, gross.Blood DopingIncreasing the amount of circulating red blood cells with their oxygen-carrying hemoglobin is a physiologic adaptation to living at a higher altitude with less atmospheric oxygen. Increasing hemoglobin by 10% will increase oxygen utilization (VO2max) by 5 to 10% for sports where endurance is essential. The quick method is blood transfusion. Such practices are banned in competitive sports, and there are continuing attempts by athletes to mask such practices while methods for detection continue to evolve. (García-Arnés and García-Casares, 2023)Why do sudden deaths occur in athletes who use human recombinant eryrthropoietin ("epo") but very infrequently in patients with anemia who really need it? The drug has predictable results in anemic patients, and raises red cell mass, but not typically above normal. In healthy persons, particularly athletes who do not need more erythropoietin, there are unpredictable results, including an increase in the number of red blood cells (RBCs) into a polycythemic range with increase in blood viscosity to the point of thrombosis (clotting). That could lead to stroke, myocardial infarction, retinal artery occlusion (blindness), and pulmonary thromboembolism. There is also another rare but frightening complication: the development of antibodies, not only to the human recombinant form but also naturally occurring erythropoietin, leading to a condition called "pure red cell aplasia" with transfusion dependence for life. How is the recombinant form detected? The recombinant products include glycan isoforms that differ from natural erythropoietin, and those can be detected in a urine sample. (John et al, 2012) (García-Arnés and García-Casares, 2023)Laboratory TestingTesting for the presence of drugs can be performed on body fluids, principally urine and blood. Urine is easier to obtain, and it is likely to contain both drugs and their metabolites, but detection is qualitativem, since quantification is modified by fluid intake. Blood is obtained when quantification is needed, as for blood ethanol.Screening can include immunoassays that require less equipment and skill in interpretation, but may have cross-reactivity with related drugs that may not be classified as drugs of abuse (e.g., codeine in cough medicines can cross react with opiate drugs of abuse).Confirmation of screening test results, or primary detection of compounds not easily detected by other means, is done by mass spectroscopy (MS). The first step is chromatography for separation of the drug compounds in a gas phase (gas chromatography (GC) or liquid phase (liquid chromatography, or LC). the next step is mass spectroscopic analysis of the separated compounds. Thus, the method can be GC-MS or LC-MS. (Liu et al, 2018)ReferencesAwtry EH, Philippides GJ. Alcoholic and cocaine-associated cardiomyopathies. Prog Cardiovasc Dis. 2010;52:289-299.Banks E, Yazidjoglou A, Brown S, et al. Electronic cigarettes and health outcomes: umbrella and systematic review of the global evidence. Med J Aust. 2023 Apr 3;218(6):267-275. doi: 10.5694/mja2.51890.Bedene A, Dahan A, Rosendaal FR, van Dorp ELA. Opioid epidemic: lessons learned and updated recommendations for misuse involving prescription versus non-prescription opioids. Expert Rev Clin Pharmacol. 2022 Sep;15(9):1081-1094. doi: 10.1080/17512433.2022.2114898.Butt YM, Smith ML, Tazelaar HD, et al.Pathology of Vaping-Associated Lung Injury. N Engl J Med. 2019 Oct 2. doi:10.1056/NEJMc1913069.Carter N, Rutty GN, Milroy CM, Forrest AR. Deaths associated with MBDB misuse. Int J Legal Med. 2000;113:168-170.Christophersen AS. Amphetamine designer drugs - an overview and epidemiology. Toxicol Lett. 2000;112-113:127-131.Day E, Daly C. Clinical management of the alcohol withdrawal syndrome. Addiction. 2022 Mar;117(3):804-814. doi: 10.1111/add.15647.Daziani G, Lo Faro AF, Montana V, et al. Synthetic Cathinones and Neurotoxicity Risks: A Systematic Review. Int J Mol Sci. 2023 Mar 25;24(7):6230. doi: 10.3390/ijms24076230.Devlin RJ, Henry JA. Clinical review: Major consequences of illicit drug consumption. Crit Care. 2008;12:202.Fineschi V, Baroldi G, Monciotti F, Reattelli LP, Turillazzi E. Anabolic steroid abuse and cardiac sudden death. Arch Pathol Lab Med. 2001;125:253-255.Fineschi V, Centini F, Mazzeo E, Turillazzi E. Adam (MDMA) and Eve (MDEA) misuse: an immunohistochemical study on three fatal cases. Forensic Sci Int. 1999;104:65-74.García-Arnés JA, García-Casares N. Doping and sports endocrinology: growth hormone, IGF-1, insulin, and erythropoietin. Rev Clin Esp (Barc). 2023 Mar;223(3):181-187. doi: 10.1016/j.rceng.2023.01.005.GBD 2017 Risk Factor Collaborators. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018 Nov 10;392(10159):1923-1994. doi: 10.1016/S0140-6736(18)32225-6.Nutt D, Hayes A, Fonville L, Zafar R, Palmer EOC, Paterson L, Lingford-Hughes A. Alcohol and the Brain. Nutrients. 2021 Nov 4;13(11):3938. doi: 10.3390/nu13113938.Gould GS, Havard A, Lim LL, The Psanz Smoking In Pregnancy Expert Group, Kumar R. Exposure to Tobacco, Environmental Tobacco Smoke and Nicotine in Pregnancy: A Pragmatic Overview of Reviews of Maternal and Child Outcomes, Effectiveness of Interventions and Barriers and Facilitators to Quitting. Int J Environ Res Public Health. 2020 Mar 19;17(6):2034. doi: 10.3390/ijerph17062034.Gouzoulis-Mayfrank E, Daumann J. Neurotoxicity of drugs of abuse--the case of methylenedioxyamphetamines (MDMA, ecstasy), and amphetamines. Dialogues Clin Neurosci. 2009;11:305-317.Hall W, Degenhardt L. Adverse health effects of non-medical cannabis use. Lancet. 2009;374:1383-1391.Hays LR. A profile of OxyContin addiction. J Addict Dis. 2004;23:1-9.John MJ, Jaison V, Jain K, Kakkar N, Jacob JJ. Erythropoietin use and abuse. Indian J Endocrinol Metab. 2012;16:220-227.Henry TS, Kligerman SJ, Raptis CA, Mann H, Sechrist JW, Kanne JP. Imaging Findings of Vaping-Associated Lung Injury. AJR Am J Roentgenol. 2019 Oct 8:1-8. doi: 10.2214/AJR.19.22251.Kiyatkin EA, Sharma HS. Acute methamphetamine intoxication brain hyperthermia, blood-brain barrier, brain edema, and morphological cell abnormalities. Int Rev Neurobiol. 2009;88:65-100.Krishnasamy VP, Hallowell BD, Ko JY, et al. Update: Characteristics of a Nationwide Outbreak of E-cigarette, or Vaping, Product Use–Associated Lung Injury — United States, August 2019–January 2020. MMWR Morb Mortal Wkly Rep 2020;69:90–94. DOI: http://dx.doi.org/10.15585/mmwr.mm6903e2.Kuczkowski KM. The effects of drug abuse on pregnancy. Curr Opin Obstet Gynecol. 2007;19:578-585.Liu L, Wheeler SE, Venkataramanan R, Rymer JA, Pizon AF, Lynch MJ, Tamama K. Newly emerging drugs of abuse and their detection methods: an ACLPS critical review. Am J Clin Pathol. 2018;149(2):105-116.Malone DT, Hill MN, Rubino T. Adolescent cannabis use and psychosis: epidemiology and neurodevelopmental models. Br J Pharmacol. 2010;160:511-522.Marks LR, Nolan NS, Liang SY, Durkin MJ, Weimer MB. Infectious Complications of Injection Drug Use. Med Clin North Am. 2022 Jan;106(1):187-200. doi: 10.1016/j.mcna.2021.08.006.McGuire P. Long term psychiatric and cognitive effects of MDMA use. Toxicol Lett. 2000;112-113:153-156.Milroy CM, Parai JL. The histopathology of drugs of abuse. Histopathology. 2011 Oct;59(4):579-93. doi: 10.1111/j.1365-2559.2010.03728.x.Mukherjee RA, Hollins S, Turk J. Fetal alcohol spectrum disorder: an overview. J R Soc Med. 2006;99:298-302.Mukhopadhyay S, Mehrad M, Dammert P, et al. Lung Biopsy Findings in Severe Pulmonary Illness Associated With E-Cigarette Use (Vaping). Am J Clin Pathol. 2020;153(1):30-39.Murtha L, Sathiadoss P, Salameh JP, Mcinnes MDF, Revah G. Chest CT Findings in Marijuana Smokers. Radiology. 2022 Nov 15:212611. doi: 10.1148/radiol.212611.Park JA, Crotty Alexander LE, Christiani DC. Vaping and Lung Inflammation and Injury. Annu Rev Physiol. 2022 Feb 10;84:611-629. doi: 10.1146/annurev-physiol-061121-040014.Patel PV, Flamm SL. Alcohol-Related Liver Disease Including New Developments. Clin Liver Dis. 2023 Feb;27(1):157-172. doi: 10.1016/j.cld.2022.08.005.Patterson DA, Smith E, Monahan M, Medvecz A, Hagerty B, Krijger L, Chauhan A, Walsh M. Cannabinoid hyperemesis and compulsive bathing: a case series and paradoxical pathophysiological explanation. J Am Board Fam Med. 2010;23:790-793.Popova S, Charness ME, Burd L, Crawford A, Hoyme HE, Mukherjee RAS, Riley EP, Elliott EJ. Fetal alcohol spectrum disorders. Nat Rev Dis Primers. 2023 Feb 23;9(1):11. doi: 10.1038/s41572-023-00420-x.Prosser JM, Nelson LS. The toxicology of bath salts: a review of synthetic cathinones. J Med Toxicol. 2012 Mar;8(1):33-42.Purohit V, Rapaka R, Shurtleff D. Role of cannabinoids in the development of fatty liver (steatosis). AAPS J. 2010;12:233-237.Roque-Bravo R, Silva RS, Malheiro RF, Carmo H, Carvalho F, da Silva DD, Silva JP. Synthetic Cannabinoids: A Pharmacological and Toxicological Overview. Annu Rev Pharmacol Toxicol. 2023 Jan 20;63:187-209. doi: 10.1146/annurev-pharmtox-031122-113758.Ross EA, Watson M. Goldberger B. "Bath salts" intoxication. N Engl J Med 2011; 365:967-968.Salihu HM, Wilson RE. Epidemiology of prenatal smoking and perinatal outcomes. Early Hum Dev. 2007;83:713-720.Scully RE, Mark EJ, McNeely WF, et al. Case 6-2001: Case records of the Massachusetts General Hospital. New Engl J Med. 2001;344:591-599.Sjöqvist F, Garle M, Rane A. Use of doping agents, particularly anabolic steroids, in sports and society. Lancet. 2008;371:1872-1882.Stockley J, Sapey E, Gompertz S, Edgar R, Cooper B. Pilot data of the short-term effects of e-cigarrette vaping on lung function. European Respiratory Journal. 2018, 52 (suppl 62) PA2420; DOI: 10.1183/13993003.congress-2018.PA2420.Sud P, Gordon M, Tortora L, Stripp M, Borg D, Berman A. Retrospective Chart Review of Synthetic Cannabinoid Intoxication with Toxicologic Analysis. West J Emerg Med. 2018 May;19(3):567-572.Tay E, Lo WKW, Murnion B. Current Insights on the Impact of Gamma-Hydroxybutyrate (GHB) Abuse. Subst Abuse Rehabil. 2022 Feb 9;13:13-23. doi: 10.2147/SAR.S315720.Timby N, Eriksson A, Bostrom K. Gamma-hydroxybutyrate associated deaths. Am J Med. 2000;108:518-519.Torres-Lockhart KE, Lu TY, Weimer MB, Stein MR, Cunningham CO. Clinical Management of Opioid Withdrawal. Addiction. 2022 Sep;117(9):2540-2550. doi: 10.1111/add.15818.Walter K. Fentanyl Overdose. JAMA. 2023 Jan 10;329(2):184. doi: 10.1001/jama.2022.22462.Walley SC, Wilson KM, Winickoff JP, Groner J. A public health crisis: electronic cigarettes, vape, and JUUL. Pediatrics. 2019;143(6). pii: e20182741. doi: 10.1542/peds.2018-2741. +Heart with hypertrophy, gross. +Heart with myocardial contraction band necrosis, trichrome stain, microscopic. +Testicular atrophy, gross. +Testicular atrophy, microscopic. +Gynecomastia, gross. +Increasing the amount of circulating red blood cells with their oxygen-carrying hemoglobin is a physiologic adaptation to living at a higher altitude with less atmospheric oxygen. Increasing hemoglobin by 10% will increase oxygen utilization (VO2max) by 5 to 10% for sports where endurance is essential. The quick method is blood transfusion. Such practices are banned in competitive sports, and there are continuing attempts by athletes to mask such practices while methods for detection continue to evolve. (García-Arnés and García-Casares, 2023) +Why do sudden deaths occur in athletes who use human recombinant eryrthropoietin ("epo") but very infrequently in patients with anemia who really need it? The drug has predictable results in anemic patients, and raises red cell mass, but not typically above normal. In healthy persons, particularly athletes who do not need more erythropoietin, there are unpredictable results, including an increase in the number of red blood cells (RBCs) into a polycythemic range with increase in blood viscosity to the point of thrombosis (clotting). That could lead to stroke, myocardial infarction, retinal artery occlusion (blindness), and pulmonary thromboembolism. There is also another rare but frightening complication: the development of antibodies, not only to the human recombinant form but also naturally occurring erythropoietin, leading to a condition called "pure red cell aplasia" with transfusion dependence for life. How is the recombinant form detected? The recombinant products include glycan isoforms that differ from natural erythropoietin, and those can be detected in a urine sample. (John et al, 2012) (García-Arnés and García-Casares, 2023) +Laboratory Testing +Testing for the presence of drugs can be performed on body fluids, principally urine and blood. Urine is easier to obtain, and it is likely to contain both drugs and their metabolites, but detection is qualitativem, since quantification is modified by fluid intake. Blood is obtained when quantification is needed, as for blood ethanol. +Screening can include immunoassays that require less equipment and skill in interpretation, but may have cross-reactivity with related drugs that may not be classified as drugs of abuse (e.g., codeine in cough medicines can cross react with opiate drugs of abuse). +Confirmation of screening test results, or primary detection of compounds not easily detected by other means, is done by mass spectroscopy (MS). The first step is chromatography for separation of the drug compounds in a gas phase (gas chromatography (GC) or liquid phase (liquid chromatography, or LC). the next step is mass spectroscopic analysis of the separated compounds. Thus, the method can be GC-MS or LC-MS. (Liu et al, 2018) +Awtry EH, Philippides GJ. Alcoholic and cocaine-associated cardiomyopathies. Prog Cardiovasc Dis. 2010;52:289-299. +Banks E, Yazidjoglou A, Brown S, et al. Electronic cigarettes and health outcomes: umbrella and systematic review of the global evidence. Med J Aust. 2023 Apr 3;218(6):267-275. doi: 10.5694/mja2.51890. +Bedene A, Dahan A, Rosendaal FR, van Dorp ELA. Opioid epidemic: lessons learned and updated recommendations for misuse involving prescription versus non-prescription opioids. Expert Rev Clin Pharmacol. 2022 Sep;15(9):1081-1094. doi: 10.1080/17512433.2022.2114898. +Butt YM, Smith ML, Tazelaar HD, et al.Pathology of Vaping-Associated Lung Injury. N Engl J Med. 2019 Oct 2. doi:10.1056/NEJMc1913069. +Carter N, Rutty GN, Milroy CM, Forrest AR. Deaths associated with MBDB misuse. Int J Legal Med. 2000;113:168-170. +Christophersen AS. Amphetamine designer drugs - an overview and epidemiology. Toxicol Lett. 2000;112-113:127-131. +Day E, Daly C. Clinical management of the alcohol withdrawal syndrome. Addiction. 2022 Mar;117(3):804-814. doi: 10.1111/add.15647. +Daziani G, Lo Faro AF, Montana V, et al. Synthetic Cathinones and Neurotoxicity Risks: A Systematic Review. Int J Mol Sci. 2023 Mar 25;24(7):6230. doi: 10.3390/ijms24076230. +Devlin RJ, Henry JA. Clinical review: Major consequences of illicit drug consumption. Crit Care. 2008;12:202. +Fineschi V, Baroldi G, Monciotti F, Reattelli LP, Turillazzi E. Anabolic steroid abuse and cardiac sudden death. Arch Pathol Lab Med. 2001;125:253-255. +Fineschi V, Centini F, Mazzeo E, Turillazzi E. Adam (MDMA) and Eve (MDEA) misuse: an immunohistochemical study on three fatal cases. Forensic Sci Int. 1999;104:65-74. +García-Arnés JA, García-Casares N. Doping and sports endocrinology: growth hormone, IGF-1, insulin, and erythropoietin. Rev Clin Esp (Barc). 2023 Mar;223(3):181-187. doi: 10.1016/j.rceng.2023.01.005. +GBD 2017 Risk Factor Collaborators. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018 Nov 10;392(10159):1923-1994. doi: 10.1016/S0140-6736(18)32225-6. +Nutt D, Hayes A, Fonville L, Zafar R, Palmer EOC, Paterson L, Lingford-Hughes A. Alcohol and the Brain. Nutrients. 2021 Nov 4;13(11):3938. doi: 10.3390/nu13113938. +Gould GS, Havard A, Lim LL, The Psanz Smoking In Pregnancy Expert Group, Kumar R. Exposure to Tobacco, Environmental Tobacco Smoke and Nicotine in Pregnancy: A Pragmatic Overview of Reviews of Maternal and Child Outcomes, Effectiveness of Interventions and Barriers and Facilitators to Quitting. Int J Environ Res Public Health. 2020 Mar 19;17(6):2034. doi: 10.3390/ijerph17062034. +Gouzoulis-Mayfrank E, Daumann J. Neurotoxicity of drugs of abuse--the case of methylenedioxyamphetamines (MDMA, ecstasy), and amphetamines. Dialogues Clin Neurosci. 2009;11:305-317. +Hall W, Degenhardt L. Adverse health effects of non-medical cannabis use. Lancet. 2009;374:1383-1391. +Hays LR. A profile of OxyContin addiction. J Addict Dis. 2004;23:1-9. +John MJ, Jaison V, Jain K, Kakkar N, Jacob JJ. Erythropoietin use and abuse. Indian J Endocrinol Metab. 2012;16:220-227. +Henry TS, Kligerman SJ, Raptis CA, Mann H, Sechrist JW, Kanne JP. Imaging Findings of Vaping-Associated Lung Injury. AJR Am J Roentgenol. 2019 Oct 8:1-8. doi: 10.2214/AJR.19.22251. +Kiyatkin EA, Sharma HS. Acute methamphetamine intoxication brain hyperthermia, blood-brain barrier, brain edema, and morphological cell abnormalities. Int Rev Neurobiol. 2009;88:65-100. +Krishnasamy VP, Hallowell BD, Ko JY, et al. Update: Characteristics of a Nationwide Outbreak of E-cigarette, or Vaping, Product Use–Associated Lung Injury — United States, August 2019–January 2020. MMWR Morb Mortal Wkly Rep 2020;69:90–94. DOI: http://dx.doi.org/10.15585/mmwr.mm6903e2. +Kuczkowski KM. The effects of drug abuse on pregnancy. Curr Opin Obstet Gynecol. 2007;19:578-585. +Liu L, Wheeler SE, Venkataramanan R, Rymer JA, Pizon AF, Lynch MJ, Tamama K. Newly emerging drugs of abuse and their detection methods: an ACLPS critical review. Am J Clin Pathol. 2018;149(2):105-116. +Malone DT, Hill MN, Rubino T. Adolescent cannabis use and psychosis: epidemiology and neurodevelopmental models. Br J Pharmacol. 2010;160:511-522. +Marks LR, Nolan NS, Liang SY, Durkin MJ, Weimer MB. Infectious Complications of Injection Drug Use. Med Clin North Am. 2022 Jan;106(1):187-200. doi: 10.1016/j.mcna.2021.08.006. +McGuire P. Long term psychiatric and cognitive effects of MDMA use. Toxicol Lett. 2000;112-113:153-156. +Milroy CM, Parai JL. The histopathology of drugs of abuse. Histopathology. 2011 Oct;59(4):579-93. doi: 10.1111/j.1365-2559.2010.03728.x. +Mukherjee RA, Hollins S, Turk J. Fetal alcohol spectrum disorder: an overview. J R Soc Med. 2006;99:298-302. +Mukhopadhyay S, Mehrad M, Dammert P, et al. Lung Biopsy Findings in Severe Pulmonary Illness Associated With E-Cigarette Use (Vaping). Am J Clin Pathol. 2020;153(1):30-39. +Murtha L, Sathiadoss P, Salameh JP, Mcinnes MDF, Revah G. Chest CT Findings in Marijuana Smokers. Radiology. 2022 Nov 15:212611. doi: 10.1148/radiol.212611. +Park JA, Crotty Alexander LE, Christiani DC. Vaping and Lung Inflammation and Injury. Annu Rev Physiol. 2022 Feb 10;84:611-629. doi: 10.1146/annurev-physiol-061121-040014. +Patel PV, Flamm SL. Alcohol-Related Liver Disease Including New Developments. Clin Liver Dis. 2023 Feb;27(1):157-172. doi: 10.1016/j.cld.2022.08.005. +Patterson DA, Smith E, Monahan M, Medvecz A, Hagerty B, Krijger L, Chauhan A, Walsh M. Cannabinoid hyperemesis and compulsive bathing: a case series and paradoxical pathophysiological explanation. J Am Board Fam Med. 2010;23:790-793. +Popova S, Charness ME, Burd L, Crawford A, Hoyme HE, Mukherjee RAS, Riley EP, Elliott EJ. Fetal alcohol spectrum disorders. Nat Rev Dis Primers. 2023 Feb 23;9(1):11. doi: 10.1038/s41572-023-00420-x. +Prosser JM, Nelson LS. The toxicology of bath salts: a review of synthetic cathinones. J Med Toxicol. 2012 Mar;8(1):33-42. +Purohit V, Rapaka R, Shurtleff D. Role of cannabinoids in the development of fatty liver (steatosis). AAPS J. 2010;12:233-237. +Roque-Bravo R, Silva RS, Malheiro RF, Carmo H, Carvalho F, da Silva DD, Silva JP. Synthetic Cannabinoids: A Pharmacological and Toxicological Overview. Annu Rev Pharmacol Toxicol. 2023 Jan 20;63:187-209. doi: 10.1146/annurev-pharmtox-031122-113758. +Ross EA, Watson M. Goldberger B. "Bath salts" intoxication. N Engl J Med 2011; 365:967-968. +Salihu HM, Wilson RE. Epidemiology of prenatal smoking and perinatal outcomes. Early Hum Dev. 2007;83:713-720. +Scully RE, Mark EJ, McNeely WF, et al. Case 6-2001: Case records of the Massachusetts General Hospital. New Engl J Med. 2001;344:591-599. +Sjöqvist F, Garle M, Rane A. Use of doping agents, particularly anabolic steroids, in sports and society. Lancet. 2008;371:1872-1882. +Stockley J, Sapey E, Gompertz S, Edgar R, Cooper B. Pilot data of the short-term effects of e-cigarrette vaping on lung function. European Respiratory Journal. 2018, 52 (suppl 62) PA2420; DOI: 10.1183/13993003.congress-2018.PA2420. +Sud P, Gordon M, Tortora L, Stripp M, Borg D, Berman A. Retrospective Chart Review of Synthetic Cannabinoid Intoxication with Toxicologic Analysis. West J Emerg Med. 2018 May;19(3):567-572. +Tay E, Lo WKW, Murnion B. Current Insights on the Impact of Gamma-Hydroxybutyrate (GHB) Abuse. Subst Abuse Rehabil. 2022 Feb 9;13:13-23. doi: 10.2147/SAR.S315720. +Timby N, Eriksson A, Bostrom K. Gamma-hydroxybutyrate associated deaths. Am J Med. 2000;108:518-519. +Torres-Lockhart KE, Lu TY, Weimer MB, Stein MR, Cunningham CO. Clinical Management of Opioid Withdrawal. Addiction. 2022 Sep;117(9):2540-2550. doi: 10.1111/add.15818. +Walter K. Fentanyl Overdose. JAMA. 2023 Jan 10;329(2):184. doi: 10.1001/jama.2022.22462. +Walley SC, Wilson KM, Winickoff JP, Groner J. A public health crisis: electronic cigarettes, vape, and JUUL. Pediatrics. 2019;143(6). pii: e20182741. doi: 10.1542/peds.2018-2741. +## 3. Hemopericardium, gross {#item-3} +![](../../images/forensic_a5087852.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is hemopericardium as demonstrated by the dark blood in the pericardial sac opened at autopsy. Penetrating trauma or massive blunt force trauma to the chest (often from the steering wheel) causes a rupture of the myocardium and/or coronary arteries with bleeding into the pericardial cavity. The extensive collection of blood in this closed space leads to cardiac tamponade. A pericardiocentesis, with needle inserted into the pericardial cavity, can be a diagnostic procedure. +## 4. Aorta, tear with laceration, gross {#item-4} +![](../../images/forensic_c52cc743.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Sometimes a sudden deceleration injury in a vehicular accident produces atearin the aorta. This usually happens just distal to the great vessels. If one's parachute fails to open, the tear is usually at the root of the aorta. The tear leads to sudden loss of blood into the chest and subsequent shock. +## 5. Liver, fractures and lacerations with blunt force injury, gross {#item-5} +![](../../images/forensic_459c1cf1.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Massive abdominal blunt force injury often leads to liver injury, since it is the largest internal organ. Note the multiplelacerationsseen here over the capsular surface of the liver. Damage to abdominal organs with lacerations, crush injuries, and rupture can lead to bleeding into the peritoneal cavity known as hemoperitoneum. A peritoneal lavage can detect such bleeding. +## 6. Skull fracture, base, orbital plate, gross {#item-6} +![](../../images/forensic_55d14e71.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Blunt force trauma to the head often leads to skull fractures. The orbital plate of the base of the skull demonstrates multiple fractures (arrow) seen here in an older patient who fell backwards. The force of the blow was transmitted forward (a contra-coup injury pattern). [Image contributed by Todd Grey, MD, University of Utah] +## 7. Skull fractures, cranial vault, gross {#item-7} +![](../../images/forensic_b5da824a.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +A direct traumatic blow to the head may produce the pattern of skull fractures seen here at the vertex. +## 8. Scalp contusions, gross {#item-8} +![](../../images/forensic_b32de2b3.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Blunt trauma to the head can be suggested by scalp contusions with subgaleal collection of blood, as shown here. [Image contributed by Todd Grey, MD, University of Utah] +## 9. Skin of arm, contusion, gross {#item-9} +![](../../images/forensic_4d3d916d.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is an example of a contusion to the arm. The blunt force injury ruptures small blood vessels in dermis and underlying soft tissue, resulting in extravasation of red blood cells. Initially, the contusion appears dull red to blue, but over time the red cells are broken down, releasing bilirubin and heme (which is processed by macrophages to hemosiderin), to give the yellow-brown hue seen here after a week. +## 10. Skin of leg, abrasions, gross {#item-10} +![](../../images/forensic_ef8dbad8.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Abrasions are made by a scraping injury to the skin surface, typically in an irregular fashion, as seen here over the knee. Sometimes the pattern of the abrasion can indicate what kind of surface the skin contacted. Sometimes foreign material is embedded onto the abraded surface, such as gravel from a road surface. The abrasions seen here are healing. +## 11. Skin of leg, abrasions, gross {#item-11} +![](../../images/forensic_f79ed9b9.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is another example of anabrasionof the skin of the leg. Note the irregularity of the superficial tearing of the epidermis. +## 12. Skin of abdomen, patterned abrasions, gross {#item-12} +![](../../images/forensic_a65baef1.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is an example of apatterned abrasionof the abdomen by scraping along a rough sooted and rusty surface of a metal tank during a fall. The pattern may give some indication of the nature of the surface and the direction of the force. +## 13. Skin of forehead, laceration, gross {#item-13} +![](../../images/forensic_ab6f4a8e.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is a very superficiallacerationof the forehead. Note that the skin surface is broken. There are some smalltags of skinwhere the surface was irregularly torn. +## 14. Skin of hand, lacerations, gross {#item-14} +![](../../images/forensic_7c4c7eb1.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Lacerationsare made when a surface, such as the skin of the hand seen here, is cut in an irregular fashion down to the underlying tissue. An incision is defined as a very regular cut made by a sharp object such as a knife. Lacerations typically occur by contact with an irregular object. Lacerations are deeper than abrasions and more irregular than incised wounds. +## 15. Skin of hand, incised wound, gross {#item-15} +![](../../images/forensic_c0cfba89.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is anincised woundof the skin of the hand. An incision has clean, straight edges made by a sharp object such as a knife (or in this case a rose thorn). Lacerations are produced from a more irregular object and appear as irregular broken areas. +## 16. Fat embolism, lung, high power microscopic {#item-16} +![](../../images/forensic_3bf85127.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Therounded clear holesseen in the small pulmonary arterial branch in this section of lung are characteristic for fat embolism. Fat embolism syndrome is most often a consequence of trauma with long bone fractures. It can also be seen with extensive soft tissue trauma, burn injuries, severe fatty liver, and very rarely with orthopedic procedures. +## 17. Fat embolism, lung, Oil red O stain, high power microscopic {#item-17} +![](../../images/forensic_c4d2dd9d.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +An Oil Red O stain demostrates thefat globuleswithin the pulmonary arterioles. The globules stain reddish-orange. The cumulative effect of many of these gobules throughout the lungs is similar to a large pulmonary embolus, but the onset of dyspnea is usually 2 to 3 days following the initiating event, such as blunt trauma with bone fractures. +## 18. Fat embolism, glomerulus, high power microscopic {#item-18} +![](../../images/forensic_e197b26e.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The capillary loops of this glomerulus contain fat globules in a patient with fat embolism syndrome. +## 19. Fat embolism, brain, gross {#item-19} +![](../../images/forensic_e7be2512.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +From several days to a week following the event initiating fat embolism syndrome, there may be loss of consciousness from lesions evidenced by the "brain purpura" as shown here. Numerouspetechial hemorrhagesare produced by fat emboli to the brain, particularly in the white matter. Subsequent to this there can be brain edema with herniation. +## 20. Fat embolism, brain, gross {#item-20} +![](../../images/forensic_d898124c.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +With cerebral fat embolism syndrome, there is loss of consciousness. Note the multitude ofpetechial hemorrhageshere, mostly within white matter. Cerebral edema and herniation may follow. Overall, few persons with a history of trauma will develop fat embolism, but it is difficult to predict which patients will. Protean manifestations include: hypoxemia, mental status changes, petechiae, fever, tachycardia, and thrombocytopenia. +## 21. Fat embolism, brain, high power microscopic {#item-21} +![](../../images/forensic_152e4b37.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Seen here with Oil red O stain in a peripheral cerebral artery branch are globules of lipid. This is fat embolism syndrome. Treatment is supportive. +## 22. Shaken baby syndrome, model, gross {#item-22} +![](../../images/forensic_fb46b15f.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Shaken baby syndrome describes a pattern of neurologic injuries caused by violent shaking of an infant. An infant's head is proportionately large in comparison to the infant's body, and the neck musculature is not well-developed, so shaking will cause the head to flop back and forth, producing extensive intracranial (often subdural) and retinal hemorrhages and can be fatal. +## 23. Shaken baby syndrome, retinal hemorrhages, gross {#item-23} +![](../../images/forensic_a941c2e2.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Shaken baby syndrome occurs most commonly when a young male left alone with the baby loses self-control because of the baby's crying and begins shaking the infant. Such injuries can be inflicted on small children as well. Seen here are the retinal hemorrhages at autopsy that document this condition and lead to a conviction against the perpetrator. [Image contributed by Todd Grey, MD, University of Utah] +## 24. Shaken baby syndrome, brain with axonal retraction balls, high power microscopic {#item-24} +![](../../images/forensic_5cc99430.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The forces generated by violent shaking or rotational injury (as in a passenger ejected from a moving vehicle) can produce stretching of axons in cerebral white matter, called diffuse axonal injury. The force may be strong enough to shear off axons, the ends of which retract into globoid shapes that appear with this silver stain of white matter as"retraction balls". CT imaging of the brain may show subtle petechial hemorrhages at the interface of gray and white matter. +## 25. Mechanical asphyxia with conjunctival petechiae, gross {#item-25} +![](../../images/forensic_9b39f1e9.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Mechanical asphyxia, including strangulation, can be marked by the appearance ofpetechial hemorrhageson the conjunctiva, as shown here. However, such a finding is not specific for this injury and can be seen with other conditions. Of course, finding ligature marks on the neck, hyoid bone fracture, and/or soft tissue hemorrhages in neck and larynx may help to determine the mechanism of injury. +## 26. Brain death, cerebral perfusion scan {#item-26} +![](../../images/forensic_28e536fa.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This cerebral scan demonstratesno apparent perfusionto the cerebral hemispheres, indicative of brain death. The patient remains in a persistent vegetative state with no higher cerebral function. This can occur following many types of injuries -- traumatic, toxic, metabolic, ischemic. Though there may be some residual brain stem function, and the patient can be kept alive with mechanical ventilation and through tube feedings, there will be no recovery. +## 27. Drowning, middle ear hemorrhages, gross {#item-27} +![](../../images/forensic_fb8e6c39.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +There are few grossly visible features of drowning. A frothy fluid may exude from mouth and nose. Prolonged immersion may produce skin wrinkling. Seen here are bilateral petrous ridge oftemporal bone hemorrhagesthat may occur in association with drowning. Drowning is defined as respiratory impairment from submersion in a liquid medium. This may range from submersion of the entire body to just submersion of the pharynx. +## 28. Drowning, lung, microscopic {#item-28} +![](../../images/forensic_856e8d18.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Drowning may not produce extensive findings. In fact, in 10 to 15% of cases, intense laryngospasm may even prevent water from entering the lungs. In the case shown here, a child drowned in a fresh water canal, and some of the plant material in the water was aspirated into a bronchus. +## 29. Sudden infant death syndrome (SIDS), model, gross {#item-29} +![](../../images/forensic_05299bdd.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Sudden infant death syndrome (SIDS) occurs between 1 month and 1 year of age, with a peak incidence at 3 to 4 months. The cause is unknown, but may relate to delayed neurologic development. The rate varies from about 0.5 to 5 per thousand livebirths. SIDS deaths can be decreased if the baby does not sleep prone, as shown here with the doll in the lower frame. The baby should sleep on its back. +## 30. Carbon monoxide poisoning, gross {#item-30} +![](../../images/forensic_f9b2ac40.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Note the bright "cherry red" or bright pink lividity to the hand. Carbon monoxide (CO) poisoning is a form of asphyxia that results when CO is inhaled, diffuses across alveoli, and binds tightly to hemoglobin. Poorly ventilated houses with faulty heaters, housefires, and motor vehicle exhaust are the most common sources. Even small atmospheric concentrations of CO are dangerous, because CO binds to hemoglobin 200 times more avidly than oxygen. Drowsiness and headache occur at carboxyhemoglobin concentrations between 10 and 20%. Levels from 20 to 30% can be fatal to persons with pre-existing cardiac or respiratory disease. Levels above 30 to 40% can be fatal to anyone. Similar lividity could be the result of cyanide poisoning or monofluoroacetate poisoning. +## 31. Hypothermia, scene {#item-31} +![](../../images/forensic_3d0587c4.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +When core body temperature falls below 35 C (95 F), this is a condition known as hypothermia. Loss of body heat can occur in a variety of situations, including falling into the cold waters of Loch Ness shown here. Lack of clothing and shelter, even in temperate climates, can predispose to hypothermia. There are no specific gross or microscopic findings with this condition. +## 32. Hyperthermia, scene {#item-32} +![](../../images/forensic_f449b2b4.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +When the ambient temperature of the environment increases considerably, a condition known as hyperthermia can occur. A hot, dry location such as southern Utah, shown here, is an obvious place for hyperthermia, particularly if the person hiking does not carry adequate water. However, an enclosed space such as an auto or a building can present a risk, particularly for infants or aged persons. In a heat-related death, core body temperature is found to be at or above 40.6 C (105 F). +## 33. Thermal burn injury from fire, gross {#item-33} +![](../../images/forensic_0b30c877.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Thermal burn injuries occur with a hot local environment. The burned skin seen here over the torso and head of a child occurred from a fire. The treatment and prognosis depend to a great extent upon the extent of the burn injury -- the total body surface area (TBSA) involved. Other factors include age of the patient, underlying diseases, and the presence of an "inhalation injury" from breathing in hot gases, which typically occurs with fires in an enclosed space such as a building. +## 34. Thermal burn injury from scalding with hot liquid, gross {#item-34} +![](../../images/forensic_1d49a976.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Thermal burn injuries can occur from hot objects or liquids. Seen here is an amputated hand that was rendered non-viable by a severe scalding injury with exposure to hot water. +## 35. Thermal burn injury, partial thickness, low power microscopic {#item-35} +![](../../images/forensic_3452d5b1.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Thermal burn injuries can be classified as "full thickness" or "partial thickness" based upon the ability of the skin to regenerate. In the partial thickness burn seen here, there are stillskin adnexa in the dermisthat are viable and from which new epithelium could grow. +## 36. Thermal burn injury, full thickness, low power microscopic {#item-36} +![](../../images/forensic_836ecced.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The viable skin at the left merges with an area of full thickness thermal burn injury without any viable epithelium either on the surface or in dermal appendages. The patient would require a skin graft to this area for recovery. +## 37. Electrocution injury, hand, gross {#item-37} +![](../../images/forensic_4cacaba9.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +![](../../images/forensic_08d59cb5.jpg) +This man accidentally grabbed a high voltage electrical line, producing the entrance wound injury seen above on the palm of the hand, with subsequent soft tissue damage and swelling extending to the forearm. The appearance is similar to a localized burn. Below on the dorsum of the hand can be seen the wounds produced as the current exited the hand. +## 38. Cerebral edema with altitude sickness, gross {#item-38} +![](../../images/forensic_cfc84a8e.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This coronal section of the cerebrum shows markedcompressionof the ventricles and flattening of gyri from extensive edema. Marked pulmonary edema may also occur. This young man was climbing a 5000 meter mountain peak and ignored the warning sign of a persistent, worsening headache along with dyspnea. Affected persons must get to a lower altitude. +## 39. Amniotic fluid embolism, lung, microscopic {#item-39} +![](../../images/forensic_4c322d11.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +A rare complication seen at term during or shortly after labor in pregnancy resulting in sudden death is amniotic fluid embolism. Amniotic fluid may gain access to uterine veins following a tear in the placental membranes and embolize to the lungs, producing acute dyspnea with cyanosis and shock. Fetal squames, lanugo hair, vernix, and mucin can embolize to small pulmonary arteries. Seen here areepithelial squamesin a peripheral pulmonary artery. +## 40. Radon gas, scene {#item-40} +![](../../images/forensic_1eb02109.jpg) + +![](../../images/atherosclerosis_d5033905.gif) + +## 41. Drug paraphernalia in box, gross {#item-41} +![](../../images/forensic_3e47f50e.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The "works" of an intravenous drug user are demonstrated here. A key part of forensic pathology is scene investigation. The appearance of the scene of injury or death can help explain how the injuries occurred or provide evidence for prosecution of criminals. [Image contributed by Todd Grey, MD, University of Utah] +## 42. Bags of cocaine in stomach, gross {#item-42} +![](../../images/forensic_65c3953f.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The bags of cocaine seen here in the stomach were swallowed by the victim as a form of concealment. This method is also used by persons smuggling drugs. A latex condom is typically used as a container. Occasionally, the containerrupturesor leaks, and a drug overdose ensues, as happened here. [Image contributed by Todd Grey, MD, University of Utah] +## 43. Hand with lacerations, gross {#item-43} +![](../../images/forensic_44210e35.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Trauma can be produced in a variety of ways. Here is the hand of a person with a cocaine intoxication who entered a state of "excited delerium" and began breaking doors and windows, leading to the appearance of the lacerations and blood on the fingers. [Image contributed by Todd Grey, MD, University of Utah] +## 44. Skin of antecubital fossa, dermal hemorrhage at injection site, gross {#item-44} +![](../../images/forensic_4a6cb4a5.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The subcutaneous hemorrhage in the antecubital fossa at the elbow, revealed by multiple incisions made at the time of autopsy, is evidence that this was an injection site for drugs. [Image contributed by Todd Grey, MD, University of Utah] +## 45. Skin of arm, irregular circular scars from "skin popping", gross {#item-45} +![](../../images/forensic_f653d30e.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The white circular and irregular scars are from "skin popping" or subcutaneous injection of drugs of abuse. Complications include abscess formation, skin necrosis, and possible pneumothorax if an injection site over the thorax is used. +## 46. Alcohol consumption, scene and discussion {#item-46} +![](../../images/forensic_7ff1ab4f.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The"Soggy Dollar Bar"at Jost Van Dyke in the B.V.I. is itself an illustration of the kinetics of alcohol (ethanol) metabolism.The drinks are served at a constant rate, no matter how many boats anchor and patrons swim ashore. Likewise, alcohol is metabolized at a constant rate of 11-22 mg/dL/hr by alcohol dehydrogenase in the liver. In general, once the blood ethanol concentration has reached 0.1 gm% (100 mg/dL, or 100 mg%, or 0.1 g/dL), the alcohol dehydrogenase enzyme system is saturated, and further ethanol consumption will increase the blood concentration.In most states in the U.S. and many other countries, legal intoxication while driving a vehicle is defined at 0.08%. Some degree of impairment can begin at 0.03%, and reaction times are impaired above 0.07%. Above 0.3%, stupor and coma can occur, and deaths may result from levels above 0.4%. The most common form of fatal drug overdose is ethanol ingestion. +The"Soggy Dollar Bar"at Jost Van Dyke in the B.V.I. is itself an illustration of the kinetics of alcohol (ethanol) metabolism. +The drinks are served at a constant rate, no matter how many boats anchor and patrons swim ashore. Likewise, alcohol is metabolized at a constant rate of 11-22 mg/dL/hr by alcohol dehydrogenase in the liver. In general, once the blood ethanol concentration has reached 0.1 gm% (100 mg/dL, or 100 mg%, or 0.1 g/dL), the alcohol dehydrogenase enzyme system is saturated, and further ethanol consumption will increase the blood concentration. +In most states in the U.S. and many other countries, legal intoxication while driving a vehicle is defined at 0.08%. Some degree of impairment can begin at 0.03%, and reaction times are impaired above 0.07%. Above 0.3%, stupor and coma can occur, and deaths may result from levels above 0.4%. The most common form of fatal drug overdose is ethanol ingestion. +## 47. Methanol poisoning, discussion {#item-47} +![](../../images/forensic_ebecb295.gif) + +![](../../images/atherosclerosis_d5033905.gif) +Methanol poisoning is not common and is usually accidental. Methanol is metabolized at one-fifth the rate of ethanol, making it more toxic. Acute methanol poisoning is characterized by weakness, nausea, vomiting, headache and epigastric pain, but not typically inebriation. Metabolic acidosis occurs. The toxic metabolites damage the retina, and permanent blindess may result from ingestion of only 10 mL, while fatalities occur with as little as 30-60 mL. Lethal blood levels occur at 0.08% (80 mg%). Administration of fomepizole (an inhibitor of alcohol dehydrogenase) or ethanol as a competitive binder to the enzyme, is used to treat methanol poisoning. +## 48. Mechanism of defense wounds, gross {#item-48} +![](../../images/forensic_37572cbe.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This scene illustrates the mechanism for "defense wounds". Such wounds result from an attempt to ward off the assailant. The victim holds up forearms and hands in front of the body. +## 49. Defense wound on forearm, gross {#item-49} +![](../../images/forensic_f8ba5fe9.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is a typical "defense wound" on the forearm of the victim of an assault with a sharp weapon, producing the laceration. [Image contributed by Todd Grey, MD, University of Utah] +## 50. Defense wounds on hand, gross {#item-50} +![](../../images/forensic_e0338ba0.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here are defense wounds on the hand of a victim whose assailant was attacking with a knife. [Image contributed by Todd Grey, MD, University of Utah] +## 51. Comparison of single and double edge knife wounds in clay model, gross {#item-51} +![](../../images/forensic_fb2758ba.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Seen in this clay model is the pattern of a stab wound from a double edge knife on the left and a single edge knife on the right. +## 52. Knife, single edge, with hilt, gross {#item-52} +![](../../images/forensic_7beb5237.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The Bowie knife shown here illustrates a single edge knife with a hilt. +## 53. Stab wound, skin, single edge blade, gross {#item-53} +![](../../images/forensic_04893c98.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is a stab wound with a single edge blade. Note the sharp point of the blade at the left and the notch of the opposite side of the knife at the right. The shape of stab wounds can vary considerably, depending upon whether the incision is along the axis of, or perpedicular to, Langer's lines. Those perpendicular will tend to pull apart and gape open, while those parallel to the lines of stress will tend to remain slit-like. [Image contributed by Todd Grey, MD, University of Utah] +## 54. Stab wound, skin, single edge blade with hilt mark, gross {#item-54} +![](../../images/forensic_9b6c7eea.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is a single-edge blade stab wound in which there is a "hilt" mark at the left. The sharp blade edge is at the right. [Image contributed by Todd Grey, MD, University of Utah] +## 55. Gun, autoloading, semi-automatic, 9 mm pistol, gross {#item-55} +![](../../images/forensic_c6c933ba.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is an autoloading, semi-automatic pistol. The force generated from each bullet fired causes a new round to be chambered from the magazine. +## 56. Gun, autoloading, semi-automatic, 9 mm pistol with clip, gross {#item-56} +![](../../images/forensic_376fa9d9.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is an autoloading, semi-automatic pistol. The detachable magazine that holds 17 rounds is placed into the grip. +## 57. Gun, revolver, .38 cal, gross {#item-57} +![](../../images/forensic_f29716ac.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is a revolver, which holds six rounds. Note the gap between the cylinder in the center and the frame. +## 58. Gun, semi-automatic rifle, .308 cal, gross {#item-58} +![](../../images/forensic_62056812.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is a semi-automatic rifle. A rifle is a firearm with a long barrel, which gives the larger rounds more accuracy and range. The energy of the fired bullets is enormous. The .308 caliber copper jacketed bullets fired by this rifle can blow a hole in plate steel 1/4" thick. +## 59. Bullet cartridges, diagram {#item-59} +![](../../images/forensic_714ea599.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Note the basic features of cartridges used in guns. The primer, when struck by the firing pin, ignites the powder. It is the residue left by the primer that is characteristic for a fired round, because it leaves traces of lead, antimony, and barium. +## 60. Gunshot residue, pattern by SEM-EDX, diagram {#item-60} +![](../../images/forensic_0128516d.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The gunshot residue deposited in a gunshot wound can be detected by using scanning electron microscopy coupled with energy-dispersive x-ray microanalysis to demonstrate the characteristic elemental pattern of the primer residue with lead, antimony, and barium, typical for many cartridges, as shown in this diagram. +## 61. Common rifle and handgun cartridges, gross {#item-61} +![](../../images/forensic_f911a66f.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The appearances of the most common handgun and rifle rounds are shown here. In general, it is difficult to tell from the wound exactly what round was used. +## 62. Deformed bullet recovered from shooting victim, gross {#item-62} +![](../../images/forensic_3315839b.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +When bullets strike a target, there can be considerable deformation and fragmentation. In this case, the lead bullet has become markedly deformed and has separated from the copper jacket at the right. +## 63. Striations on bullets, gross {#item-63} +![](../../images/forensic_96b90f8f.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Bullets fired from a gun will have "striae" (linear grooves) imparted as a consequence of traversing the barrel, and these marks help to identify the weapon. Comparison of bullets involves "class" (caliber and rifling) and "individual" characteristics based upon burrs or imperfections in the barrel, particularly the muzzle, that impart specific markings, or striae, to fired bullets. Individual characteristics are used to try and determine if a specific gun was used in a crime. The sets of bullets shown here are from the same class, but deformations in recovered bullets (the right of each pair) can complicate comparison. +## 64. Bullet track in clay model, gross {#item-64} +![](../../images/forensic_0681ef6a.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Much of the damage done by a bullet results from the tumbling motion and the cavitation in the tissue. This is the bullet track in clay of a .38 caliber round, demonstrating that the wound track is much larger than .38 inches (closer to 3 inches). +## 65. Contact range gunshot wound, gross {#item-65} +![](../../images/forensic_0d6fc765.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is an contact gunshot entrance wound. Since the barrel contacts the skin, the gases released by the fired round go into the subcutaneous tissue and cause the star-shaped laceration. Note also the grey-black discoloration from the soot, as well as the faint abrasion ring. [Image contributed by Todd Grey, MD, University of Utah] +## 66. Contact range gunshot wound, gross {#item-66} +![](../../images/forensic_dd3f4801.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +An abrasion ring, formed when the force of the gases entering below the skin blow the skin surface back against the muzzle of the gun, is seen here in this contact range gunshot wound to the right temple. [Image contributed by Todd Grey, MD, University of Utah] +## 67. Contact range gunshot wound, gross {#item-67} +![](../../images/forensic_ffd31806.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The abrasion ring, and a very clear muzzle imprint, are seen in this contact range gunshot wound. [Image contributed by Todd Grey, MD, University of Utah] +## 68. Contact range gunshot wound, gross {#item-68} +![](../../images/forensic_2049e791.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is a contact range gunshot entrance wound with grey-black discoloration from the burned powder. +## 69. Range of fire, gunshot to skull, diagram {#item-69} +![](../../images/forensic_36003909.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The upper diagram illustrates the basic differences between the skin appearance of a contact, close (intermediate), and distant (indeterminant) range gunshot wound. The appearance of the wounding characteristics in the skull is shown in the lower diagram in which there is bevelling of the skull outward away from the direction of origin of the bullet. +## 70. Skull, contact range gunshot wound, gross {#item-70} +![](../../images/forensic_b91ba772.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +The surface of the skull demonstrates the heavy soot in this contact range entrance wound, as well as radiating fracture lines. The direction of fire was thus toward the back of this picture. [Image contributed by Todd Grey, MD, University of Utah] +## 71. Gunshot entrance wound with GSR, microsopic {#item-71} +![](../../images/forensic_7ac2d969.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Histologic examination of the entrance wound site on the skin demonstrates blackgunshot residueand coagulative necrosis. +## 72. Intermediate range gunshot wound, gross {#item-72} +![](../../images/forensic_f0f41b72.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +This is an intermediate range gunshot entrance wound in which there is powder "tattooing" around the entrance site. +## 73. Intermediate range gunshot wound, gross {#item-73} +![](../../images/forensic_5f678b6e.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Powder tattooing is seen in this intermediate range gunshot wound. The actual entrance site is somewhat irregular, because the bullet can tumble in flight. +## 74. Entrance-exit wound in close proximity from low angle of bullet entrance, gross {#item-74} +![](../../images/forensic_2985e498.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Displayed here is an entrance at the left and an exit at the right. This particular bullet struck at an angle to produce the ovoid entrance. Exit wounds vary considerably in size and shape because the bullet can be deformed in its transit through the body. There may be no exit wound at all if the bullet's energy is absorbed by the tissues. Some bullets (such a "hollowpoint") are designed to deform so that all their energy will be converted to tissue damage and not exit. +## 75. Exit gunshot wound, gross {#item-75} +![](../../images/forensic_659caf45.jpg) + +![](../../images/atherosclerosis_d5033905.gif) +Here is a slit-like exit wound. The projectile becamed deformed and flattened while traversing the body, producing a laceration upon exit. Note that there is no powder or soot visible in this exit wound. [Image contributed by Todd Grey, MD, University of Utah] diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/cardiometabolic_20260701/01_heart_failure.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/cardiometabolic_20260701/01_heart_failure.txt" new file mode 100644 index 0000000..fb6d211 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/cardiometabolic_20260701/01_heart_failure.txt" @@ -0,0 +1 @@ +心力衰竭@患者可出现活动后气促、乏力、下肢水肿和夜间阵发性呼吸困难。常用检查包括心电图、超声心动图、胸部X线和脑钠肽检测。治疗中可使用呋塞米、螺内酯等药物，并应评估高血压和冠心病等相关疾病。 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/cardiometabolic_20260701/02_hypertension.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/cardiometabolic_20260701/02_hypertension.txt" new file mode 100644 index 0000000..64199e7 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/cardiometabolic_20260701/02_hypertension.txt" @@ -0,0 +1 @@ +高血压@长期血压升高可伴头晕、头痛和心悸，并可能并发脑卒中、冠心病或慢性肾病。建议进行动态血压监测、肾功能检查和心电图检查。常见治疗药物包括氨氯地平、缬沙坦和美托洛尔。 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/cardiometabolic_20260701/03_diabetes.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/cardiometabolic_20260701/03_diabetes.txt" new file mode 100644 index 0000000..3aed025 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/cardiometabolic_20260701/03_diabetes.txt" @@ -0,0 +1 @@ +2型糖尿病@患者可有多饮、多尿、乏力和体重下降，也可能合并糖尿病肾病或高血压。需要检查空腹血糖、糖化血红蛋白和尿微量白蛋白。常用药物包括二甲双胍和恩格列净。 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/cardiometabolic_20260701/README.md" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/cardiometabolic_20260701/README.md" new file mode 100644 index 0000000..7e5247d --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/cardiometabolic_20260701/README.md" @@ -0,0 +1,14 @@ +# 心血管代谢演示数据集 + +本目录包含 3 份合成医疗文本，用于 DataMate 五算子流水线、MediGraph 神经抽取、 +知识图谱构建和 Nexent 对话演示。数据不对应真实患者，不包含个人标识信息。 + +建议流水线： + +`text_clean -> chunker -> medical_ner -> medical_re -> triple_validator` + +建议问答： + +1. 心力衰竭有哪些症状和检查？ +2. 高血压可能并发哪些疾病？ +3. 2 型糖尿病常用哪些药物和检查？ diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/outpatient_batch_demo/\351\227\250\350\257\212\347\227\205\345\216\206_01_2\345\236\213\347\263\226\345\260\277\347\227\205_\345\220\210\346\210\220\346\240\267\344\276\213.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/outpatient_batch_demo/\351\227\250\350\257\212\347\227\205\345\216\206_01_2\345\236\213\347\263\226\345\260\277\347\227\205_\345\220\210\346\210\220\346\240\267\344\276\213.txt" new file mode 100644 index 0000000..22bde6c --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/outpatient_batch_demo/\351\227\250\350\257\212\347\227\205\345\216\206_01_2\345\236\213\347\263\226\345\260\277\347\227\205_\345\220\210\346\210\220\346\240\267\344\276\213.txt" @@ -0,0 +1,15 @@ +门诊病历（合成样例，非真实患者数据） + +科室：内分泌科　　就诊日期：2026-03-18 + +主诉：多饮、多尿伴乏力 6 个月，体重下降 4 公斤。 + +既往史：高血压病史 3 年，服用氨氯地平控制；否认药物过敏史。 + +辅助检查：空腹血糖 9.8 mmol/L；糖化血红蛋白 8.6%；尿微量白蛋白轻度升高； +眼底检查未见明显视网膜病变。 + +诊断：2 型糖尿病；糖尿病肾病（早期）。 + +治疗：予二甲双胍联合达格列净控制血糖，继续氨氯地平降压。低糖低盐饮食， +每日监测血糖，3 个月后复查糖化血红蛋白，评估糖尿病视网膜病变与冠心病风险。 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/outpatient_batch_demo/\351\227\250\350\257\212\347\227\205\345\216\206_02_\346\205\242\351\230\273\350\202\272_\345\220\210\346\210\220\346\240\267\344\276\213.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/outpatient_batch_demo/\351\227\250\350\257\212\347\227\205\345\216\206_02_\346\205\242\351\230\273\350\202\272_\345\220\210\346\210\220\346\240\267\344\276\213.txt" new file mode 100644 index 0000000..e53dda9 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/outpatient_batch_demo/\351\227\250\350\257\212\347\227\205\345\216\206_02_\346\205\242\351\230\273\350\202\272_\345\220\210\346\210\220\346\240\267\344\276\213.txt" @@ -0,0 +1,15 @@ +门诊病历（合成样例，非真实患者数据） + +科室：呼吸内科　　就诊日期：2026-03-20 + +主诉：反复咳嗽、咳痰 5 年，活动后气促加重 3 个月。 + +既往史：吸烟史 30 年；3 年前诊断慢性支气管炎。 + +辅助检查：肺功能检查示 FEV1/FVC 降低，符合阻塞性通气功能障碍； +胸部 X 线示肺纹理增粗、肺气肿征象；血氧饱和度 93%。 + +诊断：慢性阻塞性肺疾病（急性加重期）；肺气肿。 + +治疗：予噻托溴铵吸入维持治疗，急性期加用布地奈德雾化。戒烟宣教， +接种流感疫苗，1 个月后复查肺功能，评估肺源性心脏病与呼吸衰竭风险。 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/outpatient_batch_demo/\351\227\250\350\257\212\347\227\205\345\216\206_03_\350\204\202\350\202\252\350\202\235_\345\220\210\346\210\220\346\240\267\344\276\213.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/outpatient_batch_demo/\351\227\250\350\257\212\347\227\205\345\216\206_03_\350\204\202\350\202\252\350\202\235_\345\220\210\346\210\220\346\240\267\344\276\213.txt" new file mode 100644 index 0000000..804c838 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/outpatient_batch_demo/\351\227\250\350\257\212\347\227\205\345\216\206_03_\350\204\202\350\202\252\350\202\235_\345\220\210\346\210\220\346\240\267\344\276\213.txt" @@ -0,0 +1,15 @@ +门诊病历（合成样例，非真实患者数据） + +科室：消化内科　　就诊日期：2026-03-22 + +主诉：右上腹隐痛伴乏力 4 个月，体检发现肝功能异常 2 周。 + +既往史：肥胖症 8 年，体重指数 31；高脂血症病史 2 年，未规律服药。 + +辅助检查：腹部超声示肝脏回声增强，符合中度脂肪肝； +谷丙转氨酶 86 U/L 升高；血脂检查示甘油三酯与低密度脂蛋白升高。 + +诊断：非酒精性脂肪肝；高脂血症；肥胖症。 + +治疗：予水飞蓟宾保肝，阿托伐他汀调脂。低脂饮食联合有氧运动减重， +3 个月后复查肝功能与腹部超声，评估肝硬化与高血压风险。 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/outpatient_record_demo/\351\227\250\350\257\212\347\227\205\345\216\206_\351\253\230\350\241\200\345\216\213_\345\220\210\346\210\220\346\240\267\344\276\213.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/outpatient_record_demo/\351\227\250\350\257\212\347\227\205\345\216\206_\351\253\230\350\241\200\345\216\213_\345\220\210\346\210\220\346\240\267\344\276\213.txt" new file mode 100644 index 0000000..14f410a --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/demo_cases/outpatient_record_demo/\351\227\250\350\257\212\347\227\205\345\216\206_\351\253\230\350\241\200\345\216\213_\345\220\210\346\210\220\346\240\267\344\276\213.txt" @@ -0,0 +1,14 @@ +门诊病历（合成样例，非真实患者数据） + +科室：心内科　　就诊日期：2026-03-14 + +主诉：反复头晕、头痛 3 个月，加重 1 周，伴心悸。 + +既往史：高血压病史 5 年，未规律服药；2 型糖尿病病史 2 年。 + +辅助检查：动态血压监测提示全天血压增高；心电图示左室高电压；肾功能检查示血肌酐轻度升高。 + +诊断：高血压 2 级（高危）；2 型糖尿病。 + +治疗：予氨氯地平、缬沙坦降压，二甲双胍降糖。低盐饮食，1 个月后复诊， +评估脑卒中、冠心病及慢性肾病风险。 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/models/README.md" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/models/README.md" new file mode 100644 index 0000000..35067c1 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/models/README.md" @@ -0,0 +1,25 @@ +# 本地抽取模型产物 + +## 神经模型（主力，GPU 训练，权重随仓） + +由 `scripts/train_neural_extractor.py` 训练的 GPLinker（GlobalPointer 联合实体-关系抽取）： + +- `neural_extractor/`：主力 macbert-large 模型（CMeIE-V2 训练；实体 F1 0.766 / 端到端三元组 0.534）； +- `neural_extractor_base/`：roberta-base 模型（用于双编码器集成对照）； +- `neural_extractor_v1/`：CMeIE-V1 训练的 macbert-large（实体 0.779 / strict SPO-F1 0.6146，超公开 GPLinker/CasRel）； +- `neural_extractor_v1_base/`：CMeIE-V1 roberta-base（集成对照）。 + +每个目录含 `pytorch_model.bin`、`extractor_config.json`、tokenizer 与 `train_log.json`（训练曲线 + best epoch）。 +编码器权重在 `data/models/encoder/`（由 `scripts/download_encoder.py` 获取，已 gitignore，可重下载）。 +无 GPU/torch 时系统自动回退下面的词典基线。 + +## 词典基线产物（回退/对照，CPU 确定性生成） + +由 `python data/prep/build_fast_extractor.py` 确定性生成： + +- `fast_extractor.json`：从 CMeIE-V2 train、DIAKG gold 与 CM3KG 结构化图谱学习的 + CPU Trie Span-NER / 关系事实快速路径（无 GPU/API 时的可复现下界）； +- `entity_linker.json`：医疗术语索引 **39,372 条**（CM3KG 7,467 + CMeIE/DIAKG 31,905）——in-KB 链接准确率 0.973 / NIL 拒绝 1.0（`outputs/eval_entity_linking.json`），真实 mention 可链接率 0.733（`outputs/eval_entity_linking_real.json`）； +- `temperature_calibration.json`：开发集拟合的温度标定参数（预测级 ECE 0.026）。 + +词典基线是可复现的**非神经**下界，不冒充神经模型；神经模型与其共用相同输入输出契约。 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/models/entity_linker.json" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/models/entity_linker.json" new file mode 100644 index 0000000..6c00434 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/data/models/entity_linker.json" @@ -0,0 +1 @@ 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zG}tIXxrRzr^FW0K7jTv~PlF<5=4+t{4jgiksfvanZQK(>!=h!{ZGwOg#Mpy*B4{oQ z#FvdD0tmZQGi1maDHOuAieji`Aj<-s^g0m@!qYnWZ0sI^Vu-=97fPeov#6gEKx0qD zRveD$=iCSNe_wvWAD;d3#j}6^{y)F@{-6HG|9kCT^!ESy{@cIM4}JN;v-ci9|KQp7 z)}t3Mo^8GN{Qd2%r_Z+@zQ6t6*5jw|e6aQC>3bhMdi3JGuO5H!-dB%4*n02%7cW0} zx&8Fvd+)t?wDlDMF*?Zn;rXA)VE;ege)qROeDm}#e|q`idt#M;dj9bF_Oo~2d2jp0 zqvtOlJ%9M_ URL 发现" using the Agent +Card URL, then collaborate with it as a managed sub-agent of a supervisor. + +Implements the minimal A2A surface Nexent needs: + - GET /.well-known/agent.json -> Agent Card (A2AAgentCard schema) + - POST / -> JSON-RPC 2.0 `message/send` + +The agent routes a question to AnalysisAgent (statistics/trend/ranking) or +QAAgent (knowledge/association), reusing the local medigraph implementations. + +Run (host): python integration/a2a/a2a_server.py # serves on :8100 +Nexent(Docker) discovers: http://host.docker.internal:8100/.well-known/agent.json + +NOTE: A2A JSON-RPC has many optional fields; this is a faithful minimal server. +If Nexent's "测试连接" reports a schema mismatch, adjust the card/result shape per +nexent/backend/consts/a2a_models.py and a2a_agent_adapter.py. +""" +from __future__ import annotations + +import os +import sys +import uuid +from datetime import datetime, timezone +from pathlib import Path + +sys.path.insert(0, str(Path(__file__).resolve().parents[2])) + +from fastapi import FastAPI, Request +from fastapi.responses import JSONResponse + +from config.settings import OUTPUTS_DIR + +HOST_FOR_NEXENT = os.getenv( + "MEDIGRAPH_A2A_PUBLIC_URL", + "http://host.docker.internal:8100", +).rstrip("/") +app = FastAPI(title="MediGraphAnalyst A2A") + + +def _agent_card() -> dict: + return { + "name": "MediGraphAnalyst", + "description": "医疗知识图谱问答与数据分析智能体：基于已构建的医疗图谱做带溯源的问答，" + "以及统计/趋势/关联分析，复用 MediGraph 的 QA 与 Analysis 能力。", + "version": "1.0.0", + "url": f"{HOST_FOR_NEXENT}/", + "capabilities": { + "streaming": False, + "pushNotifications": False, + "supportedTransportTypes": ["http-json-rpc"], + "protocolVersion": "1.0", + }, + "defaultInputModes": ["text/plain"], + "defaultOutputModes": ["text/plain"], + "skills": [ + {"id": "medical_qa", "name": "医疗知识图谱问答", + "description": "基于医疗知识图谱的混合检索问答，答案附三元组溯源。", + "tags": ["medical", "graphrag", "qa"], "examples": ["嗜铬细胞瘤有哪些阳性标志物？"]}, + {"id": "medical_analysis", "name": "医疗数据分析", + "description": "统计/趋势/关联分析（NL2SQL 或图谱遍历），返回数据与洞察。", + "tags": ["medical", "analytics", "nl2sql"], "examples": ["各疾病的就诊人次是多少？"]}, + ], + "supportedInterfaces": [ + {"protocolBinding": "http-json-rpc", "url": f"{HOST_FOR_NEXENT}/", "protocolVersion": "1.0"}, + ], + } + + +_ANALYTIC_HINTS = ("多少", "数量", "平均", "比例", "占比", "趋势", "排名", "最多", "统计", "分布", "每月", "人次", "总") + + +def _route_and_answer(question: str) -> str: + """Route to AnalysisAgent (analytic) or QAAgent (knowledge) and return text.""" + from medigraph.graph.local_store import LocalGraphStore + graph_json = OUTPUTS_DIR / "graph.json" + + if any(h in question for h in _ANALYTIC_HINTS): + from medigraph.analysis.analysis_agent import AnalysisAgent + from medigraph.analysis.graph_profile import load_graph + from medigraph.analysis.relational import build_db + db = OUTPUTS_DIR / "analytics.db" + store, _ = load_graph(graph_json if graph_json.exists() else None) + build_db(db, store, n_visits=600, seed=42) + agent = AnalysisAgent(str(db), graph_json=str(graph_json) if graph_json.exists() else None) + res = agent.analyze(question, out_html=OUTPUTS_DIR / "a2a_analysis.html", verbose=False) + return f"[分析/{res['route']}] {res['insight']}\n报告: {res['html']}" + + if not graph_json.exists(): + return "知识图谱尚未构建（缺 outputs/graph.json）。请先建图再问答。" + from medigraph.agents.qa_agent import QAAgent + store = LocalGraphStore.load_json(graph_json) + res = QAAgent(store=store).answer(question) + return res["answer"] + + +def _extract_question(params: dict) -> str: + msg = (params or {}).get("message", {}) or {} + parts = msg.get("parts", []) or [] + texts = [p.get("text", "") for p in parts if isinstance(p, dict) and p.get("text")] + return "\n".join(texts).strip() + + +@app.get("/.well-known/agent.json") +def agent_card(): + return JSONResponse(_agent_card()) + + +@app.get("/.well-known/agent-card.json") +def agent_card_alt(): + return JSONResponse(_agent_card()) + + +@app.post("/") +@app.post("/v1") +@app.post("/message:send") +async def jsonrpc(request: Request): + body = await request.json() + rpc_id = body.get("id") + method = body.get("method", "") + params = body.get("params", {}) or {} + + # Nexent's A2A client appends /v1 for JSONRPC and uses method "SendMessage", + # while some A2A examples use "message/send" on the base URL. Accept both so + # discovery, direct chat and managed-agent delegation all work. + if method not in ("message/send", "message/stream", "tasks/send", "SendMessage"): + return JSONResponse({"jsonrpc": "2.0", "id": rpc_id, + "error": {"code": -32601, "message": f"method not found: {method}"}}) + question = _extract_question(params) + try: + answer = _route_and_answer(question) if question else "未收到问题文本。" + except Exception as exc: # noqa: BLE001 + answer = f"处理失败: {exc}" + + now = datetime.now(timezone.utc).isoformat() + task = { + "id": str(uuid.uuid4()), + "status": { + "state": "TASK_STATE_COMPLETED", + "timestamp": now, + "message": {"role": "ROLE_AGENT", "parts": [{"text": answer, "mediaType": "text/plain"}]}, + }, + "artifacts": [], + } + return JSONResponse({"jsonrpc": "2.0", "id": rpc_id, "result": {"task": task}}) + + +if __name__ == "__main__": + import uvicorn + print("MediGraphAnalyst A2A on http://0.0.0.0:8100 (card: /.well-known/agent.json)") + uvicorn.run(app, host="0.0.0.0", port=8100) diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/mcp_server/server.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/mcp_server/server.py" new file mode 100644 index 0000000..6ad70e3 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/mcp_server/server.py" @@ -0,0 +1,1020 @@ +"""FastMCP server exposing the MediGraph operators as Nexent MCP tools. + +Run: + python mcp_server/server.py # serves SSE at http://127.0.0.1:8000/sse by default + MEDIGRAPH_MCP_HOST=0.0.0.0 MEDIGRAPH_MCP_PORT=8011 python mcp_server/server.py + +Register in Nexent: 智能体开发 -> 选择Agent的工具 -> MCP配置, add the URL. +If Nexent runs in Docker and this server runs on the host, use +http://host.docker.internal:/sse instead of 127.0.0.1. + +This is the "Operator-as-MCP-Tool" bridge: the SAME operator implementations used +by the local agents are surfaced here as callable MCP tools. +""" +from __future__ import annotations + +import json +import os +import sys +from pathlib import Path + +sys.path.insert(0, str(Path(__file__).resolve().parent.parent)) + +from fastmcp import FastMCP # noqa: E402 +from starlette.requests import Request # noqa: E402 +from starlette.responses import FileResponse, JSONResponse, PlainTextResponse # noqa: E402 + +from medigraph.operators.base import load_default_operators, get_operator # noqa: E402 + +# Register operators once at startup (LLM-backed ones lazily create a client). +load_default_operators() + +mcp = FastMCP(name="MediGraphOperators") + +# Base URL the *user's browser* should use to fetch generated artifacts. The chat +# UI runs on the host, so container-internal paths like /app/outputs/x.html are +# useless there -- every tool that produces a file also returns a URL built from +# this, which is directly clickable in the Nexent conversation. +ARTIFACT_BASE_URL = os.getenv( + "MEDIGRAPH_ARTIFACT_BASE_URL", + f"http://localhost:{os.getenv('MEDIGRAPH_MCP_PORT', '8011')}", +).rstrip("/") + +# Whether this process runs inside a container. Matters when fetching chat-uploaded +# files: Nexent mints presigned URLs against localhost (right for the user's browser, +# wrong from in here), so those hosts get redirected to the Docker host gateway. +_IN_CONTAINER = Path("/.dockerenv").exists() + + +def _output_path(file_name: str, default: str, suffix: str) -> Path: + """Resolve a user-facing artifact name safely under outputs/.""" + from config.settings import OUTPUTS_DIR + + name = Path(file_name or default).name + if not name.lower().endswith(suffix): + name += suffix + return OUTPUTS_DIR / name + + +def _artifact_url(path: "str | Path | None") -> str: + """Map an outputs/ artifact to a browser-clickable URL served by /outputs/. + + Returns "" for anything that is not a real file under outputs/, so callers can + surface the field unconditionally without inventing dead links. + """ + if not path: + return "" + from config.settings import OUTPUTS_DIR + + try: + resolved = Path(path).resolve() + resolved.relative_to(Path(OUTPUTS_DIR).resolve()) + except (ValueError, OSError): + return "" + if not resolved.is_file(): + return "" + return f"{ARTIFACT_BASE_URL}/outputs/{resolved.name}" + + +@mcp.custom_route("/outputs/{file_name}", methods=["GET"]) +async def serve_artifact(request: Request): + """Serve a generated artifact so chat users can open/download it in one click. + + Only plain files directly under outputs/ are served: the name is reduced to its + basename and the resolved path is re-checked against outputs/, so "..", absolute + paths and symlinks escaping the directory are all rejected. + """ + from config.settings import OUTPUTS_DIR + + root = Path(OUTPUTS_DIR).resolve() + target = (root / Path(request.path_params["file_name"]).name).resolve() + try: + target.relative_to(root) + except ValueError: + return PlainTextResponse("forbidden", status_code=403) + if not target.is_file(): + return PlainTextResponse("not found", status_code=404) + # inline so .html reports render in the browser instead of downloading blindly + return FileResponse(target, headers={"Content-Disposition": f'inline; filename="{target.name}"'}) + + +@mcp.custom_route("/outputs", methods=["GET"]) +async def list_artifacts(request: Request): + """List downloadable artifacts (handy when a user lost the link from the chat).""" + from config.settings import OUTPUTS_DIR + + root = Path(OUTPUTS_DIR).resolve() + if not root.is_dir(): + return JSONResponse({"artifacts": []}) + items = [ + {"name": p.name, "size": p.stat().st_size, "url": f"{ARTIFACT_BASE_URL}/outputs/{p.name}"} + for p in sorted(root.iterdir()) + if p.is_file() and p.suffix.lower() in {".html", ".json", ".csv", ".md", ".png", ".svg"} + ] + return JSONResponse({"count": len(items), "artifacts": items}) + + +def _ontology_summary() -> dict: + from medigraph.schema.ontology import ENTITY_TYPES, RELATION_CONSTRAINTS, RELATION_TYPES + + constraints = {} + for relation, (head_types, tail_types) in RELATION_CONSTRAINTS.items(): + constraints[relation] = { + "head_types": sorted(head_types), + "tail_types": sorted(tail_types), + } + return { + "entity_types": ENTITY_TYPES, + "relation_types": RELATION_TYPES, + "relation_constraints": constraints, + "entity_type_count": len(ENTITY_TYPES), + "relation_type_count": len(RELATION_TYPES), + } + + +def _read_output_json(file_name: str) -> dict: + from config.settings import OUTPUTS_DIR + + path = OUTPUTS_DIR / file_name + if not path.exists(): + return {} + try: + return json.loads(path.read_text(encoding="utf-8")) + except Exception: + return {} + + +def _metric_view(data: dict) -> dict: + """Compact a benchmark report for chat-friendly MCP output.""" + if not data: + return {} + return { + "samples": data.get("samples"), + "extractor": data.get("extractor"), + "model_version": data.get("model_version"), + "encoder": data.get("encoder"), + "entity_micro": data.get("entity_micro"), + "end_to_end_triple_micro": data.get("end_to_end_triple_micro"), + "end_to_end_triple_micro_strict": data.get("end_to_end_triple_micro_strict"), + "latency_ms": data.get("latency_ms"), + } + + +@mcp.tool( + name="inspect_extraction_models", + description=( + "只读审计最新抽取级联：神经 GPLinker 权重是否可用、当前路由配置、CMeIE-V1/V2 实测指标、" + "双编码器集成提升、词典基线、实体链接与自产图谱规模。用于网页录屏展示新更新已接入。" + ), +) +def inspect_extraction_models() -> str: + import importlib.util + + from config.settings import get_extraction_config + from medigraph.extraction.neural_gplinker import NeuralGPLinkerExtractor + + cfg = get_extraction_config() + neural_dir = cfg.neural_model_dir + model_bin = neural_dir / "pytorch_model.bin" + checkpoint_available = NeuralGPLinkerExtractor.available(neural_dir) + torch_available = importlib.util.find_spec("torch") is not None + transformers_available = importlib.util.find_spec("transformers") is not None + neural_available = ( + checkpoint_available + and torch_available + and transformers_available + ) + ensemble_v2 = _read_output_json("eval_ensemble_cmeie_dev.json") + ensemble_v1 = _read_output_json("eval_ensemble_cmeie_v1_dev.json") + scale_report = _read_output_json("kg_scale_report.json") + return json.dumps( + { + "runtime_config": { + "backend": cfg.backend, + "priority": [ + "L1_neural_gplinker", + "L1_lexicon_fast_path", + "L2_llm_fallback" if cfg.llm_fallback else "L2_llm_disabled", + "L3_entity_linking_and_validation", + ], + "route_threshold": cfg.route_threshold, + "neural_threshold": cfg.neural_threshold, + "neural_rel_threshold": cfg.neural_rel_threshold, + }, + "neural_gplinker": { + "available": neural_available, + "checkpoint_available": checkpoint_available, + "runtime_dependencies": { + "torch": torch_available, + "transformers": transformers_available, + }, + "model_dir": str(neural_dir), + "checkpoint_bytes": model_bin.stat().st_size if model_bin.exists() else 0, + "relation_space": "full CMeIE predicate space; online graph maps safe subset to the clinical ontology and keeps cmeie_relation provenance", + "v2_dev": _metric_view(_read_output_json("eval_neural_cmeie_dev.json")), + "v1_dev_public_comparison": _metric_view(_read_output_json("eval_neural_cmeie_v1_dev.json")), + "ensemble_v2": ensemble_v2.get("triple_micro", {}), + "ensemble_v1": ensemble_v1.get("triple_micro", {}), + }, + "fallback_and_governance": { + "lexicon_baseline": _metric_view(_read_output_json("eval_fast_cmeie_dev.json")), + "confidence_calibration": _read_output_json("calibration_report.json"), + "entity_linking": _read_output_json("eval_entity_linking.json"), + }, + "self_produced_graph": { + "self_produced": scale_report.get("self_produced"), + "third_party_graph_import": scale_report.get("third_party_graph_import"), + "graph": scale_report.get("graph"), + "source": "outputs/graph_scaled.json", + }, + }, + ensure_ascii=False, + ) + + +@mcp.tool(name="text_clean", description="清洗医疗文本：去网页噪声/页眉页脚/链接/LaTeX/短碎片。输入 text，返回清洗后的 text。") +def text_clean(text: str) -> str: + return json.dumps(get_operator("text_clean").run({"text": text}), ensure_ascii=False) + + +@mcp.tool(name="chunker", description="把长文本按标题与字数切块。输入 text 和可选 max_chars，返回 chunks 列表。") +def chunker(text: str, max_chars: int = 1200) -> str: + return json.dumps(get_operator("chunker").run({"text": text, "max_chars": max_chars}), ensure_ascii=False) + + +@mcp.tool(name="medical_ner", description="从医疗文本抽取疾病/症状/药物/标志物/基因等医学实体，返回带类型与置信度的实体列表。") +def medical_ner(text: str) -> str: + out = get_operator("medical_ner").run({"text": text}) + # Compact per-entity records so the calling agent gets a small, summarizable observation. + if isinstance(out, dict) and isinstance(out.get("entities"), list): + out = dict(out) + out["entities"] = [ + {k: e[k] for k in ("name", "type", "start", "end", "confidence") if isinstance(e, dict) and k in e} + for e in out["entities"] + ] + return json.dumps(out, ensure_ascii=False) + + +@mcp.tool(name="medical_re", description="从医疗文本抽取实体间关系三元组（受本体约束）。输入 text 和可选 entities(JSON)。") +def medical_re(text: str, entities: str = "[]") -> str: + try: + ents = json.loads(entities) if isinstance(entities, str) else (entities or []) + except json.JSONDecodeError: + ents = [] + return json.dumps(get_operator("medical_re").run({"text": text, "entities": ents}), ensure_ascii=False) + + +@mcp.tool(name="triple_validator", description="校验候选三元组：schema合法性/去重/置信度/冲突检测。输入 triples(JSON 数组)。") +def triple_validator(triples: str, min_confidence: float = 0.5) -> str: + try: + tlist = json.loads(triples) if isinstance(triples, str) else (triples or []) + except json.JSONDecodeError: + tlist = [] + return json.dumps( + get_operator("triple_validator").run({"triples": tlist, "min_confidence": min_confidence}), + ensure_ascii=False, + ) + + +@mcp.tool( + name="load_documents", + description="读取 TXT/MD/HTML/CSV/JSON/JSONL/DOCX/PDF 文档并统一为文本。输入 paths(JSON 数组)。", +) +def load_documents(paths: str) -> str: + try: + values = json.loads(paths) if isinstance(paths, str) else paths + except json.JSONDecodeError: + values = [] + return json.dumps( + get_operator("document_loader").run({"paths": values if isinstance(values, list) else []}), + ensure_ascii=False, + ) + + +@mcp.tool( + name="profile_data_quality", + description=( + "检查文档空值、重复、字段缺失和长度异常。documents 可直接传一段文本，" + "也可传文档 JSON 数组；单段病历无需自行用 Python 组装或读取文件。" + ), +) +def profile_data_quality(documents: str) -> str: + try: + values = json.loads(documents) if isinstance(documents, str) else documents + except json.JSONDecodeError: + values = [{"fileName": "inline_medical_record.txt", "text": str(documents)}] + if isinstance(values, str): + values = [{"fileName": "inline_medical_record.txt", "text": values}] + return json.dumps( + get_operator("data_quality").run({"documents": values if isinstance(values, list) else []}), + ensure_ascii=False, + ) + + +@mcp.tool(name="redact_medical_pii", description="脱敏医疗文本中的身份证、电话、邮箱、银行卡和病历号，返回审计计数。") +def redact_medical_pii(text: str) -> str: + return json.dumps(get_operator("pii_redact").run({"text": text}), ensure_ascii=False) + + +@mcp.tool(name="link_medical_entities", description="把实体链接到 CM3KG/本地稳定规范 ID。输入 entities(JSON 数组)。") +def link_medical_entities(entities: str) -> str: + try: + values = json.loads(entities) if isinstance(entities, str) else entities + except json.JSONDecodeError: + values = [] + return json.dumps( + get_operator("entity_linker").run({"entities": values if isinstance(values, list) else []}), + ensure_ascii=False, + ) + + +# ---------------------------------------------------------------------------- +# High-level orchestration tools (let a Nexent agent drive the whole pipeline). +# ---------------------------------------------------------------------------- + + +@mcp.tool( + name="plan_datamate_pipeline", + description=( + "调用微调后的 Qwen3.5-0.8B 编排模型，把自然语言数据处理需求规划为可执行算子 DAG。" + "只规划、不执行；返回模型名、DAG 和可传给 run_datamate_pipeline 的 ops。输入 goal。" + ), +) +def plan_datamate_pipeline(goal: str) -> str: + from finetune.api_planner import DEFAULT_MODEL, plan_via_api + + valid_ops = {"text_clean", "chunker", "medical_ner", "medical_re", "triple_validator"} + dag = plan_via_api(goal) + selected_ops = [str(node.get("op")) for node in dag if node.get("op") in valid_ops] + if not selected_ops: + return json.dumps({"error": "fine-tuned planner returned no supported operators"}, ensure_ascii=False) + return json.dumps( + { + "planner_model": os.getenv("FINETUNED_ORCHESTRATOR_MODEL", DEFAULT_MODEL), + "goal": goal, + "dag": dag, + "ops": ",".join(selected_ops), + }, + ensure_ascii=False, + ) + + +def _fetch_uploaded_document(url: str, max_bytes: int = 2_000_000) -> dict: + """Download a chat-uploaded document (MinIO presigned URL) into a doc dict. + + Nexent appends uploaded files to the query as a `presigned_url`, so accepting a + URL here is what makes "drag a file into the chat and build a graph from it" + actually work end to end. Only http(s) is allowed and the body is size-capped. + """ + import urllib.parse + import urllib.request + + parsed = urllib.parse.urlparse(url) + if parsed.scheme not in {"http", "https"}: + raise ValueError(f"unsupported URL scheme: {parsed.scheme or '(none)'}") + # Nexent hands out presigned URLs pointing at localhost (correct for the user's + # browser). Inside this container localhost is the container itself, so redirect + # host-local addresses to the Docker host gateway. + fetch_url = url + if _IN_CONTAINER and (parsed.hostname or "") in {"localhost", "127.0.0.1"}: + fetch_url = parsed._replace( + netloc=f"host.docker.internal:{parsed.port}" if parsed.port else "host.docker.internal" + ).geturl() + with urllib.request.urlopen(fetch_url, timeout=30) as resp: # noqa: S310 - scheme checked above + raw = resp.read(max_bytes + 1) + if len(raw) > max_bytes: + raise ValueError(f"uploaded file exceeds {max_bytes} bytes") + name = Path(urllib.parse.unquote(parsed.path)).name or "uploaded.txt" + suffix = Path(name).suffix.lower() + if suffix == ".pdf": + import io + + from pypdf import PdfReader + + text = "\n".join((page.extract_text() or "") for page in PdfReader(io.BytesIO(raw)).pages) + else: + text = raw.decode("utf-8", errors="ignore") + if not text.strip(): + raise ValueError(f"no extractable text in {name}") + return {"fileName": name, "text": text} + + +@mcp.tool( + name="build_medical_kg", + description=( + "把医疗文本或语料自动编排为知识图谱：chunker→medical_ner→medical_re→triple_validator→graph_upsert。" + "输入三选一：text=一段医疗文本；source_path=项目内文件/目录（如 data/demo_cases、data/corpus）；" + "或 source_url=用户在对话中上传的文件链接（把文件信息里的 presigned_url 原样传进来即可，" + "支持 .txt/.md/.pdf，多个文件用英文逗号分隔）。" + "工具会自动读取内容——请不要自己用 python(os/urllib) 去读文件或列目录。" + "默认写入独立的 nexent_demo_graph.json，不覆盖主图；返回质量统计、样例实体/三元组、溯源与图谱链接。" + ), +) +def build_medical_kg(text: str = "", + source_path: str = "", + source_url: str = "", + source_name: str = "nexent_demo_input.txt", + graph_name: str = "nexent_demo_graph.json", + append: bool = False, + max_chunks: int = 3, + max_docs: int = 3) -> str: + from medigraph.agents.kg_agent import KGGenAgent + from medigraph.graph.local_store import LocalGraphStore + from config.settings import PROJECT_ROOT + + docs = [] + if source_url: + urls = [u.strip() for u in str(source_url).split(",") if u.strip()] + for url in urls[: max(1, min(int(max_docs), 10))]: + try: + docs.append(_fetch_uploaded_document(url)) + except Exception as exc: + return json.dumps( + {"error": f"failed to read uploaded file: {exc}"}, ensure_ascii=False + ) + if not docs and source_path: + try: + base = (PROJECT_ROOT / source_path).resolve() + if base != PROJECT_ROOT and PROJECT_ROOT not in base.parents: + return json.dumps({"error": f"source_path must be inside the project: {source_path}"}, ensure_ascii=False) + if base.is_dir(): + files = sorted(p for p in base.rglob("*") if p.suffix.lower() in {".txt", ".md"}) + files = files[: max(1, min(int(max_docs), 10))] + elif base.is_file(): + files = [base] + else: + return json.dumps({"error": f"source_path not found: {source_path}"}, ensure_ascii=False) + for p in files: + docs.append({"fileName": p.name, "text": p.read_text(encoding="utf-8", errors="ignore")}) + except Exception as exc: + return json.dumps({"error": f"failed to read source_path {source_path}: {exc}"}, ensure_ascii=False) + + text = (text or "").strip() + if not docs and text: + docs = [{"fileName": Path(source_name or "nexent_demo_input.txt").name, "text": text}] + if not docs: + return json.dumps( + {"error": "provide either text=... or source_path=data/demo_cases (a project file or directory)"}, + ensure_ascii=False, + ) + + graph_path = _output_path(graph_name, "nexent_demo_graph.json", ".json") + store = LocalGraphStore.load_json(graph_path) if append and graph_path.exists() else LocalGraphStore() + agent = KGGenAgent(store=store, build_vectors=False) + stats = agent.build( + docs, + verbose=False, + max_chunks_per_doc=max(1, min(int(max_chunks), 8)), + ) + store.export_json(graph_path) + html_path = graph_path.with_suffix(".html") + try: + store.export_html(html_path) + graph_html = str(html_path) + except Exception: + graph_html = "" + graph_data = json.loads(graph_path.read_text(encoding="utf-8")) + candidate = int(stats.get("candidate_triples", 0) or 0) + valid = int(stats.get("valid_triples", 0) or 0) + nodes = graph_data.get("nodes", []) + edges = graph_data.get("edges", []) + pass_rate = round(valid / candidate, 4) if candidate else 0.0 + # Show every entity/triple for single-document builds so the caller can name + # them all. Truncating to a handful made agents invent placeholders such as + # "Drug: 1（从病历中抽取）" for the entities they never received. + SAMPLE_LIMIT = 40 + sample_entities = [f"{n.get('id')}（{n.get('type')}）" for n in nodes[:SAMPLE_LIMIT]] + sample_triples = [ + f"{e.get('head')} -[{e.get('relation_zh') or e.get('relation')}]-> {e.get('tail')}" + for e in edges[:SAMPLE_LIMIT] + ] + # Tell the caller whether the lists are exhaustive, so it never presents a + # truncated slice as the complete extraction result. + samples_complete = len(nodes) <= SAMPLE_LIMIT and len(edges) <= SAMPLE_LIMIT + # Compact, chat-friendly result: a ready-to-echo summary + short samples (no giant JSON dump). + # The viewable link goes inside `summary` on purpose -- agents reliably echo the + # summary, so the user gets a clickable artifact without every agent prompt having + # to name the *_url fields explicitly. + html_url = _artifact_url(graph_html) + return json.dumps( + { + "summary": ( + f"知识图谱构建完成（{'增量扩充' if append else '新建'}）：抽取实体 " + f"{stats.get('entities_extracted', 0)} 个，候选三元组 {candidate} 条，" + f"有效三元组 {valid} 条，校验通过率 {pass_rate}；抽取路由 {stats.get('routing', {})}。" + + (f" 图谱可视化可直接打开：{html_url}" if html_url else "") + ), + "pipeline": ["chunker", "medical_ner", "medical_re", "triple_validator", "graph_upsert"], + "graph": stats.get("graph", {}), + "sample_entities": sample_entities, + "sample_triples": sample_triples, + "samples_complete": samples_complete, + "graph_file": str(graph_path), + "graph_html": graph_html, + # Clickable links for the chat user (container paths above are not). + "graph_json_url": _artifact_url(graph_path), + "graph_html_url": _artifact_url(graph_html), + }, + ensure_ascii=False, + ) + + +@mcp.tool( + name="medical_kg_qa", + description=( + "基于医疗知识图谱做意图感知 GraphRAG：识别问题实体与目标关系，图遍历后按关系意图排序证据，" + "返回中文答案、命中实体、检索模式、证据三元组及来源引用。默认查询 2.68 万三元组主图 graph.json。" + ), +) +def medical_kg_qa(question: str, graph_name: str = "graph.json", hops: int = 2) -> str: + from medigraph.agents.qa_agent import QAAgent + from medigraph.graph.local_store import LocalGraphStore + + graph_json = _output_path(graph_name, "graph.json", ".json") + if not graph_json.exists(): + return json.dumps( + {"error": f"graph not found: {graph_json.name}; call build_medical_kg first or use graph_name=graph.json"}, + ensure_ascii=False, + ) + store = LocalGraphStore.load_json(graph_json) + res = QAAgent(store=store, hops=max(1, min(int(hops), 3))).answer(question) + # Compact result: keep the natural-language answer + a few evidence/citation lines the agent can echo. + evidence = [ + f"{e.get('head')} -[{e.get('relation_zh') or e.get('relation')}]-> {e.get('tail')}" + if isinstance(e, dict) else str(e) + for e in (res.get("evidence") or [])[:6] + ] + return json.dumps( + { + "question": question, + "answer": res["answer"], + "refused": res.get("refused", False), + "retrieval_mode": res["retrieval_mode"], + "resolved_entities": res["resolved_entities"], + "evidence_used": res["evidence_used"], + "evidence": evidence, + "citations": (res.get("citations") or [])[:6], + "graph_file": str(graph_json), + }, + ensure_ascii=False, + ) + + +@mcp.tool( + name="inspect_medical_kg", + description=( + "只读审计医疗知识图谱能力证据：返回实体/关系类型约束、图规模、规范ID/溯源覆盖和样例，" + "并读取全量L1、标定、LLM抽取与算子性能评测。不会调用LLM，也不会修改图谱。" + ), +) +def inspect_medical_kg(graph_name: str = "graph.json", sample_limit: int = 8) -> str: + from medigraph.graph.local_store import LocalGraphStore + from config.settings import OUTPUTS_DIR + + graph_json = _output_path(graph_name, "graph.json", ".json") + if not graph_json.exists(): + return json.dumps({"error": f"graph not found: {graph_json.name}"}, ensure_ascii=False) + store = LocalGraphStore.load_json(graph_json) + graph_data = json.loads(graph_json.read_text(encoding="utf-8")) + + evaluations = {} + for key, file_name in { + "public_cmeie_diakg": "eval_extraction_public.json", + "cm3kg_controlled": "eval_extraction_cm3kg.json", + "pathology_coverage_probe": "eval_extraction_pathology.json", + }.items(): + path = OUTPUTS_DIR / file_name + if not path.exists(): + continue + data = json.loads(path.read_text(encoding="utf-8")) + evaluations[key] = { + "samples": data.get("samples"), + "model": data.get("model"), + "ner_strict_f1": (data.get("ner_strict") or {}).get("f1"), + "ner_relaxed_f1": (data.get("ner_relaxed") or {}).get("f1"), + "re_strict_f1": (data.get("re_strict") or {}).get("f1"), + "re_relaxed_f1": (data.get("re_relaxed") or {}).get("f1"), + } + + operator_benchmark = {} + benchmark_path = OUTPUTS_DIR / "benchmark_operators.json" + if benchmark_path.exists(): + operator_benchmark = json.loads(benchmark_path.read_text(encoding="utf-8")).get("operators", {}) + + offline_evaluations = {} + for key, file_name in { + "neural_gplinker_cmeie_v2_dev": "eval_neural_cmeie_dev.json", + "neural_gplinker_cmeie_v1_dev": "eval_neural_cmeie_v1_dev.json", + "neural_ensemble_cmeie_v2_dev": "eval_ensemble_cmeie_dev.json", + "neural_ensemble_cmeie_v1_dev": "eval_ensemble_cmeie_v1_dev.json", + "fast_core_250": "eval_fast_core.json", + "fast_cmeie_full_dev": "eval_fast_cmeie_dev.json", + "confidence_calibration": "calibration_report.json", + }.items(): + path = OUTPUTS_DIR / file_name + if path.exists(): + data = json.loads(path.read_text(encoding="utf-8")) + offline_evaluations[key] = { + "extractor": data.get("extractor"), + "model_version": data.get("model_version"), + "encoder": data.get("encoder"), + "samples": data.get("samples"), + "entity_micro": data.get("entity_micro"), + "end_to_end_triple_micro": data.get("end_to_end_triple_micro"), + "end_to_end_triple_micro_strict": data.get("end_to_end_triple_micro_strict"), + "triple_micro": data.get("triple_micro"), + "latency_ms": data.get("latency_ms"), + "ece_before": data.get("ece_before"), + "ece_after": data.get("ece_after"), + } + + limit = max(1, min(int(sample_limit), 20)) + return json.dumps( + { + "graph_file": str(graph_json), + "ontology": _ontology_summary(), + "graph_stats": store.stats(), + "graph_audit": store.audit(), + "sample_entities": graph_data.get("nodes", [])[:limit], + "sample_triples": graph_data.get("edges", [])[:limit], + "evaluations": evaluations, + "offline_evaluations": offline_evaluations, + "operator_benchmark": operator_benchmark, + }, + ensure_ascii=False, + ) + + +@mcp.tool( + name="analyze_medical_data", + description=( + "图谱驱动医疗分析：感知医疗知识图谱后规划 SQL(统计/排名/趋势) 或 GRAPH(关联) 路由，" + "执行只读 NL2SQL/图遍历，自动选择柱状/折线/饼图/关系网络并生成图文 HTML 报告。" + "返回路由理由、数据血缘、SQL纠错轨迹、数据、图谱证据、洞察和报告路径。" + ), +) +def analyze_medical_data(question: str, + graph_name: str = "graph.json", + report_name: str = "", + n_visits: int = 600, + seed: int = 42) -> str: + import time + from medigraph.analysis.analysis_agent import AnalysisAgent + from medigraph.analysis.graph_profile import load_graph + from medigraph.analysis.relational import build_db + from config.settings import OUTPUTS_DIR + + db = OUTPUTS_DIR / "analytics.db" + graph_json = _output_path(graph_name, "graph.json", ".json") + if not graph_json.exists(): + return json.dumps({"error": f"graph not found: {graph_json.name}"}, ensure_ascii=False) + store, used_example = load_graph(graph_json) + db_summary = build_db( + db, + store, + n_visits=max(100, min(int(n_visits), 5000)), + seed=int(seed), + ) + agent = AnalysisAgent(str(db), graph_json=str(graph_json) if graph_json.exists() else None) + default_report = f"analysis_mcp_{time.strftime('%m%d_%H%M%S')}.html" + out_html = _output_path(report_name, default_report, ".html") + res = agent.analyze(question, out_html=out_html, verbose=False) + # Keep graph evidence relation-complete within the agent's 24-row budget. + # A fixed 10-row preview could contain only one relation (for example, + # recommended drugs) and omit a lower-ranked complication entirely. + row_limit = 24 if res["route"] == "GRAPH" else 10 + return json.dumps( + { + "question": question, + "route": res["route"], + "plan": { + "route": res["route"], + "reason": res["route_reason"], + "planner": res["planner"], + }, + "chart_type": res["chart_type"], + "columns": res["columns"], + "rows": res["rows"][:row_limit], + "row_count": len(res["rows"]), + "sql": res["sql"], + "sql_attempts": res["attempts"], + "anchors": res["anchors"], + "intent_relations": res["intent_relations"], + "evidence_total": res["evidence_total"], + "evidence_used": res["evidence_used"], + "citations": res["citations"], + "insight": res["insight"], + "report_html": res["html"], + # Clickable link for the chat user (report_html above is a server path). + "report_url": _artifact_url(res["html"]), + "data_provenance": { + "medical_kg_graph": str(graph_json), + "analytics_db": str(db), + "demo_record_note": "就诊/处方/检查记录由医疗知识图谱词表按固定seed确定性生成，仅用于可复现分析演示。", + }, + }, + ensure_ascii=False, + ) + + +@mcp.tool( + name="inspect_analysis_assets", + description=( + "只读审计图谱驱动分析能力证据：知识图谱复用、分析数据库表与记录数、NL2SQL执行准确率、" + "支持的SQL/GRAPH路由和BI图表类型、已生成报告。不会调用LLM或修改数据。" + ), +) +def inspect_analysis_assets(graph_name: str = "graph.json") -> str: + import sqlite3 + from config.settings import OUTPUTS_DIR + from medigraph.analysis.graph_profile import build_profile, load_graph + from medigraph.analysis.relational import schema_text + + graph_json = _output_path(graph_name, "graph.json", ".json") + if not graph_json.exists(): + return json.dumps({"error": f"graph not found: {graph_json.name}"}, ensure_ascii=False) + store, used_example = load_graph(graph_json) + + evaluation = {} + eval_path = OUTPUTS_DIR / "eval_nl2sql.json" + if eval_path.exists(): + raw = json.loads(eval_path.read_text(encoding="utf-8")) + evaluation = { + "model": raw.get("model"), + "samples": raw.get("samples"), + "correct": raw.get("correct"), + "execution_accuracy": raw.get("execution_accuracy"), + "dual_database_execution_accuracy": raw.get("dual_database_execution_accuracy"), + "target": 0.85, + "passed": float(raw.get("execution_accuracy", 0.0) or 0.0) >= 0.85, + } + + table_counts = {} + db = OUTPUTS_DIR / "analytics.db" + if db.exists(): + conn = sqlite3.connect(f"file:{db}?mode=ro", uri=True) + try: + for table in ("patient_visits", "prescriptions", "lab_tests", "kg_entities", "kg_triples"): + table_counts[table] = conn.execute(f"SELECT COUNT(*) FROM {table}").fetchone()[0] + finally: + conn.close() + + report_paths = sorted({*OUTPUTS_DIR.glob("analysis*.html"), *OUTPUTS_DIR.glob("task3*.html")}) + reports = [ + { + "name": path.name, + "path": str(path), + "bytes": path.stat().st_size, + "url": _artifact_url(path), + } + for path in report_paths + ] + return json.dumps( + { + "kg_reuse": { + "graph_file": str(graph_json), + "used_example_graph": used_example, + "graph_profile": build_profile(store), + "kg_mirror_tables": ["kg_entities", "kg_triples"], + "analytics_vocab_from_relations": [ + "treated_in_department", + "recommend_drug", + "need_examination", + ], + }, + "analytics_schema": schema_text(), + "table_counts": table_counts, + "nl2sql_evaluation": evaluation, + "analysis_routes": { + "SQL": ["统计", "分组", "排名", "趋势", "比例", "费用", "异常率"], + "GRAPH": ["症状", "药物", "检查", "并发症", "标志物", "基因", "多跳关联"], + }, + "visualizations": ["bar", "line", "pie", "graph", "heatmap", "scatter", "table"], + "generated_reports": reports, + "provenance_note": "KG与词表来自医疗知识图谱主图；就诊/处方/检查明细为固定seed生成的可复现实验数据。", + }, + ensure_ascii=False, + ) + + +@mcp.tool( + name="run_datamate_pipeline", + description=( + "在 DataMate 运行或查询数据处理任务。新任务会建数据集→上传文档→按算子DAG提交执行，并立即返回 task_id，" + "不会在一次对话中等待长任务完成；后续把 task_id 传回本工具即可查询 status/progress，且不会重复创建任务。" + "可输入 goal，让微调后的0.8B模型先规划DAG；也可直接传 ops。" + "当 dry_run=true 时不创建DataMate任务，只做两件事：扫描 input_dir 列出将被处理的文件" + "（文件名、字数、开头预览，见返回的 corpus 字段），并调用0.8B模型规划算子DAG——" + "用户问“这批数据里有什么”或“先看看再规划”时用它。" + "file_names 可指定逗号分隔文件名，适合小批量演示。" + ), +) +def run_datamate_pipeline(input_dir: str = "data/corpus", + ops: str = "text_clean,chunker,medical_ner,medical_re,triple_validator", + max_files: int = 3, + goal: str = "", + file_names: str = "", + dry_run: bool = False, + task_id: str = "", + wait_for_completion: bool = False) -> str: + import time + from integration.datamate.datamate_client import DataMateClient + from config.settings import OUTPUTS_DIR, get_llm_config + + client = DataMateClient() + if task_id.strip(): + task = client.get_task(task_id.strip()) + progress = (task or {}).get("progress", {}) or {} + return json.dumps( + { + "mode": "status", + "task_id": task_id.strip(), + "status": (task or {}).get("status"), + "progress": progress, + "file_count": (task or {}).get("fileCount"), + "src_dataset_id": (task or {}).get("srcDatasetId"), + "dest_dataset_id": (task or {}).get("destDatasetId"), + "dest_dataset_name": (task or {}).get("destDatasetName"), + "created_at": (task or {}).get("createdAt"), + "started_at": (task or {}).get("startedAt"), + "finished_at": (task or {}).get("finishedAt"), + "terminal": (task or {}).get("status") in {"COMPLETED", "PARTIAL_SUCCESS", "STOPPED", "FAILED"}, + "datamate_url": "http://localhost:8080", + }, + ensure_ascii=False, + ) + + planner_model = None + planner_dag = [] + planner_error = None + planned_ops = [] + if goal.strip(): + try: + from finetune.api_planner import DEFAULT_MODEL, plan_via_api + + planner_dag = plan_via_api(goal) + planner_model = os.getenv("FINETUNED_ORCHESTRATOR_MODEL", DEFAULT_MODEL) + supported_ops = {"text_clean", "chunker", "medical_ner", "medical_re", "triple_validator"} + planned_ops = [ + str(node.get("op")) for node in planner_dag + if str(node.get("op")) in supported_ops + ] + if planned_ops: + ops = ",".join(planned_ops) + else: + planner_error = "planner returned no supported DataMate operators" + except Exception as exc: # keep the pipeline usable if the optional planner is offline + planner_error = f"{exc.__class__.__name__}: {exc}; using explicit ops" + + def is_corpus_file(path: Path) -> bool: + """A README sitting in a corpus folder documents the corpus, it is not + part of it. Feeding it to the medical operators fails, and when it does + not fail it pollutes the graph with entities lifted from the prose.""" + return path.suffix.lower() in (".md", ".txt") and path.stem.lower() != "readme" + + def discover_docs() -> list[Path]: + root = Path(input_dir).resolve() + if not root.is_dir(): + raise FileNotFoundError(f"input directory does not exist: {input_dir}") + if file_names.strip(): + requested = [Path(name.strip()).name for name in file_names.split(",") if name.strip()] + found = [ + path for name in requested + for path in ([root / name] if (root / name).is_file() else sorted(root.rglob(name))) + if path.is_file() and is_corpus_file(path) + ] + else: + found = sorted(p for p in root.iterdir() if p.is_file() and is_corpus_file(p)) + if not found: + # Corpora are commonly grouped into per-case subfolders (e.g. + # data/demo_cases//*.txt). Fall back to a recursive scan so a + # caller naming the parent directory gets the documents underneath + # instead of "no .md/.txt under ...". + found = sorted(p for p in root.rglob("*") if p.is_file() and is_corpus_file(p)) + return found[:max_files] + + def describe(paths: list[Path], preview_chars: int = 180) -> list[dict]: + """Name + size + opening lines, so the caller can tell the user what is + actually in the directory instead of just echoing the path back.""" + described = [] + for path in paths: + try: + text = path.read_text(encoding="utf-8", errors="replace") + except OSError as exc: + described.append({"file_name": path.name, "error": str(exc)}) + continue + snippet = " ".join(text.split()) + described.append({ + "file_name": path.name, + "relative_path": str(path.relative_to(Path(input_dir).resolve())), + "chars": len(text), + "preview": snippet[:preview_chars] + ("…" if len(snippet) > preview_chars else ""), + }) + return described + + if dry_run: + if not goal.strip(): + return json.dumps({"error": "dry_run requires a natural-language goal"}, ensure_ascii=False) + # A dry run that only prints a DAG leaves the user unable to see what + # would actually be processed, so preview the discovered corpus too. + try: + preview_docs = discover_docs() + corpus = { + "input_dir": input_dir, + "file_count": len(preview_docs), + "documents": describe(preview_docs), + "max_files": max_files, + } + except FileNotFoundError as exc: + corpus = {"input_dir": input_dir, "file_count": 0, "documents": [], "error": str(exc)} + return json.dumps( + { + "mode": "plan_only", + "planner_model": planner_model, + "goal": goal, + "corpus": corpus, + "planner_dag": planner_dag, + "selected_ops": planned_ops, + "planner_error": planner_error, + "status": "planned" if planner_dag else "planning_failed", + "datamate_task_created": False, + }, + ensure_ascii=False, + ) + + ids_file = OUTPUTS_DIR / "datamate_operator_ids.json" + if not ids_file.exists(): + return json.dumps({"error": "operators not uploaded; run integration/datamate/upload_operators.py first"}, ensure_ascii=False) + op_ids = json.loads(ids_file.read_text(encoding="utf-8")) + try: + docs = discover_docs() + except FileNotFoundError as exc: + return json.dumps({"error": str(exc)}, ensure_ascii=False) + if not docs: + return json.dumps({"error": f"no .md/.txt under {input_dir}"}, ensure_ascii=False) + + cfg = get_llm_config() + stamp = time.strftime("%m%d_%H%M%S") + ds = client.create_dataset(f"mcp_src_{stamp}", "TEXT", "MCP-triggered pipeline") + for d in docs: + client.upload_file_to_dataset(ds["id"], d) + client.wait_dataset_files(ds["id"], expected=len(docs)) + instance = [] + for name in [o.strip() for o in ops.split(",") if o.strip()]: + oid = op_ids.get(name) + if not oid: + continue + # Forward the configured LLM timeout too: the operators used to hardcode + # 120s, which times out on content-rich clinical records. + ov = ( + {"apiBase": cfg.base_url, "apiKey": cfg.api_key, "model": cfg.model, "timeout": cfg.timeout} + if name in ("medical_ner", "medical_re") + else {} + ) + instance.append({"id": oid, "name": name, "inputs": "text", "outputs": "text", "overrides": ov}) + tpl = client.create_template(f"mcp_tpl_{stamp}", "MCP pipeline", instance) + # Submit expanded instances because the current backend can accept + # templateId yet create an empty process. + task = client.create_task( + f"mcp_task_{stamp}", + ds["id"], + ds["name"], + f"mcp_out_{stamp}", + "TEXT", + instance=instance, + ) + final = client.poll_task(task["id"], max_wait=300) if wait_for_completion else client.get_task(task["id"]) + progress = (final or {}).get("progress", {}) or {} + terminal = final.get("status") in {"COMPLETED", "PARTIAL_SUCCESS", "STOPPED", "FAILED"} + if not wait_for_completion: + mode = "submitted" + elif terminal: + mode = "completed" + else: + mode = "wait_timeout" + return json.dumps( + { + "mode": mode, + "planner_model": planner_model, + "planner_dag": planner_dag, + "planner_error": planner_error, + "selected_ops": [item["name"] for item in instance], + "files": [doc.name for doc in docs], + "dataset_id": ds["id"], + "template_id": tpl["id"], + "task_id": task["id"], + "status": final.get("status"), + "progress": progress, + "terminal": terminal, + "wait_for_completion": wait_for_completion, + "datamate_url": "http://localhost:8080", + }, + ensure_ascii=False, + ) + + +if __name__ == "__main__": + host = os.getenv("MEDIGRAPH_MCP_HOST", "127.0.0.1") + port = int(os.getenv("MEDIGRAPH_MCP_PORT", "8000")) + print(f"Starting MediGraph MCP server at http://{host}:{port}/sse") + mcp.run(transport="sse", host=host, port=port) diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/__init__.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/__init__.py" new file mode 100644 index 0000000..e69de29 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/__init__.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/__init__.py" new file mode 100644 index 0000000..e69de29 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/dag_executor.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/dag_executor.py" new file mode 100644 index 0000000..3e53998 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/dag_executor.py" @@ -0,0 +1,438 @@ +"""DAG executor for data-processing pipelines. + +Takes a DAG (nodes = operator invocations, edges = data dependencies), runs nodes +in topological order with per-node status tracking, retries and timing, and +produces a processing report + per-document lineage. + +A node is: {"id": str, "op": , "args": {...}, "deps": [node_ids]} +The executor threads a `payload` dict between nodes; each operator reads/writes +known keys (text, chunks, entities, triples, valid, ...). +""" +from __future__ import annotations + +import re +import time +from concurrent.futures import ThreadPoolExecutor +from concurrent.futures import TimeoutError as FuturesTimeout +from typing import Any + +from medigraph.operators.base import get_operator + + +class NodeStatus: + PENDING = "pending" + RUNNING = "running" + SUCCESS = "success" + FAILED = "failed" + SKIPPED = "skipped" + + +def topological_order(nodes: list[dict]) -> list[str]: + """Kahn's algorithm. Raises on cycle / missing dependency.""" + ids_in_order = [str(node.get("id", "")) for node in nodes] + if not ids_in_order or any(not node_id for node_id in ids_in_order): + raise ValueError("DAG nodes must have non-empty ids") + if len(set(ids_in_order)) != len(ids_in_order): + raise ValueError("DAG node ids must be unique") + ids = set(ids_in_order) + unknown = sorted( + { + str(dependency) + for node in nodes + for dependency in node.get("deps", []) + if str(dependency) not in ids + } + ) + if unknown: + raise ValueError(f"DAG references unknown dependencies: {unknown}") + deps = {str(n["id"]): {str(d) for d in n.get("deps", [])} for n in nodes} + indeg = {nid: len(deps[nid]) for nid in ids_in_order} + queue = [nid for nid in ids_in_order if indeg[nid] == 0] + order: list[str] = [] + while queue: + cur = queue.pop(0) + order.append(cur) + for nid in ids_in_order: + if cur in deps[nid]: + deps[nid].discard(cur) + indeg[nid] -= 1 + if indeg[nid] == 0: + queue.append(nid) + if len(order) != len(ids): + raise ValueError("DAG has a cycle") + return order + + +def topological_layers(nodes: list[dict]) -> list[list[str]]: + """Group nodes into dependency layers (Kahn, level-by-level). + + Every node in a returned layer has all its dependencies satisfied by earlier + layers and none by its own layer, so a layer can run concurrently. Ordering + within a layer follows the declaration order, keeping execution reports stable. + + Validation is delegated to `topological_order`, so both entry points reject the + same malformed DAGs (missing ids, duplicate ids, unknown deps, cycles). + """ + topological_order(nodes) # validate; raises on cycle / unknown dependency + ids_in_order = [str(node["id"]) for node in nodes] + remaining = { + str(node["id"]): {str(dep) for dep in node.get("deps", [])} for node in nodes + } + layers: list[list[str]] = [] + done: set[str] = set() + while remaining: + layer = [nid for nid in ids_in_order if nid in remaining and not (remaining[nid] - done)] + if not layer: # pragma: no cover - topological_order already rejects cycles + raise ValueError("DAG has a cycle") + layers.append(layer) + done.update(layer) + for nid in layer: + remaining.pop(nid) + return layers + + +class DAGExecutor: + """Executes an operator DAG layer by layer, concurrently within each layer. + + Concurrency + Nodes are grouped by `topological_layers`; a layer's nodes are independent by + construction, so they run on a thread pool. Operators here are IO-bound + (LLM calls dominate), which is what makes threads the right primitive + despite the GIL. + + Every node in a layer reads the *same* payload snapshot, and outputs are + merged only once the layer completes ("collect in layer, merge at layer + end"). Without that, two concurrent nodes writing the same payload key + would race and the result would depend on completion order. + + Timeouts + `timeout` (executor default, overridable per node via ``"timeout"``) bounds a + single attempt. Caveat, stated plainly: Python cannot force-kill a thread, so + a timeout abandons the worker rather than stopping it -- the DAG stops waiting + and the node follows the normal failure path, but a genuinely wedged operator + keeps occupying a pool thread. Bounding that properly needs process isolation, + which is out of scope here. + """ + + def __init__( + self, + max_retries: int = 2, + max_workers: int = 4, + timeout: float | None = None, + parallel: bool = True, + ): + self.max_retries = max_retries + self.max_workers = max(1, max_workers) + self.timeout = timeout + self.parallel = parallel + + def run(self, dag: list[dict], initial_payload: dict, verbose: bool = True) -> dict: + layers = topological_layers(dag) + node_by_id = {n["id"]: n for n in dag} + payload = dict(initial_payload) + node_outputs: dict[str, dict] = {"input": dict(initial_payload)} + states: dict[str, dict] = {n["id"]: {"status": NodeStatus.PENDING} for n in dag} + lineage: list[dict] = [] + recoveries: list[dict] = [] + + for depth, layer in enumerate(layers): + runnable: list[str] = [] + for nid in layer: + node = node_by_id[nid] + failed_dependencies = [ + dep + for dep in node.get("deps", []) + if states.get(dep, {}).get("status") + in {NodeStatus.FAILED, NodeStatus.SKIPPED} + ] + if failed_dependencies: + states[nid].update( + status=NodeStatus.SKIPPED, + error=f"blocked by failed dependencies: {failed_dependencies}", + ) + lineage.append( + { + "node": nid, + "op": node["op"], + "status": NodeStatus.SKIPPED, + "blocked_by": failed_dependencies, + } + ) + else: + states[nid]["status"] = NodeStatus.RUNNING + runnable.append(nid) + + if not runnable: + continue + if verbose: + names = ", ".join(f"{nid}:{node_by_id[nid]['op']}" for nid in runnable) + print(f" [layer {depth}] {names}", flush=True) + + # Run the layer. A single node stays on this thread: no pool, no context + # switch, and tracebacks/profiles stay readable for the common linear DAG. + if len(runnable) == 1 or not self.parallel: + results = [self._run_node(node_by_id[nid], payload, node_outputs, verbose) for nid in runnable] + else: + with ThreadPoolExecutor( + max_workers=min(self.max_workers, len(runnable)), + thread_name_prefix="dag", + ) as pool: + futures = [ + pool.submit(self._run_node, node_by_id[nid], payload, node_outputs, verbose) + for nid in runnable + ] + results = [future.result() for future in futures] + + # Merge after the whole layer finishes -- see the class docstring. + for nid, outcome in zip(runnable, results): + if outcome["ok"]: + payload.update(outcome["output"]) + node_outputs[nid] = dict(outcome["output"]) + states[nid].update( + status=NodeStatus.SUCCESS, + seconds=outcome["seconds"], + attempts=outcome["attempts"], + output_keys=outcome["output_keys"], + ) + lineage.append( + { + "node": nid, + "op": outcome["op_name"], + "status": "success", + "seconds": outcome["seconds"], + "layer": depth, + } + ) + else: + states[nid].update( + status=NodeStatus.FAILED, + seconds=outcome["seconds"], + attempts=outcome["attempts"], + error=outcome["error"], + ) + lineage.append( + { + "node": nid, + "op": outcome["op_name"], + "status": "failed", + "error": outcome["error"], + "layer": depth, + } + ) + recoveries.extend(outcome["recoveries"]) + + report = self._build_report(states, payload) + report["recoveries"] = len(recoveries) + report["layers"] = len(layers) + report["max_layer_width"] = max((len(layer) for layer in layers), default=0) + return { + "payload": payload, + "states": states, + "lineage": lineage, + "recoveries": recoveries, + "layers": layers, + "report": report, + } + + # ------------------------------------------------------------------ # + def _run_node( + self, + node: dict, + payload: dict, + node_outputs: dict[str, dict], + verbose: bool, + ) -> dict: + """Execute one node with retries, timeout and fallback. Pure w.r.t. `payload`. + + Returns an outcome dict instead of mutating shared state, so it is safe to + call concurrently for every node of a layer. + """ + nid = node["id"] + op_name = node["op"] + recoveries: list[dict] = [] + op = get_operator(op_name) + inputs = {**payload, **self._resolve_args(node.get("args", {}), payload, node_outputs)} + node_timeout = node.get("timeout", self.timeout) + + attempt, ok, err, out = 0, False, None, {} + started = time.time() + while attempt <= self.max_retries and not ok: + attempt += 1 + try: + retry_args = node.get("retry_args", []) + attempt_inputs = dict(inputs) + if attempt > 1 and isinstance(retry_args, list) and len(retry_args) >= attempt - 1: + adjustment = retry_args[attempt - 2] + if isinstance(adjustment, dict): + attempt_inputs.update(adjustment) + recoveries.append( + { + "node": nid, + "strategy": "retry_with_adjusted_args", + "attempt": attempt, + "adjustment_keys": sorted(adjustment), + } + ) + out = self._call(op, attempt_inputs, node_timeout) + self._validate_output(op, out) + ok = True + except Exception as exc: # noqa: BLE001 + err = str(exc) + if verbose: + print(f" ! [{nid}] attempt {attempt} failed: {exc}") + if attempt <= self.max_retries: + time.sleep(min(2 ** (attempt - 1), 2)) + + if not ok: + fallback = node.get("on_error", {}) + if isinstance(fallback, dict) and fallback.get("fallback_op"): + try: + fallback_name = str(fallback["fallback_op"]) + fallback_operator = get_operator(fallback_name) + fallback_inputs = { + **inputs, + **( + fallback.get("args", {}) + if isinstance(fallback.get("args"), dict) + else {} + ), + } + out = self._call(fallback_operator, fallback_inputs, node_timeout) + self._validate_output(fallback_operator, out) + op_name = fallback_name + op = fallback_operator + ok = True + recoveries.append( + { + "node": nid, + "strategy": "fallback_operator", + "fallback_op": fallback_name, + } + ) + except Exception as fallback_exc: # noqa: BLE001 + err = f"{err}; fallback failed: {fallback_exc}" + + seconds = round(time.time() - started, 3) + if verbose: + if ok: + print(f" [OK] [{nid}] {seconds}s (attempts={attempt})") + else: + print(f" [X] [{nid}] failed after {attempt} attempts: {err}") + return { + "ok": ok, + "op_name": op_name, + "output": out if ok else {}, + "output_keys": self._output_keys(op) if ok else [], + "seconds": seconds, + "attempts": attempt, + "error": err, + "recoveries": recoveries, + } + + @staticmethod + def _call(op, inputs: dict, timeout: float | None): + """Run an operator, optionally bounded by `timeout` seconds.""" + if not timeout or timeout <= 0: + return op.run(inputs) + # One-off worker so the wait can be abandoned. See the timeout caveat in the + # class docstring: this stops *waiting*, it cannot stop the operator. + pool = ThreadPoolExecutor(max_workers=1, thread_name_prefix="dag-timeout") + future = pool.submit(op.run, inputs) + try: + return future.result(timeout=timeout) + except FuturesTimeout as exc: + future.cancel() + raise TimeoutError( + f"operator '{op.meta.name}' exceeded timeout of {timeout}s" + ) from exc + finally: + # wait=False: never block the DAG on an abandoned worker. + pool.shutdown(wait=False) + + @classmethod + def _resolve_args(cls, args: dict, payload: dict, node_outputs: dict[str, dict]) -> dict: + """Resolve lightweight Jinja-style references emitted by LLM planners. + + The planner is allowed to produce args such as ``{"text": "{{input_text}}"}`` + or ``{"entities": "{{n2.entities}}"}``. Older code treated those strings + literally, which could overwrite the real document text. This resolver + keeps normal constants intact, resolves known placeholders, and drops + unresolved placeholders so the threaded payload can still provide values. + """ + if not isinstance(args, dict): + return {} + out: dict[str, Any] = {} + for key, value in args.items(): + resolved, ok = cls._resolve_value(value, payload, node_outputs) + if ok: + out[key] = resolved + return out + + @classmethod + def _resolve_value(cls, value: Any, payload: dict, node_outputs: dict[str, dict]) -> tuple[Any, bool]: + if isinstance(value, dict): + resolved = {} + for k, v in value.items(): + rv, ok = cls._resolve_value(v, payload, node_outputs) + if ok: + resolved[k] = rv + return resolved, True + if isinstance(value, list): + items = [] + for v in value: + rv, ok = cls._resolve_value(v, payload, node_outputs) + if ok: + items.append(rv) + return items, True + if not isinstance(value, str): + return value, True + + match = re.fullmatch(r"\s*\{\{\s*([A-Za-z0-9_]+)(?:\.([A-Za-z0-9_]+))?\s*\}\}\s*", value) + if not match: + return value, True + + source, field = match.group(1), match.group(2) + if source in {"input", "payload"}: + if field: + return payload.get(field), field in payload + return payload, True + if source == "input_text": + return payload.get("text"), "text" in payload + if field and source in node_outputs and field in node_outputs[source]: + return node_outputs[source][field], True + if field and field in payload: + return payload[field], True + # Unresolved placeholder: do not let it clobber a real payload value. + return None, False + + @staticmethod + def _output_keys(op) -> list[str]: + props = (op.meta.output_schema or {}).get("properties", {}) + return list(props.keys()) + + @staticmethod + def _validate_output(op, output: Any) -> None: + if not isinstance(output, dict): + raise TypeError(f"operator '{op.meta.name}' returned {type(output).__name__}, expected dict") + schema = op.meta.output_schema or {} + required = schema.get("required", []) + missing = [key for key in required if key not in output] + if missing: + raise ValueError(f"operator '{op.meta.name}' missing required outputs: {missing}") + + @staticmethod + def _build_report(states: dict, payload: dict) -> dict: + n_success = sum(1 for s in states.values() if s["status"] == NodeStatus.SUCCESS) + n_failed = sum(1 for s in states.values() if s["status"] == NodeStatus.FAILED) + n_skipped = sum(1 for s in states.values() if s["status"] == NodeStatus.SKIPPED) + total_seconds = round(sum(s.get("seconds", 0) for s in states.values()), 3) + return { + "nodes_total": len(states), + "nodes_success": n_success, + "nodes_failed": n_failed, + "nodes_skipped": n_skipped, + "total_seconds": total_seconds, + "produced_chunks": len(payload.get("chunks", []) or []), + "produced_entities": len(payload.get("entities", []) or []), + "produced_valid_triples": len(payload.get("valid", []) or []), + } diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/dataproc_agent.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/dataproc_agent.py" new file mode 100644 index 0000000..edd2bed --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/dataproc_agent.py" @@ -0,0 +1,230 @@ +"""DataProc Agent (Task 1): natural-language -> operator DAG -> execution. + +The agent reads the live operator catalog (name + description + schema) and asks +the LLM to plan a valid, executable operator DAG for the user's goal. It then +runs the DAG with the DAGExecutor (status tracking + retries) and, if a node +fails, performs one ReAct-style re-plan using the error feedback. + +This shows task understanding + autonomous planning + multi-operator scheduling + +exception handling, decoupled from the operators themselves. +""" +from __future__ import annotations + +import json +from pathlib import Path +from typing import Any + +from config.settings import OUTPUTS_DIR +from medigraph.agents.dag_executor import DAGExecutor +from medigraph.agents.plan_validator import initial_available_keys, validate_plan +from medigraph.operators.base import catalog, load_default_operators + +_SYSTEM = "你是数据处理流程编排专家，只输出 JSON 描述的算子 DAG，不要解释。" + +_PLAN_PROMPT = """你可以使用以下数据处理算子（toolbox）： + +{catalog} + +用户的数据处理目标： +"{goal}" + +请规划一个**合法且可执行**的算子 DAG 来完成该目标。规则： +1. 每个节点格式：{{"id":"n1","op":"<算子名>","args":{{}},"deps":[]}}。 +2. op 只能取上面 toolbox 里的算子名。 +3. deps 用前置节点的 id 表示数据依赖；执行器会按拓扑序把上游输出(text/chunks/entities/triples/valid)透传给下游。 +4. 典型知识构建顺序：document_loader -> text_clean -> data_quality -> pii_redact -> chunker + -> medical_ner -> entity_linker -> medical_re -> triple_validator（按目标裁剪，不需要的算子不要加）。 +5. 涉及病例/患者原文时应加入 pii_redact；涉及图谱节点合并时应加入 entity_linker。 +6. 只输出 JSON：{{"dag":[ ...nodes... ]}}。 + +{feedback}""" + + +class DataProcAgent: + def __init__(self, llm: Any | None = None, local_planner: Any | None = None): + """local_planner: optional callable(goal)->dag (e.g. the fine-tuned <1B + orchestrator's `LocalOrchestrator.plan`). When set, planning runs on the + local small model instead of the big API model -- cheaper, faster, offline. + """ + if llm is None: + from medigraph.llm.client import LLMClient + llm = LLMClient() + self.llm = llm + self.local_planner = local_planner + # ensure operators are registered (idempotent) + load_default_operators(llm=llm) + self.executor = DAGExecutor(max_retries=2) + + # ------------------------------------------------------------------ # + def plan(self, goal: str, feedback: str = "") -> list[dict]: + # Use the fine-tuned local orchestrator when available (skip feedback loop). + if self.local_planner is not None and not feedback: + try: + return self._sanitize(self.local_planner(goal)) + except Exception as exc: # noqa: BLE001 - fall back to the API planner + print(f"[DataProcAgent] local planner failed ({exc}); using API planner") + prompt = _PLAN_PROMPT.format( + catalog=json.dumps(catalog(), ensure_ascii=False, indent=2), + goal=goal, + feedback=feedback, + ) + data = self.llm.chat_json(prompt, system=_SYSTEM, default={"dag": []}) + dag = data.get("dag", []) if isinstance(data, dict) else [] + return self._sanitize(dag) + + def _sanitize(self, dag: list) -> list[dict]: + valid_ops = {c["name"] for c in catalog()} + out = [] + used_ids: set[str] = set() + for i, node in enumerate(dag): + if not isinstance(node, dict) or node.get("op") not in valid_ops: + continue + node_id = str(node.get("id") or f"n{i+1}") + if node_id in used_ids: + suffix = 2 + while f"{node_id}_{suffix}" in used_ids: + suffix += 1 + node_id = f"{node_id}_{suffix}" + used_ids.add(node_id) + out.append( + { + "id": node_id, + "op": node["op"], + "args": node.get("args", {}) if isinstance(node.get("args"), dict) else {}, + "deps": [str(d) for d in node.get("deps", []) if isinstance(node.get("deps"), list)], + "retry_args": node.get("retry_args", []) if isinstance(node.get("retry_args"), list) else [], + "on_error": node.get("on_error", {}) if isinstance(node.get("on_error"), dict) else {}, + } + ) + valid_ids = {node["id"] for node in out} + for node in out: + node["deps"] = [ + dependency + for dependency in node["deps"] + if dependency in valid_ids and dependency != node["id"] + ] + return out + + @staticmethod + def reflect(goal: str, result: dict) -> dict: + """Check that execution produced the artifacts implied by the user goal.""" + goal_lower = goal.lower() + payload = result.get("payload", {}) + expectations = [ + (("清洗", "clean"), "text"), + (("切块", "分块", "chunk"), "chunks"), + (("实体", "ner"), "entities"), + (("关系", "三元组", "图谱", "relation"), "valid"), + ] + required = [ + output + for keywords, output in expectations + if any(keyword in goal_lower for keyword in keywords) + ] + missing = [ + output + for output in required + if output not in payload or payload.get(output) in (None, [], "") + ] + return { + "satisfied": not missing, + "required_outputs": required, + "missing_outputs": missing, + } + + # ------------------------------------------------------------------ # + def _validate(self, dag: list[dict], payload: dict) -> Any: + return validate_plan(dag, available=initial_available_keys(payload)) + + @staticmethod + def _record_rejected_plan(goal: str, dag: list[dict], report: Any) -> None: + """Persist a statically-rejected plan for later inspection. + + Purely an observability artefact -- these files are for debugging the planner, + not a training-data pipeline. + """ + try: + directory = Path(OUTPUTS_DIR) / "badcases" + directory.mkdir(parents=True, exist_ok=True) + existing = len(list(directory.glob("rejected_plan_*.json"))) + path = directory / f"rejected_plan_{existing + 1:04d}.json" + path.write_text( + json.dumps( + {"goal": goal, "dag": dag, "validation": report.as_dict()}, + ensure_ascii=False, + indent=2, + ), + encoding="utf-8", + ) + except OSError: # pragma: no cover - never fail a run over a debug artefact + pass + + # ------------------------------------------------------------------ # + def run(self, goal: str, payload: dict, verbose: bool = True) -> dict: + """Plan, statically validate, then execute. Re-plans once on failure. + + Validation runs *before* the executor, so an unsatisfiable plan costs nothing + to reject: the planner is asked again with the full error list instead of the + DAG failing part-way through and leaving partial artefacts behind. + """ + if verbose: + print(f"\n[DataProcAgent] goal: {goal}") + print("[DataProcAgent] planning operator DAG ...") + dag = self.plan(goal) + if not dag: + raise RuntimeError("planner produced an empty/invalid DAG; check LLM/API config") + + validation = self._validate(dag, payload) + planning_history = [{"reason": "initial", "dag": dag, "validation": validation.as_dict()}] + if not validation.ok: + if verbose: + print("[DataProcAgent] plan rejected by static validation:") + for error in validation.errors: + print(f" - {error.node or '-'} [{error.code}] {error.message} {error.missing}") + print("[DataProcAgent] re-planning without executing ...") + self._record_rejected_plan(goal, dag, validation) + repaired = self.plan(goal, feedback=validation.feedback()) + if repaired: + revalidated = self._validate(repaired, payload) + planning_history.append( + { + "reason": "static_validation", + "dag": repaired, + "validation": revalidated.as_dict(), + } + ) + if revalidated.ok: + dag, validation = repaired, revalidated + else: + self._record_rejected_plan(goal, repaired, revalidated) + + if verbose: + print("[DataProcAgent] planned DAG:") + for n in dag: + print(f" {n['id']}: {n['op']} deps={n['deps']} args={n['args']}") + print(f"[DataProcAgent] validation: ok={validation.ok} depth={len(validation.layers)}") + + result = self.executor.run(dag, payload, verbose=verbose) + executed_dag = dag + + reflection = self.reflect(goal, result) + if result["report"]["nodes_failed"] > 0 or not reflection["satisfied"]: + failed = [s for s in result["states"].values() if s["status"] == "failed"] + feedback = ( + "上一次执行未完全满足目标，请修正 DAG（可调整参数、替换算子或补充步骤）。" + f"失败信息：{json.dumps(failed, ensure_ascii=False)[:500]}；" + f"产物自检：{json.dumps(reflection, ensure_ascii=False)}" + ) + if verbose: + print("[DataProcAgent] re-planning after failure ...") + dag2 = self.plan(goal, feedback=feedback) + if dag2: + result = self.executor.run(dag2, payload, verbose=verbose) + result["replanned"] = True + executed_dag = dag2 + planning_history.append({"reason": "failure_or_reflection", "dag": dag2}) + result["dag"] = executed_dag + result["planning_history"] = planning_history + result["validation"] = validation.as_dict() + result["reflection"] = self.reflect(goal, result) + return result diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/kg_agent.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/kg_agent.py" new file mode 100644 index 0000000..541150f --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/kg_agent.py" @@ -0,0 +1,127 @@ +"""KGGen Agent (Task 2): raw documents -> knowledge graph. + +Orchestrates the operator pipeline automatically for every document: + chunker -> medical_ner -> medical_re -> triple_validator -> write to GraphStore. + +Includes lightweight ReAct-style quality self-checks: if a chunk yields no +entities it is skipped; relation extraction is fed the chunk's entities so RE +stays grounded. Supports incremental building (call build() repeatedly). +""" +from __future__ import annotations + +import hashlib +from typing import Any + +from tqdm import tqdm + +from medigraph.graph.base import GraphStore, get_graph_store +from medigraph.graph.vector_store import LocalVectorStore +from medigraph.operators.base import get_operator, load_default_operators + + +class KGGenAgent: + def __init__(self, llm: Any | None = None, store: GraphStore | None = None, + build_vectors: bool = True): + if llm is None: + from medigraph.llm.client import LLMClient + llm = LLMClient() + self.llm = llm + load_default_operators(llm=llm) + self.store = store or get_graph_store() + self.chunker = get_operator("chunker") + self.ner = get_operator("medical_ner") + self.re = get_operator("medical_re") + self.validator = get_operator("triple_validator") + # Vector index over chunks for hybrid GraphRAG (graph + vector retrieval). + self.build_vectors = build_vectors + self.vector_store = LocalVectorStore() if build_vectors else None + + def build(self, documents: list[dict], verbose: bool = True, max_chunks_per_doc: int | None = None) -> dict: + """documents: [{fileName, text, ...}]. Returns build stats. + + max_chunks_per_doc caps how many chunks of each document are processed + (useful to bound runtime / API cost on slow models). + """ + n_chunks = n_entities = n_candidate = n_valid = n_rejected = 0 + route_counts: dict[str, int] = {} + if hasattr(self.store, "begin_revision"): + self.store.begin_revision(f"kg-build:{len(documents)}-documents") + + for doc in documents: + source = doc.get("fileName", "unknown") + text = doc.get("text", "") or "" + if not text.strip(): + continue + chunks = self.chunker.run({"text": text}).get("chunks", []) + if max_chunks_per_doc: + chunks = chunks[:max_chunks_per_doc] + # Index chunks for vector retrieval (best-effort; degrades if no API). + if self.vector_store is not None and chunks: + vecs = self.llm.embed(chunks) + self.vector_store.add(chunks, [source] * len(chunks), vecs) + iterator = tqdm(chunks, desc=f"KG:{source[:24]}", disable=not verbose, leave=False) + source_hash = hashlib.sha256(text.encode("utf-8")).hexdigest() + for chunk_index, chunk in enumerate(iterator): + n_chunks += 1 + ner_result = self.ner.run({"text": chunk}) + ents = ner_result.get("entities", []) + ner_route = ner_result.get("routing", {}).get("level", "unknown") + route_counts[f"ner:{ner_route}"] = route_counts.get(f"ner:{ner_route}", 0) + 1 + if not ents: # self-check: nothing to relate + continue + n_entities += len(ents) + for e in ents: + self.store.upsert_entity( + e["name"], + e["type"], + confidence=e.get("confidence", 1.0), + canonical_id=e.get("canonical_id", ""), + canonical_name=e.get("canonical_name", e["name"]), + link_score=e.get("link_score", 0.0), + kb_source=e.get("kb_source", ""), + ) + + re_result = self.re.run({"text": chunk, "entities": ents}) + triples = re_result.get("triples", []) + re_route = re_result.get("routing", {}).get("level", "unknown") + route_counts[f"re:{re_route}"] = route_counts.get(f"re:{re_route}", 0) + 1 + n_candidate += len(triples) + checked = self.validator.run({"triples": triples, "text": chunk}) + valid = checked.get("valid", []) + n_valid += len(valid) + n_rejected += len(checked.get("rejected", [])) + chunk_id = hashlib.sha256( + f"{source}:{chunk_index}:{chunk}".encode("utf-8") + ).hexdigest()[:20] + for t in valid: + self.store.upsert_triple( + head=t["head"], head_type=t["head_type"], relation=t["relation"], + tail=t["tail"], tail_type=t["tail_type"], + confidence=t.get("confidence", 1.0), source=source, + operator_version=f"{t.get('extractor', 'medical_re')}/{t.get('model_version', '2.0.0')}", + source_doc=source, + source_hash=source_hash, + chunk_id=chunk_id, + extractor=t.get("extractor", "medical_re"), + model_version=t.get("model_version", "2.0.0"), + evidence=t.get("evidence", chunk[:240]), + cmeie_relation=t.get("cmeie_relation", ""), + cmeie_predicate=t.get("cmeie_predicate", ""), + ) + + delta = self.store.commit_revision() if hasattr(self.store, "commit_revision") else {} + build_stats = { + "documents": len(documents), + "chunks": n_chunks, + "entities_extracted": n_entities, + "candidate_triples": n_candidate, + "valid_triples": n_valid, + "rejected_triples": n_rejected, + "graph": self.store.stats(), + "graph_audit": self.store.audit() if hasattr(self.store, "audit") else {}, + "incremental_delta": delta, + "routing": route_counts, + "vector_chunks_indexed": self.vector_store.size if self.vector_store else 0, + "llm": self.llm.stats.summary(), + } + return build_stats diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/plan_validator.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/plan_validator.py" new file mode 100644 index 0000000..ec02a01 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/plan_validator.py" @@ -0,0 +1,209 @@ +"""Static validation of a planned operator DAG, before any operator runs. + +The planner is a language model, so its output is a *proposal*. `DataProcAgent` +already whitelists operator names and `topological_layers` rejects cycles and +unknown dependencies, but neither checks whether each node's declared inputs can +actually be satisfied. Without that, an unsatisfiable plan is only discovered +part-way through execution -- after earlier nodes have already spent LLM calls and +written artefacts. + +This module closes that gap by walking the DAG in dependency order and propagating +the set of payload keys that *will* exist at each node, comparing it against the +node's ``input_schema.required``. Everything wrong with the plan is reported at +once, as structured errors, so the re-plan prompt can fix all of it in one round +instead of converging one failure at a time. + +Deliberately conservative: it only rejects what it can prove unsatisfiable from +declared schemas. Operators whose `input_schema` declares no `required` keys are +accepted, so an under-annotated operator degrades to today's behaviour rather than +blocking a valid plan. + + report = validate_plan(dag, available={"paths"}) + if not report.ok: + ... # re-plan using report.feedback() +""" +from __future__ import annotations + +from dataclasses import dataclass, field +from typing import Any + +from medigraph.agents.dag_executor import topological_layers +from medigraph.operators.base import OP_REGISTRY, catalog + +#: Payload keys the executor provides before any node runs. `_resolve_args` also +#: accepts these as placeholder targets. +DEFAULT_AVAILABLE: frozenset[str] = frozenset({"text", "paths", "documents"}) + +#: Budget guard-rails. A planner loop that emits hundreds of nodes is a bug, and +#: an unbounded plan is an unbounded bill. +MAX_NODES = 32 +MAX_DEPTH = 16 + + +@dataclass +class PlanError: + """One reason a plan cannot run, addressed to whoever must fix the plan.""" + + node: str + code: str + message: str + missing: list[str] = field(default_factory=list) + + def as_dict(self) -> dict: + out = {"node": self.node, "code": self.code, "message": self.message} + if self.missing: + out["missing"] = self.missing + return out + + +@dataclass +class PlanReport: + ok: bool + errors: list[PlanError] = field(default_factory=list) + layers: list[list[str]] = field(default_factory=list) + node_count: int = 0 + produced_keys: dict[str, list[str]] = field(default_factory=dict) + + def as_dict(self) -> dict: + return { + "ok": self.ok, + "node_count": self.node_count, + "depth": len(self.layers), + "layers": self.layers, + "errors": [error.as_dict() for error in self.errors], + } + + def feedback(self) -> str: + """Chinese-language summary for the planner's re-plan prompt.""" + if self.ok: + return "" + lines = ["计划静态校验未通过，请修正后重新输出 DAG："] + for error in self.errors: + detail = f"（缺少输入：{', '.join(error.missing)}）" if error.missing else "" + lines.append(f"- 节点 {error.node or '-'}[{error.code}]：{error.message}{detail}") + lines.append( + "可用算子及其输入/输出契约见 toolbox；请确保每个节点所需的输入" + "由其上游节点产出，或由初始输入提供。" + ) + return "\n".join(lines) + + +def _required_inputs(op_name: str) -> list[str]: + op = OP_REGISTRY.get(op_name) + if op is None: + return [] + schema = op.meta.input_schema or {} + required = schema.get("required", []) + return [str(key) for key in required] if isinstance(required, list) else [] + + +def _produced_outputs(op_name: str) -> list[str]: + op = OP_REGISTRY.get(op_name) + if op is None: + return [] + schema = op.meta.output_schema or {} + properties = schema.get("properties", {}) + return list(properties.keys()) if isinstance(properties, dict) else [] + + +def _explicit_arg_keys(node: dict) -> set[str]: + """Keys the plan supplies directly via `args` (constants or placeholders).""" + args = node.get("args", {}) + return set(map(str, args)) if isinstance(args, dict) else set() + + +def validate_plan( + dag: list[dict], + available: set[str] | frozenset[str] | None = None, + max_nodes: int = MAX_NODES, + max_depth: int = MAX_DEPTH, +) -> PlanReport: + """Check a plan without executing it. + + `available` is the set of payload keys present before the first node (e.g. + ``{"paths"}`` when the caller passes file paths, ``{"text"}`` for raw text). + """ + errors: list[PlanError] = [] + + if not dag: + return PlanReport(ok=False, errors=[PlanError("", "empty_plan", "计划为空，没有任何算子节点。")]) + + if len(dag) > max_nodes: + errors.append( + PlanError( + "", + "budget_nodes", + f"计划包含 {len(dag)} 个节点，超过上限 {max_nodes}。", + ) + ) + + known = {entry["name"] for entry in catalog()} + for node in dag: + op_name = str(node.get("op", "")) + if op_name not in known: + errors.append( + PlanError( + str(node.get("id", "")), + "unknown_operator", + f"算子 '{op_name}' 不在可用算子清单中。", + ) + ) + + # Structural validation reuses the executor's own rules, so a plan accepted here + # cannot be rejected later for a different structural reason. + try: + layers = topological_layers(dag) + except ValueError as exc: + errors.append(PlanError("", "invalid_structure", str(exc))) + return PlanReport(ok=False, errors=errors, node_count=len(dag)) + + if len(layers) > max_depth: + errors.append( + PlanError( + "", + "budget_depth", + f"计划深度 {len(layers)} 超过上限 {max_depth}。", + ) + ) + + # Dataflow validation: propagate the keys that will exist, layer by layer. + node_by_id = {str(node["id"]): node for node in dag} + reachable: set[str] = set(DEFAULT_AVAILABLE if available is None else available) + produced_keys: dict[str, list[str]] = {} + + for layer in layers: + # Peers in a layer cannot see each other's outputs (the executor merges only + # at layer end), so validate the whole layer against the same snapshot. + snapshot = set(reachable) + for nid in layer: + node = node_by_id[nid] + op_name = str(node.get("op", "")) + if op_name not in known: + continue # already reported + satisfied = snapshot | _explicit_arg_keys(node) + missing = [key for key in _required_inputs(op_name) if key not in satisfied] + if missing: + errors.append( + PlanError( + nid, + "unsatisfied_input", + f"算子 '{op_name}' 所需输入在执行到该节点时不存在。", + missing=missing, + ) + ) + produced_keys[nid] = _produced_outputs(op_name) + for nid in layer: + reachable.update(produced_keys.get(nid, [])) + + return PlanReport( + ok=not errors, + errors=errors, + layers=layers, + node_count=len(dag), + produced_keys=produced_keys, + ) + + +def initial_available_keys(payload: dict[str, Any]) -> set[str]: + """Payload keys that count as present (empty values are still keys).""" + return {str(key) for key in payload} diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/qa_agent.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/qa_agent.py" new file mode 100644 index 0000000..aad2cac --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/agents/qa_agent.py" @@ -0,0 +1,382 @@ +"""GraphRAG QA Agent (Task 2): answer questions over the knowledge graph. + +Pipeline: + 1. Run medical_ner on the question to locate anchor entities. + 2. Resolve anchors to graph nodes; traverse a 1~2 hop subgraph for evidence. + 3. Feed the subgraph triples to the LLM to compose a grounded answer. + 4. Return the answer plus provenance (the triples / source documents hit). + +If no graph anchors are found, it degrades gracefully and tells the user. +""" +from __future__ import annotations + +from collections.abc import Callable +from typing import Any + +from medigraph.graph.base import GraphStore, get_graph_store +from medigraph.graph.vector_store import LocalVectorStore +from medigraph.operators.base import get_operator, load_default_operators +from medigraph.schema.cmeie_schema import predicate_zh +from medigraph.schema.ontology import RELATION_TYPES + +_SYSTEM = "你是医疗知识问答助手。优先依据提供的知识图谱三元组证据作答，可参考文本片段补充；不要编造；证据不足时如实说明。" + +_ANSWER_PROMPT = """用户问题：{question} + +【知识图谱三元组证据】（结构化、可溯源，每条含来源文档）： +{evidence} + +【相关文本片段】（向量检索补充，仅供参考）： +{passages} + +【多跳推理路径】（按路径置信度排序）： +{paths} + +请基于上述证据用中文回答问题，要求： +1. 优先使用三元组证据；文本片段仅作补充。不要臆造。 +2. 在答案末尾用「依据：」列出你引用的关键三元组。 +3. 若证据不足以回答，请明确说明。 +""" + +# Question intent -> ontology relations. This keeps the evidence budget focused +# on what the user actually asked instead of returning arbitrary high-degree +# neighbours first (important on the 26k-edge CM3KG graph). +#: Each rule maps question keywords to relation KEYS, not to one graph's naming +#: scheme -- deliberately pairing the CM3KG-import compact key (`has_symptom`, +#: `recommend_drug`, ...) with its CMeIE-V2 counterpart (`cmeie:clinical_ +#: manifestation`, `cmeie:drug_treatment`, ...) wherever both graphs express the +#: same relationship. graph.json (CM3KG import) and graph_scaled.json (self- +#: produced, neural-GPLinker-built over the full 53-row CMeIE schema) use +#: different relation vocabularies for overlapping concepts; a rule that only +#: recognised the CM3KG key returned an *empty* intent list for the same +#: question asked against the self-produced graph. With no matched intent, +#: `select_evidence` falls back to "top-24 by confidence, no relation-type +#: balancing" -- and since `cmeie:clinical_manifestation` is by far the most +#: numerous relation in the self-produced graph (~28% of all edges), it can +#: bury the specific relation type the question actually asked about (e.g. a +#: "相关（导致）" or "病因" question ends up starved of related_cause/etiology +#: evidence and answered mostly from clinical_manifestation edges instead). +#: Found via benchmarks/build_kg_qa_human.py's graph_scaled.json-grounded +#: question set, which exercises the real agent end to end rather than the +#: graph-traversal self-consistency check in eval_kg_qa.py. +_INTENT_RULES: list[tuple[tuple[str, ...], tuple[str, ...]]] = [ + (("症状", "表现", "体征", "symptom"), ("has_symptom", "cmeie:clinical_manifestation")), + (("药物", "用药", "治疗药", "吃什么药", "drug"), ("recommend_drug", "cmeie:drug_treatment")), + (("检查", "检验", "筛查", "诊断方法", "examination"), + ("need_examination", "cmeie:laboratory_examination", "cmeie:imaging_examination", + "cmeie:auxiliary_examination", "cmeie:histological_examination", "cmeie:endoscopic_examination")), + (("并发", "并发症", "风险", "complication"), ("complication", "cmeie:complication")), + (("科室", "挂号", "就诊", "department"), ("treated_in_department", "cmeie:department")), + (("手术", "操作", "procedure"), ("treated_by_procedure", "cmeie:surgical_treatment")), + (("阳性", "标志物", "marker"), ("positive_marker",)), + (("阴性",), ("negative_marker",)), + (("基因", "突变", "gene"), ("associated_gene",)), + (("形态", "镜下", "病理表现", "morphology"), ("has_morphology",)), + (("部位", "位于", "发生于", "location"), ("located_in", "cmeie:onset_site")), + (("亚型", "分型", "subtype"), ("subtype_of",)), + (("禁忌", "contraindication"), ("contraindication",)), + (("不良反应", "副作用", "adverse"), ("adverse_reaction",)), + # CMeIE-only categories with no CM3KG counterpart in the compact ontology. + (("相关", "关联", "有关", "related"), ("cmeie:related_cause", "cmeie:related_symptom", "cmeie:related_transformation")), + (("病因", "原因", "为什么会得", "etiology"), ("cmeie:etiology",)), + (("鉴别诊断", "如何区分", "differential"), ("cmeie:differential_diagnosis",)), + (("病理分型", "分类", "classification"), ("cmeie:pathological_classification",)), + (("高危因素", "危险因素", "risk factor"), ("cmeie:high_risk_factor", "cmeie:risk_assessment_factor"),), + (("辅助治疗", "非药物治疗", "adjuvant"), ("cmeie:adjuvant_therapy",)), + (("化疗", "chemotherapy"), ("cmeie:chemotherapy",)), + (("放疗", "放射治疗", "radiotherapy"), ("cmeie:radiotherapy",)), + (("预防", "prevention"), ("cmeie:prevention",)), + (("预后", "存活率", "生存率", "prognosis"), ("cmeie:prognosis_status", "cmeie:prognosis_survival_rate")), + (("多发群体", "易感人群", "susceptible"), ("cmeie:susceptible_population",)), + (("发病率", "incidence"), ("cmeie:incidence",)), + (("发病年龄", "onset age"), ("cmeie:onset_age",)), + (("遗传", "genetic"), ("cmeie:genetic_factor",)), + (("发病机制", "pathogenesis"), ("cmeie:pathogenesis",)), +] + + +def _relation_label(triple: dict) -> str: + """Chinese label for one evidence edge's relation, across both graph flavours. + + `graph.json` (CM3KG import) stores an explicit `relation_zh` per edge. + `graph_scaled.json` (self-produced, neural-GPLinker-built) does not -- its + edges carry the raw `cmeie:xxx` schema key -- so without a fallback the QA + prompt (and thus the LLM's composed answer) would show literal strings like + "cmeie:pathological_classification" instead of "病理分型". Falls through + explicit relation_zh -> CM3KG ontology label -> CMeIE predicate label -> the + raw key, so it degrades gracefully rather than raising on an unknown key. + """ + relation = triple.get("relation", "") + return ( + triple.get("relation_zh") + or RELATION_TYPES.get(relation) + or predicate_zh(relation) + ) + + +def infer_intent_relations(question: str) -> list[str]: + """Infer requested relation types deterministically from the question.""" + q = question.lower() + out: list[str] = [] + for keywords, relations in _INTENT_RULES: + if any(keyword.lower() in q for keyword in keywords): + for relation in relations: + if relation not in out: + out.append(relation) + return out + + +def rank_evidence( + evidence: list[dict], + intent_relations: list[str], + anchors: list[str] | None = None, +) -> list[dict]: + """Rank relevant relation types first, then confidence and provenance.""" + priority = {relation: index for index, relation in enumerate(intent_relations)} + anchor_set = set(anchors or []) + + def key(triple: dict) -> tuple: + relation = str(triple.get("relation", "")) + head = str(triple.get("head", "")) + tail = str(triple.get("tail", "")) + return ( + 0 if relation in priority else 1, + priority.get(relation, len(priority)), + 0 if head in anchor_set else 1 if tail in anchor_set else 2, + -float(triple.get("confidence", 0.0) or 0.0), + 0 if triple.get("source") else 1, + head, + tail, + ) + + return sorted(evidence, key=key) + + +def select_evidence( + evidence: list[dict], + intent_relations: list[str], + limit: int = 24, + anchors: list[str] | None = None, +) -> list[dict]: + """Balance evidence across requested relations and keep prompts concise.""" + if not intent_relations: + return evidence[:limit] + focused = [triple for triple in evidence if triple.get("relation") in intent_relations] + if not focused: + return evidence[:limit] + anchor_set = set(anchors or []) + direct_outgoing = [ + triple for triple in focused if str(triple.get("head", "")) in anchor_set + ] + if direct_outgoing: + return direct_outgoing[:limit] + per_relation = 12 if len(intent_relations) == 1 else 8 + counts: dict[str, int] = {} + selected = [] + for triple in focused: + relation = str(triple.get("relation", "")) + if counts.get(relation, 0) >= per_relation: + continue + selected.append(triple) + counts[relation] = counts.get(relation, 0) + 1 + if len(selected) >= limit: + break + return selected + + +def score_answer_confidence(evidence: list[dict], passages: list[dict] | None = None) -> dict: + """Compute an explainable answer-level confidence and safety grade.""" + passages = passages or [] + values = [float(item.get("confidence", 0.0) or 0.0) for item in evidence] + if values: + evidence_score = sum(values) / len(values) + source_ratio = sum(bool(item.get("source") or item.get("sources")) for item in evidence) / len(evidence) + score = 0.9 * evidence_score + 0.1 * source_ratio + elif passages: + score = 0.5 + source_ratio = sum(bool(item.get("source")) for item in passages) / len(passages) + else: + score = source_ratio = 0.0 + grade = "high" if score >= 0.85 else "medium" if score >= 0.65 else "low" + return { + "score": round(score, 4), + "grade": grade, + "evidence_mean": round(sum(values) / len(values), 4) if values else 0.0, + "source_coverage": round(source_ratio, 4), + } + + +class QAAgent: + def __init__(self, llm: Any | None = None, store: GraphStore | None = None, hops: int = 2, + vector_store: LocalVectorStore | None = None, top_k: int = 3, + min_answer_confidence: float = 0.55): + if llm is None: + from medigraph.llm.client import LLMClient + llm = LLMClient() + self.llm = llm + load_default_operators(llm=llm) + self.ner = get_operator("medical_ner") + self.store = store or get_graph_store() + self.hops = hops + self.vector_store = vector_store # optional: enables hybrid retrieval + self.top_k = top_k + self.min_answer_confidence = min_answer_confidence + + def answer( + self, + question: str, + verbose: bool = False, + on_token: Callable[[str], None] | None = None, + ) -> dict: + """Grounded answer over the graph (+ optional vector passages). + + When `on_token` is supplied the composition step streams and each delta is + handed to the callback as it arrives; the return value is unchanged, so + callers that want the whole payload (tests, CLI, MCP) are unaffected. This + is what lets the HTTP layer emit SSE without duplicating retrieval. + """ + intent_relations = infer_intent_relations(question) + # 1) anchors via NER on the question + ents = self.ner.run({"text": question}).get("entities", []) + anchor_names = [e["name"] for e in ents] + if verbose: + print(f"[QA] question anchors: {anchor_names}") + + # 2) resolve to graph nodes + traverse + resolved = self.store.find_entities(anchor_names) if anchor_names else [] + # Deterministic fallback: graph node names occurring literally in the + # question can still anchor retrieval when the LLM NER misses. + if not resolved: + resolved = self.store.find_entities([question]) + evidence: list[dict] = [] + reasoning_paths: list[dict] = [] + seen = set() + for node in resolved: + for t in self.store.neighbors(node, hops=self.hops): + key = (t["head"], t["relation"], t["tail"]) + if key not in seen: + seen.add(key) + evidence.append(t) + if hasattr(self.store, "traverse_paths"): + reasoning_paths.extend(self.store.traverse_paths(node, hops=min(3, max(1, self.hops)))) + + evidence_total = len(evidence) + evidence = rank_evidence(evidence, intent_relations, resolved) + evidence = select_evidence(evidence, intent_relations, anchors=resolved) + reasoning_paths.sort( + key=lambda path: ( + -sum(relation in intent_relations for relation in path.get("relations", [])), + -float(path.get("confidence", 0.0)), + path.get("hops", 0), + ) + ) + reasoning_paths = reasoning_paths[:12] + + # 2b) vector retrieval (hybrid GraphRAG): top-k passages for the question + passages: list[dict] = [] + if self.vector_store is not None and self.vector_store.size: + qvec = self.llm.embed([question]) + if qvec and qvec[0]: + passages = self.vector_store.search(qvec[0], k=self.top_k) + if verbose: + print(f"[QA] graph evidence: {len(evidence)} triples; vector passages: {len(passages)}") + + if not evidence and not passages: + return { + "question": question, + "answer": "知识图谱与文本库中均未找到与该问题相关的证据，无法作答。", + "anchors": anchor_names, + "resolved_entities": resolved, + "intent_relations": intent_relations, + "retrieval_mode": "none", + "evidence_total": 0, + "evidence_used": 0, + "evidence": [], + "passages": [], + "citations": [], + "reasoning_paths": [], + "answer_confidence": score_answer_confidence([], []), + "refused": True, + } + + answer_confidence = score_answer_confidence(evidence, passages) + if answer_confidence["score"] < self.min_answer_confidence: + return { + "question": question, + "answer": ( + "已检索到相关线索，但证据置信度不足，基于医疗安全策略暂不生成确定性答案。" + "建议补充高质量来源或由专业人员复核。" + ), + "anchors": anchor_names, + "resolved_entities": resolved, + "intent_relations": intent_relations, + "retrieval_mode": "hybrid" if passages else "graph", + "evidence_total": evidence_total, + "evidence_used": len(evidence), + "evidence": evidence, + "passages": passages, + "citations": [], + "reasoning_paths": reasoning_paths, + "answer_confidence": answer_confidence, + "refused": True, + } + + # 3) compose grounded answer from both evidence sources + evidence_str = "\n".join( + f" - {t['head']} --[{_relation_label(t)}]--> {t['tail']} " + f"(conf={t.get('confidence')}, 来源={t.get('source','')})" + for t in evidence[:40] + ) or " (无)" + passages_str = "\n".join( + f" - [{p.get('source','')}] {p['text'][:200].strip()}" for p in passages + ) or " (无)" + paths_str = "\n".join( + " - " + + " -> ".join( + f"{step['head']} -[{_relation_label(step)}]-> {step['tail']}" + for step in path["steps"] + ) + + f" (path_conf={path['confidence']})" + for path in reasoning_paths[:8] + ) or " (无)" + prompt = _ANSWER_PROMPT.format( + question=question, + evidence=evidence_str, + passages=passages_str, + paths=paths_str, + ) + if on_token is not None: + pieces: list[str] = [] + for piece in self.llm.chat_stream(prompt, system=_SYSTEM, temperature=0.2): + pieces.append(piece) + on_token(piece) + answer = "".join(pieces) + else: + answer = self.llm.chat(prompt, system=_SYSTEM, temperature=0.2) + citations = [ + { + "id": index, + "triple": f"{t['head']} --[{_relation_label(t)}]--> {t['tail']}", + "relation": t["relation"], + "confidence": t.get("confidence"), + "source": t.get("source", ""), + } + for index, t in enumerate(evidence[:12], start=1) + ] + + return { + "question": question, + "answer": answer, + "anchors": anchor_names, + "resolved_entities": resolved, + "intent_relations": intent_relations, + "retrieval_mode": "hybrid" if passages else "graph", + "evidence_total": evidence_total, + "evidence_used": len(evidence), + "evidence": evidence[:40], + "passages": passages, + "citations": citations, + "reasoning_paths": reasoning_paths, + "answer_confidence": answer_confidence, + "refused": False, + } diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/__init__.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/__init__.py" new file mode 100644 index 0000000..e69de29 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/analysis_agent.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/analysis_agent.py" new file mode 100644 index 0000000..769377f --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/analysis_agent.py" @@ -0,0 +1,394 @@ +"""Data Analysis Agent (Task 3): NL question -> data -> BI chart + insight. + +Reuses Task-2 outputs: the knowledge graph (associations) and the relational DB +derived from it (statistics/trends). The agent: + 1. understands the graph schema (profile injected into the LLM), + 2. plans a route -- GRAPH (association/relationship questions) vs SQL + (statistics / ranking / trend over records), + 3. executes (graph traversal or NL2SQL), 4. composes a natural-language insight, + 5. emits a BI/graph visualization (ECharts HTML). + +This is the "数据->知识->洞察" closing loop. +""" +from __future__ import annotations + +from pathlib import Path +from typing import Any + +from medigraph.analysis.graph_profile import build_profile, load_graph, profile_prompt_block +from medigraph.analysis.nl2sql import NL2SQL +from medigraph.analysis import viz +from medigraph.agents.qa_agent import _relation_label, infer_intent_relations, rank_evidence, select_evidence + +_ROUTE_SYSTEM = "你是分析任务规划器，判断问题应走关系数据库(SQL)还是知识图谱(GRAPH)，只输出 JSON。" + +_ROUTE_PROMPT = """已知两类数据源： +- SQL：就诊记录关系库（patient_visits/prescriptions/lab_tests），适合统计、排名、趋势、计数、平均等问题。 +- GRAPH：医疗知识图谱（疾病-症状/药物/检查/并发/标志物等关系），适合“某疾病有哪些并发症/用药/相关概念”等关联问题。 + +{profile} + +请判断下面的问题应使用哪个数据源，并给出理由。只输出 JSON：{{"route":"SQL"或"GRAPH","reason":"..."}} +问题：{question}""" + +_INSIGHT_SYSTEM = "你是医疗数据分析师，根据数据给出简洁、专业、可读的中文洞察，不要编造数据。" + +_INSIGHT_PROMPT = """问题：{question} + +分析得到的数据（{source}）： +{data} + +请用 2-4 句话给出洞察解读，指出关键发现/最大值/趋势/异常，便于非技术读者理解。""" + +_SQL_HINTS = ( + "统计", "多少", "人次", "数量", "计数", "平均", "总计", "总共", "排名", + "排序", "最多", "最少", "最高", "最低", "前", "趋势", "每月", "每年", + "比例", "占比", "分布", "费用", "异常率", "top", +) +_GRAPH_HINTS = ( + "关系", "关联", "症状", "并发症", "推荐药", "用药", "检查", "标志物", + "基因", "形态", "位于", "亚型", "知识图谱", "邻居", +) + +# Graph-analytics intents: global structure (who's central, what clusters +# together, how two entities relate) rather than "what is X directly linked +# to" -- the existing GRAPH route only ever does 1-hop neighbor lookup around +# a named anchor entity, which cannot answer any of these. +_CENTRALITY_HINTS = ("中心性", "核心节点", "最核心", "最重要的", "pagerank", "枢纽", "hub") +_COMMUNITY_HINTS = ("社区", "聚类", "簇", "社群", "分组", "community") +_PATH_HINTS = ("最短路径", "怎么关联", "如何关联", "路径是什么", "shortest path") + + +class AnalysisAgent: + def __init__(self, db_path: str, graph_json: str | None = None, llm: Any | None = None): + if llm is None: + from medigraph.llm.client import LLMClient + llm = LLMClient() + self.llm = llm + self.store, self.used_example_graph = load_graph(graph_json) + self.profile = build_profile(self.store) + self.nl2sql = NL2SQL(db_path, llm=llm) + + # ------------------------------------------------------------------ # + def plan_route(self, question: str) -> dict: + """Return an explainable route plan; use deterministic intents first.""" + q = question.lower() + algo_hits = [ + hint + for hint in (*_CENTRALITY_HINTS, *_COMMUNITY_HINTS, *_PATH_HINTS) + if hint.lower() in q + ] + if algo_hits: + return { + "route": "GRAPH_ALGO", + "reason": f"问题包含图算法意图：{', '.join(algo_hits[:4])}", + "planner": "deterministic_intent_router", + } + sql_hits = [hint for hint in _SQL_HINTS if hint.lower() in q] + graph_hits = [hint for hint in _GRAPH_HINTS if hint.lower() in q] + # Aggregations over the KG mirror tables are SQL tasks even when the + # wording contains "知识图谱/关联/关系". The previous rule sent + # "统计关联症状最多的 Top 10 疾病" to entity-centric graph traversal, + # which has no anchor entity and therefore returned zero rows. + if sql_hits: + return { + "route": "SQL", + "reason": f"问题包含统计/趋势意图：{', '.join(sql_hits[:4])}", + "planner": "deterministic_intent_router", + } + if graph_hits: + return { + "route": "GRAPH", + "reason": f"问题包含图谱关联意图：{', '.join(graph_hits[:4])}", + "planner": "deterministic_intent_router", + } + data = self.llm.chat_json( + _ROUTE_PROMPT.format(profile=profile_prompt_block(self.profile), question=question), + system=_ROUTE_SYSTEM, default={"route": "SQL"}, + ) + route = (data.get("route") if isinstance(data, dict) else "SQL") or "SQL" + normalized = "GRAPH" if str(route).upper().startswith("G") else "SQL" + return { + "route": normalized, + "reason": str(data.get("reason", "LLM 根据数据源能力选择")) if isinstance(data, dict) else "LLM 路由", + "planner": "llm_router", + } + + def route(self, question: str) -> str: + return self.plan_route(question)["route"] + + def _graph_answer(self, question: str) -> dict: + """Association analysis via graph traversal around question entities.""" + triples: list[dict] = [] + intent_relations = infer_intent_relations(question) + compact_question = question.lower().replace("—", "-").replace("－", "-") + generic_relation_network = ( + "疾病" in compact_question + and "症状" in compact_question + and any(term in compact_question for term in ("关系图", "关联图", "网络图", "关系网络", "疾病-症状")) + ) + + if generic_relation_network and hasattr(self.store, "g"): + # A relation-network request has no named anchor entity. Traverse a + # representative slice of the requested relation instead of asking + # NER to turn the generic words "疾病/症状" into fake anchors. + grouped: dict[str, list[dict]] = {} + for head, tail, data in self.store.g.edges(data=True): + if data.get("relation") != "has_symptom": + continue + if self.store.g.nodes[head].get("type") != "Disease": + continue + if self.store.g.nodes[tail].get("type") != "Symptom": + continue + grouped.setdefault(head, []).append(self.store._edge_dict(head, tail, data)) + ranked_heads = sorted(grouped, key=lambda name: (-len(grouped[name]), name))[:8] + anchors = ranked_heads + for head in ranked_heads: + triples.extend( + sorted(grouped[head], key=lambda item: str(item.get("tail", "")))[:3] + ) + evidence_total = sum(len(items) for items in grouped.values()) + triples = triples[:24] + else: + from medigraph.operators.base import get_operator, load_default_operators + load_default_operators(llm=self.llm) + ents = get_operator("medical_ner").run({"text": question}).get("entities", []) + anchors = self.store.find_entities([e["name"] for e in ents]) + if not anchors: + anchors = self.store.find_entities([question]) + seen = set() + for a in anchors: + for t in self.store.neighbors(a, hops=1): + k = (t["head"], t["relation"], t["tail"]) + if k not in seen: + seen.add(k) + triples.append(t) + evidence_total = len(triples) + triples = select_evidence( + rank_evidence(triples, intent_relations, anchors=anchors), + intent_relations, + anchors=anchors, + ) + triples = [ + triple for triple in triples + if str(triple.get("head", "")) != str(triple.get("tail", "")) + ] + columns = ["head", "relation", "tail"] + rows = [(t["head"], _relation_label(t), t["tail"]) for t in triples] + citations = [ + { + "id": index, + "triple": f"{t['head']} --[{_relation_label(t)}]--> {t['tail']}", + "relation": t["relation"], + "confidence": t.get("confidence"), + "source": t.get("source", ""), + } + for index, t in enumerate(triples[:24], start=1) + ] + return {"source": "GRAPH", "columns": columns, "rows": rows, "triples": triples, + "anchors": anchors, "sql": "", "attempts": [], + "intent_relations": intent_relations, "evidence_total": evidence_total, + "evidence_used": len(triples), "citations": citations} + + def _graph_algorithm_answer(self, question: str) -> dict: + """Global graph structure: centrality/PageRank ranking, community + detection, or shortest path -- as opposed to `_graph_answer`'s 1-hop + neighbor lookup around a named anchor.""" + from medigraph.analysis.graph_algorithms import ( + degree_centrality_ranking, + detect_communities, + pagerank_ranking, + shortest_path, + ) + + q = question.lower() + entity_type = None + for label, type_name in ( + ("疾病", "Disease"), ("症状", "Symptom"), ("药物", "Drug"), + ("检查", "Examination"), ("部位", "Body"), + ): + if label in question: + entity_type = type_name + break + + if any(hint.lower() in q for hint in _PATH_HINTS): + from medigraph.operators.base import get_operator, load_default_operators + + load_default_operators(llm=self.llm) + ents = get_operator("medical_ner").run({"text": question}).get("entities", []) + anchors = self.store.find_entities([e["name"] for e in ents]) + if len(anchors) >= 2: + path = shortest_path(self.store, anchors[0], anchors[1]) + else: + path = None + if not path: + return { + "source": "GRAPH_ALGO", "algorithm": "shortest_path", "columns": ["head", "relation", "tail"], + "rows": [], "triples": [], "anchors": anchors, "sql": "", "attempts": [], + "intent_relations": [], "evidence_total": 0, "evidence_used": 0, "citations": [], + } + triples = [ + {"head": step["head"], "relation": step["relation"], "tail": step["tail"], + "confidence": step.get("confidence")} + for step in path["steps"] + ] + rows = [(t["head"], _relation_label(t), t["tail"]) for t in triples] + return { + "source": "GRAPH_ALGO", "algorithm": "shortest_path", "columns": ["head", "relation", "tail"], + "rows": rows, "triples": triples, "anchors": path["path"], "sql": "", "attempts": [], + "intent_relations": [], "evidence_total": len(triples), "evidence_used": len(triples), + "citations": [{"id": i, "triple": f"{t['head']} --[{_relation_label(t)}]--> {t['tail']}", + "relation": t["relation"], "confidence": t.get("confidence")} + for i, t in enumerate(triples, start=1)], + } + + if any(hint.lower() in q for hint in _COMMUNITY_HINTS): + communities = detect_communities(self.store, top_n=8) + columns = ["community_id", "size", "representative_entities"] + rows = [(c["community_id"], c["size"], "、".join(c["representative_entities"])) for c in communities] + return { + "source": "GRAPH_ALGO", "algorithm": "community", "columns": columns, "rows": rows, + "triples": None, "anchors": [], "sql": "", "attempts": [], "intent_relations": [], + "evidence_total": len(communities), "evidence_used": len(communities), "citations": [], + "communities": communities, + } + + # Centrality/PageRank (default for this route when no community/path + # keyword matched -- _CENTRALITY_HINTS is what triggered GRAPH_ALGO). + use_pagerank = "pagerank" in q or "枢纽" in q or "hub" in q + ranking = ( + pagerank_ranking(self.store, top_n=10, entity_type=entity_type) + if use_pagerank + else degree_centrality_ranking(self.store, top_n=10, entity_type=entity_type) + ) + score_key = "pagerank" if use_pagerank else "degree_centrality" + columns = ["name", "type", score_key] + rows = [(item["name"], item["type"], item[score_key]) for item in ranking] + return { + "source": "GRAPH_ALGO", "algorithm": score_key, "columns": columns, "rows": rows, + "triples": None, "anchors": [], "sql": "", "attempts": [], "intent_relations": [], + "evidence_total": len(ranking), "evidence_used": len(ranking), "citations": [], + } + + def _sql_answer(self, question: str) -> dict: + res = self.nl2sql.query(question) + return {"source": "SQL", "columns": res["columns"], "rows": res["rows"], + "sql": res["sql"], "error": res["error"], "triples": None, + "attempts": res["attempts"], "anchors": [], "intent_relations": [], + "evidence_total": 0, "evidence_used": 0, "citations": []} + + def _insight(self, question: str, source: str, columns: list[str], rows: list) -> str: + if source == "GRAPH" and "并发" in question: + complications = list(dict.fromkeys( + str(row[2]) for row in rows + if len(row) > 2 and str(row[1]) in {"并发", "complication"} + )) + drugs = list(dict.fromkeys( + str(row[2]) for row in rows + if len(row) > 2 and str(row[1]) in {"推荐药物", "recommend_drug"} + )) + findings = [] + if complications: + findings.append( + f"当前图谱检索到 {len(complications)} 个直接并发症：" + f"{'、'.join(complications)}" + ) + if drugs: + findings.append( + f"推荐药物共 {len(drugs)} 种：{'、'.join(drugs)}" + ) + if findings: + return ( + "；".join(findings) + + "。并发症结论仅采用从问题疾病出发的有向关系，" + "未把指向该疾病的入边计作其并发症。" + ) + preview: dict[str, Any] = { + "columns": columns, + "row_count": len(rows), + "rows_preview": [list(r) for r in rows[:30]], + } + if len(columns) >= 2: + numeric_rows = [ + (r[0], float(r[1])) + for r in rows + if len(r) >= 2 and isinstance(r[1], (int, float)) + ] + if numeric_rows: + ranked = sorted(numeric_rows, key=lambda item: item[1], reverse=True) + preview["second_column_statistics"] = { + "column": columns[1], + "sum": sum(value for _, value in numeric_rows), + "max": list(ranked[0]), + "min": list(ranked[-1]), + "top5": [list(item) for item in ranked[:5]], + } + try: + return self.llm.chat( + _INSIGHT_PROMPT.format(question=question, source=source, data=preview), + system=_INSIGHT_SYSTEM, temperature=0.2, + ) + except Exception: + # Reporting must not fail merely because an optional narrative LLM + # is unavailable or out of quota. The queried rows are already the + # source of truth, so produce a compact deterministic explanation. + numeric = preview.get("second_column_statistics") + if numeric: + maximum = numeric["max"] + minimum = numeric["min"] + return ( + f"共得到 {len(rows)} 条结果。最高项为“{maximum[0]}”" + f"（{maximum[1]:g}），最低项为“{minimum[0]}”" + f"（{minimum[1]:g}）；图表与明细均来自本次只读查询。" + ) + unique_heads = len({str(row[0]) for row in rows if row}) + unique_tails = len({str(row[2]) for row in rows if len(row) > 2}) + return ( + f"共展示 {len(rows)} 条知识图谱关系，涉及 {unique_heads} 个疾病" + f"和 {unique_tails} 个症状；所有连边均来自当前图谱证据。" + ) + + # ------------------------------------------------------------------ # + def analyze(self, question: str, out_html: str | Path | None = None, verbose: bool = True) -> dict: + plan = self.plan_route(question) + route = plan["route"] + if verbose: + print(f"[AnalysisAgent] route = {route}") + if route == "GRAPH_ALGO": + result = self._graph_algorithm_answer(question) + elif route == "GRAPH": + result = self._graph_answer(question) + else: + result = self._sql_answer(question) + + if not result["rows"]: + insight = "未查询到相关数据，无法分析。" + (f"（SQL 错误：{result.get('error')}）" if result.get("error") else "") + chart_type = "table" + else: + insight = self._insight(question, result["source"], result["columns"], result["rows"]) + if route == "GRAPH_ALGO": + chart_type = "graph" if result.get("algorithm") == "shortest_path" else "bar" + else: + chart_type = "graph" if route == "GRAPH" else viz.pick_chart_type(question, result["columns"], result["rows"]) + + html_path = "" + if out_html: + html_path = viz.render_report( + out_html, question, chart_type, result["columns"], result["rows"], + insight, sql=result.get("sql", ""), triples=result.get("triples"), + ) + + return { + "question": question, "route": route, "chart_type": chart_type, + "route_reason": plan["reason"], "planner": plan["planner"], + "columns": result["columns"], "rows": result["rows"], + "sql": result.get("sql", ""), "insight": insight, "html": html_path, + "attempts": result.get("attempts", []), + "anchors": result.get("anchors", []), + "intent_relations": result.get("intent_relations", []), + "evidence_total": result.get("evidence_total", 0), + "evidence_used": result.get("evidence_used", 0), + "citations": result.get("citations", []), + "graph_profile": self.profile, + "used_example_graph": self.used_example_graph, + } diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/assets/echarts.min.js" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/assets/echarts.min.js" new file mode 100644 index 0000000..a3e9805 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/assets/echarts.min.js" @@ -0,0 +1,45 @@ + +/* +* Licensed to the Apache Software Foundation (ASF) under one +* or more contributor license agreements. See the NOTICE file +* distributed with this work for additional information +* regarding copyright ownership. The ASF licenses this file +* to you under the Apache License, Version 2.0 (the +* "License"); you may not use this file except in compliance +* with the License. You may obtain a copy of the License at +* +* http://www.apache.org/licenses/LICENSE-2.0 +* +* Unless required by applicable law or agreed to in writing, +* software distributed under the License is distributed on an +* "AS IS" BASIS, WITHOUT WARRANTIES OR CONDITIONS OF ANY +* KIND, either express or implied. See the License for the +* specific language governing permissions and limitations +* under the License. +*/ + +!function(t,e){"object"==typeof exports&&"undefined"!=typeof module?e(exports):"function"==typeof define&&define.amd?define(["exports"],e):e((t="undefined"!=typeof globalThis?globalThis:t||self).echarts={})}(this,(function(t){"use strict"; +/*! ***************************************************************************** + Copyright (c) Microsoft Corporation. + + Permission to use, copy, modify, and/or distribute this software for any + purpose with or without fee is hereby granted. + + THE SOFTWARE IS PROVIDED "AS IS" AND THE AUTHOR DISCLAIMS ALL WARRANTIES WITH + REGARD TO THIS SOFTWARE INCLUDING ALL IMPLIED WARRANTIES OF MERCHANTABILITY + AND FITNESS. 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b=g+o,w=e[2*b],S=e[2*b+1];w===v&&S===m&&y=i||MS(w,S))d=v,f=m;else{T=w-u,C=S-h;var k=v-u,L=w-v,P=m-h,O=S-m,R=void 0,N=void 0;if("x"===s){var E=T>0?1:-1;d=v-E*(R=Math.abs(k))*a,f=m,D=v+E*(N=Math.abs(L))*a,A=m}else if("y"===s){var z=C>0?1:-1;d=v,f=m-z*(R=Math.abs(P))*a,D=v,A=m+z*(N=Math.abs(O))*a}else R=Math.sqrt(k*k+P*P),d=v-T*a*(1-(I=(N=Math.sqrt(L*L+O*O))/(N+R))),f=m-C*a*(1-I),A=m+C*a*I,D=wS(D=v+T*a*I,SS(w,v)),A=wS(A,SS(S,m)),D=SS(D,wS(w,v)),f=m-(C=(A=SS(A,wS(S,m)))-m)*R/N,d=wS(d=v-(T=D-v)*R/N,SS(u,v)),f=wS(f,SS(h,m)),D=v+(T=v-(d=SS(d,wS(u,v))))*N/R,A=m+(C=m-(f=SS(f,wS(h,m))))*N/R}t.bezierCurveTo(c,p,d,f,v,m),c=D,p=A}else t.lineTo(v,m)}u=v,h=m,g+=o}return y}var TS=function(){this.smooth=0,this.smoothConstraint=!0},CS=function(t){function e(e){var n=t.call(this,e)||this;return n.type="ec-polyline",n}return n(e,t),e.prototype.getDefaultStyle=function(){return{stroke:"#000",fill:null}},e.prototype.getDefaultShape=function(){return new TS},e.prototype.buildPath=function(t,e){var n=e.points,i=0,r=n.length/2;if(e.connectNulls){for(;r>0&&MS(n[2*r-2],n[2*r-1]);r--);for(;i=0){var y=a?(h-i)*g+i:(u-n)*g+n;return a?[t,y]:[y,t]}n=u,i=h;break;case o.C:u=r[l++],h=r[l++],c=r[l++],p=r[l++],d=r[l++],f=r[l++];var v=a?_n(n,u,c,d,t,s):_n(i,h,p,f,t,s);if(v>0)for(var m=0;m=0){y=a?mn(i,h,p,f,x):mn(n,u,c,d,x);return a?[t,y]:[y,t]}}n=d,i=f}}},e}(ks),DS=function(t){function e(){return null!==t&&t.apply(this,arguments)||this}return n(e,t),e}(TS),AS=function(t){function e(e){var n=t.call(this,e)||this;return n.type="ec-polygon",n}return n(e,t),e.prototype.getDefaultShape=function(){return new DS},e.prototype.buildPath=function(t,e){var n=e.points,i=e.stackedOnPoints,r=0,o=n.length/2,a=e.smoothMonotone;if(e.connectNulls){for(;o>0&&MS(n[2*o-2],n[2*o-1]);o--);for(;r=0;a--){var s=t.getDimensionInfo(i[a].dimension);if("x"===(r=s&&s.coordDim)||"y"===r){o=i[a];break}}if(o){var l=e.getAxis(r),u=z(o.stops,(function(t){return{coord:l.toGlobalCoord(l.dataToCoord(t.value)),color:t.color}})),h=u.length,c=o.outerColors.slice();h&&u[0].coord>u[h-1].coord&&(u.reverse(),c.reverse());var p=function(t,e){var n,i,r=[],o=t.length;function a(t,e,n){var i=t.coord;return{coord:n,color:ti((n-i)/(e.coord-i),[t.color,e.color])}}for(var s=0;se){i?r.push(a(i,l,e)):n&&r.push(a(n,l,0),a(n,l,e));break}n&&(r.push(a(n,l,0)),n=null),r.push(l),i=l}}return r}(u,"x"===r?n.getWidth():n.getHeight()),d=p.length;if(!d&&h)return u[0].coord<0?c[1]?c[1]:u[h-1].color:c[0]?c[0]:u[0].color;var f=p[0].coord-10,g=p[d-1].coord+10,y=g-f;if(y<.001)return"transparent";E(p,(function(t){t.offset=(t.coord-f)/y})),p.push({offset:d?p[d-1].offset:.5,color:c[1]||"transparent"}),p.unshift({offset:d?p[0].offset:.5,color:c[0]||"transparent"});var v=new oh(0,0,0,0,p,!0);return v[r]=f,v[r+"2"]=g,v}}}function FS(t,e,n){var i=t.get("showAllSymbol"),r="auto"===i;if(!i||r){var o=n.getAxesByScale("ordinal")[0];if(o&&(!r||!function(t,e){var n=t.getExtent(),i=Math.abs(n[1]-n[0])/t.scale.count();isNaN(i)&&(i=0);for(var r=e.count(),o=Math.max(1,Math.round(r/5)),a=0;ai)return!1;return!0}(o,e))){var a=e.mapDimension(o.dim),s={};return E(o.getViewLabels(),(function(t){var e=o.scale.getRawOrdinalNumber(t.tickValue);s[e]=1})),function(t){return!s.hasOwnProperty(e.get(a,t))}}}}function GS(t,e){return[t[2*e],t[2*e+1]]}function WS(t){if(t.get(["endLabel","show"]))return!0;for(var e=0;e0&&"bolder"===t.get(["emphasis","lineStyle","width"]))&&(p.getState("emphasis").style.lineWidth=+p.style.lineWidth+1);rl(p).seriesIndex=t.seriesIndex,Zl(p,A,L,P);var O=zS(t.get("smooth")),R=t.get("smoothMonotone");if(p.setShape({smooth:O,smoothMonotone:R,connectNulls:b}),d){var N=o.getCalculationInfo("stackedOnSeries"),E=0;d.useStyle(k(s.getAreaStyle(),{fill:T,opacity:.7,lineJoin:"bevel",decal:o.getVisual("style").decal})),N&&(E=zS(N.get("smooth"))),d.setShape({smooth:O,stackedOnSmooth:E,smoothMonotone:R,connectNulls:b}),$l(d,t,"areaStyle"),rl(d).seriesIndex=t.seriesIndex,Zl(d,A,L,P)}var z=this._changePolyState;o.eachItemGraphicEl((function(t){t&&(t.onHoverStateChange=z)})),this._polyline.onHoverStateChange=z,this._data=o,this._coordSys=i,this._stackedOnPoints=x,this._points=l,this._step=I,this._valueOrigin=v,t.get("triggerLineEvent")&&(this.packEventData(t,p),d&&this.packEventData(t,d))},e.prototype.packEventData=function(t,e){rl(e).eventData={componentType:"series",componentSubType:"line",componentIndex:t.componentIndex,seriesIndex:t.seriesIndex,seriesName:t.name,seriesType:"line"}},e.prototype.highlight=function(t,e,n,i){var r=t.getData(),o=zo(r,i);if(this._changePolyState("emphasis"),!(o instanceof Array)&&null!=o&&o>=0){var a=r.getLayout("points"),s=r.getItemGraphicEl(o);if(!s){var l=a[2*o],u=a[2*o+1];if(isNaN(l)||isNaN(u))return;if(this._clipShapeForSymbol&&!this._clipShapeForSymbol.contain(l,u))return;var h=t.get("zlevel")||0,c=t.get("z")||0;(s=new fS(r,o)).x=l,s.y=u,s.setZ(h,c);var p=s.getSymbolPath().getTextContent();p&&(p.zlevel=h,p.z=c,p.z2=this._polyline.z2+1),s.__temp=!0,r.setItemGraphicEl(o,s),s.stopSymbolAnimation(!0),this.group.add(s)}s.highlight()}else Og.prototype.highlight.call(this,t,e,n,i)},e.prototype.downplay=function(t,e,n,i){var r=t.getData(),o=zo(r,i);if(this._changePolyState("normal"),null!=o&&o>=0){var a=r.getItemGraphicEl(o);a&&(a.__temp?(r.setItemGraphicEl(o,null),this.group.remove(a)):a.downplay())}else Og.prototype.downplay.call(this,t,e,n,i)},e.prototype._changePolyState=function(t){var e=this._polygon;Dl(this._polyline,t),e&&Dl(e,t)},e.prototype._newPolyline=function(t){var e=this._polyline;return e&&this._lineGroup.remove(e),e=new CS({shape:{points:t},segmentIgnoreThreshold:2,z2:10}),this._lineGroup.add(e),this._polyline=e,e},e.prototype._newPolygon=function(t,e){var n=this._polygon;return n&&this._lineGroup.remove(n),n=new AS({shape:{points:t,stackedOnPoints:e},segmentIgnoreThreshold:2}),this._lineGroup.add(n),this._polygon=n,n},e.prototype._initSymbolLabelAnimation=function(t,e,n){var i,r,o=e.getBaseAxis(),a=o.inverse;"cartesian2d"===e.type?(i=o.isHorizontal(),r=!1):"polar"===e.type&&(i="angle"===o.dim,r=!0);var s=t.hostModel,l=s.get("animationDuration");X(l)&&(l=l(null));var u=s.get("animationDelay")||0,h=X(u)?u(null):u;t.eachItemGraphicEl((function(t,o){var s=t;if(s){var c=[t.x,t.y],p=void 0,d=void 0,f=void 0;if(n)if(r){var g=n,y=e.pointToCoord(c);i?(p=g.startAngle,d=g.endAngle,f=-y[1]/180*Math.PI):(p=g.r0,d=g.r,f=y[0])}else{var v=n;i?(p=v.x,d=v.x+v.width,f=t.x):(p=v.y+v.height,d=v.y,f=t.y)}var m=d===p?0:(f-p)/(d-p);a&&(m=1-m);var x=X(u)?u(o):l*m+h,_=s.getSymbolPath(),b=_.getTextContent();s.attr({scaleX:0,scaleY:0}),s.animateTo({scaleX:1,scaleY:1},{duration:200,setToFinal:!0,delay:x}),b&&b.animateFrom({style:{opacity:0}},{duration:300,delay:x}),_.disableLabelAnimation=!0}}))},e.prototype._initOrUpdateEndLabel=function(t,e,n){var i=t.getModel("endLabel");if(WS(t)){var r=t.getData(),o=this._polyline,a=r.getLayout("points");if(!a)return o.removeTextContent(),void(this._endLabel=null);var s=this._endLabel;s||((s=this._endLabel=new Xs({z2:200})).ignoreClip=!0,o.setTextContent(this._endLabel),o.disableLabelAnimation=!0);var l=function(t){for(var e,n,i=t.length/2;i>0&&(e=t[2*i-2],n=t[2*i-1],isNaN(e)||isNaN(n));i--);return i-1}(a);l>=0&&(ic(o,rc(t,"endLabel"),{inheritColor:n,labelFetcher:t,labelDataIndex:l,defaultText:function(t,e,n){return null!=n?dS(r,n):pS(r,t)},enableTextSetter:!0},function(t,e){var n=e.getBaseAxis(),i=n.isHorizontal(),r=n.inverse,o=i?r?"right":"left":"center",a=i?"middle":r?"top":"bottom";return{normal:{align:t.get("align")||o,verticalAlign:t.get("verticalAlign")||a}}}(i,e)),o.textConfig.position=null)}else this._endLabel&&(this._polyline.removeTextContent(),this._endLabel=null)},e.prototype._endLabelOnDuring=function(t,e,n,i,r,o,a){var s=this._endLabel,l=this._polyline;if(s){t<1&&null==i.originalX&&(i.originalX=s.x,i.originalY=s.y);var u=n.getLayout("points"),h=n.hostModel,c=h.get("connectNulls"),p=o.get("precision"),d=o.get("distance")||0,f=a.getBaseAxis(),g=f.isHorizontal(),y=f.inverse,v=e.shape,m=y?g?v.x:v.y+v.height:g?v.x+v.width:v.y,x=(g?d:0)*(y?-1:1),_=(g?0:-d)*(y?-1:1),b=g?"x":"y",w=function(t,e,n){for(var i,r,o=t.length/2,a="x"===n?0:1,s=0,l=-1,u=0;u=e||i>=e&&r<=e){l=u;break}s=u,i=r}else i=r;return{range:[s,l],t:(e-i)/(r-i)}}(u,m,b),S=w.range,M=S[1]-S[0],I=void 0;if(M>=1){if(M>1&&!c){var T=GS(u,S[0]);s.attr({x:T[0]+x,y:T[1]+_}),r&&(I=h.getRawValue(S[0]))}else{(T=l.getPointOn(m,b))&&s.attr({x:T[0]+x,y:T[1]+_});var C=h.getRawValue(S[0]),D=h.getRawValue(S[1]);r&&(I=Zo(n,p,C,D,w.t))}i.lastFrameIndex=S[0]}else{var A=1===t||i.lastFrameIndex>0?S[0]:0;T=GS(u,A);r&&(I=h.getRawValue(A)),s.attr({x:T[0]+x,y:T[1]+_})}if(r){var k=pc(s);"function"==typeof k.setLabelText&&k.setLabelText(I)}}},e.prototype._doUpdateAnimation=function(t,e,n,i,r,o,a){var s=this._polyline,l=this._polygon,u=t.hostModel,h=function(t,e,n,i,r,o,a,s){for(var l=function(t,e){var n=[];return e.diff(t).add((function(t){n.push({cmd:"+",idx:t})})).update((function(t,e){n.push({cmd:"=",idx:e,idx1:t})})).remove((function(t){n.push({cmd:"-",idx:t})})).execute(),n}(t,e),u=[],h=[],c=[],p=[],d=[],f=[],g=[],y=_S(r,e,a),v=t.getLayout("points")||[],m=e.getLayout("points")||[],x=0;x3e3||l&&ES(p,f)>3e3)return s.stopAnimation(),s.setShape({points:d}),void(l&&(l.stopAnimation(),l.setShape({points:d,stackedOnPoints:f})));s.shape.__points=h.current,s.shape.points=c;var g={shape:{points:d}};h.current!==c&&(g.shape.__points=h.next),s.stopAnimation(),vh(s,g,u),l&&(l.setShape({points:c,stackedOnPoints:p}),l.stopAnimation(),vh(l,{shape:{stackedOnPoints:f}},u),s.shape.points!==l.shape.points&&(l.shape.points=s.shape.points));for(var y=[],v=h.status,m=0;me&&(e=t[n]);return isFinite(e)?e:NaN},min:function(t){for(var e=1/0,n=0;n10&&"cartesian2d"===o.type&&r){var s=o.getBaseAxis(),l=o.getOtherAxis(s),u=s.getExtent(),h=n.getDevicePixelRatio(),c=Math.abs(u[1]-u[0])*(h||1),p=Math.round(a/c);if(isFinite(p)&&p>1){"lttb"===r?t.setData(i.lttbDownSample(i.mapDimension(l.dim),1/p)):"minmax"===r&&t.setData(i.minmaxDownSample(i.mapDimension(l.dim),1/p));var d=void 0;U(r)?d=US[r]:X(r)&&(d=r),d&&t.setData(i.downSample(i.mapDimension(l.dim),1/p,d,ZS))}}}}}var qS=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n}return n(e,t),e.prototype.getInitialData=function(t,e){return _x(null,this,{useEncodeDefaulter:!0})},e.prototype.getMarkerPosition=function(t,e,n){var i=this.coordinateSystem;if(i&&i.clampData){var r=i.clampData(t),o=i.dataToPoint(r);if(n)E(i.getAxes(),(function(t,n){if("category"===t.type&&null!=e){var i=t.getTicksCoords(),a=t.getTickModel().get("alignWithLabel"),s=r[n],l="x1"===e[n]||"y1"===e[n];if(l&&!a&&(s+=1),i.length<2)return;if(2===i.length)return void(o[n]=t.toGlobalCoord(t.getExtent()[l?1:0]));for(var u=void 0,h=void 0,c=1,p=0;ps){h=(d+u)/2;break}1===p&&(c=f-i[0].tickValue)}null==h&&(u?u&&(h=i[i.length-1].coord):h=i[0].coord),o[n]=t.toGlobalCoord(h)}}));else{var a=this.getData(),s=a.getLayout("offset"),l=a.getLayout("size"),u=i.getBaseAxis().isHorizontal()?0:1;o[u]+=s+l/2}return o}return[NaN,NaN]},e.type="series.__base_bar__",e.defaultOption={z:2,coordinateSystem:"cartesian2d",legendHoverLink:!0,barMinHeight:0,barMinAngle:0,large:!1,largeThreshold:400,progressive:3e3,progressiveChunkMode:"mod"},e}(bg);bg.registerClass(qS);var KS=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n}return n(e,t),e.prototype.getInitialData=function(){return _x(null,this,{useEncodeDefaulter:!0,createInvertedIndices:!!this.get("realtimeSort",!0)||null})},e.prototype.getProgressive=function(){return!!this.get("large")&&this.get("progressive")},e.prototype.getProgressiveThreshold=function(){var t=this.get("progressiveThreshold"),e=this.get("largeThreshold");return e>t&&(t=e),t},e.prototype.brushSelector=function(t,e,n){return n.rect(e.getItemLayout(t))},e.type="series.bar",e.dependencies=["grid","polar"],e.defaultOption=kc(qS.defaultOption,{clip:!0,roundCap:!1,showBackground:!1,backgroundStyle:{color:"rgba(180, 180, 180, 0.2)",borderColor:null,borderWidth:0,borderType:"solid",borderRadius:0,shadowBlur:0,shadowColor:null,shadowOffsetX:0,shadowOffsetY:0,opacity:1},select:{itemStyle:{borderColor:"#212121"}},realtimeSort:!1}),e}(qS),$S=function(){this.cx=0,this.cy=0,this.r0=0,this.r=0,this.startAngle=0,this.endAngle=2*Math.PI,this.clockwise=!0},JS=function(t){function e(e){var n=t.call(this,e)||this;return n.type="sausage",n}return n(e,t),e.prototype.getDefaultShape=function(){return new $S},e.prototype.buildPath=function(t,e){var n=e.cx,i=e.cy,r=Math.max(e.r0||0,0),o=Math.max(e.r,0),a=.5*(o-r),s=r+a,l=e.startAngle,u=e.endAngle,h=e.clockwise,c=2*Math.PI,p=h?u-lo)return!0;o=u}return!1},e.prototype._isOrderDifferentInView=function(t,e){for(var n=e.scale,i=n.getExtent(),r=Math.max(0,i[0]),o=Math.min(i[1],n.getOrdinalMeta().categories.length-1);r<=o;++r)if(t.ordinalNumbers[r]!==n.getRawOrdinalNumber(r))return!0},e.prototype._updateSortWithinSameData=function(t,e,n,i){if(this._isOrderChangedWithinSameData(t,e,n)){var r=this._dataSort(t,n,e);this._isOrderDifferentInView(r,n)&&(this._removeOnRenderedListener(i),i.dispatchAction({type:"changeAxisOrder",componentType:n.dim+"Axis",axisId:n.index,sortInfo:r}))}},e.prototype._dispatchInitSort=function(t,e,n){var i=e.baseAxis,r=this._dataSort(t,i,(function(n){return t.get(t.mapDimension(e.otherAxis.dim),n)}));n.dispatchAction({type:"changeAxisOrder",componentType:i.dim+"Axis",isInitSort:!0,axisId:i.index,sortInfo:r})},e.prototype.remove=function(t,e){this._clear(this._model),this._removeOnRenderedListener(e)},e.prototype.dispose=function(t,e){this._removeOnRenderedListener(e)},e.prototype._removeOnRenderedListener=function(t){this._onRendered&&(t.getZr().off("rendered",this._onRendered),this._onRendered=null)},e.prototype._clear=function(t){var e=this.group,n=this._data;t&&t.isAnimationEnabled()&&n&&!this._isLargeDraw?(this._removeBackground(),this._backgroundEls=[],n.eachItemGraphicEl((function(e){wh(e,t,rl(e).dataIndex)}))):e.removeAll(),this._data=null,this._isFirstFrame=!0},e.prototype._removeBackground=function(){this.group.remove(this._backgroundGroup),this._backgroundGroup=null},e.type="bar",e}(Og),oM={cartesian2d:function(t,e){var n=e.width<0?-1:1,i=e.height<0?-1:1;n<0&&(e.x+=e.width,e.width=-e.width),i<0&&(e.y+=e.height,e.height=-e.height);var r=t.x+t.width,o=t.y+t.height,a=nM(e.x,t.x),s=iM(e.x+e.width,r),l=nM(e.y,t.y),u=iM(e.y+e.height,o),h=sr?s:a,e.y=c&&l>o?u:l,e.width=h?0:s-a,e.height=c?0:u-l,n<0&&(e.x+=e.width,e.width=-e.width),i<0&&(e.y+=e.height,e.height=-e.height),h||c},polar:function(t,e){var n=e.r0<=e.r?1:-1;if(n<0){var i=e.r;e.r=e.r0,e.r0=i}var r=iM(e.r,t.r),o=nM(e.r0,t.r0);e.r=r,e.r0=o;var a=r-o<0;if(n<0){i=e.r;e.r=e.r0,e.r0=i}return a}},aM={cartesian2d:function(t,e,n,i,r,o,a,s,l){var u=new Ws({shape:A({},i),z2:1});(u.__dataIndex=n,u.name="item",o)&&(u.shape[r?"height":"width"]=0);return u},polar:function(t,e,n,i,r,o,a,s,l){var u=!r&&l?JS:Fu,h=new u({shape:i,z2:1});h.name="item";var c,p,d=dM(r);if(h.calculateTextPosition=(c=d,p=({isRoundCap:u===JS}||{}).isRoundCap,function(t,e,n){var i=e.position;if(!i||i instanceof Array)return Dr(t,e,n);var 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KM(t,e,i,r){E(qM,(function(o,a){var s=C(C({},jM[a],!0),r,!0),l=function(t){function i(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e+"Axis."+a,n}return n(i,t),i.prototype.mergeDefaultAndTheme=function(t,e){var n=Pp(this),i=n?Rp(t):{};C(t,e.getTheme().get(a+"Axis")),C(t,this.getDefaultOption()),t.type=$M(t),n&&Op(t,i,n)},i.prototype.optionUpdated=function(){"category"===this.option.type&&(this.__ordinalMeta=Mx.createByAxisModel(this))},i.prototype.getCategories=function(t){var e=this.option;if("category"===e.type)return t?e.data:this.__ordinalMeta.categories},i.prototype.getOrdinalMeta=function(){return this.__ordinalMeta},i.type=e+"Axis."+a,i.defaultOption=s,i}(i);t.registerComponentModel(l)})),t.registerSubTypeDefaulter(e+"Axis",$M)}function $M(t){return t.type||(t.data?"category":"value")}var JM=function(){function t(t){this.type="cartesian",this._dimList=[],this._axes={},this.name=t||""}return t.prototype.getAxis=function(t){return 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this.getAxesByScale("ordinal")[0]||this.getAxesByScale("time")[0]||this.getAxis("x")},e.prototype.containPoint=function(t){var e=this.getAxis("x"),n=this.getAxis("y");return e.contain(e.toLocalCoord(t[0]))&&n.contain(n.toLocalCoord(t[1]))},e.prototype.containData=function(t){return this.getAxis("x").containData(t[0])&&this.getAxis("y").containData(t[1])},e.prototype.containZone=function(t,e){var n=this.dataToPoint(t),i=this.dataToPoint(e),r=this.getArea(),o=new ze(n[0],n[1],i[0]-n[0],i[1]-n[1]);return r.intersect(o)},e.prototype.dataToPoint=function(t,e,n){n=n||[];var i=t[0],r=t[1];if(this._transform&&null!=i&&isFinite(i)&&null!=r&&isFinite(r))return Wt(n,t,this._transform);var o=this.getAxis("x"),a=this.getAxis("y");return n[0]=o.toGlobalCoord(o.dataToCoord(i,e)),n[1]=a.toGlobalCoord(a.dataToCoord(r,e)),n},e.prototype.clampData=function(t,e){var n=this.getAxis("x").scale,i=this.getAxis("y").scale,r=n.getExtent(),o=i.getExtent(),a=n.parse(t[0]),s=i.parse(t[1]);return(e=e||[])[0]=Math.min(Math.max(Math.min(r[0],r[1]),a),Math.max(r[0],r[1])),e[1]=Math.min(Math.max(Math.min(o[0],o[1]),s),Math.max(o[0],o[1])),e},e.prototype.pointToData=function(t,e){var n=[];if(this._invTransform)return Wt(n,t,this._invTransform);var i=this.getAxis("x"),r=this.getAxis("y");return n[0]=i.coordToData(i.toLocalCoord(t[0]),e),n[1]=r.coordToData(r.toLocalCoord(t[1]),e),n},e.prototype.getOtherAxis=function(t){return this.getAxis("x"===t.dim?"y":"x")},e.prototype.getArea=function(t){t=t||0;var e=this.getAxis("x").getGlobalExtent(),n=this.getAxis("y").getGlobalExtent(),i=Math.min(e[0],e[1])-t,r=Math.min(n[0],n[1])-t,o=Math.max(e[0],e[1])-i+t,a=Math.max(n[0],n[1])-r+t;return new ze(i,r,o,a)},e}(JM),nI=function(t){function e(e,n,i,r,o){var a=t.call(this,e,n,i)||this;return a.index=0,a.type=r||"value",a.position=o||"bottom",a}return n(e,t),e.prototype.isHorizontal=function(){var t=this.position;return"top"===t||"bottom"===t},e.prototype.getGlobalExtent=function(t){var e=this.getExtent();return e[0]=this.toGlobalCoord(e[0]),e[1]=this.toGlobalCoord(e[1]),t&&e[0]>e[1]&&e.reverse(),e},e.prototype.pointToData=function(t,e){return this.coordToData(this.toLocalCoord(t["x"===this.dim?0:1]),e)},e.prototype.setCategorySortInfo=function(t){if("category"!==this.type)return!1;this.model.option.categorySortInfo=t,this.scale.setSortInfo(t)},e}(ab);function iI(t,e,n){n=n||{};var i=t.coordinateSystem,r=e.axis,o={},a=r.getAxesOnZeroOf()[0],s=r.position,l=a?"onZero":s,u=r.dim,h=i.getRect(),c=[h.x,h.x+h.width,h.y,h.y+h.height],p={left:0,right:1,top:0,bottom:1,onZero:2},d=e.get("offset")||0,f="x"===u?[c[2]-d,c[3]+d]:[c[0]-d,c[1]+d];if(a){var g=a.toGlobalCoord(a.dataToCoord(0));f[p.onZero]=Math.max(Math.min(g,f[1]),f[0])}o.position=["y"===u?f[p[l]]:c[0],"x"===u?f[p[l]]:c[3]],o.rotation=Math.PI/2*("x"===u?0:1);o.labelDirection=o.tickDirection=o.nameDirection={top:-1,bottom:1,left:-1,right:1}[s],o.labelOffset=a?f[p[s]]-f[p.onZero]:0,e.get(["axisTick","inside"])&&(o.tickDirection=-o.tickDirection),it(n.labelInside,e.get(["axisLabel","inside"]))&&(o.labelDirection=-o.labelDirection);var y=e.get(["axisLabel","rotate"]);return o.labelRotate="top"===l?-y:y,o.z2=1,o}function rI(t){return"cartesian2d"===t.get("coordinateSystem")}function oI(t){var e={xAxisModel:null,yAxisModel:null};return E(e,(function(n,i){var r=i.replace(/Model$/,""),o=t.getReferringComponents(r,Wo).models[0];e[i]=o})),e}var aI=Math.log;function sI(t,e,n){var i=Ex.prototype,r=i.getTicks.call(n),o=i.getTicks.call(n,!0),a=r.length-1,s=i.getInterval.call(n),l=x_(t,e),u=l.extent,h=l.fixMin,c=l.fixMax;if("log"===t.type){var p=aI(t.base);u=[aI(u[0])/p,aI(u[1])/p]}t.setExtent(u[0],u[1]),t.calcNiceExtent({splitNumber:a,fixMin:h,fixMax:c});var d=i.getExtent.call(t);h&&(u[0]=d[0]),c&&(u[1]=d[1]);var f=i.getInterval.call(t),g=u[0],y=u[1];if(h&&c)f=(y-g)/a;else if(h)for(y=u[0]+f*a;yu[0]&&isFinite(g)&&isFinite(u[0]);)f=Dx(f),g=u[1]-f*a;else{t.getTicks().length-1>a&&(f=Dx(f));var v=f*a;(g=Jr((y=Math.ceil(u[1]/f)*f)-v))<0&&u[0]>=0?(g=0,y=Jr(v)):y>0&&u[1]<=0&&(y=0,g=-Jr(v))}var m=(r[0].value-o[0].value)/s,x=(r[a].value-o[a].value)/s;i.setExtent.call(t,g+f*m,y+f*x),i.setInterval.call(t,f),(m||x)&&i.setNiceExtent.call(t,g+f,y-f)}var lI=function(){function t(t,e,n){this.type="grid",this._coordsMap={},this._coordsList=[],this._axesMap={},this._axesList=[],this.axisPointerEnabled=!0,this.dimensions=QM,this._initCartesian(t,e,n),this.model=t}return t.prototype.getRect=function(){return this._rect},t.prototype.update=function(t,e){var n=this._axesMap;function i(t){var e,n=G(t),i=n.length;if(i){for(var r=[],o=i-1;o>=0;o--){var a=t[+n[o]],s=a.model,l=a.scale;Tx(l)&&s.get("alignTicks")&&null==s.get("interval")?r.push(a):(__(l,s),Tx(l)&&(e=a))}r.length&&(e||__((e=r.pop()).scale,e.model),E(r,(function(t){sI(t.scale,t.model,e.scale)})))}}this._updateScale(t,this.model),i(n.x),i(n.y);var r={};E(n.x,(function(t){hI(n,"y",t,r)})),E(n.y,(function(t){hI(n,"x",t,r)})),this.resize(this.model,e)},t.prototype.resize=function(t,e,n){var i=t.getBoxLayoutParams(),r=!n&&t.get("containLabel"),o=kp(i,{width:e.getWidth(),height:e.getHeight()});this._rect=o;var a=this._axesList;function s(){E(a,(function(t){var e=t.isHorizontal(),n=e?[0,o.width]:[0,o.height],i=t.inverse?1:0;t.setExtent(n[i],n[1-i]),function(t,e){var n=t.getExtent(),i=n[0]+n[1];t.toGlobalCoord="x"===t.dim?function(t){return t+e}:function(t){return i-t+e},t.toLocalCoord="x"===t.dim?function(t){return t-e}:function(t){return i-t+e}}(t,e?o.x:o.y)}))}s(),r&&(E(a,(function(t){if(!t.model.get(["axisLabel","inside"])){var e=function(t){var 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so(o)?(r=n>0?"top":"bottom",i="center"):so(o-pI)?(r=n>0?"bottom":"top",i="center"):(r="middle",i=o>0&&o0?"right":"left":n>0?"left":"right"),{rotation:o,textAlign:i,textVerticalAlign:r}},t.makeAxisEventDataBase=function(t){var e={componentType:t.mainType,componentIndex:t.componentIndex};return e[t.mainType+"Index"]=t.componentIndex,e},t.isLabelSilent=function(t){var e=t.get("tooltip");return t.get("silent")||!(t.get("triggerEvent")||e&&e.show)},t}(),fI={axisLine:function(t,e,n,i){var r=e.get(["axisLine","show"]);if("auto"===r&&t.handleAutoShown&&(r=t.handleAutoShown("axisLine")),r){var o=e.axis.getExtent(),a=i.transform,s=[o[0],0],l=[o[1],0],u=s[0]>l[0];a&&(Wt(s,s,a),Wt(l,l,a));var h=A({lineCap:"round"},e.getModel(["axisLine","lineStyle"]).getLineStyle()),c=new Ku({shape:{x1:s[0],y1:s[1],x2:l[0],y2:l[1]},style:h,strokeContainThreshold:t.strokeContainThreshold||5,silent:!0,z2:1});zh(c.shape,c.style.lineWidth),c.anid="line",n.add(c);var p=e.get(["axisLine","symbol"]);if(null!=p){var d=e.get(["axisLine","symbolSize"]);U(p)&&(p=[p,p]),(U(d)||j(d))&&(d=[d,d]);var f=Zy(e.get(["axisLine","symbolOffset"])||0,d),g=d[0],y=d[1];E([{rotate:t.rotation+Math.PI/2,offset:f[0],r:0},{rotate:t.rotation-Math.PI/2,offset:f[1],r:Math.sqrt((s[0]-l[0])*(s[0]-l[0])+(s[1]-l[1])*(s[1]-l[1]))}],(function(e,i){if("none"!==p[i]&&null!=p[i]){var r=Xy(p[i],-g/2,-y/2,g,y,h.stroke,!0),o=e.r+e.offset,a=u?l:s;r.attr({rotation:e.rotate,x:a[0]+o*Math.cos(t.rotation),y:a[1]-o*Math.sin(t.rotation),silent:!0,z2:11}),n.add(r)}}))}}},axisTickLabel:function(t,e,n,i){var r=function(t,e,n,i){var r=n.axis,o=n.getModel("axisTick"),a=o.get("show");"auto"===a&&i.handleAutoShown&&(a=i.handleAutoShown("axisTick"));if(!a||r.scale.isBlank())return;for(var s=o.getModel("lineStyle"),l=i.tickDirection*o.get("length"),u=mI(r.getTicksCoords(),e.transform,l,k(s.getLineStyle(),{stroke:n.get(["axisLine","lineStyle","color"])}),"ticks"),h=0;hc[1]?-1:1,d=["start"===s?c[0]-p*h:"end"===s?c[1]+p*h:(c[0]+c[1])/2,vI(s)?t.labelOffset+l*h:0],f=e.get("nameRotate");null!=f&&(f=f*pI/180),vI(s)?o=dI.innerTextLayout(t.rotation,null!=f?f:t.rotation,l):(o=function(t,e,n,i){var r,o,a=ao(n-t),s=i[0]>i[1],l="start"===e&&!s||"start"!==e&&s;so(a-pI/2)?(o=l?"bottom":"top",r="center"):so(a-1.5*pI)?(o=l?"top":"bottom",r="center"):(o="middle",r=a<1.5*pI&&a>pI/2?l?"left":"right":l?"right":"left");return{rotation:a,textAlign:r,textVerticalAlign:o}}(t.rotation,s,f||0,c),null!=(a=t.axisNameAvailableWidth)&&(a=Math.abs(a/Math.sin(o.rotation)),!isFinite(a)&&(a=null)));var g=u.getFont(),y=e.get("nameTruncate",!0)||{},v=y.ellipsis,m=it(t.nameTruncateMaxWidth,y.maxWidth,a),x=new 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n=e.axisPointerModel,i=e.axis.scale,r=n.option,o=n.get("status"),a=n.get("value");null!=a&&(a=i.parse(a));var s=SI(n);null==o&&(r.status=s?"show":"hide");var l=i.getExtent().slice();l[0]>l[1]&&l.reverse(),(null==a||a>l[1])&&(a=l[1]),a0&&!c.min?c.min=0:null!=c.min&&c.min<0&&!c.max&&(c.max=0);var p=a;null!=c.color&&(p=k({color:c.color},a));var d=C(T(c),{boundaryGap:t,splitNumber:e,scale:n,axisLine:i,axisTick:r,axisLabel:o,name:c.text,showName:s,nameLocation:"end",nameGap:u,nameTextStyle:p,triggerEvent:h},!1);if(U(l)){var f=d.name;d.name=l.replace("{value}",null!=f?f:"")}else X(l)&&(d.name=l(d.name,d));var g=new Cc(d,null,this.ecModel);return R(g,D_.prototype),g.mainType="radar",g.componentIndex=this.componentIndex,g}),this);this._indicatorModels=c},e.prototype.getIndicatorModels=function(){return 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e=this._regionsGroupByName=yt(),n=yt(),i=this._regionsGroup,r=t.transformInfoRaw,o=t.mapOrGeoModel,a=t.data,s=t.geo.projection,l=s&&s.stream;function u(t,e){return e&&(t=e(t)),t&&[t[0]*r.scaleX+r.x,t[1]*r.scaleY+r.y]}function h(t){for(var e=[],n=!l&&s&&s.project,i=0;i=0)&&(p=r);var d=a?{normal:{align:"center",verticalAlign:"middle"}}:null;ic(e,rc(i),{labelFetcher:p,labelDataIndex:c,defaultText:n},d);var f=e.getTextContent();if(f&&(JT(f).ignore=f.ignore,e.textConfig&&a)){var g=e.getBoundingRect().clone();e.textConfig.layoutRect=g,e.textConfig.position=[(a[0]-g.x)/g.width*100+"%",(a[1]-g.y)/g.height*100+"%"]}e.disableLabelAnimation=!0}else e.removeTextContent(),e.removeTextConfig(),e.disableLabelAnimation=null}function rC(t,e,n,i,r,o){t.data?t.data.setItemGraphicEl(o,e):rl(e).eventData={componentType:"geo",componentIndex:r.componentIndex,geoIndex:r.componentIndex,name:n,region:i&&i.option||{}}}function 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i="ec-"+t.getName(n);r[i]=r[i]||[],isNaN(e)||r[i].push(e)}))})),n[0].map(n[0].mapDimension("value"),(function(t,e){for(var o="ec-"+n[0].getName(e),a=0,s=1/0,l=-1/0,u=r[o].length,h=0;h1?(d.width=p,d.height=p/x):(d.height=p,d.width=p*x),d.y=c[1]-d.height/2,d.x=c[0]-d.width/2;else{var b=t.getBoxLayoutParams();b.aspect=x,d=kp(b,{width:v,height:m})}this.setViewRect(d.x,d.y,d.width,d.height),this.setCenter(t.get("center"),e),this.setZoom(t.get("zoom"))}R(vC,dC);var _C=function(){function t(){this.dimensions=yC}return t.prototype.create=function(t,e){var n=[];function i(t){return{nameProperty:t.get("nameProperty"),aspectScale:t.get("aspectScale"),projection:t.get("projection")}}t.eachComponent("geo",(function(t,r){var o=t.get("map"),a=new vC(o+r,o,A({nameMap:t.get("nameMap")},i(t)));a.zoomLimit=t.get("scaleLimit"),n.push(a),t.coordinateSystem=a,a.model=t,a.resize=xC,a.resize(t,e)})),t.eachSeries((function(t){if("geo"===t.get("coordinateSystem")){var e=t.get("geoIndex")||0;t.coordinateSystem=n[e]}}));var r={};return t.eachSeriesByType("map",(function(t){if(!t.getHostGeoModel()){var e=t.getMapType();r[e]=r[e]||[],r[e].push(t)}})),E(r,(function(t,r){var o=z(t,(function(t){return t.get("nameMap")})),a=new vC(r,r,A({nameMap:D(o)},i(t[0])));a.zoomLimit=it.apply(null,z(t,(function(t){return t.get("scaleLimit")}))),n.push(a),a.resize=xC,a.resize(t[0],e),E(t,(function(t){t.coordinateSystem=a,function(t,e){E(e.get("geoCoord"),(function(e,n){t.addGeoCoord(n,e)}))}(a,t)}))})),n},t.prototype.getFilledRegions=function(t,e,n,i){for(var r=(t||[]).slice(),o=yt(),a=0;a=0;){var o=e[n];o.hierNode.prelim+=i,o.hierNode.modifier+=i,r+=o.hierNode.change,i+=o.hierNode.shift+r}}(t);var o=(n[0].hierNode.prelim+n[n.length-1].hierNode.prelim)/2;r?(t.hierNode.prelim=r.hierNode.prelim+e(t,r),t.hierNode.modifier=t.hierNode.prelim-o):t.hierNode.prelim=o}else 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e.length&&t.isExpand?e[e.length-1]:t.hierNode.thread}function OC(t){var e=t.children;return e.length&&t.isExpand?e[0]:t.hierNode.thread}function RC(t,e,n){return t.hierNode.ancestor.parentNode===e.parentNode?t.hierNode.ancestor:n}function NC(t,e,n){var i=n/(e.hierNode.i-t.hierNode.i);e.hierNode.change-=i,e.hierNode.shift+=n,e.hierNode.modifier+=n,e.hierNode.prelim+=n,t.hierNode.change+=i}function EC(t,e){return t.parentNode===e.parentNode?1:2}var zC=function(){this.parentPoint=[],this.childPoints=[]},VC=function(t){function e(e){return t.call(this,e)||this}return n(e,t),e.prototype.getDefaultStyle=function(){return{stroke:"#000",fill:null}},e.prototype.getDefaultShape=function(){return new zC},e.prototype.buildPath=function(t,e){var n=e.childPoints,i=n.length,r=e.parentPoint,o=n[0],a=n[i-1];if(1===i)return t.moveTo(r[0],r[1]),void t.lineTo(o[0],o[1]);var s=e.orient,l="TB"===s||"BT"===s?0:1,u=1-l,h=$r(e.forkPosition,1),c=[];c[l]=r[l],c[u]=r[u]+(a[u]-r[u])*h,t.moveTo(r[0],r[1]),t.lineTo(c[0],c[1]),t.moveTo(o[0],o[1]),c[l]=o[l],t.lineTo(c[0],c[1]),c[l]=a[l],t.lineTo(c[0],c[1]),t.lineTo(a[0],a[1]);for(var p=1;pm.x)||(_-=Math.PI);var S=b?"left":"right",M=s.getModel("label"),I=M.get("rotate"),T=I*(Math.PI/180),C=y.getTextContent();C&&(y.setTextConfig({position:M.get("position")||S,rotation:null==I?-_:T,origin:"center"}),C.setStyle("verticalAlign","middle"))}var D=s.get(["emphasis","focus"]),A="relative"===D?vt(a.getAncestorsIndices(),a.getDescendantIndices()):"ancestor"===D?a.getAncestorsIndices():"descendant"===D?a.getDescendantIndices():null;A&&(rl(n).focus=A),function(t,e,n,i,r,o,a,s){var l=e.getModel(),u=t.get("edgeShape"),h=t.get("layout"),c=t.getOrient(),p=t.get(["lineStyle","curveness"]),d=t.get("edgeForkPosition"),f=l.getModel("lineStyle").getLineStyle(),g=i.__edge;if("curve"===u)e.parentNode&&e.parentNode!==n&&(g||(g=i.__edge=new 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this.hostTree.data.getRawIndex(this.dataIndex)},t.prototype.getId=function(){return this.hostTree.data.getId(this.dataIndex)},t.prototype.getChildIndex=function(){if(this.parentNode){for(var t=this.parentNode.children,e=0;e=0){var i=n.getData().tree.root,r=t.targetNode;if(U(r)&&(r=i.getNodeById(r)),r&&i.contains(r))return{node:r};var o=t.targetNodeId;if(null!=o&&(r=i.getNodeById(o)))return{node:r}}}function rD(t){for(var e=[];t;)(t=t.parentNode)&&e.push(t);return e.reverse()}function oD(t,e){return P(rD(t),e)>=0}function aD(t,e){for(var n=[];t;){var i=t.dataIndex;n.push({name:t.name,dataIndex:i,value:e.getRawValue(i)}),t=t.parentNode}return n.reverse(),n}var sD=function(t){function e(){var e=null!==t&&t.apply(this,arguments)||this;return e.hasSymbolVisual=!0,e.ignoreStyleOnData=!0,e}return n(e,t),e.prototype.getInitialData=function(t){var e={name:t.name,children:t.data},n=t.leaves||{},i=new Cc(n,this,this.ecModel),r=nD.createTree(e,this,(function(t){t.wrapMethod("getItemModel",(function(t,e){var n=r.getNodeByDataIndex(e);return n&&n.children.length&&n.isExpand||(t.parentModel=i),t}))}));var o=0;r.eachNode("preorder",(function(t){t.depth>o&&(o=t.depth)}));var a=t.expandAndCollapse&&t.initialTreeDepth>=0?t.initialTreeDepth:o;return r.root.eachNode("preorder",(function(t){var e=t.hostTree.data.getRawDataItem(t.dataIndex);t.isExpand=e&&null!=e.collapsed?!e.collapsed:t.depth<=a})),r.data},e.prototype.getOrient=function(){var t=this.get("orient");return"horizontal"===t?t="LR":"vertical"===t&&(t="TB"),t},e.prototype.setZoom=function(t){this.option.zoom=t},e.prototype.setCenter=function(t){this.option.center=t},e.prototype.formatTooltip=function(t,e,n){for(var i=this.getData().tree,r=i.root.children[0],o=i.getNodeByDataIndex(t),a=o.getValue(),s=o.name;o&&o!==r;)s=o.parentNode.name+"."+s,o=o.parentNode;return og("nameValue",{name:s,value:a,noValue:isNaN(a)||null==a})},e.prototype.getDataParams=function(e){var n=t.prototype.getDataParams.apply(this,arguments),i=this.getData().tree.getNodeByDataIndex(e);return n.treeAncestors=aD(i,this),n.collapsed=!i.isExpand,n},e.type="series.tree",e.layoutMode="box",e.defaultOption={z:2,coordinateSystem:"view",left:"12%",top:"12%",right:"12%",bottom:"12%",layout:"orthogonal",edgeShape:"curve",edgeForkPosition:"50%",roam:!1,nodeScaleRatio:.4,center:null,zoom:1,orient:"LR",symbol:"emptyCircle",symbolSize:7,expandAndCollapse:!0,initialTreeDepth:2,lineStyle:{color:"#ccc",width:1.5,curveness:.5},itemStyle:{color:"lightsteelblue",borderWidth:1.5},label:{show:!0},animationEasing:"linear",animationDuration:700,animationDurationUpdate:500},e}(bg);function lD(t,e){for(var n,i=[t];n=i.pop();)if(e(n),n.isExpand){var r=n.children;if(r.length)for(var o=r.length-1;o>=0;o--)i.push(r[o])}}function uD(t,e){t.eachSeriesByType("tree",(function(t){!function(t,e){var n=function(t,e){return kp(t.getBoxLayoutParams(),{width:e.getWidth(),height:e.getHeight()})}(t,e);t.layoutInfo=n;var i=t.get("layout"),r=0,o=0,a=null;"radial"===i?(r=2*Math.PI,o=Math.min(n.height,n.width)/2,a=kC((function(t,e){return(t.parentNode===e.parentNode?1:2)/t.depth}))):(r=n.width,o=n.height,a=kC());var s=t.getData().tree.root,l=s.children[0];if(l){!function(t){var e=t;e.hierNode={defaultAncestor:null,ancestor:e,prelim:0,modifier:0,change:0,shift:0,i:0,thread:null};for(var n,i,r=[e];n=r.pop();)if(i=n.children,n.isExpand&&i.length)for(var o=i.length-1;o>=0;o--){var a=i[o];a.hierNode={defaultAncestor:null,ancestor:a,prelim:0,modifier:0,change:0,shift:0,i:o,thread:null},r.push(a)}}(s),function(t,e,n){for(var i,r=[t],o=[];i=r.pop();)if(o.push(i),i.isExpand){var a=i.children;if(a.length)for(var s=0;sh.getLayout().x&&(h=t),t.depth>c.depth&&(c=t)}));var p=u===h?1:a(u,h)/2,d=p-u.getLayout().x,f=0,g=0,y=0,v=0;if("radial"===i)f=r/(h.getLayout().x+p+d),g=o/(c.depth-1||1),lD(l,(function(t){y=(t.getLayout().x+d)*f,v=(t.depth-1)*g;var e=LC(y,v);t.setLayout({x:e.x,y:e.y,rawX:y,rawY:v},!0)}));else{var m=t.getOrient();"RL"===m||"LR"===m?(g=o/(h.getLayout().x+p+d),f=r/(c.depth-1||1),lD(l,(function(t){v=(t.getLayout().x+d)*g,y="LR"===m?(t.depth-1)*f:r-(t.depth-1)*f,t.setLayout({x:y,y:v},!0)}))):"TB"!==m&&"BT"!==m||(f=r/(h.getLayout().x+p+d),g=o/(c.depth-1||1),lD(l,(function(t){y=(t.getLayout().x+d)*f,v="TB"===m?(t.depth-1)*g:o-(t.depth-1)*g,t.setLayout({x:y,y:v},!0)})))}}}(t,e)}))}function hD(t){t.eachSeriesByType("tree",(function(t){var e=t.getData();e.tree.eachNode((function(t){var n=t.getModel().getModel("itemStyle").getItemStyle();A(e.ensureUniqueItemVisual(t.dataIndex,"style"),n)}))}))}var cD=["treemapZoomToNode","treemapRender","treemapMove"];function pD(t){var e=t.getData().tree,n={};e.eachNode((function(e){for(var i=e;i&&i.depth>1;)i=i.parentNode;var r=pd(t.ecModel,i.name||i.dataIndex+"",n);e.setVisual("decal",r)}))}var dD=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n.preventUsingHoverLayer=!0,n}return n(e,t),e.prototype.getInitialData=function(t,e){var n={name:t.name,children:t.data};fD(n);var i=t.levels||[],r=this.designatedVisualItemStyle={},o=new Cc({itemStyle:r},this,e);i=t.levels=function(t,e){var n,i,r=To(e.get("color")),o=To(e.get(["aria","decal","decals"]));if(!r)return;t=t||[],E(t,(function(t){var e=new Cc(t),r=e.get("color"),o=e.get("decal");(e.get(["itemStyle","color"])||r&&"none"!==r)&&(n=!0),(e.get(["itemStyle","decal"])||o&&"none"!==o)&&(i=!0)}));var a=t[0]||(t[0]={});n||(a.color=r.slice());!i&&o&&(a.decal=o.slice());return t}(i,e);var a=z(i||[],(function(t){return new Cc(t,o,e)}),this),s=nD.createTree(n,this,(function(t){t.wrapMethod("getItemModel",(function(t,e){var n=s.getNodeByDataIndex(e),i=n?a[n.depth]:null;return t.parentModel=i||o,t}))}));return s.data},e.prototype.optionUpdated=function(){this.resetViewRoot()},e.prototype.formatTooltip=function(t,e,n){var i=this.getData(),r=this.getRawValue(t);return og("nameValue",{name:i.getName(t),value:r})},e.prototype.getDataParams=function(e){var n=t.prototype.getDataParams.apply(this,arguments),i=this.getData().tree.getNodeByDataIndex(e);return n.treeAncestors=aD(i,this),n.treePathInfo=n.treeAncestors,n},e.prototype.setLayoutInfo=function(t){this.layoutInfo=this.layoutInfo||{},A(this.layoutInfo,t)},e.prototype.mapIdToIndex=function(t){var e=this._idIndexMap;e||(e=this._idIndexMap=yt(),this._idIndexMapCount=0);var n=e.get(t);return null==n&&e.set(t,n=this._idIndexMapCount++),n},e.prototype.getViewRoot=function(){return this._viewRoot},e.prototype.resetViewRoot=function(t){t?this._viewRoot=t:t=this._viewRoot;var e=this.getRawData().tree.root;t&&(t===e||e.contains(t))||(this._viewRoot=e)},e.prototype.enableAriaDecal=function(){pD(this)},e.type="series.treemap",e.layoutMode="box",e.defaultOption={progressive:0,left:"center",top:"middle",width:"80%",height:"80%",sort:!0,clipWindow:"origin",squareRatio:.5*(1+Math.sqrt(5)),leafDepth:null,drillDownIcon:"▶",zoomToNodeRatio:.1024,scaleLimit:null,roam:!0,nodeClick:"zoomToNode",animation:!0,animationDurationUpdate:900,animationEasing:"quinticInOut",breadcrumb:{show:!0,height:22,left:"center",top:"bottom",emptyItemWidth:25,itemStyle:{color:"rgba(0,0,0,0.7)",textStyle:{color:"#fff"}},emphasis:{itemStyle:{color:"rgba(0,0,0,0.9)"}}},label:{show:!0,distance:0,padding:5,position:"inside",color:"#fff",overflow:"truncate"},upperLabel:{show:!1,position:[0,"50%"],height:20,overflow:"truncate",verticalAlign:"middle"},itemStyle:{color:null,colorAlpha:null,colorSaturation:null,borderWidth:0,gapWidth:0,borderColor:"#fff",borderColorSaturation:null},emphasis:{upperLabel:{show:!0,position:[0,"50%"],overflow:"truncate",verticalAlign:"middle"}},visualDimension:0,visualMin:null,visualMax:null,color:[],colorAlpha:null,colorSaturation:null,colorMappingBy:"index",visibleMin:10,childrenVisibleMin:null,levels:[]},e}(bg);function fD(t){var e=0;E(t.children,(function(t){fD(t);var n=t.value;Y(n)&&(n=n[0]),e+=n}));var n=t.value;Y(n)&&(n=n[0]),(null==n||isNaN(n))&&(n=e),n<0&&(n=0),Y(t.value)?t.value[0]=n:t.value=n}var gD=function(){function t(t){this.group=new Br,t.add(this.group)}return t.prototype.render=function(t,e,n,i){var r=t.getModel("breadcrumb"),o=this.group;if(o.removeAll(),r.get("show")&&n){var a=r.getModel("itemStyle"),s=r.getModel("emphasis"),l=a.getModel("textStyle"),u=s.getModel(["itemStyle","textStyle"]),h={pos:{left:r.get("left"),right:r.get("right"),top:r.get("top"),bottom:r.get("bottom")},box:{width:e.getWidth(),height:e.getHeight()},emptyItemWidth:r.get("emptyItemWidth"),totalWidth:0,renderList:[]};this._prepare(n,h,l),this._renderContent(t,h,a,s,l,u,i),Lp(o,h.pos,h.box)}},t.prototype._prepare=function(t,e,n){for(var i=t;i;i=i.parentNode){var r=Ro(i.getModel().get("name"),""),o=n.getTextRect(r),a=Math.max(o.width+16,e.emptyItemWidth);e.totalWidth+=a+8,e.renderList.push({node:i,text:r,width:a})}},t.prototype._renderContent=function(t,e,n,i,r,o,a){for(var s,l,u,h,c,p,d,f,g,y=0,v=e.emptyItemWidth,m=t.get(["breadcrumb","height"]),x=(s=e.pos,l=e.box,h=l.width,c=l.height,p=$r(s.left,h),d=$r(s.top,c),f=$r(s.right,h),g=$r(s.bottom,c),(isNaN(p)||isNaN(parseFloat(s.left)))&&(p=0),(isNaN(f)||isNaN(parseFloat(s.right)))&&(f=h),(isNaN(d)||isNaN(parseFloat(s.top)))&&(d=0),(isNaN(g)||isNaN(parseFloat(s.bottom)))&&(g=c),u=vp(u||0),{width:Math.max(f-p-u[1]-u[3],0),height:Math.max(g-d-u[0]-u[2],0)}),_=e.totalWidth,b=e.renderList,w=i.getModel("itemStyle").getItemStyle(),S=b.length-1;S>=0;S--){var M=b[S],I=M.node,T=M.width,C=M.text;_>x.width&&(_-=T-v,T=v,C=null);var D=new Xu({shape:{points:yD(y,0,T,m,S===b.length-1,0===S)},style:k(n.getItemStyle(),{lineJoin:"bevel"}),textContent:new Xs({style:oc(r,{text:C})}),textConfig:{position:"inside"},z2:1e5,onclick:H(a,I)});D.disableLabelAnimation=!0,D.getTextContent().ensureState("emphasis").style=oc(o,{text:C}),D.ensureState("emphasis").style=w,Zl(D,i.get("focus"),i.get("blurScope"),i.get("disabled")),this.group.add(D),vD(D,t,I),y+=T+8}},t.prototype.remove=function(){this.group.removeAll()},t}();function yD(t,e,n,i,r,o){var a=[[r?t:t-5,e],[t+n,e],[t+n,e+i],[r?t:t-5,e+i]];return!o&&a.splice(2,0,[t+n+5,e+i/2]),!r&&a.push([t,e+i/2]),a}function vD(t,e,n){rl(t).eventData={componentType:"series",componentSubType:"treemap",componentIndex:e.componentIndex,seriesIndex:e.seriesIndex,seriesName:e.name,seriesType:"treemap",selfType:"breadcrumb",nodeData:{dataIndex:n&&n.dataIndex,name:n&&n.name},treePathInfo:n&&aD(n,e)}}var mD=function(){function t(){this._storage=[],this._elExistsMap={}}return t.prototype.add=function(t,e,n,i,r){return!this._elExistsMap[t.id]&&(this._elExistsMap[t.id]=!0,this._storage.push({el:t,target:e,duration:n,delay:i,easing:r}),!0)},t.prototype.finished=function(t){return this._finishedCallback=t,this},t.prototype.start=function(){for(var t=this,e=this._storage.length,n=function(){--e<=0&&(t._storage.length=0,t._elExistsMap={},t._finishedCallback&&t._finishedCallback())},i=0,r=this._storage.length;i3||Math.abs(t.dy)>3)){var e=this.seriesModel.getData().tree.root;if(!e)return;var n=e.getLayout();if(!n)return;this.api.dispatchAction({type:"treemapMove",from:this.uid,seriesId:this.seriesModel.id,rootRect:{x:n.x+t.dx,y:n.y+t.dy,width:n.width,height:n.height}})}},e.prototype._onZoom=function(t){var e=t.originX,n=t.originY,i=t.scale;if("animating"!==this._state){var r=this.seriesModel.getData().tree.root;if(!r)return;var o=r.getLayout();if(!o)return;var a,s=new ze(o.x,o.y,o.width,o.height),l=this._controllerHost;a=l.zoomLimit;var u=l.zoom=l.zoom||1;if(u*=i,a){var h=a.min||0,c=a.max||1/0;u=Math.max(Math.min(c,u),h)}var p=u/l.zoom;l.zoom=u;var d=this.seriesModel.layoutInfo,f=[1,0,0,1,0,0];we(f,f,[-(e-=d.x),-(n-=d.y)]),Me(f,f,[p,p]),we(f,f,[e,n]),s.applyTransform(f),this.api.dispatchAction({type:"treemapRender",from:this.uid,seriesId:this.seriesModel.id,rootRect:{x:s.x,y:s.y,width:s.width,height:s.height}})}},e.prototype._initEvents=function(t){var e=this;t.on("click",(function(t){if("ready"===e._state){var n=e.seriesModel.get("nodeClick",!0);if(n){var i=e.findTarget(t.offsetX,t.offsetY);if(i){var r=i.node;if(r.getLayout().isLeafRoot)e._rootToNode(i);else if("zoomToNode"===n)e._zoomToNode(i);else if("link"===n){var o=r.hostTree.data.getItemModel(r.dataIndex),a=o.get("link",!0),s=o.get("target",!0)||"blank";a&&Mp(a,s)}}}}}),this)},e.prototype._renderBreadcrumb=function(t,e,n){var i=this;n||(n=null!=t.get("leafDepth",!0)?{node:t.getViewRoot()}:this.findTarget(e.getWidth()/2,e.getHeight()/2))||(n={node:t.getData().tree.root}),(this._breadcrumb||(this._breadcrumb=new gD(this.group))).render(t,e,n.node,(function(e){"animating"!==i._state&&(oD(t.getViewRoot(),e)?i._rootToNode({node:e}):i._zoomToNode({node:e}))}))},e.prototype.remove=function(){this._clearController(),this._containerGroup&&this._containerGroup.removeAll(),this._storage={nodeGroup:[],background:[],content:[]},this._state="ready",this._breadcrumb&&this._breadcrumb.remove()},e.prototype.dispose=function(){this._clearController()},e.prototype._zoomToNode=function(t){this.api.dispatchAction({type:"treemapZoomToNode",from:this.uid,seriesId:this.seriesModel.id,targetNode:t.node})},e.prototype._rootToNode=function(t){this.api.dispatchAction({type:"treemapRootToNode",from:this.uid,seriesId:this.seriesModel.id,targetNode:t.node})},e.prototype.findTarget=function(t,e){var n;return this.seriesModel.getViewRoot().eachNode({attr:"viewChildren",order:"preorder"},(function(i){var r=this._storage.background[i.getRawIndex()];if(r){var o=r.transformCoordToLocal(t,e),a=r.shape;if(!(a.x<=o[0]&&o[0]<=a.x+a.width&&a.y<=o[1]&&o[1]<=a.y+a.height))return!1;n={node:i,offsetX:o[0],offsetY:o[1]}}}),this),n},e.type="treemap",e}(Og);var CD=E,DD=q,AD=-1,kD=function(){function t(e){var n=e.mappingMethod,i=e.type,r=this.option=T(e);this.type=i,this.mappingMethod=n,this._normalizeData=FD[n];var o=t.visualHandlers[i];this.applyVisual=o.applyVisual,this.getColorMapper=o.getColorMapper,this._normalizedToVisual=o._normalizedToVisual[n],"piecewise"===n?(LD(r),function(t){var e=t.pieceList;t.hasSpecialVisual=!1,E(e,(function(e,n){e.originIndex=n,null!=e.visual&&(t.hasSpecialVisual=!0)}))}(r)):"category"===n?r.categories?function(t){var e=t.categories,n=t.categoryMap={},i=t.visual;if(CD(e,(function(t,e){n[t]=e})),!Y(i)){var r=[];q(i)?CD(i,(function(t,e){var 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t.sort((function(t,e){return"color"===e&&"color"!==t&&0===t.indexOf("color")?1:-1})),t},t.dependsOn=function(t,e){return"color"===e?!(!t||0!==t.indexOf(e)):t===e},t.findPieceIndex=function(t,e,n){for(var i,r=1/0,o=0,a=e.length;ou[1]&&(u[1]=l);var h=e.get("colorMappingBy"),c={type:a.name,dataExtent:u,visual:a.range};"color"!==c.type||"index"!==h&&"id"!==h?c.mappingMethod="linear":(c.mappingMethod="category",c.loop=!0);var p=new kD(c);return WD(p).drColorMappingBy=h,p}(0,r,o,0,u,d);E(d,(function(t,e){if(t.depth>=n.length||t===n[t.depth]){var o=function(t,e,n,i,r,o){var a=A({},e);if(r){var s=r.type,l="color"===s&&WD(r).drColorMappingBy,u="index"===l?i:"id"===l?o.mapIdToIndex(n.getId()):n.getValue(t.get("visualDimension"));a[s]=r.mapValueToVisual(u)}return a}(r,u,t,e,f,i);YD(t,o,n,i)}}))}else s=XD(u),h.fill=s}}function XD(t){var e=UD(t,"color");if(e){var n=UD(t,"colorAlpha"),i=UD(t,"colorSaturation");return i&&(e=ni(e,null,null,i)),n&&(e=ii(e,n)),e}}function UD(t,e){var 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f="circular"===t.get("layout")&&t.get(["circular","rotateLabel"]),g=u.getLayout("cx"),y=u.getLayout("cy");u.graph.eachNode((function(t){DA(t,f,g,y)})),this._firstRender=!1},e.prototype.dispose=function(){this.remove(),this._controller&&this._controller.dispose(),this._controllerHost=null},e.prototype._startForceLayoutIteration=function(t,e){var n=this;!function i(){t.step((function(t){n.updateLayout(n._model),(n._layouting=!t)&&(e?n._layoutTimeout=setTimeout(i,16):i())}))}()},e.prototype._updateController=function(t,e,n){var i=this,r=this._controller,o=this._controllerHost,a=this.group;r.setPointerChecker((function(e,i,r){var o=a.getBoundingRect();return o.applyTransform(a.transform),o.contain(i,r)&&!hT(e,n,t)})),nk(t.coordinateSystem)?(r.enable(t.get("roam")),o.zoomLimit=t.get("scaleLimit"),o.zoom=t.coordinateSystem.getZoom(),r.off("pan").off("zoom").on("pan",(function(e){aT(o,e.dx,e.dy),n.dispatchAction({seriesId:t.id,type:"graphRoam",dx:e.dx,dy:e.dy})})).on("zoom",(function(e){sT(o,e.scale,e.originX,e.originY),n.dispatchAction({seriesId:t.id,type:"graphRoam",zoom:e.scale,originX:e.originX,originY:e.originY}),i._updateNodeAndLinkScale(),ek(t.getGraph(),wA(t)),i._lineDraw.updateLayout(),n.updateLabelLayout()}))):r.disable()},e.prototype._updateNodeAndLinkScale=function(){var t=this._model,e=t.getData(),n=wA(t);e.eachItemGraphicEl((function(t,e){t&&t.setSymbolScale(n)}))},e.prototype.updateLayout=function(t){ek(t.getGraph(),wA(t)),this._symbolDraw.updateLayout(),this._lineDraw.updateLayout()},e.prototype.remove=function(){clearTimeout(this._layoutTimeout),this._layouting=!1,this._layoutTimeout=null,this._symbolDraw&&this._symbolDraw.remove(),this._lineDraw&&this._lineDraw.remove()},e.type="graph",e}(Og);function rk(t){return"_EC_"+t}var ok=function(){function t(t){this.type="graph",this.nodes=[],this.edges=[],this._nodesMap={},this._edgesMap={},this._directed=t||!1}return t.prototype.isDirected=function(){return this._directed},t.prototype.addNode=function(t,e){t=null==t?""+e:""+t;var n=this._nodesMap;if(!n[rk(t)]){var i=new ak(t,e);return i.hostGraph=this,this.nodes.push(i),n[rk(t)]=i,i}},t.prototype.getNodeByIndex=function(t){var e=this.data.getRawIndex(t);return this.nodes[e]},t.prototype.getNodeById=function(t){return this._nodesMap[rk(t)]},t.prototype.addEdge=function(t,e,n){var i=this._nodesMap,r=this._edgesMap;if(j(t)&&(t=this.nodes[t]),j(e)&&(e=this.nodes[e]),t instanceof ak||(t=i[rk(t)]),e instanceof ak||(e=i[rk(e)]),t&&e){var o=t.id+"-"+e.id,a=new sk(t,e,n);return a.hostGraph=this,this._directed&&(t.outEdges.push(a),e.inEdges.push(a)),t.edges.push(a),t!==e&&e.edges.push(a),this.edges.push(a),r[o]=a,a}},t.prototype.getEdgeByIndex=function(t){var e=this.edgeData.getRawIndex(t);return this.edges[e]},t.prototype.getEdge=function(t,e){t instanceof ak&&(t=t.id),e instanceof ak&&(e=e.id);var n=this._edgesMap;return this._directed?n[t+"-"+e]:n[t+"-"+e]||n[e+"-"+t]},t.prototype.eachNode=function(t,e){for(var n=this.nodes,i=n.length,r=0;r=0&&t.call(e,n[r],r)},t.prototype.eachEdge=function(t,e){for(var n=this.edges,i=n.length,r=0;r=0&&n[r].node1.dataIndex>=0&&n[r].node2.dataIndex>=0&&t.call(e,n[r],r)},t.prototype.breadthFirstTraverse=function(t,e,n,i){if(e instanceof ak||(e=this._nodesMap[rk(e)]),e){for(var r="out"===n?"outEdges":"in"===n?"inEdges":"edges",o=0;o=0&&n.node2.dataIndex>=0}));for(r=0,o=i.length;r=0&&this[t][e].setItemVisual(this.dataIndex,n,i)},getVisual:function(n){return this[t][e].getItemVisual(this.dataIndex,n)},setLayout:function(n,i){this.dataIndex>=0&&this[t][e].setItemLayout(this.dataIndex,n,i)},getLayout:function(){return this[t][e].getItemLayout(this.dataIndex)},getGraphicEl:function(){return this[t][e].getItemGraphicEl(this.dataIndex)},getRawIndex:function(){return this[t][e].getRawIndex(this.dataIndex)}}}function uk(t,e,n,i,r){for(var o=new ok(i),a=0;a "+p)),u++)}var d,f=n.get("coordinateSystem");if("cartesian2d"===f||"polar"===f)d=_x(t,n);else{var g=wd.get(f),y=g&&g.dimensions||[];P(y,"value")<0&&y.concat(["value"]);var v=px(t,{coordDimensions:y,encodeDefine:n.getEncode()}).dimensions;(d=new cx(v,n)).initData(t)}var m=new cx(["value"],n);return m.initData(l,s),r&&r(d,m),ZC({mainData:d,struct:o,structAttr:"graph",datas:{node:d,edge:m},datasAttr:{node:"data",edge:"edgeData"}}),o.update(),o}R(ak,lk("hostGraph","data")),R(sk,lk("hostGraph","edgeData"));var hk=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n.hasSymbolVisual=!0,n}return n(e,t),e.prototype.init=function(e){t.prototype.init.apply(this,arguments);var n=this;function i(){return n._categoriesData}this.legendVisualProvider=new NM(i,i),this.fillDataTextStyle(e.edges||e.links),this._updateCategoriesData()},e.prototype.mergeOption=function(e){t.prototype.mergeOption.apply(this,arguments),this.fillDataTextStyle(e.edges||e.links),this._updateCategoriesData()},e.prototype.mergeDefaultAndTheme=function(e){t.prototype.mergeDefaultAndTheme.apply(this,arguments),Co(e,"edgeLabel",["show"])},e.prototype.getInitialData=function(t,e){var n,i=t.edges||t.links||[],r=t.data||t.nodes||[],o=this;if(r&&i){dA(n=this)&&(n.__curvenessList=[],n.__edgeMap={},fA(n));var a=uk(r,i,this,!0,(function(t,e){t.wrapMethod("getItemModel",(function(t){var e=o._categoriesModels[t.getShallow("category")];return e&&(e.parentModel=t.parentModel,t.parentModel=e),t}));var n=Cc.prototype.getModel;function i(t,e){var i=n.call(this,t,e);return i.resolveParentPath=r,i}function r(t){if(t&&("label"===t[0]||"label"===t[1])){var e=t.slice();return"label"===t[0]?e[0]="edgeLabel":"label"===t[1]&&(e[1]="edgeLabel"),e}return t}e.wrapMethod("getItemModel",(function(t){return t.resolveParentPath=r,t.getModel=i,t}))}));return E(a.edges,(function(t){!function(t,e,n,i){if(dA(n)){var r=gA(t,e,n),o=n.__edgeMap,a=o[yA(r)];o[r]&&!a?o[r].isForward=!0:a&&o[r]&&(a.isForward=!0,o[r].isForward=!1),o[r]=o[r]||[],o[r].push(i)}}(t.node1,t.node2,this,t.dataIndex)}),this),a.data}},e.prototype.getGraph=function(){return this.getData().graph},e.prototype.getEdgeData=function(){return this.getGraph().edgeData},e.prototype.getCategoriesData=function(){return this._categoriesData},e.prototype.formatTooltip=function(t,e,n){if("edge"===n){var i=this.getData(),r=this.getDataParams(t,n),o=i.graph.getEdgeByIndex(t),a=i.getName(o.node1.dataIndex),s=i.getName(o.node2.dataIndex),l=[];return null!=a&&l.push(a),null!=s&&l.push(s),og("nameValue",{name:l.join(" > "),value:r.value,noValue:null==r.value})}return vg({series:this,dataIndex:t,multipleSeries:e})},e.prototype._updateCategoriesData=function(){var t=z(this.option.categories||[],(function(t){return null!=t.value?t:A({value:0},t)})),e=new cx(["value"],this);e.initData(t),this._categoriesData=e,this._categoriesModels=e.mapArray((function(t){return e.getItemModel(t)}))},e.prototype.setZoom=function(t){this.option.zoom=t},e.prototype.setCenter=function(t){this.option.center=t},e.prototype.isAnimationEnabled=function(){return t.prototype.isAnimationEnabled.call(this)&&!("force"===this.get("layout")&&this.get(["force","layoutAnimation"]))},e.type="series.graph",e.dependencies=["grid","polar","geo","singleAxis","calendar"],e.defaultOption={z:2,coordinateSystem:"view",legendHoverLink:!0,layout:null,circular:{rotateLabel:!1},force:{initLayout:null,repulsion:[0,50],gravity:.1,friction:.6,edgeLength:30,layoutAnimation:!0},left:"center",top:"center",symbol:"circle",symbolSize:10,edgeSymbol:["none","none"],edgeSymbolSize:10,edgeLabel:{position:"middle",distance:5},draggable:!1,roam:!1,center:null,zoom:1,nodeScaleRatio:.6,label:{show:!1,formatter:"{b}"},itemStyle:{},lineStyle:{color:"#aaa",width:1,opacity:.5},emphasis:{scale:!0,label:{show:!0}},select:{itemStyle:{borderColor:"#212121"}}},e}(bg),ck={type:"graphRoam",event:"graphRoam",update:"none"};var pk=function(){this.angle=0,this.width=10,this.r=10,this.x=0,this.y=0},dk=function(t){function e(e){var n=t.call(this,e)||this;return n.type="pointer",n}return n(e,t),e.prototype.getDefaultShape=function(){return new pk},e.prototype.buildPath=function(t,e){var n=Math.cos,i=Math.sin,r=e.r,o=e.width,a=e.angle,s=e.x-n(a)*o*(o>=r/3?1:2),l=e.y-i(a)*o*(o>=r/3?1:2);a=e.angle-Math.PI/2,t.moveTo(s,l),t.lineTo(e.x+n(a)*o,e.y+i(a)*o),t.lineTo(e.x+n(e.angle)*r,e.y+i(e.angle)*r),t.lineTo(e.x-n(a)*o,e.y-i(a)*o),t.lineTo(s,l)},e}(ks);function fk(t,e){var n=null==t?"":t+"";return e&&(U(e)?n=e.replace("{value}",n):X(e)&&(n=e(t))),n}var gk=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n}return n(e,t),e.prototype.render=function(t,e,n){this.group.removeAll();var i=t.get(["axisLine","lineStyle","color"]),r=function(t,e){var n=t.get("center"),i=e.getWidth(),r=e.getHeight(),o=Math.min(i,r);return{cx:$r(n[0],e.getWidth()),cy:$r(n[1],e.getHeight()),r:$r(t.get("radius"),o/2)}}(t,n);this._renderMain(t,e,n,i,r),this._data=t.getData()},e.prototype.dispose=function(){},e.prototype._renderMain=function(t,e,n,i,r){var o=this.group,a=t.get("clockwise"),s=-t.get("startAngle")/180*Math.PI,l=-t.get("endAngle")/180*Math.PI,u=t.getModel("axisLine"),h=u.get("roundCap")?JS:Fu,c=u.get("show"),p=u.getModel("lineStyle"),d=p.get("width"),f=[s,l];us(f,!a);for(var g=(l=f[1])-(s=f[0]),y=s,v=[],m=0;c&&m=t&&(0===e?0:i[e-1][0])Math.PI/2&&(V+=Math.PI):"tangential"===z?V=-M-Math.PI/2:j(z)&&(V=z*Math.PI/180),0===V?c.add(new Xs({style:oc(x,{text:O,x:N,y:E,verticalAlign:h<-.8?"top":h>.8?"bottom":"middle",align:u<-.4?"left":u>.4?"right":"center"},{inheritColor:R}),silent:!0})):c.add(new Xs({style:oc(x,{text:O,x:N,y:E,verticalAlign:"middle",align:"center"},{inheritColor:R}),silent:!0,originX:N,originY:E,rotation:V}))}if(m.get("show")&&k!==_){P=(P=m.get("distance"))?P+l:l;for(var B=0;B<=b;B++){u=Math.cos(M),h=Math.sin(M);var F=new Ku({shape:{x1:u*(f-P)+p,y1:h*(f-P)+d,x2:u*(f-S-P)+p,y2:h*(f-S-P)+d},silent:!0,style:D});"auto"===D.stroke&&F.setStyle({stroke:i((k+B/b)/_)}),c.add(F),M+=T}M-=T}else M+=I}},e.prototype._renderPointer=function(t,e,n,i,r,o,a,s,l){var u=this.group,h=this._data,c=this._progressEls,p=[],d=t.get(["pointer","show"]),f=t.getModel("progress"),g=f.get("show"),y=t.getData(),v=y.mapDimension("value"),m=+t.get("min"),x=+t.get("max"),_=[m,x],b=[o,a];function w(e,n){var i,o=y.getItemModel(e).getModel("pointer"),a=$r(o.get("width"),r.r),s=$r(o.get("length"),r.r),l=t.get(["pointer","icon"]),u=o.get("offsetCenter"),h=$r(u[0],r.r),c=$r(u[1],r.r),p=o.get("keepAspect");return(i=l?Xy(l,h-a/2,c-s,a,s,null,p):new dk({shape:{angle:-Math.PI/2,width:a,r:s,x:h,y:c}})).rotation=-(n+Math.PI/2),i.x=r.cx,i.y=r.cy,i}function S(t,e){var n=f.get("roundCap")?JS:Fu,i=f.get("overlap"),a=i?f.get("width"):l/y.count(),u=i?r.r-a:r.r-(t+1)*a,h=i?r.r:r.r-t*a,c=new n({shape:{startAngle:o,endAngle:e,cx:r.cx,cy:r.cy,clockwise:s,r0:u,r:h}});return i&&(c.z2=Kr(y.get(v,t),[m,x],[100,0],!0)),c}(g||d)&&(y.diff(h).add((function(e){var n=y.get(v,e);if(d){var i=w(e,o);mh(i,{rotation:-((isNaN(+n)?b[0]:Kr(n,_,b,!0))+Math.PI/2)},t),u.add(i),y.setItemGraphicEl(e,i)}if(g){var r=S(e,o),a=f.get("clip");mh(r,{shape:{endAngle:Kr(n,_,b,a)}},t),u.add(r),ol(t.seriesIndex,y.dataType,e,r),p[e]=r}})).update((function(e,n){var i=y.get(v,e);if(d){var r=h.getItemGraphicEl(n),a=r?r.rotation:o,s=w(e,a);s.rotation=a,vh(s,{rotation:-((isNaN(+i)?b[0]:Kr(i,_,b,!0))+Math.PI/2)},t),u.add(s),y.setItemGraphicEl(e,s)}if(g){var l=c[n],m=S(e,l?l.shape.endAngle:o),x=f.get("clip");vh(m,{shape:{endAngle:Kr(i,_,b,x)}},t),u.add(m),ol(t.seriesIndex,y.dataType,e,m),p[e]=m}})).execute(),y.each((function(t){var e=y.getItemModel(t),n=e.getModel("emphasis"),r=n.get("focus"),o=n.get("blurScope"),a=n.get("disabled");if(d){var s=y.getItemGraphicEl(t),l=y.getItemVisual(t,"style"),u=l.fill;if(s instanceof Ns){var h=s.style;s.useStyle(A({image:h.image,x:h.x,y:h.y,width:h.width,height:h.height},l))}else s.useStyle(l),"pointer"!==s.type&&s.setColor(u);s.setStyle(e.getModel(["pointer","itemStyle"]).getItemStyle()),"auto"===s.style.fill&&s.setStyle("fill",i(Kr(y.get(v,t),_,[0,1],!0))),s.z2EmphasisLift=0,$l(s,e),Zl(s,r,o,a)}if(g){var c=p[t];c.useStyle(y.getItemVisual(t,"style")),c.setStyle(e.getModel(["progress","itemStyle"]).getItemStyle()),c.z2EmphasisLift=0,$l(c,e),Zl(c,r,o,a)}})),this._progressEls=p)},e.prototype._renderAnchor=function(t,e){var n=t.getModel("anchor");if(n.get("show")){var i=n.get("size"),r=n.get("icon"),o=n.get("offsetCenter"),a=n.get("keepAspect"),s=Xy(r,e.cx-i/2+$r(o[0],e.r),e.cy-i/2+$r(o[1],e.r),i,i,null,a);s.z2=n.get("showAbove")?1:0,s.setStyle(n.getModel("itemStyle").getItemStyle()),this.group.add(s)}},e.prototype._renderTitleAndDetail=function(t,e,n,i,r){var o=this,a=t.getData(),s=a.mapDimension("value"),l=+t.get("min"),u=+t.get("max"),h=new Br,c=[],p=[],d=t.isAnimationEnabled(),f=t.get(["pointer","showAbove"]);a.diff(this._data).add((function(t){c[t]=new Xs({silent:!0}),p[t]=new Xs({silent:!0})})).update((function(t,e){c[t]=o._titleEls[e],p[t]=o._detailEls[e]})).execute(),a.each((function(e){var n=a.getItemModel(e),o=a.get(s,e),g=new Br,y=i(Kr(o,[l,u],[0,1],!0)),v=n.getModel("title");if(v.get("show")){var m=v.get("offsetCenter"),x=r.cx+$r(m[0],r.r),_=r.cy+$r(m[1],r.r);(D=c[e]).attr({z2:f?0:2,style:oc(v,{x:x,y:_,text:a.getName(e),align:"center",verticalAlign:"middle"},{inheritColor:y})}),g.add(D)}var b=n.getModel("detail");if(b.get("show")){var w=b.get("offsetCenter"),S=r.cx+$r(w[0],r.r),M=r.cy+$r(w[1],r.r),I=$r(b.get("width"),r.r),T=$r(b.get("height"),r.r),C=t.get(["progress","show"])?a.getItemVisual(e,"style").fill:y,D=p[e],A=b.get("formatter");D.attr({z2:f?0:2,style:oc(b,{x:S,y:M,text:fk(o,A),width:isNaN(I)?null:I,height:isNaN(T)?null:T,align:"center",verticalAlign:"middle"},{inheritColor:C})}),dc(D,{normal:b},o,(function(t){return fk(t,A)})),d&&fc(D,e,a,t,{getFormattedLabel:function(t,e,n,i,r,a){return fk(a?a.interpolatedValue:o,A)}}),g.add(D)}h.add(g)})),this.group.add(h),this._titleEls=c,this._detailEls=p},e.type="gauge",e}(Og),yk=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n.visualStyleAccessPath="itemStyle",n}return n(e,t),e.prototype.getInitialData=function(t,e){return RM(this,["value"])},e.type="series.gauge",e.defaultOption={z:2,colorBy:"data",center:["50%","50%"],legendHoverLink:!0,radius:"75%",startAngle:225,endAngle:-45,clockwise:!0,min:0,max:100,splitNumber:10,axisLine:{show:!0,roundCap:!1,lineStyle:{color:[[1,"#E6EBF8"]],width:10}},progress:{show:!1,overlap:!0,width:10,roundCap:!1,clip:!0},splitLine:{show:!0,length:10,distance:10,lineStyle:{color:"#63677A",width:3,type:"solid"}},axisTick:{show:!0,splitNumber:5,length:6,distance:10,lineStyle:{color:"#63677A",width:1,type:"solid"}},axisLabel:{show:!0,distance:15,color:"#464646",fontSize:12,rotate:0},pointer:{icon:null,offsetCenter:[0,0],show:!0,showAbove:!0,length:"60%",width:6,keepAspect:!1},anchor:{show:!1,showAbove:!1,size:6,icon:"circle",offsetCenter:[0,0],keepAspect:!1,itemStyle:{color:"#fff",borderWidth:0,borderColor:"#5470c6"}},title:{show:!0,offsetCenter:[0,"20%"],color:"#464646",fontSize:16,valueAnimation:!1},detail:{show:!0,backgroundColor:"rgba(0,0,0,0)",borderWidth:0,borderColor:"#ccc",width:100,height:null,padding:[5,10],offsetCenter:[0,"40%"],color:"#464646",fontSize:30,fontWeight:"bold",lineHeight:30,valueAnimation:!1}},e}(bg);var vk=["itemStyle","opacity"],mk=function(t){function e(e,n){var i=t.call(this)||this,r=i,o=new Zu,a=new Xs;return r.setTextContent(a),i.setTextGuideLine(o),i.updateData(e,n,!0),i}return n(e,t),e.prototype.updateData=function(t,e,n){var i=this,r=t.hostModel,o=t.getItemModel(e),a=t.getItemLayout(e),s=o.getModel("emphasis"),l=o.get(vk);l=null==l?1:l,n||Sh(i),i.useStyle(t.getItemVisual(e,"style")),i.style.lineJoin="round",n?(i.setShape({points:a.points}),i.style.opacity=0,mh(i,{style:{opacity:l}},r,e)):vh(i,{style:{opacity:l},shape:{points:a.points}},r,e),$l(i,o),this._updateLabel(t,e),Zl(this,s.get("focus"),s.get("blurScope"),s.get("disabled"))},e.prototype._updateLabel=function(t,e){var n=this,i=this.getTextGuideLine(),r=n.getTextContent(),o=t.hostModel,a=t.getItemModel(e),s=t.getItemLayout(e).label,l=t.getItemVisual(e,"style"),u=l.fill;ic(r,rc(a),{labelFetcher:t.hostModel,labelDataIndex:e,defaultOpacity:l.opacity,defaultText:t.getName(e)},{normal:{align:s.textAlign,verticalAlign:s.verticalAlign}}),n.setTextConfig({local:!0,inside:!!s.inside,insideStroke:u,outsideFill:u});var h=s.linePoints;i.setShape({points:h}),n.textGuideLineConfig={anchor:h?new De(h[0][0],h[0][1]):null},vh(r,{style:{x:s.x,y:s.y}},o,e),r.attr({rotation:s.rotation,originX:s.x,originY:s.y,z2:10}),kb(n,Lb(a),{stroke:u})},e}(Xu),xk=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n.ignoreLabelLineUpdate=!0,n}return n(e,t),e.prototype.render=function(t,e,n){var i=t.getData(),r=this._data,o=this.group;i.diff(r).add((function(t){var e=new mk(i,t);i.setItemGraphicEl(t,e),o.add(e)})).update((function(t,e){var n=r.getItemGraphicEl(e);n.updateData(i,t),o.add(n),i.setItemGraphicEl(t,n)})).remove((function(e){wh(r.getItemGraphicEl(e),t,e)})).execute(),this._data=i},e.prototype.remove=function(){this.group.removeAll(),this._data=null},e.prototype.dispose=function(){},e.type="funnel",e}(Og),_k=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n}return n(e,t),e.prototype.init=function(e){t.prototype.init.apply(this,arguments),this.legendVisualProvider=new NM(W(this.getData,this),W(this.getRawData,this)),this._defaultLabelLine(e)},e.prototype.getInitialData=function(t,e){return RM(this,{coordDimensions:["value"],encodeDefaulter:H(ed,this)})},e.prototype._defaultLabelLine=function(t){Co(t,"labelLine",["show"]);var e=t.labelLine,n=t.emphasis.labelLine;e.show=e.show&&t.label.show,n.show=n.show&&t.emphasis.label.show},e.prototype.getDataParams=function(e){var n=this.getData(),i=t.prototype.getDataParams.call(this,e),r=n.mapDimension("value"),o=n.getSum(r);return i.percent=o?+(n.get(r,e)/o*100).toFixed(2):0,i.$vars.push("percent"),i},e.type="series.funnel",e.defaultOption={z:2,legendHoverLink:!0,colorBy:"data",left:80,top:60,right:80,bottom:60,minSize:"0%",maxSize:"100%",sort:"descending",orient:"vertical",gap:0,funnelAlign:"center",label:{show:!0,position:"outer"},labelLine:{show:!0,length:20,lineStyle:{width:1}},itemStyle:{borderColor:"#fff",borderWidth:1},emphasis:{label:{show:!0}},select:{itemStyle:{borderColor:"#212121"}}},e}(bg);function bk(t,e){t.eachSeriesByType("funnel",(function(t){var n=t.getData(),i=n.mapDimension("value"),r=t.get("sort"),o=function(t,e){return kp(t.getBoxLayoutParams(),{width:e.getWidth(),height:e.getHeight()})}(t,e),a=t.get("orient"),s=o.width,l=o.height,u=function(t,e){for(var n=t.mapDimension("value"),i=t.mapArray(n,(function(t){return t})),r=[],o="ascending"===e,a=0,s=t.count();a5)return;var i=this._model.coordinateSystem.getSlidedAxisExpandWindow([t.offsetX,t.offsetY]);"none"!==i.behavior&&this._dispatchExpand({axisExpandWindow:i.axisExpandWindow})}this._mouseDownPoint=null},mousemove:function(t){if(!this._mouseDownPoint&&Rk(this,"mousemove")){var e=this._model,n=e.coordinateSystem.getSlidedAxisExpandWindow([t.offsetX,t.offsetY]),i=n.behavior;"jump"===i&&this._throttledDispatchExpand.debounceNextCall(e.get("axisExpandDebounce")),this._throttledDispatchExpand("none"===i?null:{axisExpandWindow:n.axisExpandWindow,animation:"jump"===i?null:{duration:0}})}}};function Rk(t,e){var n=t._model;return n.get("axisExpandable")&&n.get("axisExpandTriggerOn")===e}var Nk=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n}return n(e,t),e.prototype.init=function(){t.prototype.init.apply(this,arguments),this.mergeOption({})},e.prototype.mergeOption=function(t){var e=this.option;t&&C(e,t,!0),this._initDimensions()},e.prototype.contains=function(t,e){var n=t.get("parallelIndex");return null!=n&&e.getComponent("parallel",n)===this},e.prototype.setAxisExpand=function(t){E(["axisExpandable","axisExpandCenter","axisExpandCount","axisExpandWidth","axisExpandWindow"],(function(e){t.hasOwnProperty(e)&&(this.option[e]=t[e])}),this)},e.prototype._initDimensions=function(){var t=this.dimensions=[],e=this.parallelAxisIndex=[];E(B(this.ecModel.queryComponents({mainType:"parallelAxis"}),(function(t){return(t.get("parallelIndex")||0)===this.componentIndex}),this),(function(n){t.push("dim"+n.get("dim")),e.push(n.componentIndex)}))},e.type="parallel",e.dependencies=["parallelAxis"],e.layoutMode="box",e.defaultOption={z:0,left:80,top:60,right:80,bottom:60,layout:"horizontal",axisExpandable:!1,axisExpandCenter:null,axisExpandCount:0,axisExpandWidth:50,axisExpandRate:17,axisExpandDebounce:50,axisExpandSlideTriggerArea:[-.15,.05,.4],axisExpandTriggerOn:"click",parallelAxisDefault:null},e}(zp),Ek=function(t){function e(e,n,i,r,o){var a=t.call(this,e,n,i)||this;return a.type=r||"value",a.axisIndex=o,a}return n(e,t),e.prototype.isHorizontal=function(){return"horizontal"!==this.coordinateSystem.getModel().get("layout")},e}(ab);function zk(t,e,n,i,r,o){t=t||0;var a=n[1]-n[0];if(null!=r&&(r=Bk(r,[0,a])),null!=o&&(o=Math.max(o,null!=r?r:0)),"all"===i){var s=Math.abs(e[1]-e[0]);s=Bk(s,[0,a]),r=o=Bk(s,[r,o]),i=0}e[0]=Bk(e[0],n),e[1]=Bk(e[1],n);var l=Vk(e,i);e[i]+=t;var u,h=r||0,c=n.slice();return l.sign<0?c[0]+=h:c[1]-=h,e[i]=Bk(e[i],c),u=Vk(e,i),null!=r&&(u.sign!==l.sign||u.spano&&(e[1-i]=e[i]+u.sign*o),e}function Vk(t,e){var n=t[e]-t[1-e];return{span:Math.abs(n),sign:n>0?-1:n<0?1:e?-1:1}}function Bk(t,e){return Math.min(null!=e[1]?e[1]:1/0,Math.max(null!=e[0]?e[0]:-1/0,t))}var Fk=E,Gk=Math.min,Wk=Math.max,Hk=Math.floor,Yk=Math.ceil,Xk=Jr,Uk=Math.PI,Zk=function(){function t(t,e,n){this.type="parallel",this._axesMap=yt(),this._axesLayout={},this.dimensions=t.dimensions,this._model=t,this._init(t,e,n)}return t.prototype._init=function(t,e,n){var i=t.dimensions,r=t.parallelAxisIndex;Fk(i,(function(t,n){var i=r[n],o=e.getComponent("parallelAxis",i),a=this._axesMap.set(t,new Ek(t,b_(o),[0,0],o.get("type"),i)),s="category"===a.type;a.onBand=s&&o.get("boundaryGap"),a.inverse=o.get("inverse"),o.axis=a,a.model=o,a.coordinateSystem=o.coordinateSystem=this}),this)},t.prototype.update=function(t,e){this._updateAxesFromSeries(this._model,t)},t.prototype.containPoint=function(t){var e=this._makeLayoutInfo(),n=e.axisBase,i=e.layoutBase,r=e.pixelDimIndex,o=t[1-r],a=t[r];return o>=n&&o<=n+e.axisLength&&a>=i&&a<=i+e.layoutLength},t.prototype.getModel=function(){return this._model},t.prototype._updateAxesFromSeries=function(t,e){e.eachSeries((function(n){if(t.contains(n,e)){var i=n.getData();Fk(this.dimensions,(function(t){var e=this._axesMap.get(t);e.scale.unionExtentFromData(i,i.mapDimension(t)),__(e.scale,e.model)}),this)}}),this)},t.prototype.resize=function(t,e){this._rect=kp(t.getBoxLayoutParams(),{width:e.getWidth(),height:e.getHeight()}),this._layoutAxes()},t.prototype.getRect=function(){return this._rect},t.prototype._makeLayoutInfo=function(){var t,e=this._model,n=this._rect,i=["x","y"],r=["width","height"],o=e.get("layout"),a="horizontal"===o?0:1,s=n[r[a]],l=[0,s],u=this.dimensions.length,h=jk(e.get("axisExpandWidth"),l),c=jk(e.get("axisExpandCount")||0,[0,u]),p=e.get("axisExpandable")&&u>3&&u>c&&c>1&&h>0&&s>0,d=e.get("axisExpandWindow");d?(t=jk(d[1]-d[0],l),d[1]=d[0]+t):(t=jk(h*(c-1),l),(d=[h*(e.get("axisExpandCenter")||Hk(u/2))-t/2])[1]=d[0]+t);var f=(s-t)/(u-c);f<3&&(f=0);var g=[Hk(Xk(d[0]/h,1))+1,Yk(Xk(d[1]/h,1))-1],y=f/h*d[0];return{layout:o,pixelDimIndex:a,layoutBase:n[i[a]],layoutLength:s,axisBase:n[i[1-a]],axisLength:n[r[1-a]],axisExpandable:p,axisExpandWidth:h,axisCollapseWidth:f,axisExpandWindow:d,axisCount:u,winInnerIndices:g,axisExpandWindow0Pos:y}},t.prototype._layoutAxes=function(){var t=this._rect,e=this._axesMap,n=this.dimensions,i=this._makeLayoutInfo(),r=i.layout;e.each((function(t){var e=[0,i.axisLength],n=t.inverse?1:0;t.setExtent(e[n],e[1-n])})),Fk(n,(function(e,n){var o=(i.axisExpandable?Kk:qk)(n,i),a={horizontal:{x:o.position,y:i.axisLength},vertical:{x:0,y:o.position}},s={horizontal:Uk/2,vertical:0},l=[a[r].x+t.x,a[r].y+t.y],u=s[r],h=[1,0,0,1,0,0];Se(h,h,u),we(h,h,l),this._axesLayout[e]={position:l,rotation:u,transform:h,axisNameAvailableWidth:o.axisNameAvailableWidth,axisLabelShow:o.axisLabelShow,nameTruncateMaxWidth:o.nameTruncateMaxWidth,tickDirection:1,labelDirection:1}}),this)},t.prototype.getAxis=function(t){return this._axesMap.get(t)},t.prototype.dataToPoint=function(t,e){return this.axisCoordToPoint(this._axesMap.get(e).dataToCoord(t),e)},t.prototype.eachActiveState=function(t,e,n,i){null==n&&(n=0),null==i&&(i=t.count());var r=this._axesMap,o=this.dimensions,a=[],s=[];E(o,(function(e){a.push(t.mapDimension(e)),s.push(r.get(e).model)}));for(var l=this.hasAxisBrushed(),u=n;ur*(1-h[0])?(l="jump",a=s-r*(1-h[2])):(a=s-r*h[1])>=0&&(a=s-r*(1-h[1]))<=0&&(a=0),(a*=e.axisExpandWidth/u)?zk(a,i,o,"all"):l="none";else{var p=i[1]-i[0];(i=[Wk(0,o[1]*s/p-p/2)])[1]=Gk(o[1],i[0]+p),i[0]=i[1]-p}return{axisExpandWindow:i,behavior:l}},t}();function jk(t,e){return Gk(Wk(t,e[0]),e[1])}function qk(t,e){var n=e.layoutLength/(e.axisCount-1);return{position:n*t,axisNameAvailableWidth:n,axisLabelShow:!0}}function Kk(t,e){var n,i,r=e.layoutLength,o=e.axisExpandWidth,a=e.axisCount,s=e.axisCollapseWidth,l=e.winInnerIndices,u=s,h=!1;return t=0;n--)Qr(e[n])},e.prototype.getActiveState=function(t){var e=this.activeIntervals;if(!e.length)return"normal";if(null==t||isNaN(+t))return"inactive";if(1===e.length){var n=e[0];if(n[0]<=t&&t<=n[1])return"active"}else for(var i=0,r=e.length;i6}(t)||o){if(a&&!o){"single"===s.brushMode&&vL(t);var l=T(s);l.brushType=RL(l.brushType,a),l.panelId=a===Qk?null:a.panelId,o=t._creatingCover=uL(t,l),t._covers.push(o)}if(o){var u=zL[RL(t._brushType,a)];o.__brushOption.range=u.getCreatingRange(kL(t,o,t._track)),i&&(hL(t,o),u.updateCommon(t,o)),cL(t,o),r={isEnd:i}}}else 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r=this.getGraph().getNodeByIndex(e).getLayout().value;i.value=r}return i},e.type="series.sankey",e.defaultOption={z:2,coordinateSystem:"view",left:"5%",top:"5%",right:"20%",bottom:"5%",orient:"horizontal",nodeWidth:20,nodeGap:8,draggable:!0,layoutIterations:32,label:{show:!0,position:"right",fontSize:12},edgeLabel:{show:!1,fontSize:12},levels:[],nodeAlign:"justify",lineStyle:{color:"#314656",opacity:.2,curveness:.5},emphasis:{label:{show:!0},lineStyle:{opacity:.5}},select:{itemStyle:{borderColor:"#212121"}},animationEasing:"linear",animationDuration:1e3},e}(bg);function QL(t,e){t.eachSeriesByType("sankey",(function(t){var n=t.get("nodeWidth"),i=t.get("nodeGap"),r=function(t,e){return kp(t.getBoxLayoutParams(),{width:e.getWidth(),height:e.getHeight()})}(t,e);t.layoutInfo=r;var o=r.width,a=r.height,s=t.getGraph(),l=s.nodes,u=s.edges;!function(t){E(t,(function(t){var 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pP=function(){function t(){}return t.prototype._hasEncodeRule=function(t){var e=this.getEncode();return e&&null!=e.get(t)},t.prototype.getInitialData=function(t,e){var n,i,r=e.getComponent("xAxis",this.get("xAxisIndex")),o=e.getComponent("yAxis",this.get("yAxisIndex")),a=r.get("type"),s=o.get("type");"category"===a?(t.layout="horizontal",n=r.getOrdinalMeta(),i=!this._hasEncodeRule("x")):"category"===s?(t.layout="vertical",n=o.getOrdinalMeta(),i=!this._hasEncodeRule("y")):t.layout=t.layout||"horizontal";var l=["x","y"],u="horizontal"===t.layout?0:1,h=this._baseAxisDim=l[u],c=l[1-u],p=[r,o],d=p[u].get("type"),f=p[1-u].get("type"),g=t.data;if(g&&i){var y=[];E(g,(function(t,e){var n;Y(t)?(n=t.slice(),t.unshift(e)):Y(t.value)?((n=A({},t)).value=n.value.slice(),t.value.unshift(e)):n=t,y.push(n)})),t.data=y}var v=this.defaultValueDimensions,m=[{name:h,type:Ym(d),ordinalMeta:n,otherDims:{tooltip:!1,itemName:0},dimsDef:["base"]},{name:c,type:Ym(f),dimsDef:v.slice()}];return RM(this,{coordDimensions:m,dimensionsCount:v.length+1,encodeDefaulter:H(td,m,this)})},t.prototype.getBaseAxis=function(){var t=this._baseAxisDim;return this.ecModel.getComponent(t+"Axis",this.get(t+"AxisIndex")).axis},t}(),dP=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n.defaultValueDimensions=[{name:"min",defaultTooltip:!0},{name:"Q1",defaultTooltip:!0},{name:"median",defaultTooltip:!0},{name:"Q3",defaultTooltip:!0},{name:"max",defaultTooltip:!0}],n.visualDrawType="stroke",n}return n(e,t),e.type="series.boxplot",e.dependencies=["xAxis","yAxis","grid"],e.defaultOption={z:2,coordinateSystem:"cartesian2d",legendHoverLink:!0,layout:null,boxWidth:[7,50],itemStyle:{color:"#fff",borderWidth:1},emphasis:{scale:!0,itemStyle:{borderWidth:2,shadowBlur:5,shadowOffsetX:1,shadowOffsetY:1,shadowColor:"rgba(0,0,0,0.2)"}},animationDuration:800},e}(bg);R(dP,pP,!0);var fP=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return 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n=e.points,i=0;for(t.moveTo(n[i][0],n[i][1]),i++;i<4;i++)t.lineTo(n[i][0],n[i][1]);for(t.closePath();ig){var _=[v,x];i.push(_)}}}return{boxData:n,outliers:i}}(e.getRawData(),t.config);return[{dimensions:["ItemName","Low","Q1","Q2","Q3","High"],data:i.boxData},{data:i.outliers}]}};var SP=["itemStyle","borderColor"],MP=["itemStyle","borderColor0"],IP=["itemStyle","borderColorDoji"],TP=["itemStyle","color"],CP=["itemStyle","color0"];function DP(t,e){return e.get(t>0?TP:CP)}function AP(t,e){return e.get(0===t?IP:t>0?SP:MP)}var kP={seriesType:"candlestick",plan:kg(),performRawSeries:!0,reset:function(t,e){if(!e.isSeriesFiltered(t))return!t.pipelineContext.large&&{progress:function(t,e){for(var n;null!=(n=t.next());){var i=e.getItemModel(n),r=e.getItemLayout(n).sign,o=i.getItemStyle();o.fill=DP(r,i),o.stroke=AP(r,i)||o.fill,A(e.ensureUniqueItemVisual(n,"style"),o)}}}}},LP=["color","borderColor"],PP=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return 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e=t.symbolType,n=t.color,i=t.rippleNumber,r=this.childAt(1),o=0;o0&&(o=this._getLineLength(i)/l*1e3),o!==this._period||a!==this._loop||s!==this._roundTrip){i.stopAnimation();var h=void 0;h=X(u)?u(n):u,i.__t>0&&(h=-o*i.__t),this._animateSymbol(i,o,h,a,s)}this._period=o,this._loop=a,this._roundTrip=s}},e.prototype._animateSymbol=function(t,e,n,i,r){if(e>0){t.__t=0;var o=this,a=t.animate("",i).when(r?2*e:e,{__t:r?2:1}).delay(n).during((function(){o._updateSymbolPosition(t)}));i||a.done((function(){o.remove(t)})),a.start()}},e.prototype._getLineLength=function(t){return Vt(t.__p1,t.__cp1)+Vt(t.__cp1,t.__p2)},e.prototype._updateAnimationPoints=function(t,e){t.__p1=e[0],t.__p2=e[1],t.__cp1=e[2]||[(e[0][0]+e[1][0])/2,(e[0][1]+e[1][1])/2]},e.prototype.updateData=function(t,e,n){this.childAt(0).updateData(t,e,n),this._updateEffectSymbol(t,e)},e.prototype._updateSymbolPosition=function(t){var e=t.__p1,n=t.__p2,i=t.__cp1,r=t.__t<1?t.__t:2-t.__t,o=[t.x,t.y],a=o.slice(),s=In,l=Tn;o[0]=s(e[0],i[0],n[0],r),o[1]=s(e[1],i[1],n[1],r);var u=t.__t<1?l(e[0],i[0],n[0],r):l(n[0],i[0],e[0],1-r),h=t.__t<1?l(e[1],i[1],n[1],r):l(n[1],i[1],e[1],1-r);t.rotation=-Math.atan2(h,u)-Math.PI/2,"line"!==this._symbolType&&"rect"!==this._symbolType&&"roundRect"!==this._symbolType||(void 0!==t.__lastT&&t.__lastT=0&&!(i[o]<=e);o--);o=Math.min(o,r-2)}else{for(o=a;oe);o++);o=Math.min(o-1,r-2)}var s=(e-i[o])/(i[o+1]-i[o]),l=n[o],u=n[o+1];t.x=l[0]*(1-s)+s*u[0],t.y=l[1]*(1-s)+s*u[1];var h=t.__t<1?u[0]-l[0]:l[0]-u[0],c=t.__t<1?u[1]-l[1]:l[1]-u[1];t.rotation=-Math.atan2(c,h)-Math.PI/2,this._lastFrame=o,this._lastFramePercent=e,t.ignore=!1}},e}($P),tO=function(){this.polyline=!1,this.curveness=0,this.segs=[]},eO=function(t){function e(e){var n=t.call(this,e)||this;return n._off=0,n.hoverDataIdx=-1,n}return n(e,t),e.prototype.reset=function(){this.notClear=!1,this._off=0},e.prototype.getDefaultStyle=function(){return{stroke:"#000",fill:null}},e.prototype.getDefaultShape=function(){return new tO},e.prototype.buildPath=function(t,e){var n,i=e.segs,r=e.curveness;if(e.polyline)for(n=this._off;n0){t.moveTo(i[n++],i[n++]);for(var a=1;a0){var c=(s+u)/2-(l-h)*r,p=(l+h)/2-(u-s)*r;t.quadraticCurveTo(c,p,u,h)}else t.lineTo(u,h)}this.incremental&&(this._off=n,this.notClear=!0)},e.prototype.findDataIndex=function(t,e){var n=this.shape,i=n.segs,r=n.curveness,o=this.style.lineWidth;if(n.polyline)for(var a=0,s=0;s0)for(var u=i[s++],h=i[s++],c=1;c0){if(ds(u,h,(u+p)/2-(h-d)*r,(h+d)/2-(p-u)*r,p,d,o,t,e))return a}else if(cs(u,h,p,d,o,t,e))return a;a++}return-1},e.prototype.contain=function(t,e){var n=this.transformCoordToLocal(t,e),i=this.getBoundingRect();return t=n[0],e=n[1],i.contain(t,e)?(this.hoverDataIdx=this.findDataIndex(t,e))>=0:(this.hoverDataIdx=-1,!1)},e.prototype.getBoundingRect=function(){var t=this._rect;if(!t){for(var e=this.shape.segs,n=1/0,i=1/0,r=-1/0,o=-1/0,a=0;a0&&(o.dataIndex=n+t.__startIndex)}))},t.prototype._clear=function(){this._newAdded=[],this.group.removeAll()},t}(),iO={seriesType:"lines",plan:kg(),reset:function(t){var e=t.coordinateSystem;if(e){var n=t.get("polyline"),i=t.pipelineContext.large;return{progress:function(r,o){var a=[];if(i){var s=void 0,l=r.end-r.start;if(n){for(var u=0,h=r.start;h0&&(l||s.configLayer(o,{motionBlur:!0,lastFrameAlpha:Math.max(Math.min(a/10+.9,1),0)})),r.updateData(i);var u=t.get("clip",!0)&&PS(t.coordinateSystem,!1,t);u?this.group.setClipPath(u):this.group.removeClipPath(),this._lastZlevel=o,this._finished=!0},e.prototype.incrementalPrepareRender=function(t,e,n){var i=t.getData();this._updateLineDraw(i,t).incrementalPrepareUpdate(i),this._clearLayer(n),this._finished=!1},e.prototype.incrementalRender=function(t,e,n){this._lineDraw.incrementalUpdate(t,e.getData()),this._finished=t.end===e.getData().count()},e.prototype.eachRendered=function(t){this._lineDraw&&this._lineDraw.eachRendered(t)},e.prototype.updateTransform=function(t,e,n){var i=t.getData(),r=t.pipelineContext;if(!this._finished||r.large||r.progressiveRender)return{update:!0};var o=iO.reset(t,e,n);o.progress&&o.progress({start:0,end:i.count(),count:i.count()},i),this._lineDraw.updateLayout(),this._clearLayer(n)},e.prototype._updateLineDraw=function(t,e){var n=this._lineDraw,i=this._showEffect(e),r=!!e.get("polyline"),o=e.pipelineContext.large;return n&&i===this._hasEffet&&r===this._isPolyline&&o===this._isLargeDraw||(n&&n.remove(),n=this._lineDraw=o?new nO:new YA(r?i?QP:JP:i?$P:HA),this._hasEffet=i,this._isPolyline=r,this._isLargeDraw=o),this.group.add(n.group),n},e.prototype._showEffect=function(t){return!!t.get(["effect","show"])},e.prototype._clearLayer=function(t){var e=t.getZr();"svg"===e.painter.getType()||null==this._lastZlevel||e.painter.getLayer(this._lastZlevel).clear(!0)},e.prototype.remove=function(t,e){this._lineDraw&&this._lineDraw.remove(),this._lineDraw=null,this._clearLayer(e)},e.prototype.dispose=function(t,e){this.remove(t,e)},e.type="lines",e}(Og),oO="undefined"==typeof Uint32Array?Array:Uint32Array,aO="undefined"==typeof Float64Array?Array:Float64Array;function sO(t){var e=t.data;e&&e[0]&&e[0][0]&&e[0][0].coord&&(t.data=z(e,(function(t){var e={coords:[t[0].coord,t[1].coord]};return t[0].name&&(e.fromName=t[0].name),t[1].name&&(e.toName=t[1].name),D([e,t[0],t[1]])})))}var lO=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n.visualStyleAccessPath="lineStyle",n.visualDrawType="stroke",n}return n(e,t),e.prototype.init=function(e){e.data=e.data||[],sO(e);var n=this._processFlatCoordsArray(e.data);this._flatCoords=n.flatCoords,this._flatCoordsOffset=n.flatCoordsOffset,n.flatCoords&&(e.data=new Float32Array(n.count)),t.prototype.init.apply(this,arguments)},e.prototype.mergeOption=function(e){if(sO(e),e.data){var n=this._processFlatCoordsArray(e.data);this._flatCoords=n.flatCoords,this._flatCoordsOffset=n.flatCoordsOffset,n.flatCoords&&(e.data=new Float32Array(n.count))}t.prototype.mergeOption.apply(this,arguments)},e.prototype.appendData=function(t){var e=this._processFlatCoordsArray(t.data);e.flatCoords&&(this._flatCoords?(this._flatCoords=vt(this._flatCoords,e.flatCoords),this._flatCoordsOffset=vt(this._flatCoordsOffset,e.flatCoordsOffset)):(this._flatCoords=e.flatCoords,this._flatCoordsOffset=e.flatCoordsOffset),t.data=new Float32Array(e.count)),this.getRawData().appendData(t.data)},e.prototype._getCoordsFromItemModel=function(t){var e=this.getData().getItemModel(t),n=e.option instanceof Array?e.option:e.getShallow("coords");return n},e.prototype.getLineCoordsCount=function(t){return this._flatCoordsOffset?this._flatCoordsOffset[2*t+1]:this._getCoordsFromItemModel(t).length},e.prototype.getLineCoords=function(t,e){if(this._flatCoordsOffset){for(var n=this._flatCoordsOffset[2*t],i=this._flatCoordsOffset[2*t+1],r=0;r ")})},e.prototype.preventIncremental=function(){return!!this.get(["effect","show"])},e.prototype.getProgressive=function(){var t=this.option.progressive;return null==t?this.option.large?1e4:this.get("progressive"):t},e.prototype.getProgressiveThreshold=function(){var t=this.option.progressiveThreshold;return null==t?this.option.large?2e4:this.get("progressiveThreshold"):t},e.prototype.getZLevelKey=function(){var t=this.getModel("effect"),e=t.get("trailLength");return this.getData().count()>this.getProgressiveThreshold()?this.id:t.get("show")&&e>0?e+"":""},e.type="series.lines",e.dependencies=["grid","polar","geo","calendar"],e.defaultOption={coordinateSystem:"geo",z:2,legendHoverLink:!0,xAxisIndex:0,yAxisIndex:0,symbol:["none","none"],symbolSize:[10,10],geoIndex:0,effect:{show:!1,period:4,constantSpeed:0,symbol:"circle",symbolSize:3,loop:!0,trailLength:.2},large:!1,largeThreshold:2e3,polyline:!1,clip:!0,label:{show:!1,position:"end"},lineStyle:{opacity:.5}},e}(bg);function uO(t){return t instanceof Array||(t=[t,t]),t}var hO={seriesType:"lines",reset:function(t){var e=uO(t.get("symbol")),n=uO(t.get("symbolSize")),i=t.getData();return i.setVisual("fromSymbol",e&&e[0]),i.setVisual("toSymbol",e&&e[1]),i.setVisual("fromSymbolSize",n&&n[0]),i.setVisual("toSymbolSize",n&&n[1]),{dataEach:i.hasItemOption?function(t,e){var n=t.getItemModel(e),i=uO(n.getShallow("symbol",!0)),r=uO(n.getShallow("symbolSize",!0));i[0]&&t.setItemVisual(e,"fromSymbol",i[0]),i[1]&&t.setItemVisual(e,"toSymbol",i[1]),r[0]&&t.setItemVisual(e,"fromSymbolSize",r[0]),r[1]&&t.setItemVisual(e,"toSymbolSize",r[1])}:null}}};var cO=function(){function t(){this.blurSize=30,this.pointSize=20,this.maxOpacity=1,this.minOpacity=0,this._gradientPixels={inRange:null,outOfRange:null};var t=h.createCanvas();this.canvas=t}return t.prototype.update=function(t,e,n,i,r,o){var a=this._getBrush(),s=this._getGradient(r,"inRange"),l=this._getGradient(r,"outOfRange"),u=this.pointSize+this.blurSize,h=this.canvas,c=h.getContext("2d"),p=t.length;h.width=e,h.height=n;for(var d=0;d0){var I=o(v)?s:l;v>0&&(v=v*S+w),x[_++]=I[M],x[_++]=I[M+1],x[_++]=I[M+2],x[_++]=I[M+3]*v*256}else _+=4}return c.putImageData(m,0,0),h},t.prototype._getBrush=function(){var t=this._brushCanvas||(this._brushCanvas=h.createCanvas()),e=this.pointSize+this.blurSize,n=2*e;t.width=n,t.height=n;var i=t.getContext("2d");return i.clearRect(0,0,n,n),i.shadowOffsetX=n,i.shadowBlur=this.blurSize,i.shadowColor="#000",i.beginPath(),i.arc(-e,e,this.pointSize,0,2*Math.PI,!0),i.closePath(),i.fill(),t},t.prototype._getGradient=function(t,e){for(var n=this._gradientPixels,i=n[e]||(n[e]=new Uint8ClampedArray(1024)),r=[0,0,0,0],o=0,a=0;a<256;a++)t[e](a/255,!0,r),i[o++]=r[0],i[o++]=r[1],i[o++]=r[2],i[o++]=r[3];return i},t}();function pO(t){var e=t.dimensions;return"lng"===e[0]&&"lat"===e[1]}var dO=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n}return n(e,t),e.prototype.render=function(t,e,n){var i;e.eachComponent("visualMap",(function(e){e.eachTargetSeries((function(n){n===t&&(i=e)}))})),this._progressiveEls=null,this.group.removeAll();var r=t.coordinateSystem;"cartesian2d"===r.type||"calendar"===r.type?this._renderOnCartesianAndCalendar(t,n,0,t.getData().count()):pO(r)&&this._renderOnGeo(r,t,i,n)},e.prototype.incrementalPrepareRender=function(t,e,n){this.group.removeAll()},e.prototype.incrementalRender=function(t,e,n,i){var r=e.coordinateSystem;r&&(pO(r)?this.render(e,n,i):(this._progressiveEls=[],this._renderOnCartesianAndCalendar(e,i,t.start,t.end,!0)))},e.prototype.eachRendered=function(t){Jh(this._progressiveEls||this.group,t)},e.prototype._renderOnCartesianAndCalendar=function(t,e,n,i,r){var o,a,s,l,u=t.coordinateSystem,h=OS(u,"cartesian2d");if(h){var c=u.getAxis("x"),p=u.getAxis("y");0,o=c.getBandWidth()+.5,a=p.getBandWidth()+.5,s=c.scale.getExtent(),l=p.scale.getExtent()}for(var d=this.group,f=t.getData(),g=t.getModel(["emphasis","itemStyle"]).getItemStyle(),y=t.getModel(["blur","itemStyle"]).getItemStyle(),v=t.getModel(["select","itemStyle"]).getItemStyle(),m=t.get(["itemStyle","borderRadius"]),x=rc(t),_=t.getModel("emphasis"),b=_.get("focus"),w=_.get("blurScope"),S=_.get("disabled"),M=h?[f.mapDimension("x"),f.mapDimension("y"),f.mapDimension("value")]:[f.mapDimension("time"),f.mapDimension("value")],I=n;Is[1]||Al[1])continue;var k=u.dataToPoint([D,A]);T=new Ws({shape:{x:k[0]-o/2,y:k[1]-a/2,width:o,height:a},style:C})}else{if(isNaN(f.get(M[1],I)))continue;T=new Ws({z2:1,shape:u.dataToRect([f.get(M[0],I)]).contentShape,style:C})}if(f.hasItemOption){var L=f.getItemModel(I),P=L.getModel("emphasis");g=P.getModel("itemStyle").getItemStyle(),y=L.getModel(["blur","itemStyle"]).getItemStyle(),v=L.getModel(["select","itemStyle"]).getItemStyle(),m=L.get(["itemStyle","borderRadius"]),b=P.get("focus"),w=P.get("blurScope"),S=P.get("disabled"),x=rc(L)}T.shape.r=m;var O=t.getRawValue(I),R="-";O&&null!=O[2]&&(R=O[2]+""),ic(T,x,{labelFetcher:t,labelDataIndex:I,defaultOpacity:C.opacity,defaultText:R}),T.ensureState("emphasis").style=g,T.ensureState("blur").style=y,T.ensureState("select").style=v,Zl(T,b,w,S),T.incremental=r,r&&(T.states.emphasis.hoverLayer=!0),d.add(T),f.setItemGraphicEl(I,T),this._progressiveEls&&this._progressiveEls.push(T)}},e.prototype._renderOnGeo=function(t,e,n,i){var r=n.targetVisuals.inRange,o=n.targetVisuals.outOfRange,a=e.getData(),s=this._hmLayer||this._hmLayer||new cO;s.blurSize=e.get("blurSize"),s.pointSize=e.get("pointSize"),s.minOpacity=e.get("minOpacity"),s.maxOpacity=e.get("maxOpacity");var l=t.getViewRect().clone(),u=t.getRoamTransform();l.applyTransform(u);var h=Math.max(l.x,0),c=Math.max(l.y,0),p=Math.min(l.width+l.x,i.getWidth()),d=Math.min(l.height+l.y,i.getHeight()),f=p-h,g=d-c,y=[a.mapDimension("lng"),a.mapDimension("lat"),a.mapDimension("value")],v=a.mapArray(y,(function(e,n,i){var r=t.dataToPoint([e,n]);return r[0]-=h,r[1]-=c,r.push(i),r})),m=n.getExtent(),x="visualMap.continuous"===n.type?function(t,e){var n=t[1]-t[0];return e=[(e[0]-t[0])/n,(e[1]-t[0])/n],function(t){return t>=e[0]&&t<=e[1]}}(m,n.option.range):function(t,e,n){var i=t[1]-t[0],r=(e=z(e,(function(e){return{interval:[(e.interval[0]-t[0])/i,(e.interval[1]-t[0])/i]}}))).length,o=0;return function(t){var i;for(i=o;i=0;i--){var a;if((a=e[i].interval)[0]<=t&&t<=a[1]){o=i;break}}return i>=0&&i=0?1:-1:o>0?1:-1}(n,o,r,i,c),function(t,e,n,i,r,o,a,s,l,u){var h,c=l.valueDim,p=l.categoryDim,d=Math.abs(n[p.wh]),f=t.getItemVisual(e,"symbolSize");h=Y(f)?f.slice():null==f?["100%","100%"]:[f,f];h[p.index]=$r(h[p.index],d),h[c.index]=$r(h[c.index],i?d:Math.abs(o)),u.symbolSize=h;var g=u.symbolScale=[h[0]/s,h[1]/s];g[c.index]*=(l.isHorizontal?-1:1)*a}(t,e,r,o,0,c.boundingLength,c.pxSign,u,i,c),function(t,e,n,i,r){var o=t.get(gO)||0;o&&(vO.attr({scaleX:e[0],scaleY:e[1],rotation:n}),vO.updateTransform(),o/=vO.getLineScale(),o*=e[i.valueDim.index]);r.valueLineWidth=o||0}(n,c.symbolScale,l,i,c);var p=c.symbolSize,d=Zy(n.get("symbolOffset"),p);return function(t,e,n,i,r,o,a,s,l,u,h,c){var p=h.categoryDim,d=h.valueDim,f=c.pxSign,g=Math.max(e[d.index]+s,0),y=g;if(i){var v=Math.abs(l),m=it(t.get("symbolMargin"),"15%")+"",x=!1;m.lastIndexOf("!")===m.length-1&&(x=!0,m=m.slice(0,m.length-1));var _=$r(m,e[d.index]),b=Math.max(g+2*_,0),w=x?0:2*_,S=vo(i),M=S?i:NO((v+w)/b);b=g+2*(_=(v-M*g)/2/(x?M:Math.max(M-1,1))),w=x?0:2*_,S||"fixed"===i||(M=u?NO((Math.abs(u)+w)/b):0),y=M*b-w,c.repeatTimes=M,c.symbolMargin=_}var I=f*(y/2),T=c.pathPosition=[];T[p.index]=n[p.wh]/2,T[d.index]="start"===a?I:"end"===a?l-I:l/2,o&&(T[0]+=o[0],T[1]+=o[1]);var C=c.bundlePosition=[];C[p.index]=n[p.xy],C[d.index]=n[d.xy];var D=c.barRectShape=A({},n);D[d.wh]=f*Math.max(Math.abs(n[d.wh]),Math.abs(T[d.index]+I)),D[p.wh]=n[p.wh];var k=c.clipShape={};k[p.xy]=-n[p.xy],k[p.wh]=h.ecSize[p.wh],k[d.xy]=0,k[d.wh]=n[d.wh]}(n,p,r,o,0,d,s,c.valueLineWidth,c.boundingLength,c.repeatCutLength,i,c),c}function _O(t,e){return t.toGlobalCoord(t.dataToCoord(t.scale.parse(e)))}function bO(t){var e=t.symbolPatternSize,n=Xy(t.symbolType,-e/2,-e/2,e,e);return n.attr({culling:!0}),"image"!==n.type&&n.setStyle({strokeNoScale:!0}),n}function wO(t,e,n,i){var r=t.__pictorialBundle,o=n.symbolSize,a=n.valueLineWidth,s=n.pathPosition,l=e.valueDim,u=n.repeatTimes||0,h=0,c=o[e.valueDim.index]+a+2*n.symbolMargin;for(PO(t,(function(t){t.__pictorialAnimationIndex=h,t.__pictorialRepeatTimes=u,h0:i<0)&&(r=u-1-t),e[l.index]=c*(r-u/2+.5)+s[l.index],{x:e[0],y:e[1],scaleX:n.symbolScale[0],scaleY:n.symbolScale[1],rotation:n.rotation}}}function SO(t,e,n,i){var 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l=e.coordSys.model,u=MI(l),h=t.map[u];h||(h=t.map[u]={coordSysId:l.id,coordSysIndex:l.componentIndex,coordSysType:l.type,coordSysMainType:l.mainType,dataByAxis:[]},t.list.push(h)),h.dataByAxis.push({axisDim:o.dim,axisIndex:a.componentIndex,axisType:a.type,axisId:a.id,value:i,valueLabelOpt:{precision:s.get(["label","precision"]),formatter:s.get(["label","formatter"])},seriesDataIndices:r.slice()})}}function FN(t){var e=t.axis.model,n={},i=n.axisDim=t.axis.dim;return n.axisIndex=n[i+"AxisIndex"]=e.componentIndex,n.axisName=n[i+"AxisName"]=e.name,n.axisId=n[i+"AxisId"]=e.id,n}function GN(t){return!t||null==t[0]||isNaN(t[0])||null==t[1]||isNaN(t[1])}function WN(t){TI.registerAxisPointerClass("CartesianAxisPointer",wN),t.registerComponentModel(TN),t.registerComponentView(ON),t.registerPreprocessor((function(t){if(t){(!t.axisPointer||0===t.axisPointer.length)&&(t.axisPointer={});var 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this.ecModel.eachComponent(t,(function(t){t.getCoordSysModel()===this&&(e=t)}),this),e},e.type="polar",e.dependencies=["radiusAxis","angleAxis"],e.defaultOption={z:0,center:["50%","50%"],radius:"80%"},e}(zp),UN=function(t){function e(){return null!==t&&t.apply(this,arguments)||this}return n(e,t),e.prototype.getCoordSysModel=function(){return this.getReferringComponents("polar",Wo).models[0]},e.type="polarAxis",e}(zp);R(UN,D_);var ZN=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n}return n(e,t),e.type="angleAxis",e}(UN),jN=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n}return n(e,t),e.type="radiusAxis",e}(UN),qN=function(t){function e(e,n){return t.call(this,"radius",e,n)||this}return n(e,t),e.prototype.pointToData=function(t,e){return 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t.isHorizontal()?0:1}function EE(t,e){var n=t.getRect();return[n[LE[e]],n[LE[e]]+n[PE[e]]]}var zE=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n}return n(e,t),e.type="single",e}(Ag);var VE=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n}return n(e,t),e.prototype.init=function(e,n,i){var r=Rp(e);t.prototype.init.apply(this,arguments),BE(e,r)},e.prototype.mergeOption=function(e){t.prototype.mergeOption.apply(this,arguments),BE(this.option,e)},e.prototype.getCellSize=function(){return 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r=t.coordinateSystem,o=r.getRangeInfo(),a=r.getOrient(),s=e.getLocaleModel();this._renderDayRect(t,o,i),this._renderLines(t,o,a,i),this._renderYearText(t,o,a,i),this._renderMonthText(t,s,a,i),this._renderWeekText(t,s,o,a,i)},e.prototype._renderDayRect=function(t,e,n){for(var i=t.coordinateSystem,r=t.getModel("itemStyle").getItemStyle(),o=i.getCellWidth(),a=i.getCellHeight(),s=e.start.time;s<=e.end.time;s=i.getNextNDay(s,1).time){var l=i.dataToRect([s],!1).tl,u=new Ws({shape:{x:l[0],y:l[1],width:o,height:a},cursor:"default",style:r});n.add(u)}},e.prototype._renderLines=function(t,e,n,i){var r=this,o=t.coordinateSystem,a=t.getModel(["splitLine","lineStyle"]).getLineStyle(),s=t.get(["splitLine","show"]),l=a.lineWidth;this._tlpoints=[],this._blpoints=[],this._firstDayOfMonth=[],this._firstDayPoints=[];for(var u=e.start,h=0;u.time<=e.end.time;h++){p(u.formatedDate),0===h&&(u=o.getDateInfo(e.start.y+"-"+e.start.m));var c=u.date;c.setMonth(c.getMonth()+1),u=o.getDateInfo(c)}function p(e){r._firstDayOfMonth.push(o.getDateInfo(e)),r._firstDayPoints.push(o.dataToRect([e],!1).tl);var l=r._getLinePointsOfOneWeek(t,e,n);r._tlpoints.push(l[0]),r._blpoints.push(l[l.length-1]),s&&r._drawSplitline(l,a,i)}p(o.getNextNDay(e.end.time,1).formatedDate),s&&this._drawSplitline(r._getEdgesPoints(r._tlpoints,l,n),a,i),s&&this._drawSplitline(r._getEdgesPoints(r._blpoints,l,n),a,i)},e.prototype._getEdgesPoints=function(t,e,n){var i=[t[0].slice(),t[t.length-1].slice()],r="horizontal"===n?0:1;return i[0][r]=i[0][r]-e/2,i[1][r]=i[1][r]+e/2,i},e.prototype._drawSplitline=function(t,e,n){var i=new Zu({z2:20,shape:{points:t},style:e});n.add(i)},e.prototype._getLinePointsOfOneWeek=function(t,e,n){for(var i=t.coordinateSystem,r=i.getDateInfo(e),o=[],a=0;a<7;a++){var s=i.getNextNDay(r.time,a),l=i.dataToRect([s.time],!1);o[2*s.day]=l.tl,o[2*s.day+1]=l["horizontal"===n?"bl":"tr"]}return o},e.prototype._formatterLabel=function(t,e){return U(t)&&t?(n=t,E(e,(function(t,e){n=n.replace("{"+e+"}",i?re(t):t)})),n):X(t)?t(e):e.nameMap;var n,i},e.prototype._yearTextPositionControl=function(t,e,n,i,r){var o=e[0],a=e[1],s=["center","bottom"];"bottom"===i?(a+=r,s=["center","top"]):"left"===i?o-=r:"right"===i?(o+=r,s=["center","top"]):a-=r;var l=0;return"left"!==i&&"right"!==i||(l=Math.PI/2),{rotation:l,x:o,y:a,style:{align:s[0],verticalAlign:s[1]}}},e.prototype._renderYearText=function(t,e,n,i){var r=t.getModel("yearLabel");if(r.get("show")){var o=r.get("margin"),a=r.get("position");a||(a="horizontal"!==n?"top":"left");var s=[this._tlpoints[this._tlpoints.length-1],this._blpoints[0]],l=(s[0][0]+s[1][0])/2,u=(s[0][1]+s[1][1])/2,h="horizontal"===n?0:1,c={top:[l,s[h][1]],bottom:[l,s[1-h][1]],left:[s[1-h][0],u],right:[s[h][0],u]},p=e.start.y;+e.end.y>+e.start.y&&(p=p+"-"+e.end.y);var d=r.get("formatter"),f={start:e.start.y,end:e.end.y,nameMap:p},g=this._formatterLabel(d,f),y=new Xs({z2:30,style:oc(r,{text:g}),silent:r.get("silent")});y.attr(this._yearTextPositionControl(y,c[a],n,a,o)),i.add(y)}},e.prototype._monthTextPositionControl=function(t,e,n,i,r){var o="left",a="top",s=t[0],l=t[1];return"horizontal"===n?(l+=r,e&&(o="center"),"start"===i&&(a="bottom")):(s+=r,e&&(a="middle"),"start"===i&&(o="right")),{x:s,y:l,align:o,verticalAlign:a}},e.prototype._renderMonthText=function(t,e,n,i){var r=t.getModel("monthLabel");if(r.get("show")){var o=r.get("nameMap"),a=r.get("margin"),s=r.get("position"),l=r.get("align"),u=[this._tlpoints,this._blpoints];o&&!U(o)||(o&&(e=Vc(o)||e),o=e.get(["time","monthAbbr"])||[]);var h="start"===s?0:1,c="horizontal"===n?0:1;a="start"===s?-a:a;for(var p="center"===l,d=r.get("silent"),f=0;f=i.start.time&&n.timea.end.time&&t.reverse(),t},t.prototype._getRangeInfo=function(t){var e,n=[this.getDateInfo(t[0]),this.getDateInfo(t[1])];n[0].time>n[1].time&&(e=!0,n.reverse());var i=Math.floor(n[1].time/GE)-Math.floor(n[0].time/GE)+1,r=new Date(n[0].time),o=r.getDate(),a=n[1].date.getDate();r.setDate(o+i-1);var s=r.getDate();if(s!==a)for(var l=r.getTime()-n[1].time>0?1:-1;(s=r.getDate())!==a&&(r.getTime()-n[1].time)*l>0;)i-=l,r.setDate(s-l);var u=Math.floor((i+n[0].day+6)/7),h=e?1-u:u-1;return e&&n.reverse(),{range:[n[0].formatedDate,n[1].formatedDate],start:n[0],end:n[1],allDay:i,weeks:u,nthWeek:h,fweek:n[0].day,lweek:n[1].day}},t.prototype._getDateByWeeksAndDay=function(t,e,n){var i=this._getRangeInfo(n);if(t>i.weeks||0===t&&ei.lweek)return null;var r=7*(t-1)-i.fweek+e,o=new Date(i.start.time);return o.setDate(+i.start.d+r),this.getDateInfo(o)},t.create=function(e,n){var i=[];return e.eachComponent("calendar",(function(r){var o=new t(r,e,n);i.push(o),r.coordinateSystem=o})),e.eachSeries((function(t){"calendar"===t.get("coordinateSystem")&&(t.coordinateSystem=i[t.get("calendarIndex")||0])})),i},t.dimensions=["time","value"],t}();function HE(t){var e=t.calendarModel,n=t.seriesModel;return e?e.coordinateSystem:n?n.coordinateSystem:null}function YE(t,e){var n;return E(e,(function(e){null!=t[e]&&"auto"!==t[e]&&(n=!0)})),n}var XE=["transition","enterFrom","leaveTo"],UE=XE.concat(["enterAnimation","updateAnimation","leaveAnimation"]);function ZE(t,e,n){if(n&&(!t[n]&&e[n]&&(t[n]={}),t=t[n],e=e[n]),t&&e)for(var i=n?XE:UE,r=0;r=0;l--){var p,d,f;if(f=null!=(d=Ro((p=n[l]).id,null))?r.get(d):null){var g=f.parent,y=(c=KE(g),{}),v=Lp(f,p,g===i?{width:o,height:a}:{width:c.width,height:c.height},null,{hv:p.hv,boundingMode:p.bounding},y);if(!KE(f).isNew&&v){for(var m=p.transition,x={},_=0;_=0)?x[b]=w:f[b]=w}vh(f,x,t,0)}else f.attr(y)}}},e.prototype._clear=function(){var t=this,e=this._elMap;e.each((function(n){tz(n,KE(n).option,e,t._lastGraphicModel)})),this._elMap=yt()},e.prototype.dispose=function(){this._clear()},e.type="graphic",e}(Ag);function JE(t){var e=_t(qE,t)?qE[t]:Lh(t);var n=new e({});return KE(n).type=t,n}function QE(t,e,n,i){var r=JE(n);return e.add(r),i.set(t,r),KE(r).id=t,KE(r).isNew=!0,r}function tz(t,e,n,i){t&&t.parent&&("group"===t.type&&t.traverse((function(t){tz(t,e,n,i)})),vR(t,e,i),n.removeKey(KE(t).id))}function ez(t,e,n,i){t.isGroup||E([["cursor",Da.prototype.cursor],["zlevel",i||0],["z",n||0],["z2",0]],(function(n){var i=n[0];_t(e,i)?t[i]=rt(e[i],n[1]):null==t[i]&&(t[i]=n[1])})),E(G(e),(function(n){if(0===n.indexOf("on")){var i=e[n];t[n]=X(i)?i:null}})),_t(e,"draggable")&&(t.draggable=e.draggable),null!=e.name&&(t.name=e.name),null!=e.id&&(t.id=e.id)}var nz=["x","y","radius","angle","single"],iz=["cartesian2d","polar","singleAxis"];function rz(t){return t+"Axis"}function oz(t,e){var n,i=yt(),r=[],o=yt();t.eachComponent({mainType:"dataZoom",query:e},(function(t){o.get(t.uid)||s(t)}));do{n=!1,t.eachComponent("dataZoom",a)}while(n);function a(t){!o.get(t.uid)&&function(t){var e=!1;return t.eachTargetAxis((function(t,n){var r=i.get(t);r&&r[n]&&(e=!0)})),e}(t)&&(s(t),n=!0)}function 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e=uz(t);C(this.option,t,!0),C(this.settledOption,e,!0),this._doInit(e)},e.prototype._doInit=function(t){var e=this.option;this._setDefaultThrottle(t),this._updateRangeUse(t);var n=this.settledOption;E([["start","startValue"],["end","endValue"]],(function(t,i){"value"===this._rangePropMode[i]&&(e[t[0]]=n[t[0]]=null)}),this),this._resetTarget()},e.prototype._resetTarget=function(){var t=this.get("orient",!0),e=this._targetAxisInfoMap=yt();this._fillSpecifiedTargetAxis(e)?this._orient=t||this._makeAutoOrientByTargetAxis():(this._orient=t||"horizontal",this._fillAutoTargetAxisByOrient(e,this._orient)),this._noTarget=!0,e.each((function(t){t.indexList.length&&(this._noTarget=!1)}),this)},e.prototype._fillSpecifiedTargetAxis=function(t){var e=!1;return E(nz,(function(n){var i=this.getReferringComponents(rz(n),Ho);if(i.specified){e=!0;var r=new sz;E(i.models,(function(t){r.add(t.componentIndex)})),t.set(n,r)}}),this),e},e.prototype._fillAutoTargetAxisByOrient=function(t,e){var n=this.ecModel,i=!0;if(i){var r="vertical"===e?"y":"x";o(n.findComponents({mainType:r+"Axis"}),r)}i&&o(n.findComponents({mainType:"singleAxis",filter:function(t){return t.get("orient",!0)===e}}),"single");function o(e,n){var r=e[0];if(r){var o=new sz;if(o.add(r.componentIndex),t.set(n,o),i=!1,"x"===n||"y"===n){var a=r.getReferringComponents("grid",Wo).models[0];a&&E(e,(function(t){r.componentIndex!==t.componentIndex&&a===t.getReferringComponents("grid",Wo).models[0]&&o.add(t.componentIndex)}))}}}i&&E(nz,(function(e){if(i){var r=n.findComponents({mainType:rz(e),filter:function(t){return"category"===t.get("type",!0)}});if(r[0]){var o=new sz;o.add(r[0].componentIndex),t.set(e,o),i=!1}}}),this)},e.prototype._makeAutoOrientByTargetAxis=function(){var t;return this.eachTargetAxis((function(e){!t&&(t=e)}),this),"y"===t?"vertical":"horizontal"},e.prototype._setDefaultThrottle=function(t){if(t.hasOwnProperty("throttle")&&(this._autoThrottle=!1),this._autoThrottle){var e=this.ecModel.option;this.option.throttle=e.animation&&e.animationDurationUpdate>0?100:20}},e.prototype._updateRangeUse=function(t){var e=this._rangePropMode,n=this.get("rangeMode");E([["start","startValue"],["end","endValue"]],(function(i,r){var o=null!=t[i[0]],a=null!=t[i[1]];o&&!a?e[r]="percent":!o&&a?e[r]="value":n?e[r]=n[r]:o&&(e[r]="percent")}))},e.prototype.noTarget=function(){return this._noTarget},e.prototype.getFirstTargetAxisModel=function(){var t;return this.eachTargetAxis((function(e,n){null==t&&(t=this.ecModel.getComponent(rz(e),n))}),this),t},e.prototype.eachTargetAxis=function(t,e){this._targetAxisInfoMap.each((function(n,i){E(n.indexList,(function(n){t.call(e,i,n)}))}))},e.prototype.getAxisProxy=function(t,e){var n=this.getAxisModel(t,e);if(n)return n.__dzAxisProxy},e.prototype.getAxisModel=function(t,e){var n=this._targetAxisInfoMap.get(t);if(n&&n.indexMap[e])return this.ecModel.getComponent(rz(t),e)},e.prototype.setRawRange=function(t){var e=this.option,n=this.settledOption;E([["start","startValue"],["end","endValue"]],(function(i){null==t[i[0]]&&null==t[i[1]]||(e[i[0]]=n[i[0]]=t[i[0]],e[i[1]]=n[i[1]]=t[i[1]])}),this),this._updateRangeUse(t)},e.prototype.setCalculatedRange=function(t){var e=this.option;E(["start","startValue","end","endValue"],(function(n){e[n]=t[n]}))},e.prototype.getPercentRange=function(){var t=this.findRepresentativeAxisProxy();if(t)return t.getDataPercentWindow()},e.prototype.getValueRange=function(t,e){if(null!=t||null!=e)return this.getAxisProxy(t,e).getDataValueWindow();var n=this.findRepresentativeAxisProxy();return n?n.getDataValueWindow():void 0},e.prototype.findRepresentativeAxisProxy=function(t){if(t)return t.__dzAxisProxy;for(var e,n=this._targetAxisInfoMap.keys(),i=0;i=0}(e)){var n=rz(this._dimName),i=e.getReferringComponents(n,Wo).models[0];i&&this._axisIndex===i.componentIndex&&t.push(e)}}),this),t},t.prototype.getAxisModel=function(){return this.ecModel.getComponent(this._dimName+"Axis",this._axisIndex)},t.prototype.getMinMaxSpan=function(){return T(this._minMaxSpan)},t.prototype.calculateDataWindow=function(t){var e,n=this._dataExtent,i=this.getAxisModel().axis.scale,r=this._dataZoomModel.getRangePropMode(),o=[0,100],a=[],s=[];dz(["start","end"],(function(l,u){var h=t[l],c=t[l+"Value"];"percent"===r[u]?(null==h&&(h=o[u]),c=i.parse(Kr(h,o,n))):(e=!0,h=Kr(c=null==c?n[u]:i.parse(c),n,o)),s[u]=null==c||isNaN(c)?n[u]:c,a[u]=null==h||isNaN(h)?o[u]:h})),fz(s),fz(a);var l=this._minMaxSpan;function u(t,e,n,r,o){var a=o?"Span":"ValueSpan";zk(0,t,n,"all",l["min"+a],l["max"+a]);for(var s=0;s<2;s++)e[s]=Kr(t[s],n,r,!0),o&&(e[s]=i.parse(e[s]))}return e?u(s,a,n,o,!1):u(a,s,o,n,!0),{valueWindow:s,percentWindow:a}},t.prototype.reset=function(t){if(t===this._dataZoomModel){var e=this.getTargetSeriesModels();this._dataExtent=function(t,e,n){var i=[1/0,-1/0];dz(n,(function(t){!function(t,e,n){e&&E(C_(e,n),(function(n){var i=e.getApproximateExtent(n);i[0]t[1]&&(t[1]=i[1])}))}(i,t.getData(),e)}));var r=t.getAxisModel(),o=v_(r.axis.scale,r,i).calculate();return[o.min,o.max]}(this,this._dimName,e),this._updateMinMaxSpan();var n=this.calculateDataWindow(t.settledOption);this._valueWindow=n.valueWindow,this._percentWindow=n.percentWindow,this._setAxisModel()}},t.prototype.filterData=function(t,e){if(t===this._dataZoomModel){var n=this._dimName,i=this.getTargetSeriesModels(),r=t.get("filterMode"),o=this._valueWindow;"none"!==r&&dz(i,(function(t){var e=t.getData(),i=e.mapDimensionsAll(n);if(i.length){if("weakFilter"===r){var a=e.getStore(),s=z(i,(function(t){return e.getDimensionIndex(t)}),e);e.filterSelf((function(t){for(var e,n,r,l=0;lo[1];if(h&&!c&&!p)return!0;h&&(r=!0),c&&(e=!0),p&&(n=!0)}return r&&e&&n}))}else dz(i,(function(n){if("empty"===r)t.setData(e=e.map(n,(function(t){return function(t){return t>=o[0]&&t<=o[1]}(t)?t:NaN})));else{var i={};i[n]=o,e.selectRange(i)}}));dz(i,(function(t){e.setApproximateExtent(o,t)}))}}))}},t.prototype._updateMinMaxSpan=function(){var t=this._minMaxSpan={},e=this._dataZoomModel,n=this._dataExtent;dz(["min","max"],(function(i){var r=e.get(i+"Span"),o=e.get(i+"ValueSpan");null!=o&&(o=this.getAxisModel().axis.scale.parse(o)),null!=o?r=Kr(n[0]+o,n,[0,100],!0):null!=r&&(o=Kr(r,[0,100],n,!0)-n[0]),t[i+"Span"]=r,t[i+"ValueSpan"]=o}),this)},t.prototype._setAxisModel=function(){var t=this.getAxisModel(),e=this._percentWindow,n=this._valueWindow;if(e){var i=no(n,[0,500]);i=Math.min(i,20);var r=t.axis.scale.rawExtentInfo;0!==e[0]&&r.setDeterminedMinMax("min",+n[0].toFixed(i)),100!==e[1]&&r.setDeterminedMinMax("max",+n[1].toFixed(i)),r.freeze()}},t}();var yz={getTargetSeries:function(t){function e(e){t.eachComponent("dataZoom",(function(n){n.eachTargetAxis((function(i,r){var o=t.getComponent(rz(i),r);e(i,r,o,n)}))}))}e((function(t,e,n,i){n.__dzAxisProxy=null}));var n=[];e((function(e,i,r,o){r.__dzAxisProxy||(r.__dzAxisProxy=new gz(e,i,o,t),n.push(r.__dzAxisProxy))}));var i=yt();return E(n,(function(t){E(t.getTargetSeriesModels(),(function(t){i.set(t.uid,t)}))})),i},overallReset:function(t,e){t.eachComponent("dataZoom",(function(t){t.eachTargetAxis((function(e,n){t.getAxisProxy(e,n).reset(t)})),t.eachTargetAxis((function(n,i){t.getAxisProxy(n,i).filterData(t,e)}))})),t.eachComponent("dataZoom",(function(t){var e=t.findRepresentativeAxisProxy();if(e){var n=e.getDataPercentWindow(),i=e.getDataValueWindow();t.setCalculatedRange({start:n[0],end:n[1],startValue:i[0],endValue:i[1]})}}))}};var vz=!1;function mz(t){vz||(vz=!0,t.registerProcessor(t.PRIORITY.PROCESSOR.FILTER,yz),function(t){t.registerAction("dataZoom",(function(t,e){E(oz(e,t),(function(e){e.setRawRange({start:t.start,end:t.end,startValue:t.startValue,endValue:t.endValue})}))}))}(t),t.registerSubTypeDefaulter("dataZoom",(function(){return"slider"})))}function xz(t){t.registerComponentModel(hz),t.registerComponentView(pz),mz(t)}var _z=function(){},bz={};function wz(t,e){bz[t]=e}function Sz(t){return bz[t]}var Mz=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n}return n(e,t),e.prototype.optionUpdated=function(){t.prototype.optionUpdated.apply(this,arguments);var e=this.ecModel;E(this.option.feature,(function(t,n){var i=Sz(n);i&&(i.getDefaultOption&&(i.defaultOption=i.getDefaultOption(e)),C(t,i.defaultOption))}))},e.type="toolbox",e.layoutMode={type:"box",ignoreSize:!0},e.defaultOption={show:!0,z:6,orient:"horizontal",left:"right",top:"top",backgroundColor:"transparent",borderColor:"#ccc",borderRadius:0,borderWidth:0,padding:5,itemSize:15,itemGap:8,showTitle:!0,iconStyle:{borderColor:"#666",color:"none"},emphasis:{iconStyle:{borderColor:"#3E98C5"}},tooltip:{show:!1,position:"bottom"}},e}(zp);function Iz(t,e){var n=vp(e.get("padding")),i=e.getItemStyle(["color","opacity"]);return 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a(t,"xAxis","xAxisIndex")})),iV(o.yAxisModels,(function(t){return a(t,"yAxis","yAxisIndex")})),r}function a(t,e,n){var o=t.componentIndex,a={type:"select",$fromToolbox:!0,filterMode:i.get("filterMode",!0)||"filter",id:rV+e+o};a[n]=o,r.push(a)}},lt(null==od.get(eV)&&nV),od.set(eV,nV);var lV=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n}return n(e,t),e.type="tooltip",e.dependencies=["axisPointer"],e.defaultOption={z:60,show:!0,showContent:!0,trigger:"item",triggerOn:"mousemove|click",alwaysShowContent:!1,displayMode:"single",renderMode:"auto",confine:null,showDelay:0,hideDelay:100,transitionDuration:.4,enterable:!1,backgroundColor:"#fff",shadowBlur:10,shadowColor:"rgba(0, 0, 0, .2)",shadowOffsetX:1,shadowOffsetY:2,borderRadius:4,borderWidth:1,padding:null,extraCssText:"",axisPointer:{type:"line",axis:"auto",animation:"auto",animationDurationUpdate:200,animationEasingUpdate:"exponentialOut",crossStyle:{color:"#999",width:1,type:"dashed",textStyle:{}}},textStyle:{color:"#666",fontSize:14}},e}(zp);function uV(t){var e=t.get("confine");return null!=e?!!e:"richText"===t.get("renderMode")}function hV(t){if(r.domSupported)for(var e=document.documentElement.style,n=0,i=t.length;n-1?(u+="top:50%",h+="translateY(-50%) rotate("+(a="left"===s?-225:-45)+"deg)"):(u+="left:50%",h+="translateX(-50%) rotate("+(a="top"===s?225:45)+"deg)");var c=a*Math.PI/180,p=l+r,d=p*Math.abs(Math.cos(c))+p*Math.abs(Math.sin(c)),f=e+" solid "+r+"px;";return'
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v=bf(s.formatTooltip(l,!1,u)),m=d.get("order"),x=d.get("valueFormatter"),_=v.frag,b=_?cg(x?A({valueFormatter:x},_):_,y,c,m,i.get("useUTC"),d.get("textStyle")):v.text,w="item_"+s.name+"_"+l;this._showOrMove(d,(function(){this._showTooltipContent(d,b,g,w,t.offsetX,t.offsetY,t.position,t.target,y)})),n({type:"showTip",dataIndexInside:l,dataIndex:h.getRawIndex(l),seriesIndex:o,from:this.uid})}},e.prototype._showComponentItemTooltip=function(t,e,n){var i="html"===this._renderMode,r=rl(e),o=r.tooltipConfig.option||{},a=o.encodeHTMLContent;if(U(o)){o={content:o,formatter:o},a=!0}a&&i&&o.content&&((o=T(o)).content=re(o.content));var s=[o],l=this._ecModel.getComponent(r.componentMainType,r.componentIndex);l&&s.push(l),s.push({formatter:o.content});var u=t.positionDefault,h=TV(s,this._tooltipModel,u?{position:u}:null),c=h.get("content"),p=Math.random()+"",d=new yg;this._showOrMove(h,(function(){var n=T(h.get("formatterParams")||{});this._showTooltipContent(h,c,n,p,t.offsetX,t.offsetY,t.position,e,d)})),n({type:"showTip",from:this.uid})},e.prototype._showTooltipContent=function(t,e,n,i,r,o,a,s,l){if(this._ticket="",t.get("showContent")&&t.get("show")){var u=this._tooltipContent;u.setEnterable(t.get("enterable"));var h=t.get("formatter");a=a||t.get("position");var c=e,p=this._getNearestPoint([r,o],n,t.get("trigger"),t.get("borderColor")).color;if(h)if(U(h)){var d=t.ecModel.get("useUTC"),f=Y(n)?n[0]:n;c=h,f&&f.axisType&&f.axisType.indexOf("time")>=0&&(c=Jc(f.axisValue,c,d)),c=bp(c,n,!0)}else if(X(h)){var g=W((function(e,i){e===this._ticket&&(u.setContent(i,l,t,p,a),this._updatePosition(t,a,r,o,u,n,s))}),this);this._ticket=i,c=h(n,i,g)}else c=h;u.setContent(c,l,t,p,a),u.show(t,p),this._updatePosition(t,a,r,o,u,n,s)}},e.prototype._getNearestPoint=function(t,e,n,i){return"axis"===n||Y(e)?{color:i||("html"===this._renderMode?"#fff":"none")}:Y(e)?void 0:{color:i||e.color||e.borderColor}},e.prototype._updatePosition=function(t,e,n,i,r,o,a){var s=this._api.getWidth(),l=this._api.getHeight();e=e||t.get("position");var u=r.getSize(),h=t.get("align"),c=t.get("verticalAlign"),p=a&&a.getBoundingRect().clone();if(a&&p.applyTransform(a.transform),X(e)&&(e=e([n,i],o,r.el,p,{viewSize:[s,l],contentSize:u.slice()})),Y(e))n=$r(e[0],s),i=$r(e[1],l);else if(q(e)){var d=e;d.width=u[0],d.height=u[1];var f=kp(d,{width:s,height:l});n=f.x,i=f.y,h=null,c=null}else if(U(e)&&a){var g=function(t,e,n,i){var r=n[0],o=n[1],a=Math.ceil(Math.SQRT2*i)+8,s=0,l=0,u=e.width,h=e.height;switch(t){case"inside":s=e.x+u/2-r/2,l=e.y+h/2-o/2;break;case"top":s=e.x+u/2-r/2,l=e.y-o-a;break;case"bottom":s=e.x+u/2-r/2,l=e.y+h+a;break;case"left":s=e.x-r-a,l=e.y+h/2-o/2;break;case"right":s=e.x+u+a,l=e.y+h/2-o/2}return[s,l]}(e,p,u,t.get("borderWidth"));n=g[0],i=g[1]}else{g=function(t,e,n,i,r,o,a){var s=n.getSize(),l=s[0],u=s[1];null!=o&&(t+l+o+2>i?t-=l+o:t+=o);null!=a&&(e+u+a>r?e-=u+a:e+=a);return[t,e]}(n,i,r,s,l,h?null:20,c?null:20);n=g[0],i=g[1]}if(h&&(n-=DV(h)?u[0]/2:"right"===h?u[0]:0),c&&(i-=DV(c)?u[1]/2:"bottom"===c?u[1]:0),uV(t)){g=function(t,e,n,i,r){var o=n.getSize(),a=o[0],s=o[1];return t=Math.min(t+a,i)-a,e=Math.min(e+s,r)-s,t=Math.max(t,0),e=Math.max(e,0),[t,e]}(n,i,r,s,l);n=g[0],i=g[1]}r.moveTo(n,i)},e.prototype._updateContentNotChangedOnAxis=function(t,e){var n=this._lastDataByCoordSys,i=this._cbParamsList,r=!!n&&n.length===t.length;return r&&E(n,(function(n,o){var a=n.dataByAxis||[],s=(t[o]||{}).dataByAxis||[];(r=r&&a.length===s.length)&&E(a,(function(t,n){var o=s[n]||{},a=t.seriesDataIndices||[],l=o.seriesDataIndices||[];(r=r&&t.value===o.value&&t.axisType===o.axisType&&t.axisId===o.axisId&&a.length===l.length)&&E(a,(function(t,e){var n=l[e];r=r&&t.seriesIndex===n.seriesIndex&&t.dataIndex===n.dataIndex})),i&&E(t.seriesDataIndices,(function(t){var n=t.seriesIndex,o=e[n],a=i[n];o&&a&&a.data!==o.data&&(r=!1)}))}))})),this._lastDataByCoordSys=t,this._cbParamsList=e,!!r},e.prototype._hide=function(t){this._lastDataByCoordSys=null,t({type:"hideTip",from:this.uid})},e.prototype.dispose=function(t,e){!r.node&&e.getDom()&&(Yg(this,"_updatePosition"),this._tooltipContent.dispose(),PN("itemTooltip",e))},e.type="tooltip",e}(Ag);function TV(t,e,n){var i,r=e.ecModel;n?(i=new Cc(n,r,r),i=new Cc(e.option,i,r)):i=e;for(var o=t.length-1;o>=0;o--){var a=t[o];a&&(a instanceof Cc&&(a=a.get("tooltip",!0)),U(a)&&(a={formatter:a}),a&&(i=new Cc(a,i,r)))}return i}function CV(t,e){return t.dispatchAction||W(e.dispatchAction,e)}function DV(t){return"center"===t||"middle"===t}var AV=["rect","polygon","keep","clear"];function kV(t,e){var n=To(t?t.brush:[]);if(n.length){var i=[];E(n,(function(t){var e=t.hasOwnProperty("toolbox")?t.toolbox:[];e instanceof Array&&(i=i.concat(e))}));var r=t&&t.toolbox;Y(r)&&(r=r[0]),r||(r={feature:{}},t.toolbox=[r]);var o=r.feature||(r.feature={}),a=o.brush||(o.brush={}),s=a.type||(a.type=[]);s.push.apply(s,i),function(t){var e={};E(t,(function(t){e[t]=1})),t.length=0,E(e,(function(e,n){t.push(n)}))}(s),e&&!s.length&&s.push.apply(s,AV)}}var LV=E;function PV(t){if(t)for(var e in t)if(t.hasOwnProperty(e))return!0}function OV(t,e,n){var i={};return LV(e,(function(e){var r,o=i[e]=((r=function(){}).prototype.__hidden=r.prototype,new r);LV(t[e],(function(t,i){if(kD.isValidType(i)){var r={type:i,visual:t};n&&n(r,e),o[i]=new kD(r),"opacity"===i&&((r=T(r)).type="colorAlpha",o.__hidden.__alphaForOpacity=new kD(r))}}))})),i}function RV(t,e,n){var i;E(n,(function(t){e.hasOwnProperty(t)&&PV(e[t])&&(i=!0)})),i&&E(n,(function(n){e.hasOwnProperty(n)&&PV(e[n])?t[n]=T(e[n]):delete t[n]}))}var NV={lineX:EV(0),lineY:EV(1),rect:{point:function(t,e,n){return t&&n.boundingRect.contain(t[0],t[1])},rect:function(t,e,n){return t&&n.boundingRect.intersect(t)}},polygon:{point:function(t,e,n){return t&&n.boundingRect.contain(t[0],t[1])&&P_(n.range,t[0],t[1])},rect:function(t,e,n){var i=n.range;if(!t||i.length<=1)return!1;var r=t.x,o=t.y,a=t.width,s=t.height,l=i[0];return!!(P_(i,r,o)||P_(i,r+a,o)||P_(i,r,o+s)||P_(i,r+a,o+s)||ze.create(t).contain(l[0],l[1])||Zh(r,o,r+a,o,i)||Zh(r,o,r,o+s,i)||Zh(r+a,o,r+a,o+s,i)||Zh(r,o+s,r+a,o+s,i))||void 0}}};function EV(t){var e=["x","y"],n=["width","height"];return{point:function(e,n,i){if(e){var r=i.range;return zV(e[t],r)}},rect:function(i,r,o){if(i){var a=o.range,s=[i[e[t]],i[e[t]]+i[n[t]]];return s[1]e[0][1]&&(e[0][1]=o[0]),o[1]e[1][1]&&(e[1][1]=o[1])}return e&&UV(e)}};function UV(t){return new ze(t[0][0],t[1][0],t[0][1]-t[0][0],t[1][1]-t[1][0])}var ZV=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n}return n(e,t),e.prototype.init=function(t,e){this.ecModel=t,this.api=e,this.model,(this._brushController=new lL(e.getZr())).on("brush",W(this._onBrush,this)).mount()},e.prototype.render=function(t,e,n,i){this.model=t,this._updateController(t,e,n,i)},e.prototype.updateTransform=function(t,e,n,i){GV(e),this._updateController(t,e,n,i)},e.prototype.updateVisual=function(t,e,n,i){this.updateTransform(t,e,n,i)},e.prototype.updateView=function(t,e,n,i){this._updateController(t,e,n,i)},e.prototype._updateController=function(t,e,n,i){(!i||i.$from!==t.id)&&this._brushController.setPanels(t.brushTargetManager.makePanelOpts(n)).enableBrush(t.brushOption).updateCovers(t.areas.slice())},e.prototype.dispose=function(){this._brushController.dispose()},e.prototype._onBrush=function(t){var e=this.model.id,n=this.model.brushTargetManager.setOutputRanges(t.areas,this.ecModel);(!t.isEnd||t.removeOnClick)&&this.api.dispatchAction({type:"brush",brushId:e,areas:T(n),$from:e}),t.isEnd&&this.api.dispatchAction({type:"brushEnd",brushId:e,areas:T(n),$from:e})},e.type="brush",e}(Ag),jV=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n.areas=[],n.brushOption={},n}return n(e,t),e.prototype.optionUpdated=function(t,e){var n=this.option;!e&&RV(n,t,["inBrush","outOfBrush"]);var i=n.inBrush=n.inBrush||{};n.outOfBrush=n.outOfBrush||{color:"#ddd"},i.hasOwnProperty("liftZ")||(i.liftZ=5)},e.prototype.setAreas=function(t){t&&(this.areas=z(t,(function(t){return qV(this.option,t)}),this))},e.prototype.setBrushOption=function(t){this.brushOption=qV(this.option,t),this.brushType=this.brushOption.brushType},e.type="brush",e.dependencies=["geo","grid","xAxis","yAxis","parallel","series"],e.defaultOption={seriesIndex:"all",brushType:"rect",brushMode:"single",transformable:!0,brushStyle:{borderWidth:1,color:"rgba(210,219,238,0.3)",borderColor:"#D2DBEE"},throttleType:"fixRate",throttleDelay:0,removeOnClick:!0,z:1e4},e}(zp);function qV(t,e){return C({brushType:t.brushType,brushMode:t.brushMode,transformable:t.transformable,brushStyle:new 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n(e,t),e.type="timeline",e}(Ag),iB=function(t){function e(e,n,i,r){var o=t.call(this,e,n,i)||this;return o.type=r||"value",o}return n(e,t),e.prototype.getLabelModel=function(){return this.model.getModel("label")},e.prototype.isHorizontal=function(){return"horizontal"===this.model.get("orient")},e}(ab),rB=Math.PI,oB=Vo(),aB=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n}return n(e,t),e.prototype.init=function(t,e){this.api=e},e.prototype.render=function(t,e,n){if(this.model=t,this.api=n,this.ecModel=e,this.group.removeAll(),t.get("show",!0)){var i=this._layout(t,n),r=this._createGroup("_mainGroup"),o=this._createGroup("_labelGroup"),a=this._axis=this._createAxis(i,t);t.formatTooltip=function(t){return og("nameValue",{noName:!0,value:a.scale.getLabel({value:t})})},E(["AxisLine","AxisTick","Control","CurrentPointer"],(function(e){this["_render"+e](i,r,a,t)}),this),this._renderAxisLabel(i,o,a,t),this._position(i,t)}this._doPlayStop(),this._updateTicksStatus()},e.prototype.remove=function(){this._clearTimer(),this.group.removeAll()},e.prototype.dispose=function(){this._clearTimer()},e.prototype._layout=function(t,e){var n,i,r,o,a=t.get(["label","position"]),s=t.get("orient"),l=function(t,e){return kp(t.getBoxLayoutParams(),{width:e.getWidth(),height:e.getHeight()},t.get("padding"))}(t,e),u={horizontal:"center",vertical:(n=null==a||"auto"===a?"horizontal"===s?l.y+l.height/2=0||"+"===n?"left":"right"},h={horizontal:n>=0||"+"===n?"top":"bottom",vertical:"middle"},c={horizontal:0,vertical:rB/2},p="vertical"===s?l.height:l.width,d=t.getModel("controlStyle"),f=d.get("show",!0),g=f?d.get("itemSize"):0,y=f?d.get("itemGap"):0,v=g+y,m=t.get(["label","rotate"])||0;m=m*rB/180;var x=d.get("position",!0),_=f&&d.get("showPlayBtn",!0),b=f&&d.get("showPrevBtn",!0),w=f&&d.get("showNextBtn",!0),S=0,M=p;"left"===x||"bottom"===x?(_&&(i=[0,0],S+=v),b&&(r=[S,0],S+=v),w&&(o=[M-g,0],M-=v)):(_&&(i=[M-g,0],M-=v),b&&(r=[0,0],S+=v),w&&(o=[M-g,0],M-=v));var I=[S,M];return t.get("inverse")&&I.reverse(),{viewRect:l,mainLength:p,orient:s,rotation:c[s],labelRotation:m,labelPosOpt:n,labelAlign:t.get(["label","align"])||u[s],labelBaseline:t.get(["label","verticalAlign"])||t.get(["label","baseline"])||h[s],playPosition:i,prevBtnPosition:r,nextBtnPosition:o,axisExtent:I,controlSize:g,controlGap:y}},e.prototype._position=function(t,e){var n=this._mainGroup,i=this._labelGroup,r=t.viewRect;if("vertical"===t.orient){var o=[1,0,0,1,0,0],a=r.x,s=r.y+r.height;we(o,o,[-a,-s]),Se(o,o,-rB/2),we(o,o,[a,s]),(r=r.clone()).applyTransform(o)}var l=y(r),u=y(n.getBoundingRect()),h=y(i.getBoundingRect()),c=[n.x,n.y],p=[i.x,i.y];p[0]=c[0]=l[0][0];var d,f=t.labelPosOpt;null==f||U(f)?(v(c,u,l,1,d="+"===f?0:1),v(p,h,l,1,1-d)):(v(c,u,l,1,d=f>=0?0:1),p[1]=c[1]+f);function g(t){t.originX=l[0][0]-t.x,t.originY=l[1][0]-t.y}function y(t){return[[t.x,t.x+t.width],[t.y,t.y+t.height]]}function v(t,e,n,i,r){t[i]+=n[i][r]-e[i][r]}n.setPosition(c),i.setPosition(p),n.rotation=i.rotation=t.rotation,g(n),g(i)},e.prototype._createAxis=function(t,e){var n=e.getData(),i=e.get("axisType"),r=function(t,e){if(e=e||t.get("type"),e)switch(e){case"category":return new Rx({ordinalMeta:t.getCategories(),extent:[1/0,-1/0]});case"time":return new Kx({locale:t.ecModel.getLocaleModel(),useUTC:t.ecModel.get("useUTC")});default:return new Ex}}(e,i);r.getTicks=function(){return n.mapArray(["value"],(function(t){return{value:t}}))};var o=n.getDataExtent("value");r.setExtent(o[0],o[1]),r.calcNiceTicks();var a=new iB("value",r,t.axisExtent,i);return a.model=e,a},e.prototype._createGroup=function(t){var e=this[t]=new Br;return this.group.add(e),e},e.prototype._renderAxisLine=function(t,e,n,i){var r=n.getExtent();if(i.get(["lineStyle","show"])){var o=new Ku({shape:{x1:r[0],y1:0,x2:r[1],y2:0},style:A({lineCap:"round"},i.getModel("lineStyle").getLineStyle()),silent:!0,z2:1});e.add(o);var a=this._progressLine=new Ku({shape:{x1:r[0],x2:this._currentPointer?this._currentPointer.x:r[0],y1:0,y2:0},style:k({lineCap:"round",lineWidth:o.style.lineWidth},i.getModel(["progress","lineStyle"]).getLineStyle()),silent:!0,z2:1});e.add(a)}},e.prototype._renderAxisTick=function(t,e,n,i){var r=this,o=i.getData(),a=n.scale.getTicks();this._tickSymbols=[],E(a,(function(t){var a=n.dataToCoord(t.value),s=o.getItemModel(t.value),l=s.getModel("itemStyle"),u=s.getModel(["emphasis","itemStyle"]),h=s.getModel(["progress","itemStyle"]),c={x:a,y:0,onclick:W(r._changeTimeline,r,t.value)},p=sB(s,l,e,c);p.ensureState("emphasis").style=u.getItemStyle(),p.ensureState("progress").style=h.getItemStyle(),Ul(p);var d=rl(p);s.get("tooltip")?(d.dataIndex=t.value,d.dataModel=i):d.dataIndex=d.dataModel=null,r._tickSymbols.push(p)}))},e.prototype._renderAxisLabel=function(t,e,n,i){var r=this;if(n.getLabelModel().get("show")){var o=i.getData(),a=n.getViewLabels();this._tickLabels=[],E(a,(function(i){var a=i.tickValue,s=o.getItemModel(a),l=s.getModel("label"),u=s.getModel(["emphasis","label"]),h=s.getModel(["progress","label"]),c=n.dataToCoord(i.tickValue),p=new Xs({x:c,y:0,rotation:t.labelRotation-t.rotation,onclick:W(r._changeTimeline,r,a),silent:!1,style:oc(l,{text:i.formattedLabel,align:t.labelAlign,verticalAlign:t.labelBaseline})});p.ensureState("emphasis").style=oc(u),p.ensureState("progress").style=oc(h),e.add(p),Ul(p),oB(p).dataIndex=a,r._tickLabels.push(p)}))}},e.prototype._renderControl=function(t,e,n,i){var r=t.controlSize,o=t.rotation,a=i.getModel("controlStyle").getItemStyle(),s=i.getModel(["emphasis","controlStyle"]).getItemStyle(),l=i.getPlayState(),u=i.get("inverse",!0);function h(t,n,l,u){if(t){var h=Cr(rt(i.get(["controlStyle",n+"BtnSize"]),r),r),c=function(t,e,n,i){var r=i.style,o=Uh(t.get(["controlStyle",e]),i||{},new ze(n[0],n[1],n[2],n[3]));r&&o.setStyle(r);return o}(i,n+"Icon",[0,-h/2,h,h],{x:t[0],y:t[1],originX:r/2,originY:0,rotation:u?-o:0,rectHover:!0,style:a,onclick:l});c.ensureState("emphasis").style=s,e.add(c),Ul(c)}}h(t.nextBtnPosition,"next",W(this._changeTimeline,this,u?"-":"+")),h(t.prevBtnPosition,"prev",W(this._changeTimeline,this,u?"+":"-")),h(t.playPosition,l?"stop":"play",W(this._handlePlayClick,this,!l),!0)},e.prototype._renderCurrentPointer=function(t,e,n,i){var 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n=t.getData(),i=t.coordinateSystem,r=i&&i.dimensions;if(!function(t){return!isNaN(parseFloat(t.x))&&!isNaN(parseFloat(t.y))}(e)&&!Y(e.coord)&&Y(r)){var o=bB(e,n,i,t);if((e=T(e)).type&&xB[e.type]&&o.baseAxis&&o.valueAxis){var a=P(r,o.baseAxis.dim),s=P(r,o.valueAxis.dim),l=xB[e.type](n,o.baseDataDim,o.valueDataDim,a,s);e.coord=l[0],e.value=l[1]}else e.coord=[null!=e.xAxis?e.xAxis:e.radiusAxis,null!=e.yAxis?e.yAxis:e.angleAxis]}if(null!=e.coord&&Y(r))for(var u=e.coord,h=0;h<2;h++)xB[u[h]]&&(u[h]=MB(n,n.mapDimension(r[h]),u[h]));else e.coord=[];return e}}function bB(t,e,n,i){var r={};return null!=t.valueIndex||null!=t.valueDim?(r.valueDataDim=null!=t.valueIndex?e.getDimension(t.valueIndex):t.valueDim,r.valueAxis=n.getAxis(function(t,e){var n=t.getData().getDimensionInfo(e);return 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p=n.getModel("itemStyle").getItemStyle(),d=Ay(a,"color");p.fill||(p.fill=d),u.setItemVisual(t,{symbol:i,symbolSize:r,symbolRotate:o,symbolOffset:s,symbolKeepAspect:l,style:p})})),l.updateData(u),this.group.add(l.group),u.eachItemGraphicEl((function(t){t.traverse((function(t){rl(t).dataModel=e}))})),this.markKeep(l),l.group.silent=e.get("silent")||t.get("silent")},e.type="markPoint",e}(TB);var AB=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n}return n(e,t),e.prototype.createMarkerModelFromSeries=function(t,n,i){return new e(t,n,i)},e.type="markLine",e.defaultOption={z:5,symbol:["circle","arrow"],symbolSize:[8,16],symbolOffset:0,precision:2,tooltip:{trigger:"item"},label:{show:!0,position:"end",distance:5},lineStyle:{type:"dashed"},emphasis:{label:{show:!0},lineStyle:{width:3}},animationEasing:"linear"},e}(gB),kB=Vo(),LB=function(t,e,n,i){var r,o=t.getData();if(Y(i))r=i;else{var 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d=e.get("symbol"),f=e.get("symbolSize"),g=e.get("symbolRotate"),y=e.get("symbolOffset");function v(e,n,r){var o=e.getItemModel(n);NB(e,n,r,t,i);var s=o.getModel("itemStyle").getItemStyle();null==s.fill&&(s.fill=Ay(a,"color")),e.setItemVisual(n,{symbolKeepAspect:o.get("symbolKeepAspect"),symbolOffset:rt(o.get("symbolOffset",!0),y[r?0:1]),symbolRotate:rt(o.get("symbolRotate",!0),g[r?0:1]),symbolSize:rt(o.get("symbolSize"),f[r?0:1]),symbol:rt(o.get("symbol",!0),d[r?0:1]),style:s})}Y(d)||(d=[d,d]),Y(f)||(f=[f,f]),Y(g)||(g=[g,g]),Y(y)||(y=[y,y]),u.from.each((function(t){v(h,t,!0),v(c,t,!1)})),p.each((function(t){var e=p.getItemModel(t).getModel("lineStyle").getLineStyle();p.setItemLayout(t,[h.getItemLayout(t),c.getItemLayout(t)]),null==e.stroke&&(e.stroke=h.getItemVisual(t,"style").fill),p.setItemVisual(t,{fromSymbolKeepAspect:h.getItemVisual(t,"symbolKeepAspect"),fromSymbolOffset:h.getItemVisual(t,"symbolOffset"),fromSymbolRotate:h.getItemVisual(t,"symbolRotate"),fromSymbolSize:h.getItemVisual(t,"symbolSize"),fromSymbol:h.getItemVisual(t,"symbol"),toSymbolKeepAspect:c.getItemVisual(t,"symbolKeepAspect"),toSymbolOffset:c.getItemVisual(t,"symbolOffset"),toSymbolRotate:c.getItemVisual(t,"symbolRotate"),toSymbolSize:c.getItemVisual(t,"symbolSize"),toSymbol:c.getItemVisual(t,"symbol"),style:e})})),l.updateData(p),u.line.eachItemGraphicEl((function(t){rl(t).dataModel=e,t.traverse((function(t){rl(t).dataModel=e}))})),this.markKeep(l),l.group.silent=e.get("silent")||t.get("silent")},e.type="markLine",e}(TB);var zB=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return 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e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n.newlineDisabled=!1,n}return n(e,t),e.prototype.init=function(){this.group.add(this._contentGroup=new qB),this.group.add(this._selectorGroup=new qB),this._isFirstRender=!0},e.prototype.getContentGroup=function(){return this._contentGroup},e.prototype.getSelectorGroup=function(){return this._selectorGroup},e.prototype.render=function(t,e,n){var i=this._isFirstRender;if(this._isFirstRender=!1,this.resetInner(),t.get("show",!0)){var r=t.get("align"),o=t.get("orient");r&&"auto"!==r||(r="right"===t.get("left")&&"vertical"===o?"right":"left");var a=t.get("selector",!0),s=t.get("selectorPosition",!0);!a||s&&"auto"!==s||(s="horizontal"===o?"end":"start"),this.renderInner(r,t,e,n,a,o,s);var l=t.getBoxLayoutParams(),u={width:n.getWidth(),height:n.getHeight()},h=t.get("padding"),c=kp(l,u,h),p=this.layoutInner(t,r,c,i,a,s),d=kp(k({width:p.width,height:p.height},l),u,h);this.group.x=d.x-p.x,this.group.y=d.y-p.y,this.group.markRedraw(),this.group.add(this._backgroundEl=Iz(p,t))}},e.prototype.resetInner=function(){this.getContentGroup().removeAll(),this._backgroundEl&&this.group.remove(this._backgroundEl),this.getSelectorGroup().removeAll()},e.prototype.renderInner=function(t,e,n,i,r,o,a){var s=this.getContentGroup(),l=yt(),u=e.get("selectedMode"),h=[];n.eachRawSeries((function(t){!t.get("legendHoverLink")&&h.push(t.id)})),jB(e.getData(),(function(r,o){var a=r.get("name");if(!this.newlineDisabled&&(""===a||"\n"===a)){var c=new qB;return c.newline=!0,void s.add(c)}var p=n.getSeriesByName(a)[0];if(!l.get(a)){if(p){var d=p.getData(),f=d.getVisual("legendLineStyle")||{},g=d.getVisual("legendIcon"),y=d.getVisual("style"),v=this._createItem(p,a,o,r,e,t,f,y,g,u,i);v.on("click",ZB($B,a,null,i,h)).on("mouseover",ZB(QB,p.name,null,i,h)).on("mouseout",ZB(tF,p.name,null,i,h)),n.ssr&&v.eachChild((function(t){var e=rl(t);e.seriesIndex=p.seriesIndex,e.dataIndex=o,e.ssrType="legend"})),l.set(a,!0)}else n.eachRawSeries((function(s){if(!l.get(a)&&s.legendVisualProvider){var c=s.legendVisualProvider;if(!c.containName(a))return;var p=c.indexOfName(a),d=c.getItemVisual(p,"style"),f=c.getItemVisual(p,"legendIcon"),g=qn(d.fill);g&&0===g[3]&&(g[3]=.2,d=A(A({},d),{fill:ri(g,"rgba")}));var y=this._createItem(s,a,o,r,e,t,{},d,f,u,i);y.on("click",ZB($B,null,a,i,h)).on("mouseover",ZB(QB,null,a,i,h)).on("mouseout",ZB(tF,null,a,i,h)),n.ssr&&y.eachChild((function(t){var e=rl(t);e.seriesIndex=s.seriesIndex,e.dataIndex=o,e.ssrType="legend"})),l.set(a,!0)}}),this);0}}),this),r&&this._createSelector(r,e,i,o,a)},e.prototype._createSelector=function(t,e,n,i,r){var o=this.getSelectorGroup();jB(t,(function(t){var i=t.type,r=new Xs({style:{x:0,y:0,align:"center",verticalAlign:"middle"},onclick:function(){n.dispatchAction({type:"all"===i?"legendAllSelect":"legendInverseSelect",legendId:e.id})}});o.add(r),ic(r,{normal:e.getModel("selectorLabel"),emphasis:e.getModel(["emphasis","selectorLabel"])},{defaultText:t.title}),Ul(r)}))},e.prototype._createItem=function(t,e,n,i,r,o,a,s,l,u,h){var c=t.visualDrawType,p=r.get("itemWidth"),d=r.get("itemHeight"),f=r.isSelected(e),g=i.get("symbolRotate"),y=i.get("symbolKeepAspect"),v=i.get("icon"),m=function(t,e,n,i,r,o,a){function s(t,e){"auto"===t.lineWidth&&(t.lineWidth=e.lineWidth>0?2:0),jB(t,(function(n,i){"inherit"===t[i]&&(t[i]=e[i])}))}var l=e.getModel("itemStyle"),u=l.getItemStyle(),h=0===t.lastIndexOf("empty",0)?"fill":"stroke",c=l.getShallow("decal");u.decal=c&&"inherit"!==c?mv(c,a):i.decal,"inherit"===u.fill&&(u.fill=i[r]);"inherit"===u.stroke&&(u.stroke=i[h]);"inherit"===u.opacity&&(u.opacity=("fill"===r?i:n).opacity);s(u,i);var p=e.getModel("lineStyle"),d=p.getLineStyle();if(s(d,n),"auto"===u.fill&&(u.fill=i.fill),"auto"===u.stroke&&(u.stroke=i.fill),"auto"===d.stroke&&(d.stroke=i.fill),!o){var f=e.get("inactiveBorderWidth"),g=u[h];u.lineWidth="auto"===f?i.lineWidth>0&&g?2:0:u.lineWidth,u.fill=e.get("inactiveColor"),u.stroke=e.get("inactiveBorderColor"),d.stroke=p.get("inactiveColor"),d.lineWidth=p.get("inactiveWidth")}return{itemStyle:u,lineStyle:d}}(l=v||l||"roundRect",i,a,s,c,f,h),x=new qB,_=i.getModel("textStyle");if(!X(t.getLegendIcon)||v&&"inherit"!==v){var b="inherit"===v&&t.getData().getVisual("symbol")?"inherit"===g?t.getData().getVisual("symbolRotate"):g:0;x.add(function(t){var e=t.icon||"roundRect",n=Xy(e,0,0,t.itemWidth,t.itemHeight,t.itemStyle.fill,t.symbolKeepAspect);n.setStyle(t.itemStyle),n.rotation=(t.iconRotate||0)*Math.PI/180,n.setOrigin([t.itemWidth/2,t.itemHeight/2]),e.indexOf("empty")>-1&&(n.style.stroke=n.style.fill,n.style.fill="#fff",n.style.lineWidth=2);return n}({itemWidth:p,itemHeight:d,icon:l,iconRotate:b,itemStyle:m.itemStyle,lineStyle:m.lineStyle,symbolKeepAspect:y}))}else x.add(t.getLegendIcon({itemWidth:p,itemHeight:d,icon:l,iconRotate:g,itemStyle:m.itemStyle,lineStyle:m.lineStyle,symbolKeepAspect:y}));var w="left"===o?p+5:-5,S=o,M=r.get("formatter"),I=e;U(M)&&M?I=M.replace("{name}",null!=e?e:""):X(M)&&(I=M(e));var T=f?_.getTextColor():i.get("inactiveColor");x.add(new Xs({style:oc(_,{text:I,x:w,y:d/2,fill:T,align:S,verticalAlign:"middle"},{inheritColor:T})}));var C=new Ws({shape:x.getBoundingRect(),style:{fill:"transparent"}}),D=i.getModel("tooltip");return D.get("show")&&Kh({el:C,componentModel:r,itemName:e,itemTooltipOption:D.option}),x.add(C),x.eachChild((function(t){t.silent=!0})),C.silent=!u,this.getContentGroup().add(x),Ul(x),x.__legendDataIndex=n,x},e.prototype.layoutInner=function(t,e,n,i,r,o){var a=this.getContentGroup(),s=this.getSelectorGroup();Ap(t.get("orient"),a,t.get("itemGap"),n.width,n.height);var l=a.getBoundingRect(),u=[-l.x,-l.y];if(s.markRedraw(),a.markRedraw(),r){Ap("horizontal",s,t.get("selectorItemGap",!0));var h=s.getBoundingRect(),c=[-h.x,-h.y],p=t.get("selectorButtonGap",!0),d=t.getOrient().index,f=0===d?"width":"height",g=0===d?"height":"width",y=0===d?"y":"x";"end"===o?c[d]+=l[f]+p:u[d]+=h[f]+p,c[1-d]+=l[g]/2-h[g]/2,s.x=c[0],s.y=c[1],a.x=u[0],a.y=u[1];var v={x:0,y:0};return v[f]=l[f]+p+h[f],v[g]=Math.max(l[g],h[g]),v[y]=Math.min(0,h[y]+c[1-d]),v}return a.x=u[0],a.y=u[1],this.group.getBoundingRect()},e.prototype.remove=function(){this.getContentGroup().removeAll(),this._isFirstRender=!0},e.type="legend.plain",e}(Ag);function $B(t,e,n,i){tF(t,e,n,i),n.dispatchAction({type:"legendToggleSelect",name:null!=t?t:e}),QB(t,e,n,i)}function JB(t){for(var e,n=t.getZr().storage.getDisplayList(),i=0,r=n.length;in[r],f=[-c.x,-c.y];e||(f[i]=l[s]);var g=[0,0],y=[-p.x,-p.y],v=rt(t.get("pageButtonGap",!0),t.get("itemGap",!0));d&&("end"===t.get("pageButtonPosition",!0)?y[i]+=n[r]-p[r]:g[i]+=p[r]+v);y[1-i]+=c[o]/2-p[o]/2,l.setPosition(f),u.setPosition(g),h.setPosition(y);var m={x:0,y:0};if(m[r]=d?n[r]:c[r],m[o]=Math.max(c[o],p[o]),m[a]=Math.min(0,p[a]+y[1-i]),u.__rectSize=n[r],d){var x={x:0,y:0};x[r]=Math.max(n[r]-p[r]-v,0),x[o]=m[o],u.setClipPath(new Ws({shape:x})),u.__rectSize=x[r]}else h.eachChild((function(t){t.attr({invisible:!0,silent:!0})}));var _=this._getPageInfo(t);return null!=_.pageIndex&&vh(l,{x:_.contentPosition[0],y:_.contentPosition[1]},d?t:null),this._updatePageInfoView(t,_),m},e.prototype._pageGo=function(t,e,n){var i=this._getPageInfo(e)[t];null!=i&&n.dispatchAction({type:"legendScroll",scrollDataIndex:i,legendId:e.id})},e.prototype._updatePageInfoView=function(t,e){var n=this._controllerGroup;E(["pagePrev","pageNext"],(function(i){var r=null!=e[i+"DataIndex"],o=n.childOfName(i);o&&(o.setStyle("fill",r?t.get("pageIconColor",!0):t.get("pageIconInactiveColor",!0)),o.cursor=r?"pointer":"default")}));var i=n.childOfName("pageText"),r=t.get("pageFormatter"),o=e.pageIndex,a=null!=o?o+1:0,s=e.pageCount;i&&r&&i.setStyle("text",U(r)?r.replace("{current}",null==a?"":a+"").replace("{total}",null==s?"":s+""):r({current:a,total:s}))},e.prototype._getPageInfo=function(t){var e=t.get("scrollDataIndex",!0),n=this.getContentGroup(),i=this._containerGroup.__rectSize,r=t.getOrient().index,o=lF[r],a=uF[r],s=this._findTargetItemIndex(e),l=n.children(),u=l[s],h=l.length,c=h?1:0,p={contentPosition:[n.x,n.y],pageCount:c,pageIndex:c-1,pagePrevDataIndex:null,pageNextDataIndex:null};if(!u)return p;var d=m(u);p.contentPosition[r]=-d.s;for(var f=s+1,g=d,y=d,v=null;f<=h;++f)(!(v=m(l[f]))&&y.e>g.s+i||v&&!x(v,g.s))&&(g=y.i>g.i?y:v)&&(null==p.pageNextDataIndex&&(p.pageNextDataIndex=g.i),++p.pageCount),y=v;for(f=s-1,g=d,y=d,v=null;f>=-1;--f)(v=m(l[f]))&&x(y,v.s)||!(g.i=e&&t.s<=e+i}},e.prototype._findTargetItemIndex=function(t){return this._showController?(this.getContentGroup().eachChild((function(i,r){var o=i.__legendDataIndex;null==n&&null!=o&&(n=r),o===t&&(e=r)})),null!=e?e:n):0;var e,n},e.type="legend.scroll",e}(KB);function cF(t){Vm(rF),t.registerComponentModel(oF),t.registerComponentView(hF),function(t){t.registerAction("legendScroll","legendscroll",(function(t,e){var n=t.scrollDataIndex;null!=n&&e.eachComponent({mainType:"legend",subType:"scroll",query:t},(function(t){t.setScrollDataIndex(n)}))}))}(t)}var pF=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n}return n(e,t),e.type="dataZoom.inside",e.defaultOption=kc(lz.defaultOption,{disabled:!1,zoomLock:!1,zoomOnMouseWheel:!0,moveOnMouseMove:!0,moveOnMouseWheel:!1,preventDefaultMouseMove:!0}),e}(lz),dF=Vo();function fF(t,e,n){dF(t).coordSysRecordMap.each((function(t){var i=t.dataZoomInfoMap.get(e.uid);i&&(i.getRange=n)}))}function gF(t,e){if(e){t.removeKey(e.model.uid);var n=e.controller;n&&n.dispose()}}function yF(t,e){t.isDisposed()||t.dispatchAction({type:"dataZoom",animation:{easing:"cubicOut",duration:100},batch:e})}function vF(t,e,n,i){return t.coordinateSystem.containPoint([n,i])}function mF(t){t.registerProcessor(t.PRIORITY.PROCESSOR.FILTER,(function(t,e){var n=dF(e),i=n.coordSysRecordMap||(n.coordSysRecordMap=yt());i.each((function(t){t.dataZoomInfoMap=null})),t.eachComponent({mainType:"dataZoom",subType:"inside"},(function(t){E(az(t).infoList,(function(n){var r=n.model.uid,o=i.get(r)||i.set(r,function(t,e){var n={model:e,containsPoint:H(vF,e),dispatchAction:H(yF,t),dataZoomInfoMap:null,controller:null},i=n.controller=new nT(t.getZr());return E(["pan","zoom","scrollMove"],(function(t){i.on(t,(function(e){var i=[];n.dataZoomInfoMap.each((function(r){if(e.isAvailableBehavior(r.model.option)){var o=(r.getRange||{})[t],a=o&&o(r.dzReferCoordSysInfo,n.model.mainType,n.controller,e);!r.model.get("disabled",!0)&&a&&i.push({dataZoomId:r.model.id,start:a[0],end:a[1]})}})),i.length&&n.dispatchAction(i)}))})),n}(e,n.model));(o.dataZoomInfoMap||(o.dataZoomInfoMap=yt())).set(t.uid,{dzReferCoordSysInfo:n,model:t,getRange:null})}))})),i.each((function(t){var e,n=t.controller,r=t.dataZoomInfoMap;if(r){var o=r.keys()[0];null!=o&&(e=r.get(o))}if(e){var a=function(t){var e,n="type_",i={type_true:2,type_move:1,type_false:0,type_undefined:-1},r=!0;return t.each((function(t){var o=t.model,a=!o.get("disabled",!0)&&(!o.get("zoomLock",!0)||"move");i[n+a]>i[n+e]&&(e=a),r=r&&o.get("preventDefaultMouseMove",!0)})),{controlType:e,opt:{zoomOnMouseWheel:!0,moveOnMouseMove:!0,moveOnMouseWheel:!0,preventDefaultMouseMove:!!r}}}(r);n.enable(a.controlType,a.opt),n.setPointerChecker(t.containsPoint),Hg(t,"dispatchAction",e.model.get("throttle",!0),"fixRate")}else gF(i,t)}))}))}var xF=function(t){function e(){var e=null!==t&&t.apply(this,arguments)||this;return e.type="dataZoom.inside",e}return n(e,t),e.prototype.render=function(e,n,i){t.prototype.render.apply(this,arguments),e.noTarget()?this._clear():(this.range=e.getPercentRange(),fF(i,e,{pan:W(_F.pan,this),zoom:W(_F.zoom,this),scrollMove:W(_F.scrollMove,this)}))},e.prototype.dispose=function(){this._clear(),t.prototype.dispose.apply(this,arguments)},e.prototype._clear=function(){!function(t,e){for(var n=dF(t).coordSysRecordMap,i=n.keys(),r=0;r0?s.pixelStart+s.pixelLength-s.pixel:s.pixel-s.pixelStart)/s.pixelLength*(o[1]-o[0])+o[0],u=Math.max(1/i.scale,0);o[0]=(o[0]-l)*u+l,o[1]=(o[1]-l)*u+l;var h=this.dataZoomModel.findRepresentativeAxisProxy().getMinMaxSpan();return zk(0,o,[0,100],0,h.minSpan,h.maxSpan),this.range=o,r[0]!==o[0]||r[1]!==o[1]?o:void 0}},pan:bF((function(t,e,n,i,r,o){var a=wF[i]([o.oldX,o.oldY],[o.newX,o.newY],e,r,n);return a.signal*(t[1]-t[0])*a.pixel/a.pixelLength})),scrollMove:bF((function(t,e,n,i,r,o){return wF[i]([0,0],[o.scrollDelta,o.scrollDelta],e,r,n).signal*(t[1]-t[0])*o.scrollDelta}))};function bF(t){return function(e,n,i,r){var o=this.range,a=o.slice(),s=e.axisModels[0];if(s)return zk(t(a,s,e,n,i,r),a,[0,100],"all"),this.range=a,o[0]!==a[0]||o[1]!==a[1]?a:void 0}}var wF={grid:function(t,e,n,i,r){var o=n.axis,a={},s=r.model.coordinateSystem.getRect();return t=t||[0,0],"x"===o.dim?(a.pixel=e[0]-t[0],a.pixelLength=s.width,a.pixelStart=s.x,a.signal=o.inverse?1:-1):(a.pixel=e[1]-t[1],a.pixelLength=s.height,a.pixelStart=s.y,a.signal=o.inverse?-1:1),a},polar:function(t,e,n,i,r){var o=n.axis,a={},s=r.model.coordinateSystem,l=s.getRadiusAxis().getExtent(),u=s.getAngleAxis().getExtent();return t=t?s.pointToCoord(t):[0,0],e=s.pointToCoord(e),"radiusAxis"===n.mainType?(a.pixel=e[0]-t[0],a.pixelLength=l[1]-l[0],a.pixelStart=l[0],a.signal=o.inverse?1:-1):(a.pixel=e[1]-t[1],a.pixelLength=u[1]-u[0],a.pixelStart=u[0],a.signal=o.inverse?-1:1),a},singleAxis:function(t,e,n,i,r){var o=n.axis,a=r.model.coordinateSystem.getRect(),s={};return t=t||[0,0],"horizontal"===o.orient?(s.pixel=e[0]-t[0],s.pixelLength=a.width,s.pixelStart=a.x,s.signal=o.inverse?1:-1):(s.pixel=e[1]-t[1],s.pixelLength=a.height,s.pixelStart=a.y,s.signal=o.inverse?-1:1),s}};function SF(t){mz(t),t.registerComponentModel(pF),t.registerComponentView(xF),mF(t)}var MF=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n}return n(e,t),e.type="dataZoom.slider",e.layoutMode="box",e.defaultOption=kc(lz.defaultOption,{show:!0,right:"ph",top:"ph",width:"ph",height:"ph",left:null,bottom:null,borderColor:"#d2dbee",borderRadius:3,backgroundColor:"rgba(47,69,84,0)",dataBackground:{lineStyle:{color:"#d2dbee",width:.5},areaStyle:{color:"#d2dbee",opacity:.2}},selectedDataBackground:{lineStyle:{color:"#8fb0f7",width:.5},areaStyle:{color:"#8fb0f7",opacity:.2}},fillerColor:"rgba(135,175,274,0.2)",handleIcon:"path://M-9.35,34.56V42m0-40V9.5m-2,0h4a2,2,0,0,1,2,2v21a2,2,0,0,1-2,2h-4a2,2,0,0,1-2-2v-21A2,2,0,0,1-11.35,9.5Z",handleSize:"100%",handleStyle:{color:"#fff",borderColor:"#ACB8D1"},moveHandleSize:7,moveHandleIcon:"path://M-320.9-50L-320.9-50c18.1,0,27.1,9,27.1,27.1V85.7c0,18.1-9,27.1-27.1,27.1l0,0c-18.1,0-27.1-9-27.1-27.1V-22.9C-348-41-339-50-320.9-50z M-212.3-50L-212.3-50c18.1,0,27.1,9,27.1,27.1V85.7c0,18.1-9,27.1-27.1,27.1l0,0c-18.1,0-27.1-9-27.1-27.1V-22.9C-239.4-41-230.4-50-212.3-50z M-103.7-50L-103.7-50c18.1,0,27.1,9,27.1,27.1V85.7c0,18.1-9,27.1-27.1,27.1l0,0c-18.1,0-27.1-9-27.1-27.1V-22.9C-130.9-41-121.8-50-103.7-50z",moveHandleStyle:{color:"#D2DBEE",opacity:.7},showDetail:!0,showDataShadow:"auto",realtime:!0,zoomLock:!1,textStyle:{color:"#6E7079"},brushSelect:!0,brushStyle:{color:"rgba(135,175,274,0.15)"},emphasis:{handleLabel:{show:!0},handleStyle:{borderColor:"#8FB0F7"},moveHandleStyle:{color:"#8FB0F7"}}}),e}(lz),IF=Ws,TF="horizontal",CF="vertical",DF=["line","bar","candlestick","scatter"],AF={easing:"cubicOut",duration:100,delay:0},kF=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n._displayables={},n}return n(e,t),e.prototype.init=function(t,e){this.api=e,this._onBrush=W(this._onBrush,this),this._onBrushEnd=W(this._onBrushEnd,this)},e.prototype.render=function(e,n,i,r){if(t.prototype.render.apply(this,arguments),Hg(this,"_dispatchZoomAction",e.get("throttle"),"fixRate"),this._orient=e.getOrient(),!1!==e.get("show")){if(e.noTarget())return this._clear(),void this.group.removeAll();r&&"dataZoom"===r.type&&r.from===this.uid||this._buildView(),this._updateView()}else this.group.removeAll()},e.prototype.dispose=function(){this._clear(),t.prototype.dispose.apply(this,arguments)},e.prototype._clear=function(){Yg(this,"_dispatchZoomAction");var t=this.api.getZr();t.off("mousemove",this._onBrush),t.off("mouseup",this._onBrushEnd)},e.prototype._buildView=function(){var t=this.group;t.removeAll(),this._brushing=!1,this._displayables.brushRect=null,this._resetLocation(),this._resetInterval();var e=this._displayables.sliderGroup=new Br;this._renderBackground(),this._renderHandle(),this._renderDataShadow(),t.add(e),this._positionGroup()},e.prototype._resetLocation=function(){var t=this.dataZoomModel,e=this.api,n=t.get("brushSelect")?7:0,i=this._findCoordRect(),r={width:e.getWidth(),height:e.getHeight()},o=this._orient===TF?{right:r.width-i.x-i.width,top:r.height-30-7-n,width:i.width,height:30}:{right:7,top:i.y,width:30,height:i.height},a=Rp(t.option);E(["right","top","width","height"],(function(t){"ph"===a[t]&&(a[t]=o[t])}));var s=kp(a,r);this._location={x:s.x,y:s.y},this._size=[s.width,s.height],this._orient===CF&&this._size.reverse()},e.prototype._positionGroup=function(){var t=this.group,e=this._location,n=this._orient,i=this.dataZoomModel.getFirstTargetAxisModel(),r=i&&i.get("inverse"),o=this._displayables.sliderGroup,a=(this._dataShadowInfo||{}).otherAxisInverse;o.attr(n!==TF||r?n===TF&&r?{scaleY:a?1:-1,scaleX:-1}:n!==CF||r?{scaleY:a?-1:1,scaleX:-1,rotation:Math.PI/2}:{scaleY:a?-1:1,scaleX:1,rotation:Math.PI/2}:{scaleY:a?1:-1,scaleX:1});var s=t.getBoundingRect([o]);t.x=e.x-s.x,t.y=e.y-s.y,t.markRedraw()},e.prototype._getViewExtent=function(){return[0,this._size[0]]},e.prototype._renderBackground=function(){var t=this.dataZoomModel,e=this._size,n=this._displayables.sliderGroup,i=t.get("brushSelect");n.add(new IF({silent:!0,shape:{x:0,y:0,width:e[0],height:e[1]},style:{fill:t.get("backgroundColor")},z2:-40}));var r=new IF({shape:{x:0,y:0,width:e[0],height:e[1]},style:{fill:"transparent"},z2:0,onclick:W(this._onClickPanel,this)}),o=this.api.getZr();i?(r.on("mousedown",this._onBrushStart,this),r.cursor="crosshair",o.on("mousemove",this._onBrush),o.on("mouseup",this._onBrushEnd)):(o.off("mousemove",this._onBrush),o.off("mouseup",this._onBrushEnd)),n.add(r)},e.prototype._renderDataShadow=function(){var t=this._dataShadowInfo=this._prepareDataShadowInfo();if(this._displayables.dataShadowSegs=[],t){var e=this._size,n=this._shadowSize||[],i=t.series,r=i.getRawData(),o=i.getShadowDim&&i.getShadowDim(),a=o&&r.getDimensionInfo(o)?i.getShadowDim():t.otherDim;if(null!=a){var s=this._shadowPolygonPts,l=this._shadowPolylinePts;if(r!==this._shadowData||a!==this._shadowDim||e[0]!==n[0]||e[1]!==n[1]){var u=r.getDataExtent(a),h=.3*(u[1]-u[0]);u=[u[0]-h,u[1]+h];var c,p=[0,e[1]],d=[0,e[0]],f=[[e[0],0],[0,0]],g=[],y=d[1]/(r.count()-1),v=0,m=Math.round(r.count()/e[0]);r.each([a],(function(t,e){if(m>0&&e%m)v+=y;else{var n=null==t||isNaN(t)||""===t,i=n?0:Kr(t,u,p,!0);n&&!c&&e?(f.push([f[f.length-1][0],0]),g.push([g[g.length-1][0],0])):!n&&c&&(f.push([v,0]),g.push([v,0])),f.push([v,i]),g.push([v,i]),v+=y,c=n}})),s=this._shadowPolygonPts=f,l=this._shadowPolylinePts=g}this._shadowData=r,this._shadowDim=a,this._shadowSize=[e[0],e[1]];for(var x=this.dataZoomModel,_=0;_<3;_++){var b=w(1===_);this._displayables.sliderGroup.add(b),this._displayables.dataShadowSegs.push(b)}}}function w(t){var e=x.getModel(t?"selectedDataBackground":"dataBackground"),n=new Br,i=new Xu({shape:{points:s},segmentIgnoreThreshold:1,style:e.getModel("areaStyle").getAreaStyle(),silent:!0,z2:-20}),r=new Zu({shape:{points:l},segmentIgnoreThreshold:1,style:e.getModel("lineStyle").getLineStyle(),silent:!0,z2:-19});return n.add(i),n.add(r),n}},e.prototype._prepareDataShadowInfo=function(){var t=this.dataZoomModel,e=t.get("showDataShadow");if(!1!==e){var n,i=this.ecModel;return t.eachTargetAxis((function(r,o){E(t.getAxisProxy(r,o).getTargetSeriesModels(),(function(t){if(!(n||!0!==e&&P(DF,t.get("type"))<0)){var a,s=i.getComponent(rz(r),o).axis,l=function(t){var e={x:"y",y:"x",radius:"angle",angle:"radius"};return e[t]}(r),u=t.coordinateSystem;null!=l&&u.getOtherAxis&&(a=u.getOtherAxis(s).inverse),l=t.getData().mapDimension(l),n={thisAxis:s,series:t,thisDim:r,otherDim:l,otherAxisInverse:a}}}),this)}),this),n}},e.prototype._renderHandle=function(){var t=this.group,e=this._displayables,n=e.handles=[null,null],i=e.handleLabels=[null,null],r=this._displayables.sliderGroup,o=this._size,a=this.dataZoomModel,s=this.api,l=a.get("borderRadius")||0,u=a.get("brushSelect"),h=e.filler=new IF({silent:u,style:{fill:a.get("fillerColor")},textConfig:{position:"inside"}});r.add(h),r.add(new IF({silent:!0,subPixelOptimize:!0,shape:{x:0,y:0,width:o[0],height:o[1],r:l},style:{stroke:a.get("dataBackgroundColor")||a.get("borderColor"),lineWidth:1,fill:"rgba(0,0,0,0)"}})),E([0,1],(function(e){var o=a.get("handleIcon");!Wy[o]&&o.indexOf("path://")<0&&o.indexOf("image://")<0&&(o="path://"+o);var s=Xy(o,-1,0,2,2,null,!0);s.attr({cursor:LF(this._orient),draggable:!0,drift:W(this._onDragMove,this,e),ondragend:W(this._onDragEnd,this),onmouseover:W(this._showDataInfo,this,!0),onmouseout:W(this._showDataInfo,this,!1),z2:5});var l=s.getBoundingRect(),u=a.get("handleSize");this._handleHeight=$r(u,this._size[1]),this._handleWidth=l.width/l.height*this._handleHeight,s.setStyle(a.getModel("handleStyle").getItemStyle()),s.style.strokeNoScale=!0,s.rectHover=!0,s.ensureState("emphasis").style=a.getModel(["emphasis","handleStyle"]).getItemStyle(),Ul(s);var h=a.get("handleColor");null!=h&&(s.style.fill=h),r.add(n[e]=s);var c=a.getModel("textStyle"),p=(a.get("handleLabel")||{}).show||!1;t.add(i[e]=new Xs({silent:!0,invisible:!p,style:oc(c,{x:0,y:0,text:"",verticalAlign:"middle",align:"center",fill:c.getTextColor(),font:c.getFont()}),z2:10}))}),this);var c=h;if(u){var p=$r(a.get("moveHandleSize"),o[1]),d=e.moveHandle=new Ws({style:a.getModel("moveHandleStyle").getItemStyle(),silent:!0,shape:{r:[0,0,2,2],y:o[1]-.5,height:p}}),f=.8*p,g=e.moveHandleIcon=Xy(a.get("moveHandleIcon"),-f/2,-f/2,f,f,"#fff",!0);g.silent=!0,g.y=o[1]+p/2-.5,d.ensureState("emphasis").style=a.getModel(["emphasis","moveHandleStyle"]).getItemStyle();var y=Math.min(o[1]/2,Math.max(p,10));(c=e.moveZone=new Ws({invisible:!0,shape:{y:o[1]-y,height:p+y}})).on("mouseover",(function(){s.enterEmphasis(d)})).on("mouseout",(function(){s.leaveEmphasis(d)})),r.add(d),r.add(g),r.add(c)}c.attr({draggable:!0,cursor:LF(this._orient),drift:W(this._onDragMove,this,"all"),ondragstart:W(this._showDataInfo,this,!0),ondragend:W(this._onDragEnd,this),onmouseover:W(this._showDataInfo,this,!0),onmouseout:W(this._showDataInfo,this,!1)})},e.prototype._resetInterval=function(){var t=this._range=this.dataZoomModel.getPercentRange(),e=this._getViewExtent();this._handleEnds=[Kr(t[0],[0,100],e,!0),Kr(t[1],[0,100],e,!0)]},e.prototype._updateInterval=function(t,e){var n=this.dataZoomModel,i=this._handleEnds,r=this._getViewExtent(),o=n.findRepresentativeAxisProxy().getMinMaxSpan(),a=[0,100];zk(e,i,r,n.get("zoomLock")?"all":t,null!=o.minSpan?Kr(o.minSpan,a,r,!0):null,null!=o.maxSpan?Kr(o.maxSpan,a,r,!0):null);var s=this._range,l=this._range=Qr([Kr(i[0],r,a,!0),Kr(i[1],r,a,!0)]);return!s||s[0]!==l[0]||s[1]!==l[1]},e.prototype._updateView=function(t){var e=this._displayables,n=this._handleEnds,i=Qr(n.slice()),r=this._size;E([0,1],(function(t){var i=e.handles[t],o=this._handleHeight;i.attr({scaleX:o/2,scaleY:o/2,x:n[t]+(t?-1:1),y:r[1]/2-o/2})}),this),e.filler.setShape({x:i[0],y:0,width:i[1]-i[0],height:r[1]});var o={x:i[0],width:i[1]-i[0]};e.moveHandle&&(e.moveHandle.setShape(o),e.moveZone.setShape(o),e.moveZone.getBoundingRect(),e.moveHandleIcon&&e.moveHandleIcon.attr("x",o.x+o.width/2));for(var a=e.dataShadowSegs,s=[0,i[0],i[1],r[0]],l=0;le[0]||n[1]<0||n[1]>e[1])){var i=this._handleEnds,r=(i[0]+i[1])/2,o=this._updateInterval("all",n[0]-r);this._updateView(),o&&this._dispatchZoomAction(!1)}},e.prototype._onBrushStart=function(t){var e=t.offsetX,n=t.offsetY;this._brushStart=new De(e,n),this._brushing=!0,this._brushStartTime=+new Date},e.prototype._onBrushEnd=function(t){if(this._brushing){var e=this._displayables.brushRect;if(this._brushing=!1,e){e.attr("ignore",!0);var n=e.shape;if(!(+new Date-this._brushStartTime<200&&Math.abs(n.width)<5)){var i=this._getViewExtent(),r=[0,100];this._range=Qr([Kr(n.x,i,r,!0),Kr(n.x+n.width,i,r,!0)]),this._handleEnds=[n.x,n.x+n.width],this._updateView(),this._dispatchZoomAction(!1)}}}},e.prototype._onBrush=function(t){this._brushing&&(de(t.event),this._updateBrushRect(t.offsetX,t.offsetY))},e.prototype._updateBrushRect=function(t,e){var n=this._displayables,i=this.dataZoomModel,r=n.brushRect;r||(r=n.brushRect=new IF({silent:!0,style:i.getModel("brushStyle").getItemStyle()}),n.sliderGroup.add(r)),r.attr("ignore",!1);var o=this._brushStart,a=this._displayables.sliderGroup,s=a.transformCoordToLocal(t,e),l=a.transformCoordToLocal(o.x,o.y),u=this._size;s[0]=Math.max(Math.min(u[0],s[0]),0),r.setShape({x:l[0],y:0,width:s[0]-l[0],height:u[1]})},e.prototype._dispatchZoomAction=function(t){var e=this._range;this.api.dispatchAction({type:"dataZoom",from:this.uid,dataZoomId:this.dataZoomModel.id,animation:t?AF:null,start:e[0],end:e[1]})},e.prototype._findCoordRect=function(){var t,e=az(this.dataZoomModel).infoList;if(!t&&e.length){var n=e[0].model.coordinateSystem;t=n.getRect&&n.getRect()}if(!t){var i=this.api.getWidth(),r=this.api.getHeight();t={x:.2*i,y:.2*r,width:.6*i,height:.6*r}}return t},e.type="dataZoom.slider",e}(cz);function LF(t){return"vertical"===t?"ns-resize":"ew-resize"}function PF(t){t.registerComponentModel(MF),t.registerComponentView(kF),mz(t)}var OF=function(t,e,n){var i=T((RF[t]||{})[e]);return n&&Y(i)?i[i.length-1]:i},RF={color:{active:["#006edd","#e0ffff"],inactive:["rgba(0,0,0,0)"]},colorHue:{active:[0,360],inactive:[0,0]},colorSaturation:{active:[.3,1],inactive:[0,0]},colorLightness:{active:[.9,.5],inactive:[0,0]},colorAlpha:{active:[.3,1],inactive:[0,0]},opacity:{active:[.3,1],inactive:[0,0]},symbol:{active:["circle","roundRect","diamond"],inactive:["none"]},symbolSize:{active:[10,50],inactive:[0,0]}},NF=kD.mapVisual,EF=kD.eachVisual,zF=Y,VF=E,BF=Qr,FF=Kr,GF=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n.stateList=["inRange","outOfRange"],n.replacableOptionKeys=["inRange","outOfRange","target","controller","color"],n.layoutMode={type:"box",ignoreSize:!0},n.dataBound=[-1/0,1/0],n.targetVisuals={},n.controllerVisuals={},n}return n(e,t),e.prototype.init=function(t,e,n){this.mergeDefaultAndTheme(t,n)},e.prototype.optionUpdated=function(t,e){var n=this.option;!e&&RV(n,t,this.replacableOptionKeys),this.textStyleModel=this.getModel("textStyle"),this.resetItemSize(),this.completeVisualOption()},e.prototype.resetVisual=function(t){var e=this.stateList;t=W(t,this),this.controllerVisuals=OV(this.option.controller,e,t),this.targetVisuals=OV(this.option.target,e,t)},e.prototype.getItemSymbol=function(){return null},e.prototype.getTargetSeriesIndices=function(){var t=this.option.seriesIndex,e=[];return null==t||"all"===t?this.ecModel.eachSeries((function(t,n){e.push(n)})):e=To(t),e},e.prototype.eachTargetSeries=function(t,e){E(this.getTargetSeriesIndices(),(function(n){var i=this.ecModel.getSeriesByIndex(n);i&&t.call(e,i)}),this)},e.prototype.isTargetSeries=function(t){var e=!1;return this.eachTargetSeries((function(n){n===t&&(e=!0)})),e},e.prototype.formatValueText=function(t,e,n){var i,r=this.option,o=r.precision,a=this.dataBound,s=r.formatter;n=n||["<",">"],Y(t)&&(t=t.slice(),i=!0);var l=e?t:i?[u(t[0]),u(t[1])]:u(t);return U(s)?s.replace("{value}",i?l[0]:l).replace("{value2}",i?l[1]:l):X(s)?i?s(t[0],t[1]):s(t):i?t[0]===a[0]?n[0]+" "+l[1]:t[1]===a[1]?n[1]+" "+l[0]:l[0]+" - "+l[1]:l;function u(t){return t===a[0]?"min":t===a[1]?"max":(+t).toFixed(Math.min(o,20))}},e.prototype.resetExtent=function(){var t=this.option,e=BF([t.min,t.max]);this._dataExtent=e},e.prototype.getDataDimensionIndex=function(t){var e=this.option.dimension;if(null!=e)return t.getDimensionIndex(e);for(var n=t.dimensions,i=n.length-1;i>=0;i--){var r=n[i],o=t.getDimensionInfo(r);if(!o.isCalculationCoord)return o.storeDimIndex}},e.prototype.getExtent=function(){return this._dataExtent.slice()},e.prototype.completeVisualOption=function(){var t=this.ecModel,e=this.option,n={inRange:e.inRange,outOfRange:e.outOfRange},i=e.target||(e.target={}),r=e.controller||(e.controller={});C(i,n),C(r,n);var o=this.isCategory();function a(n){zF(e.color)&&!n.inRange&&(n.inRange={color:e.color.slice().reverse()}),n.inRange=n.inRange||{color:t.get("gradientColor")}}a.call(this,i),a.call(this,r),function(t,e,n){var i=t[e],r=t[n];i&&!r&&(r=t[n]={},VF(i,(function(t,e){if(kD.isValidType(e)){var n=OF(e,"inactive",o);null!=n&&(r[e]=n,"color"!==e||r.hasOwnProperty("opacity")||r.hasOwnProperty("colorAlpha")||(r.opacity=[0,0]))}})))}.call(this,i,"inRange","outOfRange"),function(t){var e=(t.inRange||{}).symbol||(t.outOfRange||{}).symbol,n=(t.inRange||{}).symbolSize||(t.outOfRange||{}).symbolSize,i=this.get("inactiveColor"),r=this.getItemSymbol()||"roundRect";VF(this.stateList,(function(a){var s=this.itemSize,l=t[a];l||(l=t[a]={color:o?i:[i]}),null==l.symbol&&(l.symbol=e&&T(e)||(o?r:[r])),null==l.symbolSize&&(l.symbolSize=n&&T(n)||(o?s[0]:[s[0],s[0]])),l.symbol=NF(l.symbol,(function(t){return"none"===t?r:t}));var u=l.symbolSize;if(null!=u){var h=-1/0;EF(u,(function(t){t>h&&(h=t)})),l.symbolSize=NF(u,(function(t){return FF(t,[0,h],[0,s[0]],!0)}))}}),this)}.call(this,r)},e.prototype.resetItemSize=function(){this.itemSize=[parseFloat(this.get("itemWidth")),parseFloat(this.get("itemHeight"))]},e.prototype.isCategory=function(){return!!this.option.categories},e.prototype.setSelected=function(t){},e.prototype.getSelected=function(){return null},e.prototype.getValueState=function(t){return null},e.prototype.getVisualMeta=function(t){return null},e.type="visualMap",e.dependencies=["series"],e.defaultOption={show:!0,z:4,seriesIndex:"all",min:0,max:200,left:0,right:null,top:null,bottom:0,itemWidth:null,itemHeight:null,inverse:!1,orient:"vertical",backgroundColor:"rgba(0,0,0,0)",borderColor:"#ccc",contentColor:"#5793f3",inactiveColor:"#aaa",borderWidth:0,padding:5,textGap:10,precision:0,textStyle:{color:"#333"}},e}(zp),WF=[20,140],HF=function(t){function e(){var n=null!==t&&t.apply(this,arguments)||this;return n.type=e.type,n}return n(e,t),e.prototype.optionUpdated=function(e,n){t.prototype.optionUpdated.apply(this,arguments),this.resetExtent(),this.resetVisual((function(t){t.mappingMethod="linear",t.dataExtent=this.getExtent()})),this._resetRange()},e.prototype.resetItemSize=function(){t.prototype.resetItemSize.apply(this,arguments);var e=this.itemSize;(null==e[0]||isNaN(e[0]))&&(e[0]=WF[0]),(null==e[1]||isNaN(e[1]))&&(e[1]=WF[1])},e.prototype._resetRange=function(){var t=this.getExtent(),e=this.option.range;!e||e.auto?(t.auto=1,this.option.range=t):Y(e)&&(e[0]>e[1]&&e.reverse(),e[0]=Math.max(e[0],t[0]),e[1]=Math.min(e[1],t[1]))},e.prototype.completeVisualOption=function(){t.prototype.completeVisualOption.apply(this,arguments),E(this.stateList,(function(t){var e=this.option.controller[t].symbolSize;e&&e[0]!==e[1]&&(e[0]=e[1]/3)}),this)},e.prototype.setSelected=function(t){this.option.range=t.slice(),this._resetRange()},e.prototype.getSelected=function(){var t=this.getExtent(),e=Qr((this.get("range")||[]).slice());return e[0]>t[1]&&(e[0]=t[1]),e[1]>t[1]&&(e[1]=t[1]),e[0]=n[1]||t<=e[1])?"inRange":"outOfRange"},e.prototype.findTargetDataIndices=function(t){var e=[];return this.eachTargetSeries((function(n){var i=[],r=n.getData();r.each(this.getDataDimensionIndex(r),(function(e,n){t[0]<=e&&e<=t[1]&&i.push(n)}),this),e.push({seriesId:n.id,dataIndex:i})}),this),e},e.prototype.getVisualMeta=function(t){var e=YF(this,"outOfRange",this.getExtent()),n=YF(this,"inRange",this.option.range.slice()),i=[];function r(e,n){i.push({value:e,color:t(e,n)})}for(var o=0,a=0,s=n.length,l=e.length;at[1])break;n.push({color:this.getControllerVisual(o,"color",e),offset:r/100})}return n.push({color:this.getControllerVisual(t[1],"color",e),offset:1}),n},e.prototype._createBarPoints=function(t,e){var n=this.visualMapModel.itemSize;return[[n[0]-e[0],t[0]],[n[0],t[0]],[n[0],t[1]],[n[0]-e[1],t[1]]]},e.prototype._createBarGroup=function(t){var e=this._orient,n=this.visualMapModel.get("inverse");return new Br("horizontal"!==e||n?"horizontal"===e&&n?{scaleX:"bottom"===t?-1:1,rotation:-Math.PI/2}:"vertical"!==e||n?{scaleX:"left"===t?1:-1}:{scaleX:"left"===t?1:-1,scaleY:-1}:{scaleX:"bottom"===t?1:-1,rotation:Math.PI/2})},e.prototype._updateHandle=function(t,e){if(this._useHandle){var n=this._shapes,i=this.visualMapModel,r=n.handleThumbs,o=n.handleLabels,a=i.itemSize,s=i.getExtent(),l=this._applyTransform("left",n.mainGroup);KF([0,1],(function(u){var h=r[u];h.setStyle("fill",e.handlesColor[u]),h.y=t[u];var c=qF(t[u],[0,a[1]],s,!0),p=this.getControllerVisual(c,"symbolSize");h.scaleX=h.scaleY=p/a[0],h.x=a[0]-p/2;var d=Fh(n.handleLabelPoints[u],Bh(h,this.group));if("horizontal"===this._orient){var f="left"===l||"top"===l?(a[0]-p)/2:(a[0]-p)/-2;d[1]+=f}o[u].setStyle({x:d[0],y:d[1],text:i.formatValueText(this._dataInterval[u]),verticalAlign:"middle",align:"vertical"===this._orient?this._applyTransform("left",n.mainGroup):"center"})}),this)}},e.prototype._showIndicator=function(t,e,n,i){var r=this.visualMapModel,o=r.getExtent(),a=r.itemSize,s=[0,a[1]],l=this._shapes,u=l.indicator;if(u){u.attr("invisible",!1);var h=this.getControllerVisual(t,"color",{convertOpacityToAlpha:!0}),c=this.getControllerVisual(t,"symbolSize"),p=qF(t,o,s,!0),d=a[0]-c/2,f={x:u.x,y:u.y};u.y=p,u.x=d;var g=Fh(l.indicatorLabelPoint,Bh(u,this.group)),y=l.indicatorLabel;y.attr("invisible",!1);var v=this._applyTransform("left",l.mainGroup),m="horizontal"===this._orient;y.setStyle({text:(n||"")+r.formatValueText(e),verticalAlign:m?v:"middle",align:m?"center":v});var x={x:d,y:p,style:{fill:h}},_={style:{x:g[0],y:g[1]}};if(r.ecModel.isAnimationEnabled()&&!this._firstShowIndicator){var b={duration:100,easing:"cubicInOut",additive:!0};u.x=f.x,u.y=f.y,u.animateTo(x,b),y.animateTo(_,b)}else u.attr(x),y.attr(_);this._firstShowIndicator=!1;var w=this._shapes.handleLabels;if(w)for(var S=0;Sr[1]&&(u[1]=1/0),e&&(u[0]===-1/0?this._showIndicator(l,u[1],"< ",a):u[1]===1/0?this._showIndicator(l,u[0],"> ",a):this._showIndicator(l,l,"≈ ",a));var h=this._hoverLinkDataIndices,c=[];(e||eG(n))&&(c=this._hoverLinkDataIndices=n.findTargetDataIndices(u));var p=function(t,e){var n={},i={};return r(t||[],n),r(e||[],i,n),[o(n),o(i)];function r(t,e,n){for(var i=0,r=t.length;i=0&&(r.dimension=o,i.push(r))}})),t.getData().setVisual("visualMeta",i)}}];function aG(t,e,n,i){for(var r=e.targetVisuals[i],o=kD.prepareVisualTypes(r),a={color:Ay(t.getData(),"color")},s=0,l=o.length;s0:t.splitNumber>0)&&!t.calculable?"piecewise":"continuous"})),t.registerAction(iG,rG),E(oG,(function(e){t.registerVisual(t.PRIORITY.VISUAL.COMPONENT,e)})),t.registerPreprocessor(lG))}function 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c=n.get(h.key);c||(c={oldSeries:[{dataGroupId:h.dataGroupId,data:h.data,divide:DW(h.data)}],newSeries:[]},n.set(h.key,c)),c.newSeries.push({dataGroupId:e,data:o,divide:DW(o)})}}}})),n}(i,n);E(o.keys(),(function(t){var n=o.get(t);IW(n.oldSeries,n.newSeries,e)}))}E(n.updatedSeries,(function(t){t[_g]&&(t[_g]=!1)}))}for(var a=t.getSeries(),s=i.oldSeries=[],l=i.oldDataGroupIds=[],u=i.oldData=[],h=0;h nx.Graph: + """Collapse the MultiDiGraph to a simple undirected Graph. + + PageRank and centrality are computed on the directed multigraph directly + (they support it natively); only community detection needs this -- Louvain + modularity is defined over undirected simple graphs, and collapsing parallel + edges (multiple relations between the same pair) to one is the right + behaviour for "are these two entities in the same cluster", not a + simplification that changes what's being measured. + """ + return nx.Graph(store.g) + + +def pagerank_ranking(store, top_n: int = 10, entity_type: str | None = None) -> list[dict]: + """Top entities by PageRank (confidence-weighted). + + Edge confidence is used as the PageRank weight, so a low-confidence + extracted edge contributes less to a node's importance than a high- + confidence one -- otherwise a node with many uncertain edges could + outrank one with fewer but well-evidenced ones. + + Directedness matters here: this project's edges point disease -> attribute + (`disease -[has_symptom]-> symptom`, `disease -[recommend_drug]-> drug`, ...), + so PageRank -- which accumulates rank at nodes that are *pointed to* -- + naturally surfaces heavily-shared attributes (a symptom common to many + diseases) rather than the diseases themselves. That is a different, equally + valid question from "which disease is best-connected" (answered by + `degree_centrality_ranking`, which counts edges regardless of direction); + filtering by `entity_type="Disease"` still works and is meaningful, but a + disease's PageRank reflects its in-edges (e.g. `complication` edges from + other diseases pointing to it), not its out-edges. + """ + scores = nx.pagerank(store.g, weight="confidence") + return _ranked(store, scores, top_n, entity_type, "pagerank") + + +def degree_centrality_ranking(store, top_n: int = 10, entity_type: str | None = None) -> list[dict]: + """Top entities by degree centrality (in+out edges, normalised by graph size). + + Cheap structural-importance proxy independent of edge confidence -- pairs + with `pagerank_ranking` to show a query-independent "hub" view distinct + from PageRank's confidence-weighted, propagated-importance view. + """ + scores = nx.degree_centrality(store.g) + return _ranked(store, scores, top_n, entity_type, "degree_centrality") + + +def _ranked(store, scores: dict, top_n: int, entity_type: str | None, score_key: str) -> list[dict]: + items = scores.items() + if entity_type: + items = ( + (node, score) + for node, score in items + if store.g.nodes[node].get("type") == entity_type + ) + ranked = sorted(items, key=lambda kv: -kv[1])[:top_n] + return [ + { + "name": node, + "type": store.g.nodes[node].get("type", "Unknown"), + score_key: round(score, 6), + "degree": store.g.degree[node], + } + for node, score in ranked + ] + + +def detect_communities(store, top_n: int = 5, min_size: int = 3) -> list[dict]: + """Top-N Louvain communities by size, each summarised by its most-central + member entities (so a community reads as "the diabetes/nephropathy + cluster" rather than an opaque node-id list). + + `min_size` drops singleton/near-singleton communities -- an entity with one + edge trivially forms its own "community" under modularity optimisation, + which is noise for this use case, not a meaningful cluster. + """ + undirected = _simple_undirected(store) + communities = nx.community.louvain_communities(undirected, weight="confidence", seed=20260730) + ranked = sorted((c for c in communities if len(c) >= min_size), key=len, reverse=True)[:top_n] + result = [] + for index, members in enumerate(ranked): + subgraph = undirected.subgraph(members) + centrality = nx.degree_centrality(subgraph) + top_members = sorted(centrality, key=lambda n: -centrality[n])[:5] + type_counts: dict[str, int] = {} + for node in members: + node_type = store.g.nodes[node].get("type", "Unknown") + type_counts[node_type] = type_counts.get(node_type, 0) + 1 + result.append( + { + "community_id": index, + "size": len(members), + "representative_entities": top_members, + "type_breakdown": dict(sorted(type_counts.items(), key=lambda kv: -kv[1])), + } + ) + return result + + +def shortest_path(store, source: str, target: str) -> dict | None: + """Shortest relation path between two entities (BFS, hop count as distance). + + Direction-agnostic (built on the undirected collapse): a clinically useful + "how is X related to Y" answer should not depend on which direction the + extractor happened to record the edge in. + """ + undirected = _simple_undirected(store) + if source not in undirected or target not in undirected: + return None + try: + node_path = nx.shortest_path(undirected, source, target) + except nx.NetworkXNoPath: + return None + steps = [] + for head, tail in zip(node_path, node_path[1:]): + edge_data = store.g.get_edge_data(head, tail) or store.g.get_edge_data(tail, head) or {} + first_edge = next(iter(edge_data.values()), {}) if edge_data else {} + steps.append( + { + "head": head, + "tail": tail, + "relation": first_edge.get("relation", ""), + "confidence": first_edge.get("confidence"), + } + ) + return {"source": source, "target": target, "hops": len(steps), "path": node_path, "steps": steps} diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/graph_profile.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/graph_profile.py" new file mode 100644 index 0000000..808fbcc --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/graph_profile.py" @@ -0,0 +1,66 @@ +"""Graph perception: load the task-2 knowledge graph and build a profile. + +The analysis agent uses the profile to (a) understand the graph schema (entity +types, relation types, top entities) and (b) answer association questions by +graph traversal. If no task-2 graph exists yet, an embedded example graph is +returned so Task 3 runs standalone (placeholder for the real task-2 output). +""" +from __future__ import annotations + +from pathlib import Path + +from medigraph.graph.local_store import LocalGraphStore + +# Embedded example graph (used only when no task-2 graph.json is present). Mirrors +# the seed corpus so the relational layer and graph stay consistent. +_EXAMPLE_TRIPLES = [ + ("高血压", "Disease", "has_symptom", "头痛", "Symptom"), + ("高血压", "Disease", "has_symptom", "头晕", "Symptom"), + ("高血压", "Disease", "recommend_drug", "硝苯地平", "Drug"), + ("高血压", "Disease", "recommend_drug", "氨氯地平", "Drug"), + ("高血压", "Disease", "need_examination", "心电图", "Examination"), + ("高血压", "Disease", "complication", "冠心病", "Disease"), + ("高血压", "Disease", "treated_in_department", "心内科", "Department"), + ("2型糖尿病", "Disease", "recommend_drug", "二甲双胍", "Drug"), + ("2型糖尿病", "Disease", "complication", "糖尿病肾病", "Disease"), + ("2型糖尿病", "Disease", "need_examination", "糖化血红蛋白", "Examination"), + ("2型糖尿病", "Disease", "treated_in_department", "内分泌科", "Department"), + ("急性心肌梗死", "Disease", "has_symptom", "胸痛", "Symptom"), + ("急性心肌梗死", "Disease", "recommend_drug", "阿司匹林", "Drug"), + ("急性心肌梗死", "Disease", "treated_in_department", "心内科", "Department"), + ("嗜铬细胞瘤", "Tumor", "positive_marker", "嗜铬粒蛋白", "Biomarker"), + ("嗜铬细胞瘤", "Tumor", "associated_gene", "RET", "Gene"), + ("嗜铬细胞瘤", "Tumor", "treated_in_department", "内分泌科", "Department"), +] + + +def load_graph(graph_json: str | Path | None) -> tuple[LocalGraphStore, bool]: + """Return (store, used_example). Loads task-2 graph.json if available.""" + if graph_json and Path(graph_json).exists(): + return LocalGraphStore.load_json(graph_json), False + store = LocalGraphStore() + for h, ht, r, t, tt in _EXAMPLE_TRIPLES: + store.upsert_triple(h, ht, r, t, tt, confidence=1.0, source="example_graph") + return store, True + + +def build_profile(store: LocalGraphStore) -> dict: + """Structured profile of the graph for schema injection / understanding.""" + stats = store.stats() + return { + "num_entities": stats["num_entities"], + "num_triples": stats["num_triples"], + "entity_types": stats["entity_type_counts"], + "relation_types": stats["relation_counts"], + "top_entities": stats["top_entities"], + } + + +def profile_prompt_block(profile: dict) -> str: + """Human/LLM-readable graph schema summary.""" + ets = ", ".join(f"{k}({v})" for k, v in profile["entity_types"].items()) + rels = ", ".join(f"{k}({v})" for k, v in profile["relation_types"].items()) + return ( + f"知识图谱概览：实体 {profile['num_entities']} 个，三元组 {profile['num_triples']} 条。\n" + f"实体类型分布：{ets}\n关系类型分布：{rels}" + ) diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/nl2sql.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/nl2sql.py" new file mode 100644 index 0000000..379b0d8 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/nl2sql.py" @@ -0,0 +1,520 @@ +"""NL2SQL engine targeting the SQLite analytics DB. + +Pipeline (each step is a known accuracy lever; they stack): + 1. Schema injection + dynamic few-shot (most-similar (question, SQL) examples). + 2. LLM generates a single SELECT (Qwen3.5). + 3. Read-only guard: parse to an AST and require a single projection statement with + no DDL/DML anywhere in the tree (see `medigraph.analysis.sql_guard`). The + executor then adds a read-only connection, `PRAGMA query_only` and a SQLite + authorizer, so a parser gap still cannot become a write. + 4. Execution on SQLite; on error, feed the DB error back and re-generate + (execution-guided self-correction), up to `max_correction` rounds. + +Returns the SQL, the executed columns/rows, and a trace of attempts. +""" +from __future__ import annotations + +import re +import sqlite3 +import time +from typing import Any + +from medigraph.analysis.relational import schema_text +from medigraph.analysis.schema_linking import MedicalSchemaLinker +from medigraph.analysis.sql_guard import ensure_read_only, is_read_only + +_SYSTEM = "你是资深数据分析师，只输出可在 SQLite 上执行的单条 SELECT 语句，不要解释、不要 markdown。" + +# Curated few-shot pool (question -> gold SQL). Dynamic selection picks the most +# lexically similar ones to inject, DAIL-SQL style. +_FEWSHOT: list[tuple[str, str]] = [ + ("每个科室的就诊量是多少", + "SELECT department, COUNT(*) AS visits FROM patient_visits GROUP BY department ORDER BY visits DESC"), + ("高血压患者的平均年龄是多少", + "SELECT AVG(age) AS avg_age FROM patient_visits WHERE disease = '高血压'"), + ("各疾病的就诊人次按从多到少排序", + "SELECT disease, COUNT(*) AS cnt FROM patient_visits GROUP BY disease ORDER BY cnt DESC"), + ("2024年每个月的就诊量趋势", + "SELECT substr(visit_date,1,7) AS month, COUNT(*) AS visits FROM patient_visits GROUP BY month ORDER BY month"), + ("开具次数最多的5种药物", + "SELECT drug, COUNT(*) AS cnt FROM prescriptions GROUP BY drug ORDER BY cnt DESC LIMIT 5"), + ("男性和女性的就诊比例", + "SELECT gender, COUNT(*) AS cnt FROM patient_visits GROUP BY gender"), + ("检查结果异常率最高的检查项目", + "SELECT test_name, AVG(abnormal) AS abnormal_rate FROM lab_tests GROUP BY test_name ORDER BY abnormal_rate DESC"), + ("内科的平均就诊费用", + "SELECT AVG(cost) AS avg_cost FROM patient_visits WHERE department = '内科'"), +] + + +class NL2SQL: + def __init__( + self, + db_path: str, + llm: Any | None = None, + max_correction: int = 2, + num_shots: int = 4, + backend: str | None = None, + ): + """`backend`: 'sqlite' (default) or 'postgres'. + + Generation is engine-agnostic (prompt + templates emit SQLite-flavoured + SQL); on the postgres backend the vetted statement is transpiled via + sqlglot AST and executed on the pooled server. Schema linking always + reads the SQLite file -- it is the vocabulary source and exists offline. + """ + self.db_path = db_path + if llm is None: + from medigraph.llm.client import LLMClient + llm = LLMClient() + self.llm = llm + self.max_correction = max_correction + self.num_shots = num_shots + self.schema_linker = MedicalSchemaLinker(db_path) + if backend is None: + from config.settings import get_analytics_config + backend = get_analytics_config().backend + self.backend = backend if backend in {"sqlite", "postgres"} else "sqlite" + + # ------------------------------------------------------------------ # + def _select_shots(self, question: str) -> list[tuple[str, str]]: + """Lexical-overlap ranking of few-shot examples (lightweight schema/intent linking).""" + q = set(question) + scored = sorted(_FEWSHOT, key=lambda ex: len(q & set(ex[0])), reverse=True) + return scored[: self.num_shots] + + def _build_prompt(self, question: str, error: str = "", prev_sql: str = "") -> str: + links = self.schema_linker.link(question) + shots = "\n".join(f"问题：{q}\nSQL：{s}" for q, s in self._select_shots(question)) + fix = "" + if error: + fix = ( + f"\n上一次生成的 SQL 执行报错，请修正：\n上次SQL：{prev_sql}\n报错：{error}\n" + "请输出修正后的 SQL。" + ) + return ( + f"数据库 schema：\n{schema_text()}\n\n" + f"Schema-Linking 结果（已用知识图谱词表消歧）：\n{links}\n\n" + f"参考示例：\n{shots}\n\n" + f"请为下面的问题生成一条 SQLite SELECT 语句（只输出 SQL）：\n问题：{question}{fix}" + ) + + @staticmethod + def _extract_sql(text: str) -> str: + if not text: + return "" + m = re.search(r"```(?:sql)?\s*(.+?)```", text, flags=re.DOTALL | re.IGNORECASE) + if m: + text = m.group(1) + text = text.strip().rstrip(";").strip() + # keep from the first SELECT/WITH + m2 = re.search(r"\b(SELECT|WITH)\b", text, flags=re.IGNORECASE) + return text[m2.start():].strip() if m2 else text + + @staticmethod + def _superlative_order(q: str, explicit_n: int | None) -> tuple[str, str]: + """(direction, limit_clause) for a ranking ORDER BY. + + Handles the asymmetry between "最高/最多/最大" (DESC) and "最低/最少/ + 最小" (ASC) -- the three ranking branches below used to hard-code DESC + unconditionally, so "平均就诊费用最低的科室是哪个" silently returned the + *highest*-cost department first with no LIMIT at all (the full ranked + list), which happened to still contain the right answer buried inside + it but is not what "是哪个" (asking for one) was asking for. + + limit_clause is empty for a plain "各X的..." listing (no superlative, + no explicit top-N -- return every group), "LIMIT 1" for a bare + superlative with no explicit count ("最低的是哪个"), or "LIMIT N" when + the question gave one ("前3个"). + """ + ascending = any(w in q for w in ("最低", "最少", "最小")) + descending = any(w in q for w in ("最高", "最多", "最大", "top", "前")) + direction = "ASC" if ascending else "DESC" + if explicit_n is not None: + return direction, f" LIMIT {explicit_n}" + if ascending or descending: + return direction, " LIMIT 1" + return direction, "" + + @staticmethod + def _is_readonly(sql: str) -> bool: + """Structural read-only check (see `medigraph.analysis.sql_guard`). + + Kept as a method for backwards compatibility; the decision itself is an AST + walk rather than a keyword blacklist. + """ + return is_read_only(sql) + + def _execute(self, sql: str, timeout_seconds: float = 5.0, max_rows: int = 5000) -> tuple[list[str], list[tuple], str]: + if self.backend == "postgres": + from medigraph.analysis.pg_relational import execute_readonly_pg + from medigraph.analysis.sql_guard import transpile + + try: + pg_sql = transpile(sql, write="postgres") + except Exception as exc: # noqa: BLE001 - feed back into self-correction + return [], [], f"dialect transpile failed: {exc}" + return execute_readonly_pg(pg_sql, timeout_seconds=timeout_seconds, max_rows=max_rows) + try: + conn = sqlite3.connect(f"file:{self.db_path}?mode=ro", uri=True) + conn.execute("PRAGMA query_only=ON") + denied = { + sqlite3.SQLITE_INSERT, + sqlite3.SQLITE_UPDATE, + sqlite3.SQLITE_DELETE, + sqlite3.SQLITE_CREATE_INDEX, + sqlite3.SQLITE_CREATE_TABLE, + sqlite3.SQLITE_CREATE_TEMP_INDEX, + sqlite3.SQLITE_CREATE_TEMP_TABLE, + sqlite3.SQLITE_CREATE_TEMP_TRIGGER, + sqlite3.SQLITE_CREATE_TEMP_VIEW, + sqlite3.SQLITE_CREATE_TRIGGER, + sqlite3.SQLITE_CREATE_VIEW, + sqlite3.SQLITE_DROP_INDEX, + sqlite3.SQLITE_DROP_TABLE, + sqlite3.SQLITE_DROP_TEMP_INDEX, + sqlite3.SQLITE_DROP_TEMP_TABLE, + sqlite3.SQLITE_DROP_TEMP_TRIGGER, + sqlite3.SQLITE_DROP_TEMP_VIEW, + sqlite3.SQLITE_DROP_TRIGGER, + sqlite3.SQLITE_DROP_VIEW, + sqlite3.SQLITE_ALTER_TABLE, + sqlite3.SQLITE_ATTACH, + sqlite3.SQLITE_DETACH, + } + conn.set_authorizer( + lambda action, arg1, arg2, db, source: ( + sqlite3.SQLITE_DENY if action in denied else sqlite3.SQLITE_OK + ) + ) + started = time.monotonic() + conn.set_progress_handler( + lambda: 1 if time.monotonic() - started > timeout_seconds else 0, + 10_000, + ) + cur = conn.cursor() + cur.execute(sql) + rows = cur.fetchmany(max_rows + 1) + if len(rows) > max_rows: + conn.close() + return [], [], f"result exceeds safety limit ({max_rows} rows)" + cols = [d[0] for d in cur.description] if cur.description else [] + conn.close() + return cols, rows, "" + except Exception as exc: # noqa: BLE001 - surface SQL errors for self-correction + return [], [], str(exc) + + @staticmethod + def _router_should_defer(q: str) -> bool: + """Conservative gate: the deterministic router only expresses single-table + group/filter/aggregate SQL. Questions needing subqueries, cross-table + JOINs, HAVING or a column-specific SUM are handed to the LLM instead of + being answered with structurally-wrong template SQL. + """ + # 1) comparison against an aggregate -> needs a subquery + if re.search(r"(高于|超过|大于|低于|小于|多于|少于).{0,5}(平均|均值|全院|平均值|中位)", q): + return True + # 2) HAVING / distinct-count combinations + if "及以上" in q or re.search(r"(两|二|三|四|五|多)\s*种", q): + return True + if re.search(r"不同.{0,4}(检验|检查|药|项目|科室|病人|患者)", q) or re.search(r"(病人|患者).{0,3}不同", q): + return True + # distinct COUNT the router emits as COUNT(*) + if "不同" in q and any(t in q for t in ("多少", "几", "数量", "个数")): + return True + # attribute-of-the-extreme-row (e.g. "花费最高的那次就诊是什么疾病") -> the + # router wrongly groups; this needs ORDER BY LIMIT 1 then project attr + if re.search(r"(最高|最贵|最低|最少|最大|最小|最多).{0,6}(那次|哪次|这次|一次|一位|那位|哪位)", q): + return True + # 3) column-specific SUM the router does not emit + if re.search(r"总(天数|时长|用药天数|住院天数)", q): + return True + # 4) cross-table: a drug/prescription term together with a patient-visit + # attribute or a disease filter -> needs prescriptions JOIN patient_visits + drug_ctx = any(t in q for t in ("药", "处方", "开具", "用药", "服用")) + attr_ctx = any(t in q for t in ("年龄", "岁", "费用", "花费", "住院费")) + disease_ctx = bool(re.search(r"[一-鿿]{2,8}(病|症|癌|炎)", q)) + if drug_ctx and (attr_ctx or disease_ctx): + return True + # 5) lab abnormality asking for a disease -> needs lab_tests JOIN patient_visits + if any(t in q for t in ("异常", "检验", "检查")) and ("疾病" in q or "最常见" in q): + return True + # 6) Nth-rank ("第二多", "倒数第三", "排第二") -> needs LIMIT/OFFSET the + # router has no template for; a naive match would silently return the + # unranked full list instead of the Nth row. + if re.search(r"第\s*[一二三四五六七八九十\d]+\s*(多|少|高|低|大|小|名|位)", q) or "倒数第" in q: + return True + # 7) exclusion/negation ("除了X以外", "不包括X", "排除X") -> the router's + # group/filter templates have no NOT-filter support; matching one + # anyway would silently drop the exclusion and answer the un-excluded + # question instead. + if re.search(r"除了.{0,10}(以外|之外)", q) or any(t in q for t in ("不包括", "排除", "不含")): + return True + # 8) half-year/quarter date phrases -- the router's date handling only + # covers an exact "YYYY-MM" equality or an unfiltered month-trend + # GROUP BY; a range like "2024年上半年" combined with another filter + # (e.g. a disease) would otherwise silently drop the date qualifier. + if any(t in q for t in ("上半年", "下半年", "季度")): + return True + # 9) HAVING-style count threshold asking for a *list*, not a scalar + # ("超过50次的科室有哪些") -- distinct from the "及以上"/quantifier + # check above, which catches a different phrasing. + if re.search(r"(超过|多于|达到|不少于|至少)\s*\d+\s*(次|人次)", q) and any( + t in q for t in ("哪些", "哪几个", "有哪") + ): + return True + return False + + def _deterministic_sql(self, question: str) -> tuple[str, dict]: + """Cover common analytics intents without an LLM call.""" + links = self.schema_linker.link(question) + q = links["normalized_question"].lower() + if self._router_should_defer(q): + return "", links + values = {item["field"]: item["value"] for item in links["values"]} + department_match = re.search(r"([\u4e00-\u9fff]{0,6}(?:内科|外科|全科))", q) + if department_match and not any(token in department_match.group(1) for token in ("每个", "各个")): + values["department"] = department_match.group(1) + # Regex fallback for a drug name not already resolved via the (case-exact) + # vocabulary literal match above. Only fills the gap -- it must not + # overwrite a real match with its own capture, because `q` is lower-cased + # and Python's str.lower() *does* remap Unicode Roman numerals (Ⅰ -> ⅰ, + # U+2160 -> U+2170), a suffix pattern common in Chinese drug names + # ("硝苯地平缓释片Ⅰ"); overwriting would silently query for a drug that + # cannot exist in the database, without the query claiming to be exact. + if "drug" not in values: + drug_match = re.search(r"(.{2,20}?)(?:一共|总共)?被开具了?多少次", q) + if drug_match: + values["drug"] = drug_match.group(1).strip() + graph_value = values.get("kg_entity") + if graph_value: + if any(term in q for term in ("药", "处方", "开具")): + values.setdefault("drug", graph_value) + elif any(term in q for term in ("检查", "检验")): + values.setdefault("test_name", graph_value) + elif any(term in q for term in ("科室", "挂号", "内科", "外科")): + values.setdefault("department", graph_value) + else: + values.setdefault("disease", graph_value) + top_n = self.schema_linker.extract_top_n(q) + + # Knowledge-graph aggregate analysis. ``kg_triples`` is a read-only + # relational mirror of the Task-2 graph and is the right source for + # rankings/counts across many graph entities. Keep this deterministic + # so the recording prompt works without LLM retries or prompt + # reformulation. + kg_context = any( + term in q + for term in ("知识图谱", "图谱", "kg_triples", "has_symptom", "关联症状") + ) + aggregate_context = any( + term in q + for term in ("统计", "数量", "计数", "最多", "最少", "排名", "排序", "top", "前") + ) + symptom_context = any(term in q for term in ("症状", "has_symptom")) + if kg_context and aggregate_context and symptom_context: + return ( + "SELECT head, COUNT(DISTINCT tail) AS symptom_count " + "FROM kg_triples " + "WHERE head_type = 'Disease' AND relation = 'has_symptom' " + "GROUP BY head ORDER BY symptom_count DESC " + f"LIMIT {top_n}", + links, + ) + + # Highest-cost patient/visit ranking used by the recording script. + # Keep it deterministic so this core NL2SQL demo remains available + # even when the optional external LLM quota is exhausted. + # + # Guarded against "平均"/"科室" so this individual-*visit* ranking does + # not also swallow a department-*aggregate* question: "平均就诊费用最高 + # 的科室是哪个" contains 费用+最高+就诊 (matching the three checks above) + # but is asking which department has the highest *average*, which is the + # grouped branch further below -- this branch used to win the race and + # silently return a list of (patient_id, cost) instead. + if ( + any(term in q for term in ("费用", "住院费", "花费", "cost")) + and any(term in q for term in ("最高", "最多", "top", "前")) + and any(term in q for term in ("患者", "病人", "就诊")) + and "平均" not in q + and "科室" not in q + ): + return ( + "SELECT patient_id, cost FROM patient_visits " + f"ORDER BY cost DESC LIMIT {top_n}", + links, + ) + + # Time series. + if ( + any(term in q for term in ("每月", "每个月", "月度", "月份", "各月")) + and any(term in q for term in ("就诊", "人次", "患者")) + ): + return ( + "SELECT substr(visit_date,1,7) AS month, COUNT(*) AS visits " + "FROM patient_visits GROUP BY month ORDER BY month", + links, + ) + # Lab analysis. A specific test_name filter must be checked *before* the + # generic per-test_name GROUP BY below -- otherwise "血压检查的异常次数 + # 是多少" (asking about one named test) matches the same "异常"+"检查" + # keywords as "每个检查项目的异常次数" (asking for all of them grouped) + # and silently answers the wrong, unfiltered question. + if "test_name" in values and "异常" in q: + return ( + f"SELECT SUM(abnormal) AS abnormal_count FROM lab_tests " + f"WHERE test_name={self.schema_linker.quoted(values['test_name'])}", + links, + ) + if "异常" in q and ("率" in q or "比例" in q): + return ( + "SELECT test_name, AVG(abnormal) AS abnormal_rate FROM lab_tests " + "GROUP BY test_name ORDER BY abnormal_rate DESC", + links, + ) + if "异常" in q and ("检查" in q or "项目" in q): + return ( + "SELECT test_name, SUM(abnormal) AS abnormal_count FROM lab_tests " + "GROUP BY test_name ORDER BY abnormal_count DESC", + links, + ) + # Prescription analysis. + if ("药物" in q or "开具" in q or "处方" in q) and any(term in q for term in ("最多", "最高", "top", "前")): + return ( + f"SELECT drug, COUNT(*) AS cnt FROM prescriptions GROUP BY drug " + f"ORDER BY cnt DESC LIMIT {top_n}", + links, + ) + if "drug" in values and any(term in q for term in ("多少", "次数", "几次", "开具")): + return ( + f"SELECT COUNT(*) AS cnt FROM prescriptions WHERE drug={self.schema_linker.quoted(values['drug'])}", + links, + ) + # Grouped visit metrics. These templates express exactly one dimension + # (GROUP BY {group}); if the question also carries a resolved filter + # value for a *different* field (e.g. "接诊高血压病人最多的前三个科室" + # groups by department but also names a specific disease), the template + # cannot express both and silently answering with the filter dropped is + # worse than deferring -- so `group` is cleared and the LLM path handles + # the compound question instead. + group = "" + if "科室" in q: + group = "department" + elif "疾病" in q or "病种" in q: + group = "disease" + elif "性别" in q or ("男性" in q and "女性" in q) or "男女" in q: + group = "gender" + if group and any(field in values for field in ("disease", "department", "drug") if field != group): + group = "" + explicit_n = self.schema_linker.explicit_top_n(q) + if group and any(term in q for term in ("平均费用", "平均就诊费用")): + direction, limit = self._superlative_order(q, explicit_n) + return ( + f"SELECT {group}, AVG(cost) AS avg_cost FROM patient_visits " + f"GROUP BY {group} ORDER BY avg_cost {direction}{limit}", + links, + ) + # "平均就诊年龄" is the same request as "平均年龄" but the inserted 就诊 + # used to miss this check, fall through to the visit-count branch below + # (which matches on the bare "多少") and silently answer with a COUNT(*) + # ranking instead of an average age -- a different metric, not a + # degraded one. The evaluation sets never caught it because their one + # such question spelled "平均年龄" out in a trailing clause. + if group and any(term in q for term in ("平均年龄", "平均就诊年龄", "平均患者年龄")): + direction, limit = self._superlative_order(q, explicit_n) + return ( + f"SELECT {group}, AVG(age) AS avg_age FROM patient_visits " + f"GROUP BY {group} ORDER BY avg_age {direction}{limit}", + links, + ) + if group and any( + term in q for term in ("就诊量", "人次", "多少", "数量", "次数", "排名", "最高", "最多", "最少") + ): + direction, limit = self._superlative_order(q, explicit_n) + return ( + f"SELECT {group}, COUNT(*) AS cnt FROM patient_visits " + f"GROUP BY {group} ORDER BY cnt {direction}{limit}", + links, + ) + # Filtered scalar visit metrics. + filters = [] + if "disease" in values: + filters.append(f"disease={self.schema_linker.quoted(values['disease'])}") + if "department" in values: + filters.append(f"department={self.schema_linker.quoted(values['department'])}") + if "女性" in q or re.search(r"(?" if age_match.group(2) in {"以上", "大于", "超过"} else "<" + filters.append(f"age{operator}{int(age_match.group(1))}") + where = " WHERE " + " AND ".join(filters) if filters else "" + if any(term in q for term in ("平均年龄", "平均就诊年龄", "平均患者年龄")): + return f"SELECT AVG(age) AS avg_age FROM patient_visits{where}", links + if "平均" in q and ("费用" in q or "花费" in q): + return f"SELECT AVG(cost) AS avg_cost FROM patient_visits{where}", links + if ("总费用" in q or "费用总计" in q) and not filters: + return "SELECT SUM(cost) AS total_cost FROM patient_visits", links + if any(term in q for term in ("多少次就诊", "多少人次", "人次是多少", "就诊总数", "总共有多少", "就诊次数")): + return f"SELECT COUNT(*) AS cnt FROM patient_visits{where}", links + return "", links + + # ------------------------------------------------------------------ # + def query(self, question: str) -> dict: + """NL question -> {sql, columns, rows, error, attempts}.""" + attempts: list[dict] = [] + deterministic_sql, links = self._deterministic_sql(question) + if deterministic_sql: + cols, rows, error = self._execute(deterministic_sql) + attempts.append( + { + "sql": deterministic_sql, + "error": error, + "source": "deterministic_template", + } + ) + if not error: + return { + "question": question, + "normalized_question": links["normalized_question"], + "schema_links": links, + "sql": deterministic_sql, + "columns": cols, + "rows": rows, + "error": "", + "attempts": attempts, + "generation_mode": "deterministic_template", + } + error = prev_sql = "" + for _ in range(self.max_correction + 1): + raw = self.llm.chat(self._build_prompt(question, error, prev_sql), system=_SYSTEM, temperature=0.0) + sql = self._extract_sql(raw) + readonly, reason = ensure_read_only(sql) + if not readonly: + # Feed the *specific* structural reason back rather than a generic + # refusal: "forbidden construct: Delete" is actionable for the model, + # "not allowed" is not. + error, prev_sql = f"rejected by read-only guard: {reason}", sql + attempts.append({"sql": sql, "error": error, "source": "llm"}) + continue + cols, rows, err = self._execute(sql) + attempts.append({"sql": sql, "error": err, "source": "llm"}) + if not err: + return {"question": question, "sql": sql, "columns": cols, + "rows": rows, "error": "", "attempts": attempts, + "schema_links": links, "generation_mode": "llm"} + error, prev_sql = err, sql + return {"question": question, "sql": prev_sql, "columns": [], "rows": [], + "error": error, "attempts": attempts, "schema_links": links, + "generation_mode": "llm_failed"} diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/numerals.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/numerals.py" new file mode 100644 index 0000000..9dc2fcf --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/numerals.py" @@ -0,0 +1,184 @@ +"""Chinese-numeral normalization for medical NL2SQL. + +Why this exists +--------------- +The deterministic NL2SQL router builds filters with regexes that only recognise +ASCII digits (``(\\d+)\\s*岁``, ``(?:前|top\\s*)(\\d+)`` ...). A question phrased +with Chinese numerals therefore lost its predicate *silently* -- no error, just a +wrong answer: + + 六十岁以上高血压患者的平均住院费用是多少？ + -> SELECT AVG(cost) ... WHERE disease='高血压' # age>60 dropped + 60岁以上高血压患者的平均住院费用是多少？ + -> SELECT AVG(cost) ... WHERE disease='高血压' AND age>60 # correct + +Rewriting every Chinese numeral is *not* safe, because medical terminology is +full of them. Measured against the 7,465 distinct disease/department/drug/test/ +entity values in the analytics DB, a naive rewrite corrupts 124+ of them +(``十二指肠白点综合征``, ``二十五味松石丸``, ``血液生化六项检查``, +``一秒用力呼出量``, ``百日咳`` ...). + +So normalization is gated twice: + +1. **Unit gate** -- a numeral run is only rewritten when it is immediately + followed by a counter/unit that marks a quantity (``岁``/``个``/``种`` ...), + or immediately preceded by a ranking prefix (``前``). ``十二指肠`` is left + alone because ``指`` is not a counter. +2. **Vocabulary mask** -- callers may pass the known value vocabulary as + ``protected``; any numeral run inside one of those terms is skipped. This is + what makes otherwise-ambiguous counters such as ``天``/``年``/``项``/``味`` + safe to enable (``二天油``, ``复方万年青胶囊``, ``血液生化六项检查``, + ``二十五味松石丸`` are all in the vocabulary). + +Vague quantifiers (``十几岁``, ``几十个``) are deliberately **not** rewritten: +mapping ``十几`` to ``10`` would reintroduce exactly the class of silent wrong +answer this module removes. +""" +from __future__ import annotations + +import re +from typing import Iterable + +_DIGITS: dict[str, int] = { + "零": 0, "〇": 0, "一": 1, "二": 2, "两": 2, "俩": 2, "三": 3, "四": 4, + "五": 5, "六": 6, "七": 7, "八": 8, "九": 9, +} +_SMALL_UNITS: dict[str, int] = {"十": 10, "百": 100, "千": 1000} +_MYRIAD = "万" + +_NUMERAL_CHARS = "".join(_DIGITS) + "".join(_SMALL_UNITS) + _MYRIAD +_NUMERAL_RUN = re.compile(f"[{_NUMERAL_CHARS}]+") + +#: Counters/units that mark a *quantity* rather than part of a term name. Every +#: entry was verified to produce zero collisions against the analytics DB +#: vocabulary, except the four marked below which rely on the ``protected`` mask. +SAFE_UNITS: tuple[str, ...] = ( + "岁", "个", "种", "型", "名", "位", "次", "周", "月", + "条", "例", "人", "份", "度", "级", "期", "分", + # vocabulary-mask dependent (1-38 collisions each, all in the value lists) + "天", "年", "项", "味", +) + +#: Prefixes after which a bare numeral denotes a rank ("前三" -> "前3"). +RANK_PREFIXES: tuple[str, ...] = ("前", "top", "TOP", "Top") + +#: Characters that make a numeral vague; never rewrite when adjacent. +_VAGUE = "几多" + + +def chinese_to_int(text: str) -> int | None: + """Parse a pure Chinese numeral run into an int, or None if unparseable. + + Handles 十五 / 二十 / 二十五 / 一百零八 / 三千五百 / 一万 / 两 / 十. + """ + if not text: + return None + total = 0 + section = 0 + number = 0 + seen_digit = False + for char in text: + if char in _DIGITS: + number = _DIGITS[char] + seen_digit = True + elif char in _SMALL_UNITS: + unit = _SMALL_UNITS[char] + # "十五" -> the leading 十 carries an implicit 1. + section += (number if number else 1) * unit + number = 0 + seen_digit = True + elif char == _MYRIAD: + section += number + total += (section if section else 1) * 10_000 + section = 0 + number = 0 + seen_digit = True + else: + return None + if not seen_digit: + return None + return total + section + number + + +def _protected_spans(text: str, protected: Iterable[str] | None) -> list[tuple[int, int]]: + """Spans of `text` covered by a protected vocabulary term.""" + if not protected: + return [] + spans: list[tuple[int, int]] = [] + for term in protected: + if not term or len(term) < 2: + continue + start = text.find(term) + while start >= 0: + spans.append((start, start + len(term))) + start = text.find(term, start + 1) + return spans + + +def _gate(text: str, start: int, end: int) -> str | None: + """Return the reason this numeral run is a quantity, or None to skip it.""" + after = text[end:] + for unit in SAFE_UNITS: + if after.startswith(unit): + return f"unit:{unit}" + before = text[:start] + for prefix in RANK_PREFIXES: + if before.endswith(prefix): + return f"rank:{prefix}" + return None + + +def normalize_numerals( + text: str, + protected: Iterable[str] | None = None, +) -> tuple[str, list[dict]]: + """Rewrite quantity-bearing Chinese numerals to ASCII digits. + + Returns ``(normalized_text, rewrites)`` where each rewrite records the + original surface form, its replacement and why it was considered a quantity. + The rewrite log is surfaced in the schema-linking result so a reviewer can + see exactly what the router did to the question. + """ + if not text: + return text, [] + blocked = _protected_spans(text, protected) + pieces: list[str] = [] + rewrites: list[dict] = [] + cursor = 0 + for match in _NUMERAL_RUN.finditer(text): + start, end = match.span() + run = match.group() + # Adjacent vague quantifier ("十几岁", "几十个") -> leave untouched. + neighbours = text[max(0, start - 1):start] + text[end:end + 1] + if any(char in _VAGUE for char in neighbours): + continue + if any(start < b_end and b_start < end for b_start, b_end in blocked): + continue + reason = _gate(text, start, end) + if reason is None: + continue + value = chinese_to_int(run) + if value is None: + continue + pieces.append(text[cursor:start]) + pieces.append(str(value)) + cursor = end + rewrites.append({"surface": run, "value": value, "reason": reason}) + if not rewrites: + return text, [] + pieces.append(text[cursor:]) + return "".join(pieces), rewrites + + +def normalize(text: str, protected: Iterable[str] | None = None) -> str: + """`normalize_numerals` without the rewrite log.""" + return normalize_numerals(text, protected)[0] + + +def numeral_bearing(terms: Iterable[str]) -> list[str]: + """Filter a vocabulary down to the terms a rewrite could damage. + + Only terms containing a Chinese numeral can be corrupted, so callers keep the + protected set small (~200 of 7,465 values) instead of scanning everything. + """ + return [term for term in terms if term and _NUMERAL_RUN.search(term)] diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/pg_relational.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/pg_relational.py" new file mode 100644 index 0000000..2089e38 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/pg_relational.py" @@ -0,0 +1,256 @@ +"""PostgreSQL analytics backend: pooled connections, real indexes, EXPLAIN. + +SQLite (`relational.py`) stays the zero-config default -- CI, demos and the +deterministic evals never need a server. This module is the production-shaped +swap the SQLite docstring has always promised: + + * one shared `psycopg_pool.ConnectionPool` per process instead of a connection + per query (connection setup is the dominant cost of naive PG usage); + * composite indexes chosen for the query shapes the NL2SQL router actually + emits (see `INDEX_DDL`), with `EXPLAIN ANALYZE` evidence rather than folklore; + * read-only execution with a server-side `statement_timeout`, mirroring the + SQLite executor's authorizer + progress-handler guard rails. + +Both engines ingest *exactly* the same rows (`relational.generate_rows`), so a +query returning different results across engines indicates non-portable SQL, not +different data. `visit_date` stays TEXT on both engines for the same reason: the +generated SQL uses `substr(visit_date,1,7)`, which is portable, whereas DATE would +make the SQLite and PG type systems diverge. +""" +from __future__ import annotations + +import threading +import time +from typing import Any + +from psycopg_pool import ConnectionPool + +from config.settings import AnalyticsConfig, get_analytics_config +from medigraph.analysis.relational import generate_rows +from medigraph.graph.local_store import LocalGraphStore + +PG_SCHEMA = """ +DROP TABLE IF EXISTS prescriptions; +DROP TABLE IF EXISTS lab_tests; +DROP TABLE IF EXISTS patient_visits; +DROP TABLE IF EXISTS kg_entities; +DROP TABLE IF EXISTS kg_triples; +CREATE TABLE patient_visits ( + visit_id INTEGER PRIMARY KEY, + patient_id INTEGER NOT NULL, + age INTEGER NOT NULL, + gender TEXT NOT NULL, + disease TEXT NOT NULL, + department TEXT NOT NULL, + visit_date TEXT NOT NULL, + cost DOUBLE PRECISION NOT NULL +); +CREATE TABLE prescriptions ( + rx_id INTEGER PRIMARY KEY, + visit_id INTEGER NOT NULL REFERENCES patient_visits(visit_id), + drug TEXT NOT NULL, + days INTEGER NOT NULL +); +CREATE TABLE lab_tests ( + test_id INTEGER PRIMARY KEY, + visit_id INTEGER NOT NULL REFERENCES patient_visits(visit_id), + test_name TEXT NOT NULL, + abnormal INTEGER NOT NULL +); +CREATE TABLE kg_entities (name TEXT, type TEXT); +CREATE TABLE kg_triples ( + head TEXT, head_type TEXT, relation TEXT, + tail TEXT, tail_type TEXT, confidence DOUBLE PRECISION, source TEXT +); +""" + +#: Indexes matched to the router's actual query shapes: +#: WHERE disease=? [AND age>?] -> ix_visits_disease (age in the key keeps +#: the age filter inside the index scan) +#: GROUP BY department / disease -> ix_visits_department +#: substr(visit_date,1,7) trends -> ix_visits_date +#: WHERE drug=? / GROUP BY drug -> ix_rx_drug +#: lab JOIN + abnormal filter -> ix_lab_visit +#: kg_triples head/relation lookups -> ix_kg_head_rel +INDEX_DDL: dict[str, str] = { + "ix_visits_disease": "CREATE INDEX ix_visits_disease ON patient_visits (disease, age)", + "ix_visits_department": "CREATE INDEX ix_visits_department ON patient_visits (department)", + "ix_visits_date": "CREATE INDEX ix_visits_date ON patient_visits (visit_date)", + "ix_rx_drug": "CREATE INDEX ix_rx_drug ON prescriptions (drug)", + "ix_lab_visit": "CREATE INDEX ix_lab_visit ON lab_tests (visit_id, abnormal)", + "ix_kg_head_rel": "CREATE INDEX ix_kg_head_rel ON kg_triples (head, relation)", +} + +_pool: ConnectionPool | None = None +_pool_lock = threading.Lock() + + +def get_pool(config: AnalyticsConfig | None = None) -> ConnectionPool: + """Process-wide connection pool (lazily created). + + `open=True` connects eagerly so a bad DSN fails at first use, not first query; + `max_idle` trims connections the load spike no longer needs. + """ + global _pool + if _pool is None: + with _pool_lock: + if _pool is None: + config = config or get_analytics_config() + _pool = ConnectionPool( + conninfo=config.pg_dsn, + min_size=config.pool_min, + max_size=config.pool_max, + max_idle=60.0, + open=True, + name="medigraph-analytics", + ) + return _pool + + +def close_pool() -> None: + global _pool + if _pool is not None: + _pool.close() + _pool = None + + +# --------------------------------------------------------------------------- # +# build +# --------------------------------------------------------------------------- # +def build_pg_db( + store: LocalGraphStore, + n_visits: int = 600, + seed: int = 42, + year: int = 2024, + with_indexes: bool = True, + config: AnalyticsConfig | None = None, +) -> dict: + """(Re)create the analytics schema in PostgreSQL from the same row generator. + + Loads via ``COPY`` -- at 100k+ rows executemany is minutes, COPY is seconds. + """ + rows = generate_rows(store, n_visits=n_visits, seed=seed, year=year) + pool = get_pool(config) + started = time.perf_counter() + with pool.connection() as conn: + conn.execute(PG_SCHEMA) + with conn.cursor() as cur: + with cur.copy("COPY patient_visits FROM STDIN") as copy: + for row in rows["patient_visits"]: + copy.write_row(row) + with cur.copy("COPY prescriptions FROM STDIN") as copy: + for row in rows["prescriptions"]: + copy.write_row(row) + with cur.copy("COPY lab_tests FROM STDIN") as copy: + for row in rows["lab_tests"]: + copy.write_row(row) + with cur.copy("COPY kg_entities FROM STDIN") as copy: + for row in rows["kg_entities"]: + copy.write_row(row) + with cur.copy("COPY kg_triples FROM STDIN") as copy: + for row in rows["kg_triples"]: + copy.write_row(row) + if with_indexes: + for ddl in INDEX_DDL.values(): + conn.execute(ddl) + conn.execute("ANALYZE") + conn.commit() + return { + "backend": "postgres", + "n_visits": n_visits, + "n_prescriptions": len(rows["prescriptions"]), + "n_lab_tests": len(rows["lab_tests"]), + "n_kg_triples": len(rows["kg_triples"]), + "indexes": list(INDEX_DDL) if with_indexes else [], + "load_seconds": round(time.perf_counter() - started, 3), + } + + +def drop_indexes(config: AnalyticsConfig | None = None) -> None: + pool = get_pool(config) + with pool.connection() as conn: + for name in INDEX_DDL: + conn.execute(f"DROP INDEX IF EXISTS {name}") + conn.execute("ANALYZE") + conn.commit() + + +def create_indexes(config: AnalyticsConfig | None = None) -> None: + pool = get_pool(config) + with pool.connection() as conn: + for name, ddl in INDEX_DDL.items(): + conn.execute(f"DROP INDEX IF EXISTS {name}") + conn.execute(ddl) + conn.execute("ANALYZE") + conn.commit() + + +# --------------------------------------------------------------------------- # +# execution +# --------------------------------------------------------------------------- # +def execute_readonly_pg( + sql: str, + timeout_seconds: float = 5.0, + max_rows: int = 5000, + config: AnalyticsConfig | None = None, +) -> tuple[list[str], list[tuple], str]: + """Run one read-only statement on the pool. Mirrors the SQLite executor's + contract: ``(columns, rows, error)`` with the error string empty on success. + + Defence in depth, same shape as SQLite's (authorizer + query_only + progress + handler): the AST guard has already vetted the SQL upstream, and here the + transaction is forced read-only and time-boxed *server-side*, so even a guard + gap cannot write or run forever. + """ + pool = get_pool(config) + try: + with pool.connection() as conn: + # `read_only` must be set while the connection is idle: psycopg begins a + # transaction implicitly on the first execute, and session defaults like + # `default_transaction_read_only` would only take effect for the *next* + # transaction -- i.e. never for this statement. Setting the connection + # property makes the very transaction that runs `sql` read-only, which + # PostgreSQL then enforces server-side ("cannot execute ... in a + # read-only transaction"). + conn.read_only = True + try: + conn.execute(f"SET statement_timeout = {int(timeout_seconds * 1000)}") + with conn.cursor() as cur: + cur.execute(sql) # type: ignore[arg-type] + rows = cur.fetchmany(max_rows + 1) + if len(rows) > max_rows: + return [], [], f"result exceeds safety limit ({max_rows} rows)" + columns = [d.name for d in cur.description] if cur.description else [] + conn.rollback() # release the snapshot promptly + return columns, rows, "" + finally: + # The pool reuses connections and build/index DDL shares this pool, + # so the read-only characteristic must not leak past this call. + conn.rollback() + conn.read_only = False + except Exception as exc: # noqa: BLE001 - surfaced to the self-correction loop + return [], [], str(exc) + + +def explain_analyze(sql: str, config: AnalyticsConfig | None = None) -> dict[str, Any]: + """Structured EXPLAIN ANALYZE, for the index benchmark and for debugging.""" + pool = get_pool(config) + with pool.connection() as conn: + conn.execute("SET default_transaction_read_only = on") + cur = conn.execute(f"EXPLAIN (ANALYZE, FORMAT JSON) {sql}") # type: ignore[arg-type] + plan = cur.fetchone()[0][0] + conn.rollback() + return { + "node_type": plan["Plan"]["Node Type"], + "execution_ms": plan["Execution Time"], + "planning_ms": plan["Planning Time"], + "plan": plan["Plan"], + } + + +def ping(config: AnalyticsConfig | None = None) -> bool: + try: + columns, rows, error = execute_readonly_pg("SELECT 1", config=config) + return not error and rows == [(1,)] + except Exception: # noqa: BLE001 + return False diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/relational.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/relational.py" new file mode 100644 index 0000000..ea875b6 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/relational.py" @@ -0,0 +1,266 @@ +"""Relational layer for Task 3: build a SQLite analytics DB. + +Zero-config (file-based SQLite; the plan's PostgreSQL is a documented production +swap). The clinical *vocabulary and relationships* are derived from the task-2 +knowledge graph (disease->department via treated_in_department, disease->drug via +recommend_drug, disease->exam via need_examination) -- this is the concrete +"effective reuse" of Task 2. On top of that vocabulary we generate deterministic +(seeded) synthetic visit records so statistical/trend analysis has data to query. + +Tables: + patient_visits(visit_id, patient_id, age, gender, disease, department, visit_date, cost) + prescriptions(rx_id, visit_id, drug, days) + lab_tests(test_id, visit_id, test_name, abnormal) + kg_entities(name, type) + kg_triples(head, head_type, relation, tail, tail_type, confidence, source) +""" +from __future__ import annotations + +import random +import sqlite3 +from datetime import date, timedelta +from pathlib import Path + +from medigraph.graph.local_store import LocalGraphStore + +SCHEMA = """ +CREATE TABLE patient_visits ( + visit_id INTEGER PRIMARY KEY, + patient_id INTEGER NOT NULL, + age INTEGER NOT NULL, + gender TEXT NOT NULL, -- '男' | '女' + disease TEXT NOT NULL, -- diagnosed disease name + department TEXT NOT NULL, -- visited department + visit_date TEXT NOT NULL, -- 'YYYY-MM-DD' + cost REAL NOT NULL -- visit cost in CNY +); +CREATE TABLE prescriptions ( + rx_id INTEGER PRIMARY KEY, + visit_id INTEGER NOT NULL, + drug TEXT NOT NULL, + days INTEGER NOT NULL, + FOREIGN KEY (visit_id) REFERENCES patient_visits(visit_id) +); +CREATE TABLE lab_tests ( + test_id INTEGER PRIMARY KEY, + visit_id INTEGER NOT NULL, + test_name TEXT NOT NULL, + abnormal INTEGER NOT NULL, -- 1 if result abnormal else 0 + FOREIGN KEY (visit_id) REFERENCES patient_visits(visit_id) +); +CREATE TABLE kg_entities (name TEXT, type TEXT); +CREATE TABLE kg_triples ( + head TEXT, head_type TEXT, relation TEXT, + tail TEXT, tail_type TEXT, confidence REAL, source TEXT +); +""" + +# Fallback vocabulary if the KG lacks the needed relations. +_FALLBACK = { + "高血压": {"department": "心内科", "drugs": ["硝苯地平", "氨氯地平"], "exams": ["心电图"]}, + "2型糖尿病": {"department": "内分泌科", "drugs": ["二甲双胍"], "exams": ["糖化血红蛋白"]}, + "急性心肌梗死": {"department": "心内科", "drugs": ["阿司匹林", "氯吡格雷"], "exams": ["冠状动脉造影"]}, + "冠心病": {"department": "心内科", "drugs": ["阿司匹林"], "exams": ["心电图"]}, + "糖尿病肾病": {"department": "肾内科", "drugs": ["缬沙坦"], "exams": ["尿微量白蛋白"]}, +} + +#: Diseases the rest of the codebase already names by literal string (NL2SQL +#: few-shot pool, the stress-set generator, hand-written gold questions, +#: `_MEDICAL_ALIASES`). Force-included in the curated vocabulary below so those +#: literals are guaranteed to resolve to real, non-empty visit/prescription rows +#: instead of an accidental empty-set match against an equally-empty gold query. +ANCHOR_DISEASES: tuple[str, ...] = ( + "高血压", "冠心病", "糖尿病肾病", "急性心肌梗死", "糖尿病足", "糖尿病酮症酸中毒", + "小儿肺炎", "急性阑尾炎", "肺炎", "强直性脊柱炎", "骨关节炎", "老年痴呆", + "肝硬化", "急性胃炎", +) + +#: Cap on distinct diseases sampled into the synthetic visit generator. +DEFAULT_MAX_DISEASES = 50 + + +def derive_vocab( + store: LocalGraphStore, + max_diseases: int = DEFAULT_MAX_DISEASES, + anchors: tuple[str, ...] = ANCHOR_DISEASES, +) -> dict: + """Build {disease: {department, drugs[], exams[]}} from KG triples. + + Why curate rather than use every Disease node + ---------------------------------------------- + The full CM3KG import carries ~1,200 diseases with a department/drug edge. + Spreading 600 synthetic visits across all of them leaves most diseases with + zero or one visit -- any NL2SQL question that filters on a specific disease + or drug name then has an *empty* result set on both the gold and the + predicted side, so it "passes" by vacuous agreement rather than by the + predicted SQL being structurally correct. That silently inflates reported + accuracy without validating anything. + + Curating to the `max_diseases` richest entries (ranked by how many drugs + and exams the KG associates with them, a proxy for how well-documented the + disease is) keeps a synthetic hospital's realistic diagnosis mix instead of + a uniform draw over rare/obscure conditions, and gives literal-filter + questions real, countable rows to match against. + """ + vocab: dict[str, dict] = {} + for head, tail, data in store.g.edges(data=True): + htype = store.g.nodes[head].get("type", "") + if htype not in ("Disease", "Tumor"): + continue + rel = data.get("relation") + slot = vocab.setdefault(head, {"department": None, "drugs": [], "exams": []}) + if rel == "treated_in_department" and not slot["department"]: + slot["department"] = tail + elif rel == "recommend_drug": + slot["drugs"].append(tail) + elif rel == "need_examination": + slot["exams"].append(tail) + # keep only diseases that have at least a department or drug; fill gaps + cleaned = {} + for dz, slot in vocab.items(): + if not slot["department"] and not slot["drugs"]: + continue + slot["department"] = slot["department"] or "全科" + slot["drugs"] = slot["drugs"] or ["对症治疗药"] + slot["exams"] = slot["exams"] or ["常规检查"] + cleaned[dz] = slot + if not cleaned: + return dict(_FALLBACK) + if max_diseases and len(cleaned) > max_diseases: + ranked = sorted( + cleaned.items(), + key=lambda item: (len(item[1]["drugs"]) * 2 + len(item[1]["exams"]), item[0]), + reverse=True, + ) + selected = dict(ranked[:max_diseases]) + for name in anchors: + if name in cleaned: + selected[name] = cleaned[name] + cleaned = selected + return cleaned + + +def generate_rows( + store: LocalGraphStore, + n_visits: int = 600, + seed: int = 42, + year: int = 2024, + max_diseases: int = DEFAULT_MAX_DISEASES, +) -> dict: + """Deterministically generate all analytics rows from the Task-2 KG vocabulary. + + Engine-independent on purpose: the SQLite builder below and the PostgreSQL + builder (`pg_relational.build_pg_db`) both insert exactly these rows, so + running the same generated SQL on both engines is a true logical-equivalence + check rather than a comparison across two different datasets. + """ + vocab = derive_vocab(store, max_diseases=max_diseases) + diseases = list(vocab.keys()) + rng = random.Random(seed) + + visits: list[tuple] = [] + prescriptions: list[tuple] = [] + lab_tests: list[tuple] = [] + + # disease popularity weights (stable), age profiles per disease + weights = [rng.randint(2, 10) for _ in diseases] + rx_id = test_id = 1 + start = date(year, 1, 1) + for vid in range(1, n_visits + 1): + dz = rng.choices(diseases, weights=weights, k=1)[0] + slot = vocab[dz] + # age skewed older for cardiac/diabetes + age = max(18, min(95, int(rng.gauss(58, 14)))) + gender = rng.choice(["男", "女"]) + # visits trend upward across the year (seasonality-ish) + day_offset = int(abs(rng.gauss(0, 1)) / 3 * 364) % 365 + # bias later months a bit to create a visible trend + day_offset = min(364, int(day_offset * 0.6 + (vid / n_visits) * 364 * 0.4)) + vdate = (start + timedelta(days=day_offset)).isoformat() + cost = round(rng.uniform(120, 3200), 2) + visits.append( + (vid, rng.randint(10000, 99999), age, gender, dz, slot["department"], vdate, cost) + ) + for drug in rng.sample(slot["drugs"], k=min(len(slot["drugs"]), rng.randint(1, 2))): + prescriptions.append((rx_id, vid, drug, rng.choice([7, 14, 28, 30]))) + rx_id += 1 + for exam in rng.sample(slot["exams"], k=min(len(slot["exams"]), rng.randint(1, 2))): + lab_tests.append((test_id, vid, exam, 1 if rng.random() < 0.35 else 0)) + test_id += 1 + + entities = [(n, d.get("type", "")) for n, d in store.g.nodes(data=True)] + triples = [ + (head, store.g.nodes[head].get("type", ""), data.get("relation", ""), + tail, store.g.nodes[tail].get("type", ""), + data.get("confidence", 1.0), data.get("source", "")) + for head, tail, data in store.g.edges(data=True) + ] + return { + "diseases": diseases, + "patient_visits": visits, + "prescriptions": prescriptions, + "lab_tests": lab_tests, + "kg_entities": entities, + "kg_triples": triples, + } + + +def build_db( + db_path: str | Path, + store: LocalGraphStore, + n_visits: int = 600, + seed: int = 42, + year: int = 2024, + max_diseases: int = DEFAULT_MAX_DISEASES, +) -> dict: + """Create the SQLite analytics DB. Returns a summary dict.""" + db_path = Path(db_path) + db_path.parent.mkdir(parents=True, exist_ok=True) + if db_path.exists(): + db_path.unlink() + + rows = generate_rows(store, n_visits=n_visits, seed=seed, year=year, max_diseases=max_diseases) + + conn = sqlite3.connect(db_path) + conn.executescript(SCHEMA) + cur = conn.cursor() + cur.executemany("INSERT INTO patient_visits VALUES (?,?,?,?,?,?,?,?)", rows["patient_visits"]) + cur.executemany("INSERT INTO prescriptions VALUES (?,?,?,?)", rows["prescriptions"]) + cur.executemany("INSERT INTO lab_tests VALUES (?,?,?,?)", rows["lab_tests"]) + # KG mirror tables (for graph-aware SQL and reuse traceability) + cur.executemany("INSERT INTO kg_entities VALUES (?,?)", rows["kg_entities"]) + cur.executemany("INSERT INTO kg_triples VALUES (?,?,?,?,?,?,?)", rows["kg_triples"]) + conn.commit() + conn.close() + return { + "db_path": str(db_path), + "diseases": rows["diseases"], + "n_visits": n_visits, + "n_prescriptions": len(rows["prescriptions"]), + "n_lab_tests": len(rows["lab_tests"]), + } + + +def schema_text() -> str: + """Schema description injected into the NL2SQL prompt. + + The `relation` hint spells out that kg_triples.relation stores the English + ontology key, not the Chinese word the question used -- without it, a model + asked "冠心病的并发症有哪些" reasonably generates `relation = '并发症'` + (the Chinese word it just read in the question), which matches zero rows + because the column actually holds `'complication'`. Found via + benchmarks/nl2sql_hard_natural.json's kg-aware questions, which return + genuinely wrong (not just differently-shaped) results without this hint. + """ + from medigraph.schema.ontology import RELATION_TYPES + + relation_hint = "、".join(f"{key}({label})" for key, label in RELATION_TYPES.items()) + return ( + "表 patient_visits(visit_id, patient_id, age 年龄, gender 性别('男'/'女'), " + "disease 疾病, department 科室, visit_date 就诊日期'YYYY-MM-DD', cost 费用)\n" + "表 prescriptions(rx_id, visit_id, drug 药物, days 用药天数)\n" + "表 lab_tests(test_id, visit_id, test_name 检查名称, abnormal 是否异常(1/0))\n" + "表 kg_entities(name 实体名, type 类型)\n" + "表 kg_triples(head, head_type, relation 关系, tail, tail_type, confidence, source)\n" + f"kg_triples.relation 的取值是英文代码，不是中文，例如：{relation_hint}" + ) diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/schema_linking.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/schema_linking.py" new file mode 100644 index 0000000..0da15ed --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/schema_linking.py" @@ -0,0 +1,164 @@ +"""Graph-aware schema/value linking for medical NL2SQL.""" +from __future__ import annotations + +import re +import sqlite3 +from pathlib import Path + +from medigraph.analysis.numerals import normalize, normalize_numerals, numeral_bearing + +_TABLE_TERMS = { + "patient_visits": ("就诊", "患者", "疾病", "科室", "年龄", "性别", "费用", "日期", "人次"), + "prescriptions": ("处方", "药物", "用药", "开具", "天数"), + "lab_tests": ("检查", "检验", "异常", "项目"), + "kg_entities": ("实体", "类型", "知识图谱"), + "kg_triples": ("关系", "三元组", "置信度", "来源", "图谱"), +} + +_COLUMN_TERMS = { + "age": ("年龄", "岁"), + "gender": ("性别", "男性", "女性", "男", "女"), + "disease": ("疾病", "病种", "诊断"), + "department": ("科室", "挂号"), + "visit_date": ("日期", "时间", "月份", "季度", "年度"), + "cost": ("费用", "花费", "金额"), + "drug": ("药物", "用药", "处方", "开具"), + "days": ("天数", "疗程"), + "test_name": ("检查", "检验", "项目"), + "abnormal": ("异常", "阳性"), +} + +_MEDICAL_ALIASES = { + "糖网": "糖尿病视网膜病变", + "糖肾": "糖尿病肾病", + "高血压病": "高血压", + "二甲": "二甲双胍", + "心梗": "急性心肌梗死", +} + + +class MedicalSchemaLinker: + def __init__(self, db_path: str): + self.db_path = str(Path(db_path)) + self.values = self._load_values() + # Terms a Chinese-numeral rewrite could corrupt ("血液生化六项检查", + # "二十五味松石丸", "百日咳" ...). Kept as a mask for normalize_numerals so + # quantity counters stay enabled without damaging vocabulary matches. + self._numeral_protected = numeral_bearing( + {value for values in self.values.values() for value in values} + ) + + def _load_values(self) -> dict[str, list[str]]: + result: dict[str, list[str]] = {} + queries = { + "disease": "SELECT DISTINCT disease FROM patient_visits LIMIT 1000", + "department": "SELECT DISTINCT department FROM patient_visits LIMIT 1000", + "drug": "SELECT DISTINCT drug FROM prescriptions LIMIT 1000", + "test_name": "SELECT DISTINCT test_name FROM lab_tests LIMIT 1000", + "kg_entity": "SELECT DISTINCT name FROM kg_entities LIMIT 3000", + } + try: + connection = sqlite3.connect(f"file:{self.db_path}?mode=ro", uri=True) + for field, sql in queries.items(): + try: + result[field] = [str(row[0]) for row in connection.execute(sql) if row[0]] + except sqlite3.Error: + result[field] = [] + connection.close() + except sqlite3.Error: + return {field: [] for field in queries} + return result + + def link(self, question: str) -> dict: + # Chinese numerals first, so "二型糖尿病" can still match the "2型糖尿病" + # value literal below and the downstream ASCII-digit regexes fire. + normalized, numerals = normalize_numerals(question, self._numeral_protected) + aliases = {} + for alias, canonical in _MEDICAL_ALIASES.items(): + if alias in normalized: + normalized = normalized.replace(alias, canonical) + aliases[alias] = canonical + table_scores = { + table: sum(term in normalized for term in terms) + for table, terms in _TABLE_TERMS.items() + } + tables = [ + table + for table, score in sorted(table_scores.items(), key=lambda item: (-item[1], item[0])) + if score > 0 + ] + columns = [ + column + for column, terms in _COLUMN_TERMS.items() + if any(term in normalized for term in terms) + ] + value_matches = [] + for field, values in self.values.items(): + for value in values: + if len(value) >= 2 and value in normalized: + value_matches.append({"field": field, "value": value, "match": "literal"}) + # Longest values first avoids selecting both 糖尿病 and 2型糖尿病. + value_matches.sort(key=lambda item: (-len(item["value"]), item["field"], item["value"])) + selected = [] + occupied: list[tuple[int, int]] = [] + for match in value_matches: + start = normalized.find(match["value"]) + span = (start, start + len(match["value"])) + if start >= 0 and not any(max(span[0], old[0]) < min(span[1], old[1]) for old in occupied): + selected.append(match) + occupied.append(span) + result = { + "normalized_question": normalized, + "aliases": aliases, + "tables": tables[:3], + "columns": columns, + "values": selected[:12], + } + # NL2SQL._build_prompt embeds this dict verbatim in the LLM prompt, so an + # always-present key would perturb every prompt (and re-roll the model's + # output) even for questions containing no numerals. Report the rewrite log + # only when a rewrite actually happened. + if numerals: + result["numerals"] = numerals + return result + + @staticmethod + def quoted(value: str) -> str: + return "'" + value.replace("'", "''") + "'" + + # Threshold phrasings put a number in front of a counter without asking for + # a top-N list ("就诊人次超过50次的科室"). Reading that 50 as a LIMIT would + # answer a different question, so a question carrying one of these words is + # treated as having no explicit N. + _THRESHOLD_WORDS = ("超过", "多于", "达到", "不少于", "至少", "大于", + "小于", "低于", "少于", "以上", "以下", "不满") + + @staticmethod + def explicit_top_n(question: str) -> int | None: + """Parsed "前N"/"topN"/"N个"/"N种"/"N次"/"N位" count, or None if the + question has no explicit number. Split out from `extract_top_n` so a + caller can tell "no number was given" apart from "the number happened to + be the default" -- needed to pick LIMIT 1 for a bare superlative + ("最高的是哪个") vs the requested N for an explicit list ("前3个"). + + 个/种 alone did not cover ranking questions counted in visits or people + ("费用最高的3次就诊"), which silently fell back to the default 5 and + returned two rows more than were asked for. + """ + question = normalize(question) + counters = "个|种|次|位|名|条" + if any(word in question for word in MedicalSchemaLinker._THRESHOLD_WORDS): + counters = "个|种" + match = re.search(rf"(?:前|top\s*)(\d+)|(\d+)\s*(?:{counters})", + question, flags=re.IGNORECASE) + if not match: + return None + value = int(next(group for group in match.groups() if group)) + return max(1, min(100, value)) + + @staticmethod + def extract_top_n(question: str, default: int = 5) -> int: + # Idempotent on already-normalized text; also makes the helper correct for + # direct callers that pass a raw question ("前三个科室" -> 3, not `default`). + value = MedicalSchemaLinker.explicit_top_n(question) + return value if value is not None else default diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/sql_guard.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/sql_guard.py" new file mode 100644 index 0000000..02994b2 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/sql_guard.py" @@ -0,0 +1,105 @@ +"""AST-level read-only validation for generated SQL. + +The previous check was a regex blacklist over the query string (``insert``, +``update``, ``drop`` ...). Blacklists enumerate what is forbidden, so they fail +open: anything the author did not think of gets through, and string-level matching +is confused by comments, casing, whitespace and nesting. It also produced false +*positives* -- a legitimate column named ``updated_at`` contains "update". + +This module parses the statement instead and decides structurally: + +1. exactly one statement (a trailing ``;`` is fine, a second statement is not); +2. the root must be a projection -- ``SELECT``/``WITH``, or a set operation over + them (``UNION``/``INTERSECT``/``EXCEPT``); +3. no node anywhere in the tree may be DDL/DML or a session-level command; +4. no calls to SQLite functions that touch the filesystem or load code. + +Rule 3 is the important one: it holds for arbitrarily nested constructs, so a +``DELETE`` hidden inside a CTE or a scalar subquery is rejected on structure rather +than on spelling. + +This is the outer layer of a defence-in-depth pair. The executor additionally opens +the database read-only, sets ``PRAGMA query_only`` and installs a SQLite authorizer +that denies write actions -- so a parser gap still does not become a write. +""" +from __future__ import annotations + +import sqlglot +from sqlglot import expressions as exp + +DIALECT = "sqlite" + +#: Statement/clause types that must never appear anywhere in the tree. +FORBIDDEN_NODES: tuple[type, ...] = ( + exp.Insert, + exp.Update, + exp.Delete, + exp.Drop, + exp.Create, + exp.Alter, + exp.Attach, + exp.Detach, + exp.Pragma, + exp.Set, + exp.Transaction, + exp.Commit, + exp.Rollback, + # `Command` is sqlglot's catch-all for statements it does not model (VACUUM, + # REINDEX, ANALYZE ...). Unmodelled means unvalidatable, so refuse it. + exp.Command, +) + +#: Statement roots that are acceptable: a projection or a set operation over them. +ALLOWED_ROOTS: tuple[type, ...] = (exp.Select, exp.Union, exp.Intersect, exp.Except) + +#: SQLite functions that read/write files or load native code. +FORBIDDEN_FUNCTIONS: frozenset[str] = frozenset( + {"load_extension", "readfile", "writefile", "edit", "fts3_tokenizer"} +) + + +def ensure_read_only(sql: str) -> tuple[bool, str]: + """Return ``(ok, reason)``. `reason` is empty when the statement is accepted.""" + if not sql or not sql.strip(): + return False, "empty statement" + + try: + statements = [statement for statement in sqlglot.parse(sql, dialect=DIALECT) if statement] + except Exception as exc: # noqa: BLE001 - sqlglot raises several parse error types + return False, f"unparseable SQL: {exc}" + + if not statements: + return False, "no statement parsed" + if len(statements) > 1: + kinds = ", ".join(type(statement).__name__ for statement in statements) + return False, f"multiple statements are not allowed ({kinds})" + + root = statements[0] + if not isinstance(root, ALLOWED_ROOTS): + return False, f"statement root must be a SELECT/WITH, got {type(root).__name__}" + + for node in root.walk(): + # sqlglot versions differ on whether walk() yields nodes or (node, ...) tuples. + current = node[0] if isinstance(node, tuple) else node + if isinstance(current, FORBIDDEN_NODES): + return False, f"forbidden construct: {type(current).__name__}" + if isinstance(current, exp.Anonymous): + name = str(current.this or "").lower() + if name in FORBIDDEN_FUNCTIONS: + return False, f"forbidden function: {name}" + + return True, "" + + +def is_read_only(sql: str) -> bool: + """Boolean form of `ensure_read_only`.""" + return ensure_read_only(sql)[0] + + +def transpile(sql: str, write: str) -> str: + """Re-render a validated statement for another dialect. + + Used to run the same generated query against SQLite and PostgreSQL without + string-patching quoting or function names by hand. + """ + return sqlglot.transpile(sql, read=DIALECT, write=write)[0] diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/viz.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/viz.py" new file mode 100644 index 0000000..ee841d6 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/analysis/viz.py" @@ -0,0 +1,254 @@ +"""BI + graph visualization: render analysis results to a self-contained HTML. + +Uses a vendored ECharts build to draw bar / line / pie charts for tabular analysis +results, and a relationship network for graph-driven association analysis. Each +chart is paired with an LLM-generated natural-language insight (图文结合). + +The ECharts runtime is inlined rather than pulled from a CDN so every generated +report opens correctly offline; the CDN URL is kept only as a fallback for the +case where the vendored asset is missing. +""" +from __future__ import annotations + +import html as html_lib +import json +from functools import lru_cache +from pathlib import Path + +_ECHARTS_CDN = "https://cdn.jsdelivr.net/npm/echarts@5/dist/echarts.min.js" +# Vendored copy (Apache-2.0, see THIRD_PARTY_NOTICES.md) so generated reports are +# self-contained: a reviewer opening the HTML offline -- or behind a network where +# jsdelivr is unreachable -- still sees the charts instead of a blank panel. +_ECHARTS_LOCAL = Path(__file__).resolve().parent / "assets" / "echarts.min.js" + + +@lru_cache(maxsize=1) +def _echarts_script() -> str: + """Inline ' + # ECharts is minified JS with no literal "", but guard anyway so a + # future asset swap cannot break out of the tag. + source = source.replace("", "<\\/script>") + return f"" + + +def pick_chart_type(question: str, columns: list[str], rows: list) -> str: + """Heuristic chart selection by question intent + result shape.""" + q = question.lower() + if not rows or len(columns) < 2: + return "table" + if any(k in q for k in ("热力", "矩阵", "交叉")) and len(columns) >= 3: + return "heatmap" + if any(k in q for k in ("散点", "相关性", "相关关系")): + return "scatter" + if any(k in question for k in ("趋势", "随时间", "每月", "每年", "变化", "trend")) or "month" in " ".join(columns).lower(): + return "line" + if any(k in question for k in ("比例", "占比", "分布", "构成", "ratio", "proportion")): + return "pie" + return "bar" + + +def _bar_or_line_option(title: str, columns: list[str], rows: list, kind: str) -> dict: + cats = [str(r[0]) for r in rows] + vals = [r[1] for r in rows] + # Long Chinese disease names at the 12px ECharts default are unreadable once + # the page is captured and rescaled, so set type sizes explicitly. + return { + "title": {"text": title, "left": "center", "textStyle": {"fontSize": 18}}, + "tooltip": {"trigger": "axis"}, + "grid": {"bottom": 130 if len(cats) > 6 else 70, "left": 70, "right": 40, "top": 70}, + "xAxis": {"type": "category", "data": cats, "name": columns[0], + "nameTextStyle": {"fontSize": 14}, + "axisLabel": {"rotate": 30 if len(cats) > 6 else 0, "fontSize": 14, + "interval": 0, "hideOverlap": False}}, + "yAxis": {"type": "value", "name": columns[1], + "nameTextStyle": {"fontSize": 14}, + "axisLabel": {"fontSize": 14}}, + "series": [{"type": kind, "data": vals, "smooth": kind == "line", + "label": {"show": kind == "bar", "position": "top", "fontSize": 14}}], + } + + +def _pie_option(title: str, columns: list[str], rows: list) -> dict: + return { + "title": {"text": title, "left": "center"}, + "tooltip": {"trigger": "item"}, + "legend": {"bottom": 0}, + "series": [{"type": "pie", "radius": "60%", + "data": [{"name": str(r[0]), "value": r[1]} for r in rows]}], + } + + +def _scatter_option(title: str, columns: list[str], rows: list) -> dict: + return { + "title": {"text": title, "left": "center"}, + "tooltip": {"trigger": "item"}, + "xAxis": {"type": "value", "name": columns[0]}, + "yAxis": {"type": "value", "name": columns[1]}, + "series": [ + { + "type": "scatter", + "data": [[row[0], row[1]] for row in rows], + "symbolSize": 12, + } + ], + } + + +def _heatmap_option(title: str, columns: list[str], rows: list) -> dict: + x_values = list(dict.fromkeys(str(row[0]) for row in rows)) + y_values = list(dict.fromkeys(str(row[1]) for row in rows)) + data = [ + [x_values.index(str(row[0])), y_values.index(str(row[1])), row[2]] + for row in rows + ] + numeric = [float(row[2]) for row in rows if isinstance(row[2], (int, float))] + return { + "title": {"text": title, "left": "center"}, + "tooltip": {"position": "top"}, + "grid": {"top": 70, "bottom": 80}, + "xAxis": {"type": "category", "data": x_values, "name": columns[0], "splitArea": {"show": True}}, + "yAxis": {"type": "category", "data": y_values, "name": columns[1], "splitArea": {"show": True}}, + "visualMap": { + "min": min(numeric) if numeric else 0, + "max": max(numeric) if numeric else 1, + "calculable": True, + "orient": "horizontal", + "left": "center", + "bottom": 10, + }, + "series": [{"type": "heatmap", "data": data, "label": {"show": True}}], + } + + +def _graph_option(title: str, triples: list[dict]) -> dict: + degree: dict[str, int] = {} + for t in triples: + for name in (t["head"], t["tail"]): + degree[name] = degree.get(name, 0) + 1 + nodes, seen = [], set() + for t in triples: + for name in (t["head"], t["tail"]): + if name not in seen: + seen.add(name) + # Hubs read as hubs: size grows with degree instead of every node + # being an identical dot. + nodes.append({"name": name, "symbolSize": min(30 + 6 * degree[name], 72), + "draggable": True}) + links = [{"source": t["head"], "target": t["tail"], + "value": t.get("relation_zh", t.get("relation", ""))} for t in triples] + # Scale type and spacing to the graph size: ECharts' 12px default is + # unreadable at the zoom level the page opens at. + n = len(nodes) + node_font = 20 if n <= 20 else (17 if n <= 45 else 14) + edge_font = 15 if n <= 20 else (13 if n <= 45 else 11) + repulsion = 900 if n <= 20 else (600 if n <= 45 else 380) + edge_length = 190 if n <= 20 else (150 if n <= 45 else 110) + return { + "title": {"text": title, "left": "center", "textStyle": {"fontSize": 18}}, + "tooltip": {}, + "series": [{ + "type": "graph", "layout": "force", "roam": True, + "label": { + "show": True, "position": "right", "fontSize": node_font, + "color": "#1b2a2e", "textBorderColor": "#ffffff", "textBorderWidth": 3, + }, + "edgeSymbol": ["none", "arrow"], "edgeSymbolSize": 9, + "lineStyle": {"color": "#8fa6ad", "width": 1.6, "curveness": 0.08, "opacity": 0.9}, + "emphasis": {"focus": "adjacency", "lineStyle": {"width": 3}}, + "force": {"repulsion": repulsion, "edgeLength": edge_length, "gravity": 0.08}, + "data": nodes, + "links": [{ + "source": l["source"], "target": l["target"], + "label": { + "show": True, "formatter": l["value"], "fontSize": edge_font, + "color": "#4a5f66", "textBorderColor": "#ffffff", "textBorderWidth": 3, + }, + } for l in links], + }], + } + + +def render_report( + path: str | Path, + question: str, + chart_type: str, + columns: list[str], + rows: list, + insight: str, + sql: str = "", + triples: list[dict] | None = None, +) -> str: + """Write a self-contained HTML report (chart + table + insight).""" + chart_rows = rows + chart_note = "" + if chart_type in {"bar", "pie"} and len(rows) > 30 and len(columns) >= 2: + numeric_rows = [r for r in rows if len(r) >= 2 and isinstance(r[1], (int, float))] + if len(numeric_rows) == len(rows): + chart_rows = sorted(numeric_rows, key=lambda r: r[1], reverse=True)[:30] + chart_note = "（图表展示数值最高的 Top 30；下表保留完整结果的前 200 行）" + if chart_type == "graph" and triples: + option = _graph_option(question, triples) + elif chart_type == "heatmap" and len(columns) >= 3: + option = _heatmap_option(question, columns, chart_rows) + elif chart_type == "scatter": + option = _scatter_option(question, columns, chart_rows) + elif chart_type == "pie": + option = _pie_option(question, columns, chart_rows) + elif chart_type in ("bar", "line"): + option = _bar_or_line_option(question, columns, chart_rows, chart_type) + else: + option = None + + # data table + head = "".join(f"{html_lib.escape(str(c))}" for c in columns) + body = "".join( + "" + "".join(f"{html_lib.escape(str(c))}" for c in r) + "" + for r in rows[:200] + ) + table_html = f"{head}{body}
" if columns else "" + + chart_div = "" + chart_js = "" + if option is not None: + chart_div = "
" + option_json = ( + json.dumps(option, ensure_ascii=False) + .replace("<", "\\u003c") + .replace(">", "\\u003e") + .replace("&", "\\u0026") + ) + chart_js = ( + f"var ch=echarts.init(document.getElementById('chart'));ch.setOption({option_json});" + "ch.on('click',function(p){var d=document.getElementById('drilldown');" + "d.textContent='钻取：'+p.name+' / '+JSON.stringify(p.value);});" + "window.addEventListener('resize',function(){ch.resize();});" + ) + + sql_html = f"
{html_lib.escape(sql)}
" if sql else "" + safe_question = html_lib.escape(question) + safe_insight = html_lib.escape(insight).replace("\n", "
") + html = f""" +分析报告 - {safe_question} +{_echarts_script()} + + +

📊 数据分析报告

+

问题：{safe_question}

+

图表：{html_lib.escape(chart_type)}结果行：{len(rows)} {html_lib.escape(chart_note)}

+{chart_div} +
点击图表元素可查看钻取值
+
💡 洞察：
{safe_insight}
+

数据明细

{table_html} +

执行的查询

{sql_html} + +""" + p = Path(path) + p.parent.mkdir(parents=True, exist_ok=True) + p.write_text(html, encoding="utf-8") + return str(p) diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/__init__.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/__init__.py" new file mode 100644 index 0000000..d4f0557 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/__init__.py" @@ -0,0 +1,17 @@ +"""Local-first extraction building blocks. + +The package contains the fast-path baseline, confidence calibration and entity +linking used by the neuro-symbolic cascade. Heavy neural models are optional; +the deterministic lexicon path remains runnable on a CPU-only machine. +""" + +from medigraph.extraction.calibration import TemperatureCalibrator, expected_calibration_error +from medigraph.extraction.entity_linker import EntityLinker +from medigraph.extraction.fast_path import FastSpanRelationExtractor + +__all__ = [ + "EntityLinker", + "FastSpanRelationExtractor", + "TemperatureCalibrator", + "expected_calibration_error", +] diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/calibration.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/calibration.py" new file mode 100644 index 0000000..7659d2b --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/calibration.py" @@ -0,0 +1,210 @@ +"""Dependency-free confidence calibration and reliability diagnostics.""" +from __future__ import annotations + +import json +import math +from dataclasses import dataclass +from pathlib import Path +from typing import Iterable, Sequence + + +def _clip(value: float, eps: float = 1e-6) -> float: + return min(1.0 - eps, max(eps, float(value))) + + +def _logit(probability: float) -> float: + p = _clip(probability) + return math.log(p / (1.0 - p)) + + +def _sigmoid(value: float) -> float: + if value >= 0: + z = math.exp(-value) + return 1.0 / (1.0 + z) + z = math.exp(value) + return z / (1.0 + z) + + +def reliability_bins( + confidences: Sequence[float], + labels: Sequence[int | bool], + n_bins: int = 10, +) -> list[dict]: + """Return data for a reliability diagram. + + Empty bins are retained so two experiment reports are directly comparable. + """ + if len(confidences) != len(labels): + raise ValueError("confidences and labels must have equal length") + if n_bins < 2: + raise ValueError("n_bins must be >= 2") + buckets: list[list[tuple[float, int]]] = [[] for _ in range(n_bins)] + for confidence, label in zip(confidences, labels): + conf = min(1.0, max(0.0, float(confidence))) + index = min(n_bins - 1, int(conf * n_bins)) + buckets[index].append((conf, int(bool(label)))) + result = [] + for index, bucket in enumerate(buckets): + lower, upper = index / n_bins, (index + 1) / n_bins + count = len(bucket) + result.append( + { + "lower": round(lower, 4), + "upper": round(upper, 4), + "count": count, + "mean_confidence": round(sum(v[0] for v in bucket) / count, 6) if count else None, + "accuracy": round(sum(v[1] for v in bucket) / count, 6) if count else None, + } + ) + return result + + +def expected_calibration_error( + confidences: Sequence[float], + labels: Sequence[int | bool], + n_bins: int = 10, +) -> float: + """Compute the standard weighted Expected Calibration Error (ECE).""" + total = len(confidences) + if not total: + return 0.0 + error = 0.0 + for bucket in reliability_bins(confidences, labels, n_bins=n_bins): + if not bucket["count"]: + continue + error += (bucket["count"] / total) * abs(bucket["accuracy"] - bucket["mean_confidence"]) + return round(error, 6) + + +@dataclass +class TemperatureCalibrator: + """Binary temperature scaling with an optional calibration bias. + + The bias is important when a candidate generator's base precision is below + 50%; temperature-only scaling cannot move a probability across 0.5. Fitting + uses deterministic two-parameter Newton updates (equivalent to constrained + Platt scaling) and requires no ML framework. + """ + + temperature: float = 1.0 + bias: float = 0.0 + fitted_samples: int = 0 + nll_before: float | None = None + nll_after: float | None = None + + @staticmethod + def _nll( + confidences: Sequence[float], + labels: Sequence[int | bool], + temperature: float, + bias: float = 0.0, + ) -> float: + losses = [] + for confidence, label in zip(confidences, labels): + calibrated = _sigmoid(_logit(float(confidence)) / temperature + bias) + y = int(bool(label)) + losses.append(-(y * math.log(_clip(calibrated)) + (1 - y) * math.log(_clip(1 - calibrated)))) + return sum(losses) / len(losses) if losses else 0.0 + + def fit( + self, + confidences: Sequence[float], + labels: Sequence[int | bool], + min_temperature: float = 0.2, + max_temperature: float = 5.0, + steps: int = 60, + ) -> "TemperatureCalibrator": + if len(confidences) != len(labels): + raise ValueError("confidences and labels must have equal length") + if not confidences: + self.temperature = 1.0 + self.bias = 0.0 + self.fitted_samples = 0 + self.nll_before = self.nll_after = 0.0 + return self + if min_temperature <= 0 or max_temperature <= min_temperature or steps < 2: + raise ValueError("invalid temperature search range") + logits = [_logit(value) for value in confidences] + targets = [int(bool(value)) for value in labels] + slope, bias = 1.0, 0.0 + best = (self._nll(confidences, labels, 1.0, 0.0), slope, bias) + for _ in range(steps): + grad_slope = grad_bias = 0.0 + h_ss = h_sb = h_bb = 0.0 + for logit_value, target in zip(logits, targets): + predicted = _sigmoid(slope * logit_value + bias) + residual = predicted - target + weight = max(1e-8, predicted * (1.0 - predicted)) + grad_slope += residual * logit_value + grad_bias += residual + h_ss += weight * logit_value * logit_value + h_sb += weight * logit_value + h_bb += weight + # Tiny L2 term prevents singular Hessians on very small sets. + h_ss += 1e-6 + h_bb += 1e-6 + determinant = h_ss * h_bb - h_sb * h_sb + if abs(determinant) < 1e-12: + break + delta_slope = (h_bb * grad_slope - h_sb * grad_bias) / determinant + delta_bias = (-h_sb * grad_slope + h_ss * grad_bias) / determinant + candidate_slope = min( + 1.0 / min_temperature, + max(1.0 / max_temperature, slope - delta_slope), + ) + candidate_bias = min(10.0, max(-10.0, bias - delta_bias)) + candidate_temperature = 1.0 / candidate_slope + loss = self._nll(confidences, labels, candidate_temperature, candidate_bias) + if loss > best[0] and (abs(delta_slope) > 1e-6 or abs(delta_bias) > 1e-6): + # Damped step when the full Newton update overshoots. + candidate_slope = (slope + candidate_slope) / 2 + candidate_bias = (bias + candidate_bias) / 2 + candidate_temperature = 1.0 / candidate_slope + loss = self._nll(confidences, labels, candidate_temperature, candidate_bias) + slope, bias = candidate_slope, candidate_bias + if loss < best[0]: + best = (loss, slope, bias) + if abs(delta_slope) < 1e-8 and abs(delta_bias) < 1e-8: + break + self.temperature = round(1.0 / best[1], 8) + self.bias = round(best[2], 8) + self.fitted_samples = len(confidences) + self.nll_before = round(self._nll(confidences, labels, 1.0, 0.0), 8) + self.nll_after = round(self._nll(confidences, labels, self.temperature, self.bias), 8) + return self + + def transform_one(self, confidence: float) -> float: + return round( + _sigmoid(_logit(confidence) / max(self.temperature, 1e-6) + self.bias), + 6, + ) + + def transform(self, confidences: Iterable[float]) -> list[float]: + return [self.transform_one(value) for value in confidences] + + def to_dict(self) -> dict: + return { + "method": "temperature_scaling", + "temperature": self.temperature, + "bias": self.bias, + "fitted_samples": self.fitted_samples, + "nll_before": self.nll_before, + "nll_after": self.nll_after, + } + + def save(self, path: str | Path) -> str: + target = Path(path) + target.parent.mkdir(parents=True, exist_ok=True) + target.write_text(json.dumps(self.to_dict(), ensure_ascii=False, indent=2), encoding="utf-8") + return str(target) + + @classmethod + def load(cls, path: str | Path) -> "TemperatureCalibrator": + data = json.loads(Path(path).read_text(encoding="utf-8")) + return cls( + temperature=float(data.get("temperature", 1.0)), + bias=float(data.get("bias", 0.0)), + fitted_samples=int(data.get("fitted_samples", 0)), + nll_before=data.get("nll_before"), + nll_after=data.get("nll_after"), + ) diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/cascade.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/cascade.py" new file mode 100644 index 0000000..f0f5d50 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/cascade.py" @@ -0,0 +1,110 @@ +"""Shared resources and merge logic for the confidence-routed cascade.""" +from __future__ import annotations + +from functools import lru_cache +from pathlib import Path + +from config.settings import get_extraction_config +from medigraph.extraction.entity_linker import EntityLinker +from medigraph.extraction.fast_path import FastSpanRelationExtractor +from medigraph.schema.normalize import canonical_key + + +@lru_cache(maxsize=4) +def load_fast_extractor( + artifact_path: str = "", + calibration_path: str = "", +) -> FastSpanRelationExtractor | None: + config = get_extraction_config() + artifact = Path(artifact_path) if artifact_path else config.fast_artifact + calibration = Path(calibration_path) if calibration_path else config.calibration_artifact + if not artifact.exists(): + return None + return FastSpanRelationExtractor.load( + artifact, + calibration_path=calibration if calibration.exists() else None, + ) + + +@lru_cache(maxsize=2) +def load_neural_extractor(model_dir: str = ""): + """Load the trained neural GPLinker L1 if its checkpoint and the ML stack are + present; otherwise return ``None`` so callers fall back to the lexicon path. + + Kept lazy so importing the cascade never requires torch. + """ + from config.settings import get_extraction_config + + target = Path(model_dir) if model_dir else get_extraction_config().neural_model_dir + try: + from medigraph.extraction.neural_gplinker import NeuralGPLinkerExtractor + except Exception: # noqa: BLE001 (torch/transformers absent) + return None + if not NeuralGPLinkerExtractor.available(target): + return None + try: + return NeuralGPLinkerExtractor(target) + except Exception: # noqa: BLE001 (no GPU / corrupt checkpoint) + return None + + +@lru_cache(maxsize=4) +def load_entity_linker(path: str = "") -> EntityLinker | None: + config = get_extraction_config() + artifact = Path(path) if path else config.linker_artifact + if not artifact.exists(): + return None + return EntityLinker.load(artifact) + + +def merge_entities(primary: list[dict], secondary: list[dict]) -> list[dict]: + """Confidence-aware union retaining provenance from both extraction levels.""" + merged: dict[tuple[str, str], dict] = {} + for item in [*primary, *secondary]: + key = (str(item.get("type", "")), canonical_key(str(item.get("name", "")))) + if not key[1]: + continue + value = dict(item) + if key not in merged: + merged[key] = value + continue + old = merged[key] + sources = set(old.get("cascade_sources", [old.get("extractor", "unknown")])) + sources.update(value.get("cascade_sources", [value.get("extractor", "unknown")])) + if float(value.get("confidence", 0.0)) > float(old.get("confidence", 0.0)): + merged[key] = value + merged[key]["cascade_sources"] = sorted(str(source) for source in sources if source) + return sorted( + merged.values(), + key=lambda item: ( + int(item.get("start", 10**9)), + str(item.get("type", "")), + str(item.get("name", "")), + ), + ) + + +def merge_triples(primary: list[dict], secondary: list[dict]) -> list[dict]: + merged: dict[tuple[str, str, str], dict] = {} + for item in [*primary, *secondary]: + key = ( + canonical_key(str(item.get("head", ""))), + str(item.get("relation", "")), + canonical_key(str(item.get("tail", ""))), + ) + if not all(key): + continue + value = dict(item) + if key not in merged: + merged[key] = value + continue + old = merged[key] + sources = set(old.get("cascade_sources", [old.get("extractor", "unknown")])) + sources.update(value.get("cascade_sources", [value.get("extractor", "unknown")])) + if float(value.get("confidence", 0.0)) > float(old.get("confidence", 0.0)): + merged[key] = value + merged[key]["cascade_sources"] = sorted(str(source) for source in sources if source) + return sorted( + merged.values(), + key=lambda item: (-float(item.get("confidence", 0.0)), item["head"], item["relation"], item["tail"]), + ) diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/entity_linker.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/entity_linker.py" new file mode 100644 index 0000000..99e1e27 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/entity_linker.py" @@ -0,0 +1,179 @@ +"""Entity normalization/linking with stable IDs and auditable match scores.""" +from __future__ import annotations + +import hashlib +import json +from dataclasses import dataclass, field +from difflib import SequenceMatcher +from pathlib import Path +from typing import Iterable + +from medigraph.schema.normalize import ALIASES, canonical_key, canonical_name + + +def stable_entity_id(name: str, entity_type: str = "") -> str: + """Generate a deterministic local canonical ID. + + External identifiers can be supplied in a knowledge-base artifact. When + none is available, this stable ID supports repeatable cross-document merges + without pretending to be an ICD identifier. + """ + payload = f"{entity_type}:{canonical_key(name)}".encode("utf-8") + return f"MEDIGRAPH:{hashlib.sha256(payload).hexdigest()[:16]}" + + +@dataclass +class LinkEntry: + canonical_id: str + name: str + type: str = "" + aliases: list[str] = field(default_factory=list) + source: str = "MediGraph" + + def surfaces(self) -> list[str]: + return [self.name, *self.aliases] + + +class EntityLinker: + """Exact alias linking followed by conservative fuzzy matching.""" + + def __init__(self, entries: Iterable[LinkEntry] = (), fuzzy_threshold: float = 0.85): + self.fuzzy_threshold = float(fuzzy_threshold) + self.entries: dict[str, LinkEntry] = {} + self._surface_to_id: dict[str, str] = {} + self._prefix: dict[str, list[str]] = {} + for entry in entries: + self.add(entry) + + def add(self, entry: LinkEntry) -> None: + if not entry.canonical_id: + entry.canonical_id = stable_entity_id(entry.name, entry.type) + self.entries[entry.canonical_id] = entry + for surface in entry.surfaces(): + key = canonical_key(surface) + if not key: + continue + self._surface_to_id.setdefault(key, entry.canonical_id) + self._prefix.setdefault(key[:1], []).append(key) + + def link(self, surface: str, entity_type: str = "") -> dict: + # Preserve the submitted surface for audit; applying canonical_name here + # would erase whether a match came from the explicit alias table. + cleaned = " ".join(str(surface or "").split()) + key = canonical_key(cleaned) + exact_id = self._surface_to_id.get(key) + if exact_id: + return self._result(cleaned, self.entries[exact_id], 1.0, "exact") + + alias_target = ALIASES.get(cleaned.lower()) + if alias_target: + alias_id = self._surface_to_id.get(canonical_key(alias_target)) + if alias_id: + return self._result(cleaned, self.entries[alias_id], 0.99, "alias") + + best_key, best_score = "", 0.0 + # The first-character bucket makes fuzzy matching practical for 50K+ KBs. + candidates = self._prefix.get(key[:1], []) if key else [] + for candidate in candidates: + candidate_id = self._surface_to_id[candidate] + entry = self.entries[candidate_id] + if entity_type and entry.type and entity_type != entry.type: + continue + length_ratio = min(len(key), len(candidate)) / max(len(key), len(candidate)) + if length_ratio < 0.65: + continue + score = SequenceMatcher(None, key, candidate).ratio() + if score > best_score: + best_key, best_score = candidate, score + if best_key and best_score >= self.fuzzy_threshold: + entry = self.entries[self._surface_to_id[best_key]] + return self._result(cleaned, entry, round(best_score, 4), "fuzzy") + + return { + "surface_form": cleaned, + "canonical_id": stable_entity_id(cleaned, entity_type), + "canonical_name": cleaned, + "type": entity_type, + "link_score": 0.0, + "match_method": "unlinked_local_id", + "kb_source": "MediGraph-local", + } + + def link_entities(self, entities: Iterable[dict]) -> list[dict]: + result = [] + for entity in entities: + linked = self.link(str(entity.get("name", "")), str(entity.get("type", ""))) + result.append({**entity, **linked}) + return result + + @staticmethod + def _result(surface: str, entry: LinkEntry, score: float, method: str) -> dict: + return { + "surface_form": surface, + "canonical_id": entry.canonical_id, + "canonical_name": entry.name, + "type": entry.type, + "link_score": score, + "match_method": method, + "kb_source": entry.source, + } + + def to_dict(self) -> dict: + return { + "version": 1, + "entries": [ + { + "canonical_id": entry.canonical_id, + "name": entry.name, + "type": entry.type, + "aliases": entry.aliases, + "source": entry.source, + } + for entry in sorted(self.entries.values(), key=lambda item: item.canonical_id) + ], + } + + def save(self, path: str | Path) -> str: + target = Path(path) + target.parent.mkdir(parents=True, exist_ok=True) + target.write_text(json.dumps(self.to_dict(), ensure_ascii=False, separators=(",", ":")), encoding="utf-8") + return str(target) + + @classmethod + def from_dict(cls, data: dict, fuzzy_threshold: float = 0.85) -> "EntityLinker": + entries = [ + LinkEntry( + canonical_id=str(item.get("canonical_id", "")), + name=str(item.get("name", "")), + type=str(item.get("type", "")), + aliases=[str(alias) for alias in item.get("aliases", [])], + source=str(item.get("source", "MediGraph")), + ) + for item in data.get("entries", []) + if item.get("name") + ] + return cls(entries, fuzzy_threshold=fuzzy_threshold) + + @classmethod + def load(cls, path: str | Path, fuzzy_threshold: float = 0.85) -> "EntityLinker": + return cls.from_dict(json.loads(Path(path).read_text(encoding="utf-8")), fuzzy_threshold) + + @classmethod + def from_graph_json(cls, path: str | Path, source: str = "CM3KG") -> "EntityLinker": + data = json.loads(Path(path).read_text(encoding="utf-8")) + entries = [] + for node in data.get("nodes", []): + name = str(node.get("canonical_name") or node.get("id") or "").strip() + if not name: + continue + entity_type = str(node.get("type", "")) + entries.append( + LinkEntry( + canonical_id=str(node.get("canonical_id") or stable_entity_id(name, entity_type)), + name=name, + type=entity_type, + aliases=[str(value) for value in node.get("aliases", [])], + source=str(node.get("kb_source") or source), + ) + ) + return cls(entries) diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/fast_path.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/fast_path.py" new file mode 100644 index 0000000..a9b97c2 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/fast_path.py" @@ -0,0 +1,424 @@ +"""Millisecond CPU fast path for span and relation extraction. + +This is an honest deterministic baseline trained from public gold annotations +and a structured medical KB. It is not presented as a neural model: its job is +to provide a zero-download fast path, a reproducible lower bound, and the L1 +interface into which a GLiNER/OneRel checkpoint can later be plugged. +""" +from __future__ import annotations + +import gzip +import json +import math +from pathlib import Path +from typing import Iterable + +from medigraph.extraction.calibration import TemperatureCalibrator +from medigraph.schema.ontology import check_relation_constraint +from medigraph.schema.normalize import canonical_key, canonical_name, is_valid_entity_name + +_END = "\0" + +# Conservative lexical triggers used only for unseen pairs. Exact supervised/KB +# facts do not need a trigger. +_RELATION_CUES: dict[str, tuple[str, ...]] = { + "has_symptom": ("症状", "表现", "伴有", "出现", "可见"), + "recommend_drug": ("药物", "用药", "治疗", "首选", "给予", "可用"), + "need_examination": ("检查", "检测", "检验", "筛查", "诊断"), + "complication": ("并发", "并发症", "可引起", "导致"), + "treated_in_department": ("科室", "就诊", "诊治"), + "located_in": ("位于", "部位", "好发于", "发生于"), + "treated_by_procedure": ("手术", "切除", "化疗", "放疗"), + "adverse_reaction": ("不良反应", "副作用", "可引起"), + "contraindication": ("禁忌", "禁用于", "慎用"), + "positive_marker": ("阳性", "升高", "表达"), + "negative_marker": ("阴性", "不表达"), + "associated_gene": ("基因", "突变", "扩增", "相关"), + "has_morphology": ("镜下", "形态", "可见"), + "subtype_of": ("亚型", "分型", "属于"), +} + + +class FastSpanRelationExtractor: + """Trie-based span NER plus schema-constrained relation extraction.""" + + def __init__( + self, + artifact: dict, + calibrator: TemperatureCalibrator | None = None, + min_entity_confidence: float = 0.5, + min_relation_confidence: float = 0.55, + ): + self.artifact = artifact + self.version = str(artifact.get("version", "unknown")) + self.min_entity_confidence = min_entity_confidence + self.min_relation_confidence = min_relation_confidence + self.calibrator = calibrator or TemperatureCalibrator() + self._trie: dict = {} + self._entries: dict[tuple[str, str], dict] = {} + for entry in artifact.get("entities", []): + name = canonical_name(str(entry.get("name", ""))) + if not is_valid_entity_name(name): + continue + key = name.casefold() + normalized = { + "name": name, + "type": str(entry.get("type", "")), + "count": max(1, int(entry.get("count", 1))), + "source": str(entry.get("source", "public_train")), + "canonical_id": str(entry.get("canonical_id", "")), + } + typed_key = (key, normalized["type"]) + current = self._entries.get(typed_key) + if current is None or normalized["count"] > current["count"]: + self._entries[typed_key] = normalized + for (key, _), entry in self._entries.items(): + node = self._trie + for char in key: + node = node.setdefault(char, {}) + node.setdefault(_END, []).append(entry) + + self._facts_by_head: dict[str, list[dict]] = {} + for fact in artifact.get("relations", []): + head_key = canonical_key(str(fact.get("head", ""))) + tail_key = canonical_key(str(fact.get("tail", ""))) + relation = str(fact.get("relation", "")) + if not head_key or not tail_key or not relation: + continue + normalized = { + "head_key": head_key, + "tail_key": tail_key, + "relation": relation, + "count": max(1, int(fact.get("count", 1))), + "source": str(fact.get("source", "public_train")), + } + self._facts_by_head.setdefault(head_key, []).append(normalized) + self._cmeie_facts_by_head: dict[str, list[dict]] = {} + for fact in artifact.get("cmeie_benchmark_relations", []): + head_key = canonical_key(str(fact.get("head", ""))) + tail_key = canonical_key(str(fact.get("tail", ""))) + if not head_key or not tail_key: + continue + self._cmeie_facts_by_head.setdefault(head_key, []).append( + { + "head_key": head_key, + "tail_key": tail_key, + "head_type": str(fact.get("head_type", "")), + "tail_type": str(fact.get("tail_type", "")), + "relation": str(fact.get("relation", "")), + "predicate": str(fact.get("predicate", "")), + "count": max(1, int(fact.get("count", 1))), + } + ) + + @classmethod + def load( + cls, + path: str | Path, + calibration_path: str | Path | None = None, + **kwargs, + ) -> "FastSpanRelationExtractor": + """Load the dictionary artifact, transparently accepting a gzipped copy. + + The uncompressed artifact is 23 MiB, over the 10 MiB per-file ceiling this + repository enforces, so it ships as `fast_extractor.json.gz` (2.3 MiB). + Falling back to the `.gz` beside the requested path keeps the offline + dictionary route working with no unpacking step for the user, and callers + that already have the plain file keep working unchanged. + """ + path = Path(path) + if path.exists(): + artifact = json.loads(path.read_text(encoding="utf-8")) + else: + packed = path.with_suffix(path.suffix + ".gz") + if not packed.exists(): + raise FileNotFoundError( + f"neither {path.name} nor {packed.name} found in {path.parent}" + ) + with gzip.open(packed, "rt", encoding="utf-8") as handle: + artifact = json.load(handle) + calibrator = ( + TemperatureCalibrator.load(calibration_path) + if calibration_path and Path(calibration_path).exists() + else None + ) + return cls(artifact, calibrator=calibrator, **kwargs) + + @staticmethod + def _frequency_confidence(count: int, floor: float = 0.62) -> float: + # Smooth, deliberately conservative confidence prior. + return min(0.97, floor + 0.075 * math.log1p(max(1, count))) + + def extract_entities( + self, + text: str, + allowed_types: set[str] | None = None, + include_type_alternatives: bool = False, + overlap_policy: str = "nested", + ) -> list[dict]: + raw = str(text or "") + folded = raw.casefold() + candidates: list[dict] = [] + for start in range(len(folded)): + node = self._trie + cursor = start + while cursor < len(folded) and folded[cursor] in node: + node = node[folded[cursor]] + cursor += 1 + for entry in node.get(_END, []): + if allowed_types and entry["type"] not in allowed_types: + continue + confidence = self.calibrator.transform_one( + self._frequency_confidence(entry["count"]) + ) + if confidence < self.min_entity_confidence: + continue + candidates.append( + { + "name": raw[start:cursor], + "type": entry["type"], + "start": start, + "end": cursor, + "confidence": round(confidence, 3), + "extractor": "fast_span_lexicon", + "model_version": self.version, + "canonical_id": entry.get("canonical_id", ""), + "training_source": entry["source"], + } + ) + # Retain nested spans, but remove exact duplicates and prefer the + # higher-confidence type if the same boundary has conflicting labels. + best: dict[tuple[int, int, str], dict] = {} + for entity in candidates: + key = (entity["start"], entity["end"], entity["type"]) + if key not in best or entity["confidence"] > best[key]["confidence"]: + best[key] = entity + if not include_type_alternatives: + by_span: dict[tuple[int, int], dict] = {} + for entity in best.values(): + span = (entity["start"], entity["end"]) + current = by_span.get(span) + if current is None or ( + entity["confidence"], + entity["type"], + ) > ( + current["confidence"], + current["type"], + ): + by_span[span] = entity + best = { + (entity["start"], entity["end"], entity["type"]): entity + for entity in by_span.values() + } + values = list(best.values()) + if overlap_policy == "maximal": + selected: list[dict] = [] + for entity in sorted( + values, + key=lambda item: ( + -float(item["confidence"]), + -(int(item["end"]) - int(item["start"])), + int(item["start"]), + ), + ): + if any(self._spans_overlap(entity, accepted) for accepted in selected): + continue + selected.append(entity) + values = selected + elif overlap_policy != "nested": + raise ValueError("overlap_policy must be 'nested' or 'maximal'") + return sorted(values, key=lambda item: (item["start"], -(item["end"] - item["start"]), item["type"])) + + def extract_relations(self, text: str, entities: Iterable[dict] | None = None) -> list[dict]: + entity_list = list(entities) if entities is not None else self.extract_entities(text) + by_key: dict[str, list[dict]] = {} + for entity in entity_list: + by_key.setdefault(canonical_key(str(entity.get("name", ""))), []).append(entity) + + triples: dict[tuple[str, str, str], dict] = {} + # High-precision path: memorized relation facts from public train/KB. + for head_key, heads in by_key.items(): + for fact in self._facts_by_head.get(head_key, []): + tails = by_key.get(fact["tail_key"], []) + for head in heads: + for tail in tails: + if self._spans_overlap(head, tail): + continue + relation = fact["relation"] + if not check_relation_constraint(relation, str(head.get("type", "")), str(tail.get("type", ""))): + continue + confidence = self.calibrator.transform_one( + self._frequency_confidence(fact["count"], floor=0.68) + ) + self._keep_triple( + triples, + head, + relation, + tail, + confidence, + "memorized_fact", + fact["source"], + ) + + # Schema/cue path for unseen pairs. Only nearby entities and explicit + # lexical evidence are allowed, preventing a combinatorial hallucination. + positioned = [ + entity + for entity in entity_list + if "start" in entity + and "end" in entity + and not self._shadowed_same_type(entity, entity_list) + ] + for head in positioned: + for tail in positioned: + if head is tail: + continue + distance = max(0, max(head["start"], tail["start"]) - min(head["end"], tail["end"])) + if distance > 96: + continue + left = max(0, min(head["start"], tail["start"]) - 12) + right = min(len(text), max(head["end"], tail["end"]) + 12) + context = text[left:right] + for relation, cues in _RELATION_CUES.items(): + if not check_relation_constraint(relation, str(head.get("type", "")), str(tail.get("type", ""))): + continue + matched = next((cue for cue in cues if cue in context), "") + if not matched: + continue + confidence = self.calibrator.transform_one( + min(float(head.get("confidence", 0.5)), float(tail.get("confidence", 0.5))) * 0.86 + ) + if confidence >= self.min_relation_confidence: + self._keep_triple( + triples, + head, + relation, + tail, + confidence, + "schema_cue", + f"cue:{matched}", + ) + return sorted( + triples.values(), + key=lambda item: (-item["confidence"], item["head"], item["relation"], item["tail"]), + ) + + def extract_cmeie_relations( + self, + text: str, + entities: Iterable[dict] | None = None, + ) -> list[dict]: + """Predict in the complete official CMeIE predicate label space. + + The deterministic baseline emits only supervised entity-pair facts; it + does not guess unseen relations. This makes the full-schema metric + honest (often recall-limited) and provides a reproducible comparison + target for the later OneRel checkpoint. + """ + entity_list = ( + list(entities) + if entities is not None + else self.extract_entities(text, include_type_alternatives=True) + ) + by_key: dict[str, list[dict]] = {} + for entity in entity_list: + by_key.setdefault(canonical_key(str(entity.get("name", ""))), []).append(entity) + predictions: dict[tuple[str, str, str], dict] = {} + for head_key, heads in by_key.items(): + for fact in self._cmeie_facts_by_head.get(head_key, []): + for head in heads: + if str(head.get("type", "")) != fact["head_type"]: + continue + for tail in by_key.get(fact["tail_key"], []): + if str(tail.get("type", "")) != fact["tail_type"] or self._spans_overlap(head, tail): + continue + confidence = self.calibrator.transform_one( + self._frequency_confidence(fact["count"], floor=0.68) + ) + key = ( + canonical_key(str(head.get("name", ""))), + fact["predicate"], + canonical_key(str(tail.get("name", ""))), + ) + predictions[key] = { + "head": str(head.get("name", "")), + "head_type": fact["head_type"], + "relation": fact["relation"], + "predicate": fact["predicate"], + "tail": str(tail.get("name", "")), + "tail_type": fact["tail_type"], + "confidence": round(confidence, 3), + "extractor": "fast_cmeie_fact", + "model_version": self.version, + } + return sorted( + predictions.values(), + key=lambda item: (-item["confidence"], item["head"], item["predicate"], item["tail"]), + ) + + @staticmethod + def _spans_overlap(left: dict, right: dict) -> bool: + if not all(key in left and key in right for key in ("start", "end")): + return False + return max(int(left["start"]), int(right["start"])) < min(int(left["end"]), int(right["end"])) + + @staticmethod + def _shadowed_same_type(entity: dict, entities: Iterable[dict]) -> bool: + """Suppress shorter same-type spans only for relation inference. + + Span NER still returns nested mentions for honest nested-entity metrics. + """ + start, end = int(entity["start"]), int(entity["end"]) + entity_type = str(entity.get("type", "")) + for other in entities: + if other is entity or str(other.get("type", "")) != entity_type: + continue + if "start" not in other or "end" not in other: + continue + o_start, o_end = int(other["start"]), int(other["end"]) + if o_start <= start and end <= o_end and (o_end - o_start) > (end - start): + return True + return False + + def _keep_triple( + self, + bucket: dict, + head: dict, + relation: str, + tail: dict, + confidence: float, + method: str, + evidence: str, + ) -> None: + key = ( + canonical_key(str(head.get("name", ""))), + relation, + canonical_key(str(tail.get("name", ""))), + ) + value = { + "head": str(head.get("name", "")), + "head_type": str(head.get("type", "")), + "relation": relation, + "tail": str(tail.get("name", "")), + "tail_type": str(tail.get("type", "")), + "confidence": round(float(confidence), 3), + "extractor": "fast_joint_relation", + "model_version": self.version, + "evidence_method": method, + "evidence": evidence, + } + if key not in bucket or value["confidence"] > bucket[key]["confidence"]: + bucket[key] = value + + def uncertainty(self, items: Iterable[dict], threshold: float = 0.72) -> dict: + values = [float(item.get("confidence", 0.0)) for item in items] + if not values: + return {"uncertain": True, "reason": "no_prediction", "mean_confidence": 0.0, "minimum_confidence": 0.0} + mean = sum(values) / len(values) + minimum = min(values) + return { + "uncertain": mean < threshold or minimum < self.min_entity_confidence, + "reason": "below_route_threshold" if mean < threshold else "accepted", + "mean_confidence": round(mean, 4), + "minimum_confidence": round(minimum, 4), + } diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/neural_gplinker.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/neural_gplinker.py" new file mode 100644 index 0000000..aef33fb --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/extraction/neural_gplinker.py" @@ -0,0 +1,269 @@ +"""Neural joint entity-relation extractor (GPLinker / GlobalPointer). + +This is the trained L1 *neural* fast path that supersedes the deterministic +lexicon baseline for accuracy-critical extraction. A single model jointly +predicts: + + * typed entity spans (GlobalPointer with one head per entity type), and + * (subject, predicate, object) triples (head-to-head and tail-to-tail + GlobalPointers over the full CMeIE-V2 predicate space), + +so there is **no NER -> RE error-propagation pipeline**: entities and relations +are decoded from the same forward pass. + +The module is dependency-light at import time: ``torch``/``transformers`` are +imported lazily inside the classes that need them, so the rest of the package +(and the CPU lexicon path) keeps working when the ML stack is absent. +""" +from __future__ import annotations + +import json +from pathlib import Path +from typing import Any + +# ----------------------------------------------------------------------------- # +# Model definition (torch). Imported lazily by training / inference entrypoints. +# ----------------------------------------------------------------------------- # +def _build_torch_modules(): + import torch + from torch import nn + + class GlobalPointer(nn.Module): + """Span-scoring head (Su Jianlin, 2021) with optional rotary embeddings.""" + + def __init__(self, hidden_size: int, heads: int, head_size: int = 64, + rope: bool = True, tril_mask: bool = True): + super().__init__() + self.heads = heads + self.head_size = head_size + self.rope = rope + self.tril_mask = tril_mask + self.dense = nn.Linear(hidden_size, heads * head_size * 2) + + @staticmethod + def _rope(pos_dim: int, seq_len: int, device, dtype): + idx = torch.arange(0, pos_dim, 2, dtype=torch.float32, device=device) + theta = 1.0 / (10000 ** (idx / pos_dim)) + pos = torch.arange(seq_len, dtype=torch.float32, device=device) + freqs = torch.einsum("n,d->nd", pos, theta) # [L, pos_dim/2] + emb = torch.stack([freqs, freqs], dim=-1).reshape(seq_len, pos_dim) + return emb.sin().to(dtype), emb.cos().to(dtype) + + def forward(self, hidden: "torch.Tensor", mask: "torch.Tensor"): + b, l, _ = hidden.shape + x = self.dense(hidden).view(b, l, self.heads, 2 * self.head_size) + qw, kw = x[..., : self.head_size], x[..., self.head_size:] + if self.rope: + sin, cos = self._rope(self.head_size, l, hidden.device, hidden.dtype) + sin = sin[None, :, None, :] + cos = cos[None, :, None, :] + + def rotate(t): + t2 = torch.stack([-t[..., 1::2], t[..., 0::2]], dim=-1).reshape_as(t) + return t * cos + t2 * sin + + qw, kw = rotate(qw), rotate(kw) + logits = torch.einsum("blhd,bmhd->bhlm", qw, kw) # [B, heads, L, L] + pad = mask[:, None, None, :] * mask[:, None, :, None] + logits = logits - (1 - pad) * 1e12 + if self.tril_mask: + tril = torch.tril(torch.ones(l, l, device=hidden.device), -1).bool() + logits = logits - tril[None, None] * 1e12 + return logits / (self.head_size ** 0.5) + + class GPLinker(nn.Module): + def __init__(self, encoder_name: str, num_entity_types: int, + num_predicates: int, head_size: int = 64): + super().__init__() + from transformers import AutoModel + + self.encoder = AutoModel.from_pretrained(encoder_name) + hidden = self.encoder.config.hidden_size + self.entity = GlobalPointer(hidden, num_entity_types, head_size, + rope=True, tril_mask=True) + self.head = GlobalPointer(hidden, num_predicates, head_size, + rope=False, tril_mask=False) + self.tail = GlobalPointer(hidden, num_predicates, head_size, + rope=False, tril_mask=False) + + def forward(self, input_ids, attention_mask, token_type_ids=None): + out = self.encoder(input_ids=input_ids, attention_mask=attention_mask) + h = out.last_hidden_state + mask = attention_mask.float() + return ( + self.entity(h, mask), + self.head(h, mask), + self.tail(h, mask), + ) + + def multilabel_cce(y_pred: "torch.Tensor", y_true: "torch.Tensor") -> "torch.Tensor": + """Sparse-free multilabel categorical cross-entropy over the last dim.""" + y_pred = (1 - 2 * y_true) * y_pred + y_pred_neg = y_pred - y_true * 1e12 + y_pred_pos = y_pred - (1 - y_true) * 1e12 + zeros = torch.zeros_like(y_pred[..., :1]) + y_pred_neg = torch.cat([y_pred_neg, zeros], dim=-1) + y_pred_pos = torch.cat([y_pred_pos, zeros], dim=-1) + neg = torch.logsumexp(y_pred_neg, dim=-1) + pos = torch.logsumexp(y_pred_pos, dim=-1) + return (neg + pos).mean() + + return GlobalPointer, GPLinker, multilabel_cce + + +# ----------------------------------------------------------------------------- # +# Inference wrapper used by the extraction cascade. +# ----------------------------------------------------------------------------- # +class NeuralGPLinkerExtractor: + """Loads a trained checkpoint and emits entities/triples for the cascade.""" + + def __init__(self, model_dir: str | Path, device: str | None = None, + max_length: int = 256): + import os + + os.environ.setdefault("HF_HUB_DISABLE_PROGRESS_BARS", "1") + os.environ.setdefault("TRANSFORMERS_VERBOSITY", "error") + import torch + from transformers import AutoTokenizer + from transformers.utils import logging as hf_logging + + hf_logging.set_verbosity_error() + if hasattr(hf_logging, "disable_progress_bar"): + hf_logging.disable_progress_bar() + + self.dir = Path(model_dir) + cfg = json.loads((self.dir / "extractor_config.json").read_text(encoding="utf-8")) + self.entity_types: list[str] = cfg["entity_types"] + self.predicates: list[str] = cfg["predicates"] + self.pred_schema: dict[str, dict] = cfg.get("predicate_schema", {}) + self.encoder_name: str = cfg["encoder_name"] + self.max_length = int(cfg.get("max_length", max_length)) + self.max_span = int(cfg.get("max_span", 30)) + self.version = cfg.get("version", "neural-gplinker-1.0.0") + encoder_name = Path(self.encoder_name) + if not encoder_name.is_absolute() and not encoder_name.exists(): + try: + from config.settings import PROJECT_ROOT + + candidate = PROJECT_ROOT / encoder_name + if candidate.exists(): + self.encoder_name = str(candidate) + except Exception: + pass + + _, GPLinker, _ = _build_torch_modules() + self.torch = torch + self.device = device or ("cuda" if torch.cuda.is_available() else "cpu") + self.tokenizer = AutoTokenizer.from_pretrained(str(self.dir), use_fast=True) + self.model = GPLinker(self.encoder_name, len(self.entity_types), + len(self.predicates)) + state = torch.load(self.dir / "pytorch_model.bin", map_location="cpu") + self.model.load_state_dict(state) + self.model.to(self.device).eval() + + @classmethod + def available(cls, model_dir: str | Path) -> bool: + d = Path(model_dir) + return (d / "extractor_config.json").exists() and (d / "pytorch_model.bin").exists() + + def _encode(self, text: str): + enc = self.tokenizer(text[: self.max_length * 4], return_offsets_mapping=True, + max_length=self.max_length, truncation=True, + return_tensors="pt") + offsets = enc.pop("offset_mapping")[0].tolist() + enc = {k: v.to(self.device) for k, v in enc.items()} + return enc, offsets + + def extract(self, text: str, threshold: float = 0.0, + rel_threshold: float | None = None) -> dict[str, list[dict]]: + torch = self.torch + text = str(text or "") + if not text.strip(): + return {"entities": [], "triples": []} + enc, offsets = self._encode(text) + with torch.no_grad(): + ent_logit, head_logit, tail_logit = self.model( + enc["input_ids"], enc["attention_mask"], + enc.get("token_type_ids")) + ent_logit = ent_logit[0] + head_logit = head_logit[0] + tail_logit = tail_logit[0] + + def span_text(ts: int, te: int) -> tuple[str, int, int]: + if ts >= len(offsets) or te >= len(offsets): + return "", -1, -1 + cs = offsets[ts][0] + ce = offsets[te][1] + return text[cs:ce], cs, ce + + # --- typed entities -------------------------------------------------- + entities: list[dict] = [] + seen: set[tuple[int, int, str]] = set() + for ti in range(len(self.entity_types)): + idx = (ent_logit[ti] > threshold).nonzero(as_tuple=False).tolist() + for ts, te in idx: + surface, cs, ce = span_text(ts, te) + if not surface.strip() or (cs, ce, self.entity_types[ti]) in seen: + continue + seen.add((cs, ce, self.entity_types[ti])) + entities.append({ + "name": surface, "type": self.entity_types[ti], + "start": cs, "end": ce, + "confidence": round(float(torch.sigmoid(ent_logit[ti, ts, te])), 3), + "extractor": "neural_gplinker", "model_version": self.version, + "canonical_id": "", "training_source": "CMeIE-V2", + }) + + # --- triples (entity-gated GPLinker decode) -------------------------- + # Candidate argument spans are the typed entity-head predictions (keeps + # precision high); a triple needs the subject/object spans linked by both + # the head head (sh,oh) and the tail head (st,ot). The relation heads use + # a separate, typically lower threshold so triple *recall* can be raised + # without admitting low-quality entity spans. + if rel_threshold is None: + rel_threshold = threshold + ent_spans: list[tuple[int, int]] = [] + for ti in range(len(self.entity_types)): + for ts, te in (ent_logit[ti] > threshold).nonzero(as_tuple=False).tolist(): + ent_spans.append((ts, te)) + ent_spans = sorted(set(ent_spans)) + starts: dict[int, list[int]] = {} + ends: dict[int, list[int]] = {} + for (s, e) in ent_spans: + starts.setdefault(s, []).append(e) + + triples: list[dict] = [] + tkey: set[tuple[str, str, str]] = set() + for p, predicate in enumerate(self.predicates): + head_pairs = {(int(a), int(b)) for a, b in + (head_logit[p] > rel_threshold).nonzero(as_tuple=False).tolist()} + if not head_pairs: + continue + tail_set = {(int(a), int(b)) for a, b in + (tail_logit[p] > rel_threshold).nonzero(as_tuple=False).tolist()} + if not tail_set: + continue + for (sh, oh) in head_pairs: + for st in starts.get(sh, ()): # subject span (sh, st) is an entity + for ot in starts.get(oh, ()): # object span (oh, ot) is an entity + if (st, ot) not in tail_set: + continue + subj, _, _ = span_text(sh, st) + obj, _, _ = span_text(oh, ot) + if not subj.strip() or not obj.strip(): + continue + key = (subj, predicate, obj) + if key in tkey: + continue + tkey.add(key) + schema = self.pred_schema.get(predicate, {}) + triples.append({ + "head": subj, "head_type": schema.get("subject_type_en", ""), + "relation": f"cmeie:{schema.get('key', '')}", + "predicate": predicate, + "tail": obj, "tail_type": schema.get("object_type_en", ""), + "confidence": round(float(torch.sigmoid(head_logit[p, sh, oh])), 3), + "extractor": "neural_gplinker", + "model_version": self.version, + }) + return {"entities": entities, "triples": triples} diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/__init__.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/__init__.py" new file mode 100644 index 0000000..e69de29 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/base.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/base.py" new file mode 100644 index 0000000..05cf3d5 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/base.py" @@ -0,0 +1,55 @@ +"""Abstract knowledge-graph store interface. + +Two backends implement it: LocalGraphStore (NetworkX + JSON, default) and +Neo4jGraphStore (optional). Agents depend only on this interface. +""" +from __future__ import annotations + +from abc import ABC, abstractmethod + + +class GraphStore(ABC): + @abstractmethod + def upsert_entity(self, name: str, etype: str, **props) -> None: + ... + + @abstractmethod + def upsert_triple( + self, + head: str, + head_type: str, + relation: str, + tail: str, + tail_type: str, + confidence: float = 1.0, + source: str = "", + operator_version: str = "", + **props, + ) -> None: + ... + + @abstractmethod + def neighbors(self, name: str, hops: int = 1) -> list[dict]: + """Return triples within `hops` of the entity named `name`.""" + + @abstractmethod + def find_entities(self, names: list[str]) -> list[str]: + """Resolve free-text names to existing entity node names (fuzzy).""" + + @abstractmethod + def stats(self) -> dict: + ... + + +def get_graph_store(config=None) -> GraphStore: + """Factory: pick backend from GraphConfig.""" + from config.settings import get_graph_config + + cfg = config or get_graph_config() + if cfg.backend == "neo4j": + from medigraph.graph.neo4j_store import Neo4jGraphStore + + return Neo4jGraphStore(cfg.neo4j_uri, cfg.neo4j_user, cfg.neo4j_password) + from medigraph.graph.local_store import LocalGraphStore + + return LocalGraphStore() diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/local_store.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/local_store.py" new file mode 100644 index 0000000..de1cb0e --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/local_store.py" @@ -0,0 +1,505 @@ +"""Default knowledge-graph backend: NetworkX MultiDiGraph + JSON persistence. + +Zero external services -- runs immediately. Edges carry relation, confidence, +source document and operator version for explainability / provenance. +""" +from __future__ import annotations + +from datetime import datetime, timezone +import json +import math +from pathlib import Path + +import networkx as nx + +from medigraph.graph.base import GraphStore +from medigraph.extraction.cascade import load_entity_linker +from medigraph.schema.ontology import ENTITY_TYPES, RELATION_TYPES, check_relation_constraint +from medigraph.schema.normalize import canonical_key, canonical_name, is_valid_entity_name +from medigraph.utils.io import write_json + + +class LocalGraphStore(GraphStore): + def __init__(self, linker=None): + self.g = nx.MultiDiGraph() + # canonical_key -> display node name, so case/space variants merge. + self._canon: dict[str, str] = {} + self.linker = linker if linker is not None else load_entity_linker() + self._revision_snapshot: dict | None = None + + @classmethod + def load_json(cls, path: str | Path) -> "LocalGraphStore": + """Rebuild a store from a graph.json produced by export_json().""" + import json + + store = cls() + data = json.loads(Path(path).read_text(encoding="utf-8")) + for node in data.get("nodes", []): + nid = node.get("id") + if nid: + props = {k: v for k, v in node.items() if k not in ("id", "type")} + store.upsert_entity(nid, node.get("type", "Unknown"), **props) + for e in data.get("edges", []): + store.upsert_triple( + head=e["head"], head_type=e.get("head_type", ""), relation=e["relation"], + tail=e["tail"], tail_type=e.get("tail_type", ""), + confidence=e.get("confidence", 1.0), source=e.get("source", ""), + operator_version=e.get("operator_version", ""), + timestamp=e.get("timestamp", ""), + ) + return store + + # ------------------------------------------------------------------ # + def _link(self, name: str, etype: str = "") -> dict: + if self.linker is None: + cleaned = canonical_name(name) + return { + "surface_form": cleaned, + "canonical_name": cleaned, + "canonical_id": "", + "link_score": 0.0, + "match_method": "normalization_only", + "kb_source": "", + } + linked = self.linker.link(name, etype) + # Fuzzy matches are useful as candidates but are too risky to silently + # rename graph nodes. Exact/alias links are safe for merging. + if linked["match_method"] == "fuzzy": + linked["canonical_name"] = canonical_name(name) + return linked + + def _resolve(self, name: str, etype: str = "") -> str: + """Map a surface name to its canonical node name, merging variants.""" + name = self._link(name, etype)["canonical_name"] + key = canonical_key(name) + if key in self._canon: + return self._canon[key] + self._canon[key] = name + return name + + def upsert_entity(self, name: str, etype: str, **props) -> None: + linked = self._link(name, etype) + surface = canonical_name(name) + name = self._resolve(name, etype) + if not name or not is_valid_entity_name(name): + return + node_props = { + "canonical_id": linked.get("canonical_id", ""), + "canonical_name": linked.get("canonical_name", name), + "surface_forms": [surface], + "link_score": linked.get("link_score", 0.0), + "link_method": linked.get("match_method", ""), + "kb_source": linked.get("kb_source", ""), + **props, + } + if self.g.has_node(name): + self.g.nodes[name].setdefault("type", etype) + surfaces = self.g.nodes[name].setdefault("surface_forms", []) + if surface and surface not in surfaces: + surfaces.append(surface) + if float(node_props.get("confidence", 0.0) or 0.0) > float( + self.g.nodes[name].get("confidence", 0.0) or 0.0 + ): + self.g.nodes[name]["confidence"] = node_props["confidence"] + for key, value in node_props.items(): + if value not in ("", None, [], {}): + self.g.nodes[name].setdefault(key, value) + else: + self.g.add_node(name, type=etype, **node_props) + + def upsert_triple( + self, + head: str, + head_type: str, + relation: str, + tail: str, + tail_type: str, + confidence: float = 1.0, + source: str = "", + operator_version: str = "", + timestamp: str = "", + **props, + ) -> None: + if not is_valid_entity_name(head) or not is_valid_entity_name(tail): + return + self.upsert_entity(head, head_type, confidence=props.get("head_confidence", 0.0)) + self.upsert_entity(tail, tail_type, confidence=props.get("tail_confidence", 0.0)) + head = self._resolve(head, head_type) + tail = self._resolve(tail, tail_type) + event_time = timestamp or datetime.now(timezone.utc).isoformat() + provenance = props.get("provenance") + if isinstance(provenance, dict): + provenance = [provenance] + if not isinstance(provenance, list): + provenance = [] + event = { + "source_doc": props.get("source_doc") or source, + "source_hash": props.get("source_hash", ""), + "chunk_id": props.get("chunk_id", ""), + "sentence_id": props.get("sentence_id", ""), + "extractor": props.get("extractor") or operator_version, + "model_version": props.get("model_version", ""), + "evidence": props.get("evidence", ""), + "confidence": round(float(confidence), 3), + "timestamp": event_time, + } + if any(value not in ("", None) for key, value in event.items() if key not in {"confidence", "timestamp"}): + provenance.append(event) + # dedup edges by (relation) between same pair; keep max confidence + existing = [ + k + for k in self.g.get_edge_data(head, tail, default={}).keys() + if self.g[head][tail][k].get("relation") == relation + ] if self.g.has_edge(head, tail) else [] + if existing: + k = existing[0] + if confidence > self.g[head][tail][k].get("confidence", 0): + self.g[head][tail][k]["confidence"] = round(confidence, 3) + if source: + sources = self.g[head][tail][k].setdefault( + "sources", + [self.g[head][tail][k].get("source", "")] if self.g[head][tail][k].get("source") else [], + ) + if source not in sources: + sources.append(source) + self.g[head][tail][k]["source"] = sources[0] + if operator_version: + self.g[head][tail][k]["operator_version"] = operator_version + existing_provenance = self.g[head][tail][k].setdefault("provenance", []) + for item in provenance: + marker = json.dumps(item, ensure_ascii=False, sort_keys=True) + if all(json.dumps(old, ensure_ascii=False, sort_keys=True) != marker for old in existing_provenance): + existing_provenance.append(item) + return + self.g.add_edge( + head, + tail, + relation=relation, + confidence=round(confidence, 3), + source=source, + sources=[source] if source else [], + operator_version=operator_version, + timestamp=event_time, + provenance=provenance, + ) + + # ------------------------------------------------------------------ # + def find_entities(self, names: list[str]) -> list[str]: + resolved: list[str] = [] + nodes = list(self.g.nodes) + for q in names: + ql = q.strip().lower() + if not ql: + continue + # exact (case-insensitive) then substring match + exact = [n for n in nodes if n.lower() == ql] + if exact: + resolved.extend(exact) + continue + sub = [n for n in nodes if ql in n.lower() or n.lower() in ql] + resolved.extend(sub[:3]) + # dedup preserve order + seen, out = set(), [] + for n in resolved: + if n not in seen: + seen.add(n) + out.append(n) + return out + + def neighbors(self, name: str, hops: int = 1) -> list[dict]: + if not self.g.has_node(name): + return [] + triples: list[dict] = [] + frontier = {name} + visited = set() + for _ in range(max(1, hops)): + nxt = set() + for node in frontier: + if node in visited: + continue + visited.add(node) + for _, tail, data in self.g.out_edges(node, data=True): + triples.append(self._edge_dict(node, tail, data)) + nxt.add(tail) + for head, _, data in self.g.in_edges(node, data=True): + triples.append(self._edge_dict(head, node, data)) + nxt.add(head) + frontier = nxt - visited + # dedup + seen, out = set(), [] + for t in triples: + key = (t["head"], t["relation"], t["tail"]) + if key not in seen: + seen.add(key) + out.append(t) + return out + + def traverse_paths(self, name: str, hops: int = 3, max_paths: int = 60) -> list[dict]: + """Return cycle-free 1..N hop reasoning paths over the undirected view.""" + if not self.g.has_node(name): + return [] + paths: list[dict] = [] + queue: list[tuple[str, list[str], list[dict]]] = [(name, [name], [])] + while queue and len(paths) < max_paths: + node, visited_nodes, steps = queue.pop(0) + if len(steps) >= max(1, hops): + continue + adjacent = [] + for _, tail, data in self.g.out_edges(node, data=True): + adjacent.append((tail, self._edge_dict(node, tail, data))) + for head, _, data in self.g.in_edges(node, data=True): + adjacent.append((head, self._edge_dict(head, node, data))) + for next_node, step in adjacent: + if next_node in visited_nodes: + continue + next_steps = [*steps, step] + confidences = [float(item.get("confidence", 0.0) or 0.0) for item in next_steps] + path = { + "path_id": f"path-{len(paths) + 1}", + "anchor": name, + "hops": len(next_steps), + "nodes": [*visited_nodes, next_node], + "relations": [item["relation"] for item in next_steps], + "confidence": round( + math.prod(confidences) ** (1 / len(confidences)), + 4, + ), + "steps": next_steps, + "sources": sorted( + { + source + for item in next_steps + for source in item.get("sources", [item.get("source", "")]) + if source + } + ), + } + paths.append(path) + queue.append((next_node, [*visited_nodes, next_node], next_steps)) + if len(paths) >= max_paths: + break + return paths + + def _edge_dict(self, head: str, tail: str, data: dict) -> dict: + return { + "head": head, + "head_type": self.g.nodes[head].get("type", ""), + "relation": data.get("relation", ""), + "relation_zh": RELATION_TYPES.get(data.get("relation", ""), data.get("relation", "")), + "tail": tail, + "tail_type": self.g.nodes[tail].get("type", ""), + "confidence": data.get("confidence", 1.0), + "source": data.get("source", ""), + "sources": data.get("sources", [data.get("source", "")] if data.get("source") else []), + "operator_version": data.get("operator_version", ""), + "timestamp": data.get("timestamp", ""), + "provenance": data.get("provenance", []), + } + + # ------------------------------------------------------------------ # + def stats(self) -> dict: + type_counts: dict[str, int] = {} + for _, d in self.g.nodes(data=True): + t = d.get("type", "Unknown") + type_counts[t] = type_counts.get(t, 0) + 1 + rel_counts: dict[str, int] = {} + for _, _, d in self.g.edges(data=True): + r = d.get("relation", "Unknown") + rel_counts[r] = rel_counts.get(r, 0) + 1 + top = sorted(self.g.degree, key=lambda x: x[1], reverse=True)[:10] + return { + "num_entities": self.g.number_of_nodes(), + "num_triples": self.g.number_of_edges(), + "entity_type_counts": type_counts, + "relation_counts": rel_counts, + "top_entities": [{"name": n, "degree": d} for n, d in top], + } + + # ------------------------------------------------------------------ # + def export_json(self, path: str | Path) -> str: + nodes = [{"id": n, **d} for n, d in self.g.nodes(data=True)] + edges = [self._edge_dict(h, t, d) for h, t, d in self.g.edges(data=True)] + return write_json( + { + "metadata": { + "format": "medigraph_graph", + "schema_version": "2.0.0", + "exported_at": datetime.now(timezone.utc).isoformat(), + "stats": self.stats(), + }, + "nodes": nodes, + "edges": edges, + }, + path, + ) + + # ------------------------------------------------------------------ # + def begin_revision(self, label: str = "") -> None: + """Start an incremental graph revision for delta reporting.""" + self._revision_snapshot = { + "label": label, + "started_at": datetime.now(timezone.utc).isoformat(), + "nodes": set(self.g.nodes), + "edges": { + (head, data.get("relation", ""), tail) + for head, tail, data in self.g.edges(data=True) + }, + } + + def commit_revision(self) -> dict: + before = self._revision_snapshot or { + "label": "", + "started_at": "", + "nodes": set(), + "edges": set(), + } + current_edges = { + (head, data.get("relation", ""), tail) + for head, tail, data in self.g.edges(data=True) + } + added_nodes = sorted(set(self.g.nodes) - before["nodes"]) + added_edge_keys = current_edges - before["edges"] + added_edges = [ + self._edge_dict(head, tail, data) + for head, tail, data in self.g.edges(data=True) + if (head, data.get("relation", ""), tail) in added_edge_keys + ] + delta = { + "label": before["label"], + "started_at": before["started_at"], + "committed_at": datetime.now(timezone.utc).isoformat(), + "added_entity_count": len(added_nodes), + "added_triple_count": len(added_edges), + "added_entities": [ + {"id": name, **self.g.nodes[name]} + for name in added_nodes + ], + "added_triples": added_edges, + "graph_stats": self.stats(), + } + self._revision_snapshot = None + return delta + + def audit(self) -> dict: + """Measure schema legality, canonical coverage and edge provenance.""" + illegal = [] + provenance_count = 0 + for head, tail, data in self.g.edges(data=True): + relation = data.get("relation", "") + head_type = self.g.nodes[head].get("type", "") + tail_type = self.g.nodes[tail].get("type", "") + if not check_relation_constraint(relation, head_type, tail_type): + illegal.append( + { + "head": head, + "head_type": head_type, + "relation": relation, + "tail": tail, + "tail_type": tail_type, + } + ) + if data.get("source") or data.get("provenance"): + provenance_count += 1 + total_edges = self.g.number_of_edges() + linked_nodes = sum(1 for _, data in self.g.nodes(data=True) if data.get("canonical_id")) + total_nodes = self.g.number_of_nodes() + return { + "entities": total_nodes, + "triples": total_edges, + "canonical_id_coverage": round(linked_nodes / total_nodes, 4) if total_nodes else 1.0, + "provenance_coverage": round(provenance_count / total_edges, 4) if total_edges else 1.0, + "illegal_triples": len(illegal), + "illegal_examples": illegal[:20], + } + + def export_html(self, path: str | Path, height: str = "800px") -> str: + """Interactive visualization via pyvis.""" + from pyvis.network import Network + + # color per entity type + palette = [ + "#e6194B", "#3cb44b", "#4363d8", "#f58231", "#911eb4", + "#42d4f4", "#f032e6", "#bfef45", "#fabed4", "#469990", "#9A6324", + ] + types = list(ENTITY_TYPES.keys()) + color_of = {t: palette[i % len(palette)] for i, t in enumerate(types)} + + net = Network( + height=height, + width="100%", + directed=True, + notebook=False, + cdn_resources="in_line", + bgcolor="#ffffff", + font_color="#1b2a2e", + ) + # pyvis defaults render node labels at ~14px and let barnes_hut fling nodes + # far apart, so the auto-fit zoom shrinks everything into unreadable dots. + # Scale node/edge typography up and pull the layout tighter instead. Node + # size adapts to graph size: small demo graphs get big, readable nodes; + # large graphs stay legible without overlapping into a blob. + n_nodes = self.g.number_of_nodes() + node_size = 34 if n_nodes <= 30 else (26 if n_nodes <= 120 else 18) + node_font = 26 if n_nodes <= 30 else (20 if n_nodes <= 120 else 15) + edge_font = 18 if n_nodes <= 30 else (15 if n_nodes <= 120 else 12) + spring_len = 220 if n_nodes <= 30 else (160 if n_nodes <= 120 else 110) + net.set_options( + json.dumps( + { + "nodes": { + "size": node_size, + "borderWidth": 2, + "borderWidthSelected": 4, + "font": { + "size": node_font, + "face": "sans-serif", + "color": "#1b2a2e", + "strokeWidth": 4, + "strokeColor": "#ffffff", + }, + }, + "edges": { + "color": {"color": "#9aa7ad", "highlight": "#e6194B"}, + "width": 2, + "font": { + "size": edge_font, + "face": "sans-serif", + "color": "#5b6a6c", + "strokeWidth": 5, + "strokeColor": "#ffffff", + "align": "middle", + }, + "arrows": {"to": {"enabled": True, "scaleFactor": 0.9}}, + "smooth": {"type": "continuous"}, + }, + "physics": { + "barnesHut": { + "gravitationalConstant": -12000, + "centralGravity": 0.55, + "springLength": spring_len, + "springConstant": 0.05, + "damping": 0.4, + "avoidOverlap": 0.35, + }, + "stabilization": {"enabled": True, "iterations": 220}, + }, + "interaction": {"hover": True, "navigationButtons": True, "tooltipDelay": 120}, + }, + ensure_ascii=False, + ) + ) + for n, d in self.g.nodes(data=True): + t = d.get("type", "Unknown") + label_zh = ENTITY_TYPES.get(t, t) + net.add_node(n, label=n, title=f"{n} ({label_zh})", color=color_of.get(t, "#cccccc")) + for h, t, d in self.g.edges(data=True): + rel = d.get("relation", "") + net.add_edge(h, t, label=RELATION_TYPES.get(rel, rel), title=f"{rel} (conf={d.get('confidence')})") + + p = Path(path) + p.parent.mkdir(parents=True, exist_ok=True) + # Write UTF-8 ourselves; pyvis.save_graph uses the locale codec (GBK on + # Windows) and crashes on chars like the copyright sign. + html = net.generate_html(notebook=False) + p.write_text(html, encoding="utf-8") + return str(p) diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/neo4j_store.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/neo4j_store.py" new file mode 100644 index 0000000..0664878 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/neo4j_store.py" @@ -0,0 +1,111 @@ +"""Optional Neo4j knowledge-graph backend. + +Activate by setting GRAPH_BACKEND=neo4j and NEO4J_* in .env, with a running +Neo4j (e.g. `docker run -p 7687:7687 -p 7474:7474 neo4j:5`). Same interface as +LocalGraphStore so agents need no changes. +""" +from __future__ import annotations + +from medigraph.graph.base import GraphStore +from medigraph.schema.ontology import RELATION_TYPES + + +class Neo4jGraphStore(GraphStore): + def __init__(self, uri: str, user: str, password: str): + from neo4j import GraphDatabase + + self.driver = GraphDatabase.driver(uri, auth=(user, password)) + + def close(self) -> None: + self.driver.close() + + def upsert_entity(self, name: str, etype: str, **props) -> None: + name = name.strip() + if not name: + return + with self.driver.session() as s: + s.run( + "MERGE (e:Entity {name:$name}) " + "ON CREATE SET e.type=$etype " + "SET e.type = coalesce(e.type, $etype)", + name=name, + etype=etype, + ) + + def upsert_triple( + self, + head: str, + head_type: str, + relation: str, + tail: str, + tail_type: str, + confidence: float = 1.0, + source: str = "", + operator_version: str = "", + **props, + ) -> None: + self.upsert_entity(head, head_type) + self.upsert_entity(tail, tail_type) + with self.driver.session() as s: + s.run( + "MATCH (h:Entity {name:$head}), (t:Entity {name:$tail}) " + "MERGE (h)-[r:REL {relation:$relation}]->(t) " + "ON CREATE SET r.confidence=$confidence, r.source=$source, " + " r.operator_version=$opv, r.timestamp=timestamp() " + "ON MATCH SET r.confidence = CASE WHEN $confidence > r.confidence " + " THEN $confidence ELSE r.confidence END", + head=head, tail=tail, relation=relation, + confidence=float(confidence), source=source, opv=operator_version, + ) + + def find_entities(self, names: list[str]) -> list[str]: + out: list[str] = [] + with self.driver.session() as s: + for q in names: + q = q.strip() + if not q: + continue + rec = s.run( + "MATCH (e:Entity) WHERE toLower(e.name) = toLower($q) " + "OR toLower(e.name) CONTAINS toLower($q) RETURN e.name AS name LIMIT 3", + q=q, + ) + out.extend(r["name"] for r in rec) + seen, res = set(), [] + for n in out: + if n not in seen: + seen.add(n) + res.append(n) + return res + + def neighbors(self, name: str, hops: int = 1) -> list[dict]: + hops = max(1, hops) + with self.driver.session() as s: + rec = s.run( + f"MATCH p=(a:Entity {{name:$name}})-[*1..{hops}]-(b:Entity) " + "UNWIND relationships(p) AS r " + "WITH startNode(r) AS h, endNode(r) AS t, r " + "RETURN DISTINCT h.name AS head, h.type AS head_type, r.relation AS relation, " + " t.name AS tail, t.type AS tail_type, r.confidence AS confidence, r.source AS source", + name=name, + ) + triples = [] + for r in rec: + d = dict(r) + d["relation_zh"] = RELATION_TYPES.get(d.get("relation", ""), d.get("relation", "")) + triples.append(d) + return triples + + def stats(self) -> dict: + with self.driver.session() as s: + n = s.run("MATCH (e:Entity) RETURN count(e) AS c").single()["c"] + m = s.run("MATCH ()-[r:REL]->() RETURN count(r) AS c").single()["c"] + tc = { + r["t"]: r["c"] + for r in s.run("MATCH (e:Entity) RETURN e.type AS t, count(*) AS c") + } + rc = { + r["rel"]: r["c"] + for r in s.run("MATCH ()-[r:REL]->() RETURN r.relation AS rel, count(*) AS c") + } + return {"num_entities": n, "num_triples": m, "entity_type_counts": tc, "relation_counts": rc} diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/pg_vector_store.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/pg_vector_store.py" new file mode 100644 index 0000000..0a7d70d --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/pg_vector_store.py" @@ -0,0 +1,160 @@ +"""pgvector-backed ANN store: the indexed upgrade of `LocalVectorStore`. + +`LocalVectorStore` is a numpy matrix and a dot product -- exact, zero-dependency, +and O(N) per query with no index. That is the right default for a corpus of a few +thousand chunks and for offline runs. This store is the production-shaped path: +vectors live in PostgreSQL under an HNSW index, so search cost stops scaling +linearly with corpus size, at the price of approximate results. + +The interface mirrors `LocalVectorStore` (`add` / `search` / `size`) so the QA +agent can take either. Two extra knobs matter and are exposed rather than hidden: + +* build-time: ``m`` (graph degree) and ``ef_construction`` (build beam width) -- + larger values improve the graph's recall ceiling at the cost of build time; +* query-time: ``ef_search`` (search beam width) -- the recall/latency dial. The + benchmark (`scripts/bench_vector_search.py`) publishes the measured curve + instead of a single cherry-picked point. + +Cosine everywhere: embeddings are L2-normalised on insert (matching +`LocalVectorStore`), and the index uses ``vector_cosine_ops`` with the ``<=>`` +operator, so scores are directly comparable between the two stores. +""" +from __future__ import annotations + +import threading + +import numpy as np + +from config.settings import AnalyticsConfig + +TABLE = "vector_chunks" + + +class PgVectorStore: + def __init__( + self, + dim: int, + config: AnalyticsConfig | None = None, + m: int = 16, + ef_construction: int = 64, + table: str = TABLE, + ): + from config.settings import get_analytics_config + from medigraph.analysis.pg_relational import get_pool + + self.dim = int(dim) + self.m = m + self.ef_construction = ef_construction + self.table = table + self._config = config or get_analytics_config() + self._pool = get_pool(self._config) + self._lock = threading.Lock() + self._size: int | None = None # lazy COUNT cache, invalidated on add + self._ensure_schema() + + # ------------------------------------------------------------------ # + def _ensure_schema(self) -> None: + with self._pool.connection() as conn: + conn.execute("CREATE EXTENSION IF NOT EXISTS vector") + conn.execute( + f"CREATE TABLE IF NOT EXISTS {self.table} (" + " id BIGSERIAL PRIMARY KEY," + " text TEXT NOT NULL," + " source TEXT NOT NULL DEFAULT ''," + f" embedding vector({self.dim}) NOT NULL" + ")" + ) + conn.commit() + + def create_index(self, maintenance_work_mem: str = "1GB", parallel_workers: int = 4) -> None: + """Build (or rebuild) the HNSW index. + + Called once after bulk load rather than before: inserting through an + existing HNSW index is much slower than indexing a loaded table. + + The two session settings matter enormously at scale: with the default + 64 MB ``maintenance_work_mem`` a 100k x 1024-dim build does not fit the + graph in memory and pgvector falls back to a much slower on-disk path + (measured: >8 min vs ~1 min). Session-scoped, so nothing leaks to other + pool users. + """ + with self._pool.connection() as conn: + conn.execute(f"SET maintenance_work_mem = '{maintenance_work_mem}'") + conn.execute(f"SET max_parallel_maintenance_workers = {parallel_workers}") + conn.execute(f"DROP INDEX IF EXISTS {self.table}_hnsw") + conn.execute( + f"CREATE INDEX {self.table}_hnsw ON {self.table} " + f"USING hnsw (embedding vector_cosine_ops) " + f"WITH (m = {self.m}, ef_construction = {self.ef_construction})" + ) + conn.commit() + + def clear(self) -> None: + with self._pool.connection() as conn: + conn.execute(f"TRUNCATE {self.table} RESTART IDENTITY") + conn.commit() + self._size = None + + # ------------------------------------------------------------------ # + @staticmethod + def _normalize(matrix: np.ndarray) -> np.ndarray: + return matrix / (np.linalg.norm(matrix, axis=1, keepdims=True) + 1e-8) + + @staticmethod + def _vec_literal(vector: np.ndarray) -> str: + # pgvector's text input format; float32 precision is plenty for cosine. + return "[" + ",".join(f"{value:.6f}" for value in vector) + "]" + + def add(self, texts: list[str], sources: list[str], vectors: list[list[float]]) -> int: + """Bulk-insert via COPY. Returns the number of rows written.""" + rows = [ + (text, source, vector) + for text, source, vector in zip(texts, sources, vectors) + if vector + ] + if not rows: + return 0 + matrix = self._normalize(np.asarray([vector for _, _, vector in rows], dtype=np.float32)) + with self._pool.connection() as conn: + with conn.cursor() as cur: + with cur.copy(f"COPY {self.table} (text, source, embedding) FROM STDIN") as copy: + for (text, source, _), embedding in zip(rows, matrix): + copy.write_row((text, source, self._vec_literal(embedding))) + conn.commit() + self._size = None + return len(rows) + + def search(self, query_vec: list[float], k: int = 3, ef_search: int | None = None) -> list[dict]: + """Approximate top-k by cosine similarity. + + `ef_search` must be >= k (pgvector requirement); when unset, the server + default (40) applies. Returns the same shape as `LocalVectorStore.search`. + """ + if not query_vec: + return [] + query = np.asarray(query_vec, dtype=np.float32) + query = query / (np.linalg.norm(query) + 1e-8) + literal = self._vec_literal(query) + with self._pool.connection() as conn: + if ef_search is not None: + conn.execute(f"SET hnsw.ef_search = {max(int(ef_search), k)}") + cur = conn.execute( + f"SELECT text, source, 1 - (embedding <=> %s::vector) AS score " + f"FROM {self.table} ORDER BY embedding <=> %s::vector LIMIT %s", + (literal, literal, k), + ) + hits = cur.fetchall() + conn.rollback() + return [ + {"text": text, "source": source, "score": round(float(score), 3)} + for text, source, score in hits + ] + + @property + def size(self) -> int: + if self._size is None: + with self._lock: + if self._size is None: + with self._pool.connection() as conn: + self._size = conn.execute(f"SELECT COUNT(*) FROM {self.table}").fetchone()[0] + return self._size diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/vector_store.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/vector_store.py" new file mode 100644 index 0000000..fa23c8d --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/graph/vector_store.py" @@ -0,0 +1,63 @@ +"""Lightweight local vector store for GraphRAG hybrid retrieval. + +Stores text chunks with their embeddings and does cosine top-k search in numpy. +No external service required (Milvus is the documented production upgrade). Used +by the QA agent to fuse vector-retrieved passages with graph subgraph evidence. +""" +from __future__ import annotations + +import json +from pathlib import Path + +import numpy as np + + +class LocalVectorStore: + def __init__(self): + self.chunks: list[dict] = [] # [{text, source}] + self._matrix: np.ndarray | None = None # (N, dim), L2-normalized + + def add(self, texts: list[str], sources: list[str], vectors: list[list[float]]) -> None: + rows = [] + for text, source, vec in zip(texts, sources, vectors): + if not vec: # embedding failed for this item + continue + self.chunks.append({"text": text, "source": source}) + rows.append(vec) + if rows: + arr = np.array(rows, dtype=np.float32) + arr = arr / (np.linalg.norm(arr, axis=1, keepdims=True) + 1e-8) + self._matrix = arr if self._matrix is None else np.vstack([self._matrix, arr]) + + def search(self, query_vec: list[float], k: int = 3) -> list[dict]: + if not query_vec or self._matrix is None or len(self.chunks) == 0: + return [] + q = np.array(query_vec, dtype=np.float32) + q = q / (np.linalg.norm(q) + 1e-8) + scores = self._matrix @ q + idx = np.argsort(-scores)[:k] + return [{**self.chunks[i], "score": round(float(scores[i]), 3)} for i in idx] + + @property + def size(self) -> int: + return len(self.chunks) + + # -- persistence --------------------------------------------------- # + def save_json(self, path: str | Path) -> str: + p = Path(path) + p.parent.mkdir(parents=True, exist_ok=True) + data = { + "chunks": self.chunks, + "matrix": self._matrix.tolist() if self._matrix is not None else [], + } + p.write_text(json.dumps(data, ensure_ascii=False), encoding="utf-8") + return str(p) + + @classmethod + def load_json(cls, path: str | Path) -> "LocalVectorStore": + store = cls() + data = json.loads(Path(path).read_text(encoding="utf-8")) + store.chunks = data.get("chunks", []) + matrix = data.get("matrix", []) + store._matrix = np.array(matrix, dtype=np.float32) if matrix else None + return store diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/llm/__init__.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/llm/__init__.py" new file mode 100644 index 0000000..e69de29 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/llm/client.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/llm/client.py" new file mode 100644 index 0000000..06d49fb --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/llm/client.py" @@ -0,0 +1,292 @@ +"""OpenAI-compatible LLM client with provider switching, retries and JSON mode. + +Used by the LLM-backed operators (NER / RE / validator fallback) and by the +agents (DataProc planner, GraphRAG answerer). Works against SiliconFlow or +Aliyun DashScope -- both expose an OpenAI-compatible /chat/completions endpoint. +""" +from __future__ import annotations + +import json +import re +import sys +import time +from collections.abc import Iterator +from dataclasses import dataclass, field +from typing import Any + +from openai import OpenAI + +# Allow running both as a package (medigraph.llm.client) and standalone. +try: + from config.settings import LLMConfig, get_llm_config +except ModuleNotFoundError: # pragma: no cover - fallback for odd sys.path + from CCF.config.settings import LLMConfig, get_llm_config # type: ignore + + +@dataclass +class CallStats: + """Lightweight latency / token accounting for benchmarking operators.""" + + calls: int = 0 + total_seconds: float = 0.0 + prompt_tokens: int = 0 + completion_tokens: int = 0 + latencies: list[float] = field(default_factory=list) + #: Time-to-first-token, recorded for streaming calls only. This is the metric + #: streaming actually improves -- total latency is unchanged, but the user sees + #: output after the first chunk instead of after the whole completion. + ttfts: list[float] = field(default_factory=list) + stream_calls: int = 0 + + def record(self, seconds: float, usage: Any) -> None: + self.calls += 1 + self.total_seconds += seconds + self.latencies.append(seconds) + if usage is not None: + self.prompt_tokens += getattr(usage, "prompt_tokens", 0) or 0 + self.completion_tokens += getattr(usage, "completion_tokens", 0) or 0 + + def record_stream(self, ttft: float, seconds: float, usage: Any = None) -> None: + """Record a streaming call: TTFT plus the usual total-latency accounting.""" + self.stream_calls += 1 + self.ttfts.append(ttft) + self.record(seconds, usage) + + def summary(self) -> dict: + avg = self.total_seconds / self.calls if self.calls else 0.0 + out = { + "calls": self.calls, + "total_seconds": round(self.total_seconds, 3), + "avg_latency_s": round(avg, 3), + "prompt_tokens": self.prompt_tokens, + "completion_tokens": self.completion_tokens, + } + if self.ttfts: + out["stream_calls"] = self.stream_calls + out["avg_ttft_s"] = round(sum(self.ttfts) / len(self.ttfts), 3) + out["p50_ttft_s"] = round(sorted(self.ttfts)[len(self.ttfts) // 2], 3) + return out + + +class LLMClient: + """Thin wrapper over the OpenAI SDK pointed at an OpenAI-compatible host.""" + + def __init__(self, config: LLMConfig | None = None): + self.config = config or get_llm_config() + if not self.config.api_key: + print( + f"[LLMClient] WARNING: no API key for provider " + f"'{self.config.provider}'. Set it in mcp服务/.env (copy .env.example first).", + file=sys.stderr, + ) + self.client = OpenAI( + api_key=self.config.api_key or "EMPTY", + base_url=self.config.base_url, + timeout=self.config.timeout, + max_retries=0, # we handle retries ourselves for clearer logging + ) + self.stats = CallStats() + + # ------------------------------------------------------------------ # + def chat( + self, + prompt: str, + system: str | None = None, + temperature: float | None = None, + json_mode: bool = False, + enable_thinking: bool | None = None, + ) -> str: + """Single-turn chat completion with retry. Returns raw text content. + + enable_thinking controls Qwen3/3.5/3.6 "thinking" mode. Defaults to the + client config (off for low-latency extraction). The flag is only sent to + Qwen3* models; it is dropped automatically if the host rejects it. + """ + messages: list[dict] = [] + if system: + messages.append({"role": "system", "content": system}) + messages.append({"role": "user", "content": prompt}) + + kwargs: dict[str, Any] = { + "model": self.config.model, + "messages": messages, + "temperature": self.config.temperature if temperature is None else temperature, + } + if json_mode: + # Most OpenAI-compatible hosts accept this; if not, we still rely on + # prompt instructions + _extract_json below. + kwargs["response_format"] = {"type": "json_object"} + + think = self.config.enable_thinking if enable_thinking is None else enable_thinking + if "qwen3" in self.config.model.lower(): + kwargs["extra_body"] = {"enable_thinking": think} + + last_err: Exception | None = None + for attempt in range(1, self.config.max_retries + 1): + start = time.time() + try: + resp = self.client.chat.completions.create(**kwargs) + elapsed = time.time() - start + self.stats.record(elapsed, getattr(resp, "usage", None)) + return resp.choices[0].message.content or "" + except Exception as exc: # noqa: BLE001 - surface provider errors + last_err = exc + # Drop optional params some hosts reject, then retry. + if json_mode and "response_format" in kwargs: + kwargs.pop("response_format", None) + kwargs.pop("extra_body", None) + if attempt < self.config.max_retries: + wait = min(2 ** attempt, 10) + print( + f"[LLMClient] call failed (attempt {attempt}/{self.config.max_retries}): " + f"{exc}. retrying in {wait}s", + file=sys.stderr, + ) + time.sleep(wait) + else: + print( + f"[LLMClient] call failed (attempt {attempt}/{self.config.max_retries}): {exc}.", + file=sys.stderr, + ) + raise RuntimeError(f"LLM call failed after {self.config.max_retries} attempts: {last_err}") + + def chat_json( + self, + prompt: str, + system: str | None = None, + temperature: float | None = None, + default: Any = None, + ) -> Any: + """Chat completion that returns parsed JSON, with robust extraction.""" + raw = self.chat(prompt, system=system, temperature=temperature, json_mode=True) + parsed = self._extract_json(raw) + if parsed is None: + return default + return parsed + + # ------------------------------------------------------------------ # + def _build_kwargs( + self, + prompt: str, + system: str | None, + temperature: float | None, + enable_thinking: bool | None, + ) -> dict[str, Any]: + messages: list[dict] = [] + if system: + messages.append({"role": "system", "content": system}) + messages.append({"role": "user", "content": prompt}) + kwargs: dict[str, Any] = { + "model": self.config.model, + "messages": messages, + "temperature": self.config.temperature if temperature is None else temperature, + } + think = self.config.enable_thinking if enable_thinking is None else enable_thinking + if "qwen3" in self.config.model.lower(): + kwargs["extra_body"] = {"enable_thinking": think} + return kwargs + + def chat_stream( + self, + prompt: str, + system: str | None = None, + temperature: float | None = None, + enable_thinking: bool | None = None, + ) -> Iterator[str]: + """Yield content deltas as the model produces them. + + Retries are attempted only *before the first token is emitted*: once a + delta has been handed to the caller it cannot be un-yielded, so a mid-stream + failure propagates instead of silently restarting and duplicating output. + + Records TTFT and total latency into `self.stats`, so a caller can report the + streaming win (first byte) separately from total generation time. + """ + kwargs = self._build_kwargs(prompt, system, temperature, enable_thinking) + kwargs["stream"] = True + + last_err: Exception | None = None + for attempt in range(1, self.config.max_retries + 1): + start = time.time() + first_token_at: float | None = None + emitted = False + try: + stream = self.client.chat.completions.create(**kwargs) + for chunk in stream: + if not getattr(chunk, "choices", None): + continue + delta = getattr(chunk.choices[0], "delta", None) + piece = getattr(delta, "content", None) if delta else None + if not piece: + continue + if first_token_at is None: + first_token_at = time.time() + emitted = True + yield piece + elapsed = time.time() - start + ttft = (first_token_at - start) if first_token_at else elapsed + self.stats.record_stream(ttft, elapsed) + return + except Exception as exc: # noqa: BLE001 - surface provider errors + last_err = exc + if emitted: + # Partial output already delivered; retrying would duplicate it. + raise + kwargs.pop("extra_body", None) + if attempt < self.config.max_retries: + wait = min(2 ** attempt, 10) + print( + f"[LLMClient] stream failed before first token " + f"(attempt {attempt}/{self.config.max_retries}): {exc}. retrying in {wait}s", + file=sys.stderr, + ) + time.sleep(wait) + raise RuntimeError( + f"LLM stream failed after {self.config.max_retries} attempts: {last_err}" + ) + + # ------------------------------------------------------------------ # + def embed(self, texts: list[str], model: str | None = None) -> list[list[float]]: + """Embed texts via the OpenAI-compatible embeddings endpoint. + + Default model is a small, fast embedder available on SiliconFlow. Returns + one vector per input; on failure returns empty lists (callers degrade to + graph-only retrieval). + """ + if not texts: + return [] + model = model or self.config.embedding_model + try: + resp = self.client.embeddings.create(model=model, input=texts) + return [d.embedding for d in resp.data] + except Exception as exc: # noqa: BLE001 + print(f"[LLMClient] embeddings failed ({exc}); falling back to no-vector.", + file=sys.stderr) + return [[] for _ in texts] + + # ------------------------------------------------------------------ # + @staticmethod + def _extract_json(text: str) -> Any: + """Best-effort JSON extraction from an LLM response.""" + if not text: + return None + text = text.strip() + # Strip ```json ... ``` fences if present. + fence = re.search(r"```(?:json)?\s*(.+?)```", text, flags=re.DOTALL) + if fence: + text = fence.group(1).strip() + try: + return json.loads(text) + except json.JSONDecodeError: + pass + # Fallback: grab the outermost JSON object/array. + for opener, closer in (("{", "}"), ("[", "]")): + start = text.find(opener) + end = text.rfind(closer) + if start != -1 and end != -1 and end > start: + snippet = text[start : end + 1] + try: + return json.loads(snippet) + except json.JSONDecodeError: + continue + return None diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/__init__.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/__init__.py" new file mode 100644 index 0000000..e69de29 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/base.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/base.py" new file mode 100644 index 0000000..7fcdef1 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/base.py" @@ -0,0 +1,111 @@ +"""Unified operator contract -- the "Operator-as-MCP-Tool" abstraction layer. + +A single operator implementation can be: + 1. called directly in-process by the agents (DataProc / KGGen), + 2. exposed as a Nexent MCP tool via `to_mcp_tool()` (see mcp_server/server.py), + 3. mirrored as a DataMate marketplace operator (see CCF/datamate_ops/). + +Every operator declares an `OperatorMeta` (name, description, JSON schemas) so the +planning agent can discover and reason about it from `meta.description` alone -- +no hard-coded operator list in the agent. +""" +from __future__ import annotations + +import time +from abc import ABC, abstractmethod +from typing import Any, Callable + +from pydantic import BaseModel, Field + + +class OperatorMeta(BaseModel): + name: str + version: str = "1.0.0" + description: str # natural-language description shown to the LLM / MCP + input_schema: dict = Field(default_factory=dict) + output_schema: dict = Field(default_factory=dict) + backend: str = "cpu" # "cpu" | "npu" (npu reserved for future acceleration) + + +class BaseOperator(ABC): + """All operators implement run(inputs: dict) -> dict.""" + + meta: OperatorMeta + + @abstractmethod + def run(self, inputs: dict, **kwargs) -> dict: + """Core execution. Subclasses implement this.""" + + # -- timing wrapper used by the DAG executor / benchmarks ----------- # + def run_timed(self, inputs: dict, **kwargs) -> tuple[dict, float]: + start = time.time() + out = self.run(inputs, **kwargs) + return out, time.time() - start + + # -- Nexent MCP tool adapter --------------------------------------- # + def to_mcp_tool(self) -> dict: + """Return a descriptor used by mcp_server to register an MCP tool.""" + return { + "name": self.meta.name, + "description": self.meta.description, + "input_schema": self.meta.input_schema, + "func": self.run, + } + + +# ---------------------------------------------------------------------- # +# Global operator registry. Operators register themselves at import time so the +# DataProc planning agent can enumerate the available toolbox. +# ---------------------------------------------------------------------- # +OP_REGISTRY: dict[str, BaseOperator] = {} + + +def register(operator: BaseOperator) -> BaseOperator: + OP_REGISTRY[operator.meta.name] = operator + return operator + + +def get_operator(name: str) -> BaseOperator: + if name not in OP_REGISTRY: + raise KeyError(f"operator '{name}' not registered. available: {list(OP_REGISTRY)}") + return OP_REGISTRY[name] + + +def catalog() -> list[dict]: + """Operator catalog (name + description + schema) for the planner prompt.""" + return [ + { + "name": op.meta.name, + "description": op.meta.description, + "input_schema": op.meta.input_schema, + "output_schema": op.meta.output_schema, + } + for op in OP_REGISTRY.values() + ] + + +def load_default_operators(llm: Any | None = None) -> None: + """Instantiate and register the built-in operators. + + Pass a shared LLMClient so the LLM-backed operators reuse one connection and + aggregate latency stats. Import is local to avoid circular imports. + """ + from medigraph.operators.text_clean import TextCleanOperator + from medigraph.operators.chunker import ChunkerOperator + from medigraph.operators.medical_ner import MedicalNEROperator + from medigraph.operators.medical_re import MedicalREOperator + from medigraph.operators.triple_validator import TripleValidatorOperator + from medigraph.operators.document_loader import DocumentLoaderOperator + from medigraph.operators.data_quality import DataQualityOperator + from medigraph.operators.pii_redact import PIIRedactOperator + from medigraph.operators.entity_linker import EntityLinkerOperator + + register(DocumentLoaderOperator()) + register(TextCleanOperator()) + register(DataQualityOperator()) + register(PIIRedactOperator()) + register(ChunkerOperator()) + register(MedicalNEROperator(llm=llm)) + register(EntityLinkerOperator()) + register(MedicalREOperator(llm=llm)) + register(TripleValidatorOperator(llm=llm)) diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/chunker.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/chunker.py" new file mode 100644 index 0000000..d9f4682 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/chunker.py" @@ -0,0 +1,86 @@ +"""Heading-aware text chunking operator. + +Splits long markdown/plain text into semantically coherent chunks bounded by a +target character length. Chunk boundaries prefer markdown headings, then blank +lines, so each chunk stays topical for downstream NER/RE. +""" +from __future__ import annotations + +import re + +from medigraph.operators.base import BaseOperator, OperatorMeta + +_HEADING_RE = re.compile(r"^(#{1,6}\s+.+|第[一二三四五六七八九十百千\d]+[章节篇卷].*)$") + + +class ChunkerOperator(BaseOperator): + def __init__(self, max_chars: int = 1200, overlap: int = 80): + self.max_chars = max_chars + self.overlap = overlap + self.meta = OperatorMeta( + name="chunker", + description=( + "把清洗后的长文本按标题层级和字数上限切分成语义连贯的文本块(chunks)，" + "便于后续抽取。输入 {text, max_chars?}, 输出 {chunks: [str]}。" + ), + input_schema={ + "type": "object", + "properties": { + "text": {"type": "string"}, + "max_chars": {"type": "integer"}, + }, + "required": ["text"], + }, + output_schema={"type": "object", "properties": {"chunks": {"type": "array"}}}, + ) + + def run(self, inputs: dict, **kwargs) -> dict: + text = inputs.get("text", "") or "" + max_chars = int(inputs.get("max_chars") or self.max_chars) + if not text.strip(): + return {"chunks": []} + + # 1) Split into heading-led sections. + sections: list[str] = [] + buf: list[str] = [] + for line in text.split("\n"): + if _HEADING_RE.match(line.strip()) and buf: + sections.append("\n".join(buf)) + buf = [line] + else: + buf.append(line) + if buf: + sections.append("\n".join(buf)) + + # 2) Further split oversized sections by length (paragraph-aware). + chunks: list[str] = [] + for sec in sections: + sec = sec.strip() + if not sec: + continue + if len(sec) <= max_chars: + chunks.append(sec) + else: + chunks.extend(self._split_long(sec, max_chars)) + return {"chunks": chunks} + + def _split_long(self, text: str, max_chars: int) -> list[str]: + paras = re.split(r"\n\s*\n", text) + out: list[str] = [] + cur = "" + for p in paras: + if len(cur) + len(p) + 2 <= max_chars: + cur = f"{cur}\n\n{p}" if cur else p + else: + if cur: + out.append(cur) + if len(p) <= max_chars: + cur = p + else: + # hard wrap very long paragraph + for i in range(0, len(p), max_chars - self.overlap): + out.append(p[i : i + max_chars]) + cur = "" + if cur: + out.append(cur) + return out diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/data_quality.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/data_quality.py" new file mode 100644 index 0000000..c32e1fa --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/data_quality.py" @@ -0,0 +1,84 @@ +"""Deterministic dataset quality profiling and duplicate detection.""" +from __future__ import annotations + +import hashlib +import statistics + +from medigraph.operators.base import BaseOperator, OperatorMeta + + +class DataQualityOperator(BaseOperator): + def __init__(self): + self.meta = OperatorMeta( + name="data_quality", + version="1.0.0", + description=( + "检查文档/记录的数据质量：空值、重复、长度异常和字段缺失；默认去重。" + "输入 {documents?或text?,required_fields?}, 输出 {documents,text,quality_report}。" + ), + input_schema={"type": "object", "properties": {"documents": {"type": "array"}}}, + output_schema={ + "type": "object", + "properties": { + "documents": {"type": "array"}, + "text": {"type": "string"}, + "quality_report": {"type": "object"}, + }, + "required": ["quality_report"], + }, + ) + + def run(self, inputs: dict, **kwargs) -> dict: + documents = inputs.get("documents") + if not isinstance(documents, list): + documents = [{"fileName": "inline", "text": str(inputs.get("text", "") or "")}] + required = inputs.get("required_fields", []) + required = required if isinstance(required, list) else [] + deduplicate = bool(inputs.get("deduplicate", True)) + clean, duplicates, empty, missing_fields = [], [], [], [] + seen: dict[str, int] = {} + lengths = [] + for index, document in enumerate(documents): + if not isinstance(document, dict): + empty.append(index) + continue + text = str(document.get("text", "") or "").strip() + if not text: + empty.append(index) + continue + missing = [field for field in required if document.get(field) in (None, "", [])] + if missing: + missing_fields.append({"index": index, "fields": missing}) + digest = hashlib.sha256(" ".join(text.split()).encode("utf-8")).hexdigest() + if digest in seen: + duplicates.append({"index": index, "duplicate_of": seen[digest], "sha256": digest}) + if deduplicate: + continue + else: + seen[digest] = index + value = dict(document) + value["content_sha256"] = digest + clean.append(value) + lengths.append(len(text)) + report = { + "input_records": len(documents), + "output_records": len(clean), + "empty_records": len(empty), + "duplicate_records": len(duplicates), + "missing_field_records": len(missing_fields), + "completeness": round((len(documents) - len(empty)) / len(documents), 4) if documents else 1.0, + "uniqueness": round((len(documents) - len(duplicates)) / len(documents), 4) if documents else 1.0, + "length": { + "min": min(lengths) if lengths else 0, + "max": max(lengths) if lengths else 0, + "mean": round(statistics.fmean(lengths), 2) if lengths else 0.0, + "median": round(statistics.median(lengths), 2) if lengths else 0.0, + }, + "duplicate_details": duplicates[:100], + "missing_field_details": missing_fields[:100], + } + return { + "documents": clean, + "text": "\n\n".join(str(document.get("text", "")) for document in clean), + "quality_report": report, + } diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/document_loader.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/document_loader.py" new file mode 100644 index 0000000..89158f5 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/document_loader.py" @@ -0,0 +1,150 @@ +"""Multi-format document ingestion operator (7+ common data formats).""" +from __future__ import annotations + +import csv +import html +import json +import re +import zipfile +from html.parser import HTMLParser +from pathlib import Path +from xml.etree import ElementTree + +from medigraph.operators.base import BaseOperator, OperatorMeta + + +class _HTMLTextExtractor(HTMLParser): + def __init__(self): + super().__init__() + self.parts: list[str] = [] + self._ignored = 0 + + def handle_starttag(self, tag: str, attrs) -> None: + if tag in {"script", "style", "noscript"}: + self._ignored += 1 + if tag in {"p", "div", "br", "li", "tr", "h1", "h2", "h3", "h4"}: + self.parts.append("\n") + + def handle_endtag(self, tag: str) -> None: + if tag in {"script", "style", "noscript"} and self._ignored: + self._ignored -= 1 + + def handle_data(self, data: str) -> None: + if not self._ignored: + self.parts.append(data) + + def text(self) -> str: + return re.sub(r"\n{3,}", "\n\n", html.unescape("".join(self.parts))).strip() + + +class DocumentLoaderOperator(BaseOperator): + SUPPORTED = {".txt", ".md", ".html", ".htm", ".csv", ".json", ".jsonl", ".docx", ".pdf"} + + def __init__(self, max_file_bytes: int = 20 * 1024 * 1024): + self.max_file_bytes = max_file_bytes + self.meta = OperatorMeta( + name="document_loader", + version="1.0.0", + description=( + "读取 TXT/Markdown/HTML/CSV/JSON/JSONL/DOCX/PDF 等文档并统一为文本。" + "输入 {path} 或 {paths:[...]}, 输出 {documents,text,formats,errors}。" + ), + input_schema={ + "type": "object", + "properties": { + "path": {"type": "string"}, + "paths": {"type": "array"}, + }, + }, + output_schema={ + "type": "object", + "properties": { + "documents": {"type": "array"}, + "text": {"type": "string"}, + "formats": {"type": "array"}, + "errors": {"type": "array"}, + }, + "required": ["documents", "text"], + }, + ) + + def run(self, inputs: dict, **kwargs) -> dict: + raw_paths = inputs.get("paths", []) + if not isinstance(raw_paths, list): + raw_paths = [] + if inputs.get("path"): + raw_paths = [inputs["path"], *raw_paths] + documents, errors = [], [] + for raw_path in raw_paths: + path = Path(str(raw_path)).expanduser().resolve() + try: + if not path.is_file(): + raise FileNotFoundError(path) + if path.suffix.lower() not in self.SUPPORTED: + raise ValueError(f"unsupported format: {path.suffix}") + if path.stat().st_size > self.max_file_bytes: + raise ValueError(f"file exceeds {self.max_file_bytes} bytes") + text = self._read(path) + documents.append( + { + "fileName": path.name, + "path": str(path), + "format": path.suffix.lower().lstrip("."), + "bytes": path.stat().st_size, + "text": text, + } + ) + except Exception as exc: # noqa: BLE001 - report per-file ingestion errors + errors.append({"path": str(path), "error": f"{exc.__class__.__name__}: {exc}"}) + return { + "documents": documents, + "text": "\n\n".join(document["text"] for document in documents), + "formats": sorted({document["format"] for document in documents}), + "errors": errors, + } + + def _read(self, path: Path) -> str: + suffix = path.suffix.lower() + if suffix in {".txt", ".md"}: + return path.read_text(encoding="utf-8-sig") + if suffix in {".html", ".htm"}: + parser = _HTMLTextExtractor() + parser.feed(path.read_text(encoding="utf-8-sig")) + return parser.text() + if suffix == ".csv": + with path.open(encoding="utf-8-sig", newline="") as handle: + return "\n".join( + " | ".join(str(value) for value in row) + for row in csv.reader(handle) + ) + if suffix == ".json": + data = json.loads(path.read_text(encoding="utf-8-sig")) + return json.dumps(data, ensure_ascii=False, indent=2) + if suffix == ".jsonl": + rows = [] + for line in path.read_text(encoding="utf-8-sig").splitlines(): + if line.strip(): + rows.append(json.dumps(json.loads(line), ensure_ascii=False)) + return "\n".join(rows) + if suffix == ".docx": + return self._read_docx(path) + if suffix == ".pdf": + try: + from pypdf import PdfReader + except ImportError as exc: + raise RuntimeError("PDF support requires pypdf; install requirements.txt") from exc + return "\n".join(page.extract_text() or "" for page in PdfReader(str(path)).pages) + raise ValueError(f"unsupported format: {suffix}") + + @staticmethod + def _read_docx(path: Path) -> str: + with zipfile.ZipFile(path) as archive: + xml_bytes = archive.read("word/document.xml") + root = ElementTree.fromstring(xml_bytes) + namespace = "{http://schemas.openxmlformats.org/wordprocessingml/2006/main}" + paragraphs = [] + for paragraph in root.iter(f"{namespace}p"): + text = "".join(node.text or "" for node in paragraph.iter(f"{namespace}t")) + if text: + paragraphs.append(text) + return "\n".join(paragraphs) diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/entity_linker.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/entity_linker.py" new file mode 100644 index 0000000..d4b9100 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/entity_linker.py" @@ -0,0 +1,45 @@ +"""Operator wrapper for CM3KG-backed entity normalization.""" +from __future__ import annotations + +from medigraph.extraction.cascade import load_entity_linker +from medigraph.operators.base import BaseOperator, OperatorMeta + + +class EntityLinkerOperator(BaseOperator): + def __init__(self): + self.meta = OperatorMeta( + name="entity_linker", + version="1.0.0", + description=( + "把实体链接到 CM3KG/本地稳定规范 ID，输出 canonical_id、规范名、匹配方法和分数。" + "输入 {entities}, 输出 {entities,linking_report}。" + ), + input_schema={ + "type": "object", + "properties": {"entities": {"type": "array"}}, + "required": ["entities"], + }, + output_schema={ + "type": "object", + "properties": {"entities": {"type": "array"}, "linking_report": {"type": "object"}}, + "required": ["entities", "linking_report"], + }, + ) + + def run(self, inputs: dict, **kwargs) -> dict: + entities = inputs.get("entities", []) + entities = entities if isinstance(entities, list) else [] + linker = load_entity_linker() + linked = linker.link_entities(entities) if linker is not None else entities + exact = sum(item.get("match_method") in {"exact", "alias"} for item in linked) + fuzzy = sum(item.get("match_method") == "fuzzy" for item in linked) + return { + "entities": linked, + "linking_report": { + "entities": len(linked), + "exact_or_alias": exact, + "fuzzy": fuzzy, + "local_id": len(linked) - exact - fuzzy, + "linked_rate": round((exact + fuzzy) / len(linked), 4) if linked else 0.0, + }, + } diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/medical_ner.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/medical_ner.py" new file mode 100644 index 0000000..33e55e3 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/medical_ner.py" @@ -0,0 +1,214 @@ +"""Medical NER with a confidence-routed local fast path and LLM fallback. + +Extracts typed medical entities (disease/symptom/drug/exam/biomarker/gene/...) +from a text chunk using constrained JSON decoding. The LLM is reused across +operators for shared latency stats. +""" +from __future__ import annotations + +from typing import Any + +from config.settings import get_extraction_config +from medigraph.extraction.cascade import ( + load_entity_linker, + load_fast_extractor, + load_neural_extractor, + merge_entities, +) +from medigraph.operators.base import BaseOperator, OperatorMeta +from medigraph.schema.ontology import is_valid_entity_type, ontology_prompt_block +from medigraph.schema.normalize import canonical_key, canonical_name, is_structural_noise + +_SYSTEM = "你是严谨的医学信息抽取引擎，只输出 JSON，不要任何解释。" + +_FEWSHOT = """示例（学习抽取粒度与类型，不要照抄示例内容）： + +示例文本1："2型糖尿病患者常有多饮、多尿和体重减轻，治疗首选二甲双胍，建议检查糖化血红蛋白，可并发糖尿病肾病。" +示例输出1：{{"entities": [{{"name": "2型糖尿病", "type": "Disease", "confidence": 0.97}}, {{"name": "多饮", "type": "Symptom", "confidence": 0.95}}, {{"name": "多尿", "type": "Symptom", "confidence": 0.95}}, {{"name": "体重减轻", "type": "Symptom", "confidence": 0.92}}, {{"name": "二甲双胍", "type": "Drug", "confidence": 0.96}}, {{"name": "糖化血红蛋白", "type": "Examination", "confidence": 0.93}}, {{"name": "糖尿病肾病", "type": "Disease", "confidence": 0.9}}]}} + +示例文本2："嗜铬细胞瘤多位于肾上腺髓质，CgA 常呈阳性，与 RET 基因突变相关，可表现为阵发性高血压。" +示例输出2：{{"entities": [{{"name": "嗜铬细胞瘤", "type": "Tumor", "confidence": 0.96}}, {{"name": "肾上腺髓质", "type": "Body", "confidence": 0.9}}, {{"name": "CgA", "type": "Biomarker", "confidence": 0.92}}, {{"name": "RET", "type": "Gene", "confidence": 0.9}}, {{"name": "阵发性高血压", "type": "Symptom", "confidence": 0.88}}]}} +""" + +_PROMPT = """从下面的医学文本中抽取医学实体。严格遵循给定本体的实体类型。 + +{ontology} + +{fewshot} +要求： +1. 只抽取文本中明确出现的、有医学含义的实体，不要臆造。 +2. type 字段必须是上面实体类型的英文 key（如 Disease/Symptom/Drug/Biomarker/Gene/Tumor 等）。 +3. name 取**最小可识别的医学术语**（如「多尿」而非「出现多尿的症状」、「高血压」而非「阵发性血压升高表现」），去掉编号与修饰性整句，保持原文大小写；同一术语只输出一次。 +4. **不要把文档结构当作实体**：忽略章节标题/导航/目录，例如 + "Definition / general"、"Laboratory"、"Radiology images"、"Gross description"、 + "Microscopic description"、"Differential diagnosis"、"Treatment"、"Case reports" + 这类页面小节标题——它们不是医学实体。 +5. confidence 为 0~1 的抽取置信度。 +6. 输出 JSON 对象：{{"entities": [{{"name": "...", "type": "...", "confidence": 0.0}}]}} + +文本： +\"\"\" +{text} +\"\"\" +""" + + +class MedicalNEROperator(BaseOperator): + def __init__(self, llm: Any | None = None, backend: str | None = None): + self.llm = llm + self.config = get_extraction_config() + self.backend = backend or self.config.backend + self.meta = OperatorMeta( + name="medical_ner", + version="2.0.0", + description=( + "置信度路由的医疗实体抽取：auto 模式优先运行自训练 neural GPLinker，" + "环境不可用或低置信时退回本地词典快路/LLM，并链接到规范实体 ID。" + "输入 {text}, 输出 {entities, routing}。" + ), + input_schema={"type": "object", "properties": {"text": {"type": "string"}}, "required": ["text"]}, + output_schema={"type": "object", "properties": {"entities": {"type": "array"}}}, + ) + + def _ensure_llm(self): + if self.llm is None: + from medigraph.llm.client import LLMClient + self.llm = LLMClient() + return self.llm + + def run(self, inputs: dict, **kwargs) -> dict: + text = (inputs.get("text", "") or "").strip() + if not text: + return {"entities": [], "routing": {"level": "none", "reason": "empty_text"}} + + neural_entities: list[dict] = [] + fast_entities: list[dict] = [] + uncertainty = {"uncertain": True, "reason": "local_path_disabled", "mean_confidence": 0.0} + + if self.backend in {"auto", "neural"}: + neural = load_neural_extractor() + if neural is not None: + result = neural.extract( + text[:4000], + threshold=self.config.neural_threshold, + rel_threshold=self.config.neural_rel_threshold, + ) + neural_entities = result.get("entities", []) + uncertainty = self._uncertainty(neural_entities) + if self.backend == "neural" or ( + neural_entities and not uncertainty["uncertain"] + ): + return { + "entities": self._link(neural_entities), + "routing": { + "level": "L1_neural", + "llm_called": False, + "model_version": getattr(neural, "version", "neural_gplinker"), + **uncertainty, + }, + } + elif self.backend == "neural": + return { + "entities": [], + "routing": { + "level": "L1_neural_unavailable", + "llm_called": False, + "uncertain": True, + "reason": "neural_model_or_dependencies_unavailable", + "mean_confidence": 0.0, + }, + } + + fast = None + if self.backend != "llm": + fast = load_fast_extractor() + if fast is not None: + fast_entities = fast.extract_entities(text[:4000], overlap_policy="maximal") + uncertainty = fast.uncertainty(fast_entities, self.config.route_threshold) + if self.backend == "fast" or ( + not uncertainty["uncertain"] and fast_entities + ): + entities = self._link(fast_entities) + return { + "entities": entities, + "routing": { + "level": "L1_fast", + "llm_called": False, + **uncertainty, + }, + } + + if self.backend == "fast" or not self.config.llm_fallback: + return { + "entities": self._link(fast_entities), + "routing": {"level": "L1_fast", "llm_called": False, **uncertainty}, + } + + llm_entities = self._run_llm(text) + entities = merge_entities(merge_entities(neural_entities, fast_entities), llm_entities) + return { + "entities": self._link(entities), + "routing": { + "level": ( + "L1_neural+L1_fast+L2_llm" if neural_entities and fast_entities + else "L1_neural+L2_llm" if neural_entities + else "L1_fast+L2_llm" if fast_entities + else "L2_llm" + ), + "llm_called": True, + "neural_predictions": len(neural_entities), + "fast_predictions": len(fast_entities), + "llm_predictions": len(llm_entities), + **uncertainty, + }, + } + + def _run_llm(self, text: str) -> list[dict]: + llm = self._ensure_llm() + prompt = _PROMPT.format(ontology=ontology_prompt_block(), fewshot=_FEWSHOT, text=text[:4000]) + data = llm.chat_json(prompt, system=_SYSTEM, default={"entities": []}) + + raw_entities = data.get("entities", []) if isinstance(data, dict) else [] + seen: set[str] = set() + entities = [] + for e in raw_entities: + if not isinstance(e, dict): + continue + name = canonical_name(str(e.get("name", ""))) + etype = str(e.get("type", "")).strip() + if not name or not is_valid_entity_type(etype): + continue + if is_structural_noise(name): # drop section-title / navigation noise + continue + key = f"{etype}::{canonical_key(name)}" + if key in seen: + continue + seen.add(key) + try: + conf = float(e.get("confidence", 0.8)) + except (TypeError, ValueError): + conf = 0.8 + entities.append( + { + "name": name, + "type": etype, + "confidence": round(max(0.0, min(1.0, conf)), 3), + "extractor": "llm_schema", + } + ) + return entities + + @staticmethod + def _link(entities: list[dict]) -> list[dict]: + linker = load_entity_linker() + return linker.link_entities(entities) if linker is not None else entities + + def _uncertainty(self, items: list[dict]) -> dict: + if not items: + return {"uncertain": True, "reason": "no_prediction", "mean_confidence": 0.0} + mean_conf = sum(float(item.get("confidence", 0.0) or 0.0) for item in items) / len(items) + return { + "uncertain": mean_conf < self.config.route_threshold, + "reason": "below_route_threshold" if mean_conf < self.config.route_threshold else "confident", + "mean_confidence": round(mean_conf, 4), + } diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/medical_re.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/medical_re.py" new file mode 100644 index 0000000..8bcdf1e --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/medical_re.py" @@ -0,0 +1,210 @@ +"""Medical relation extraction with local joint fast path and LLM fallback. + +Given a text chunk and a list of entities, extracts relation triples +(head, relation, tail) limited to the ontology's relation types. If no entities +are supplied it can still run by asking the model to extract both ends. +""" +from __future__ import annotations + +from typing import Any + +from config.settings import get_extraction_config +from medigraph.extraction.cascade import load_fast_extractor, load_neural_extractor, merge_triples +from medigraph.operators.base import BaseOperator, OperatorMeta +from medigraph.schema.relation_mapping import map_cmeie_triples_to_clinical +from medigraph.schema.ontology import is_valid_relation, ontology_prompt_block + +_SYSTEM = "你是严谨的医学关系抽取引擎，只输出 JSON，不要任何解释。" + +_FEWSHOT = """示例（学习关系方向与三元组粒度，不要照抄示例内容）： + +示例文本1："2型糖尿病患者常有多饮、多尿，治疗首选二甲双胍，建议检查糖化血红蛋白，可并发糖尿病肾病。" +示例输出1：{{"triples": [{{"head":"2型糖尿病","head_type":"Disease","relation":"has_symptom","tail":"多饮","tail_type":"Symptom","confidence":0.95}}, {{"head":"2型糖尿病","head_type":"Disease","relation":"has_symptom","tail":"多尿","tail_type":"Symptom","confidence":0.95}}, {{"head":"2型糖尿病","head_type":"Disease","relation":"recommend_drug","tail":"二甲双胍","tail_type":"Drug","confidence":0.94}}, {{"head":"2型糖尿病","head_type":"Disease","relation":"need_examination","tail":"糖化血红蛋白","tail_type":"Examination","confidence":0.9}}, {{"head":"2型糖尿病","head_type":"Disease","relation":"complication","tail":"糖尿病肾病","tail_type":"Disease","confidence":0.88}}]}} + +示例文本2："嗜铬细胞瘤多位于肾上腺髓质，CgA 常呈阳性，与 RET 基因突变相关，可表现为阵发性高血压。" +示例输出2：{{"triples": [{{"head":"嗜铬细胞瘤","head_type":"Tumor","relation":"located_in","tail":"肾上腺髓质","tail_type":"Body","confidence":0.9}}, {{"head":"嗜铬细胞瘤","head_type":"Tumor","relation":"positive_marker","tail":"CgA","tail_type":"Biomarker","confidence":0.92}}, {{"head":"嗜铬细胞瘤","head_type":"Tumor","relation":"associated_gene","tail":"RET","tail_type":"Gene","confidence":0.9}}, {{"head":"嗜铬细胞瘤","head_type":"Tumor","relation":"has_symptom","tail":"阵发性高血压","tail_type":"Symptom","confidence":0.85}}]}} +""" + +_PROMPT = """根据给定的医学本体，从文本中抽取实体之间的关系三元组。 + +{ontology} + +{fewshot} +已识别的实体（name#type）： +{entities} + +要求： +1. relation 必须是上面关系类型的英文 key（如 has_symptom/recommend_drug/positive_marker 等）。 +2. head/tail 必须使用已识别实体里**原文一致**的最小术语名；head_type/tail_type 必须符合该关系的两端类型约束。 +3. 关系方向以疾病/肿瘤为 head（如 疾病-has_symptom-症状），不要颠倒。 +4. 文本明确支持的关系尽量都抽出（提高召回），但不要臆造未提及的关系。 +5. confidence 为 0~1。 +6. 输出 JSON：{{"triples": [{{"head":"...","head_type":"...","relation":"...","tail":"...","tail_type":"...","confidence":0.0}}]}} + +文本： +\"\"\" +{text} +\"\"\" +""" + + +class MedicalREOperator(BaseOperator): + def __init__(self, llm: Any | None = None, backend: str | None = None): + self.llm = llm + self.config = get_extraction_config() + self.backend = backend or self.config.backend + self.meta = OperatorMeta( + name="medical_re", + version="2.0.0", + description=( + "联合式医疗关系抽取：auto 模式优先运行自训练 neural GPLinker，并把可安全映射的" + " CMeIE 谓词转换到临床图谱本体；环境不可用或低置信时退回词典快路/LLM。" + "输入 {text, entities?}, 输出 {triples,routing}。" + ), + input_schema={ + "type": "object", + "properties": {"text": {"type": "string"}, "entities": {"type": "array"}}, + "required": ["text"], + }, + output_schema={"type": "object", "properties": {"triples": {"type": "array"}}}, + ) + + def _ensure_llm(self): + if self.llm is None: + from medigraph.llm.client import LLMClient + self.llm = LLMClient() + return self.llm + + def run(self, inputs: dict, **kwargs) -> dict: + text = (inputs.get("text", "") or "").strip() + if not text: + return {"triples": [], "routing": {"level": "none", "reason": "empty_text"}} + entities = inputs.get("entities", []) or [] + + neural_triples: list[dict] = [] + fast_triples: list[dict] = [] + uncertainty = {"uncertain": True, "reason": "local_path_disabled", "mean_confidence": 0.0} + + if self.backend in {"auto", "neural"}: + neural = load_neural_extractor() + if neural is not None: + result = neural.extract( + text[:4000], + threshold=self.config.neural_threshold, + rel_threshold=self.config.neural_rel_threshold, + ) + neural_triples = map_cmeie_triples_to_clinical( + result.get("triples", []), + entities, + result.get("entities", []), + ) + uncertainty = self._uncertainty(neural_triples) + if self.backend == "neural" or ( + neural_triples and not uncertainty["uncertain"] + ): + return { + "triples": neural_triples, + "routing": { + "level": "L1_neural", + "llm_called": False, + "raw_cmeie_triples": len(result.get("triples", [])), + "mapped_triples": len(neural_triples), + "model_version": getattr(neural, "version", "neural_gplinker"), + **uncertainty, + }, + } + elif self.backend == "neural": + return { + "triples": [], + "routing": { + "level": "L1_neural_unavailable", + "llm_called": False, + "uncertain": True, + "reason": "neural_model_or_dependencies_unavailable", + "mean_confidence": 0.0, + }, + } + + fast = None + if self.backend != "llm": + fast = load_fast_extractor() + if fast is not None: + fast_triples = fast.extract_relations(text[:4000], entities or None) + uncertainty = fast.uncertainty(fast_triples, self.config.route_threshold) + if self.backend == "fast" or ( + not uncertainty["uncertain"] and fast_triples + ): + return { + "triples": fast_triples, + "routing": {"level": "L1_fast", "llm_called": False, **uncertainty}, + } + + if self.backend == "fast" or not self.config.llm_fallback: + return { + "triples": fast_triples, + "routing": {"level": "L1_fast", "llm_called": False, **uncertainty}, + } + + llm_triples = self._run_llm(text, entities) + triples = merge_triples(merge_triples(neural_triples, fast_triples), llm_triples) + return { + "triples": triples, + "routing": { + "level": ( + "L1_neural+L1_fast+L2_llm" if neural_triples and fast_triples + else "L1_neural+L2_llm" if neural_triples + else "L1_fast+L2_llm" if fast_triples + else "L2_llm" + ), + "llm_called": True, + "neural_predictions": len(neural_triples), + "fast_predictions": len(fast_triples), + "llm_predictions": len(llm_triples), + **uncertainty, + }, + } + + def _run_llm(self, text: str, entities: list[dict]) -> list[dict]: + ent_lines = "\n".join( + f" - {e.get('name')}#{e.get('type')}" for e in entities if isinstance(e, dict) and e.get("name") + ) or " (无，请你同时识别实体两端)" + + llm = self._ensure_llm() + prompt = _PROMPT.format(ontology=ontology_prompt_block(), fewshot=_FEWSHOT, entities=ent_lines, text=text[:4000]) + data = llm.chat_json(prompt, system=_SYSTEM, default={"triples": []}) + + raw = data.get("triples", []) if isinstance(data, dict) else [] + triples = [] + for t in raw: + if not isinstance(t, dict): + continue + head, tail = str(t.get("head", "")).strip(), str(t.get("tail", "")).strip() + rel = str(t.get("relation", "")).strip() + if not head or not tail or not is_valid_relation(rel): + continue + try: + conf = float(t.get("confidence", 0.7)) + except (TypeError, ValueError): + conf = 0.7 + triples.append( + { + "head": head, + "head_type": str(t.get("head_type", "")).strip(), + "relation": rel, + "tail": tail, + "tail_type": str(t.get("tail_type", "")).strip(), + "confidence": round(max(0.0, min(1.0, conf)), 3), + "extractor": "llm_schema", + } + ) + return triples + + def _uncertainty(self, items: list[dict]) -> dict: + if not items: + return {"uncertain": True, "reason": "no_prediction", "mean_confidence": 0.0} + mean_conf = sum(float(item.get("confidence", 0.0) or 0.0) for item in items) / len(items) + return { + "uncertain": mean_conf < self.config.route_threshold, + "reason": "below_route_threshold" if mean_conf < self.config.route_threshold else "confident", + "mean_confidence": round(mean_conf, 4), + } diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/pii_redact.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/pii_redact.py" new file mode 100644 index 0000000..6c6cfdf --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/pii_redact.py" @@ -0,0 +1,61 @@ +"""Medical-text PII redaction with deterministic audit counts.""" +from __future__ import annotations + +import re + +from medigraph.operators.base import BaseOperator, OperatorMeta + +_PATTERNS = { + "id_card": re.compile(r"(?患者编号|病历号|住院号|门诊号|patient\s*id)\s*[:：]?\s*[A-Za-z0-9-]{4,}"), +} + + +class PIIRedactOperator(BaseOperator): + def __init__(self): + self.meta = OperatorMeta( + name="pii_redact", + version="1.0.0", + description=( + "脱敏医疗文本中的手机号、身份证、邮箱、银行卡号、病历号，返回逐类计数审计。" + "输入 {text}, 输出 {text,redaction_report}。" + ), + input_schema={ + "type": "object", + "properties": {"text": {"type": "string"}}, + "required": ["text"], + }, + output_schema={ + "type": "object", + "properties": {"text": {"type": "string"}, "redaction_report": {"type": "object"}}, + "required": ["text", "redaction_report"], + }, + ) + + def run(self, inputs: dict, **kwargs) -> dict: + text = str(inputs.get("text", "") or "") + counts = {} + for category, pattern in _PATTERNS.items(): + counter = 0 + + def replacement(match: re.Match) -> str: + nonlocal counter + counter += 1 + if category == "patient_id" and match.groupdict().get("label"): + return f"{match.group('label')}:[{category.upper()}_{counter}]" + return f"[{category.upper()}_{counter}]" + + text = pattern.sub(replacement, text) + counts[category] = counter + return { + "text": text, + "redaction_report": { + "total": sum(counts.values()), + "by_type": counts, + "policy": "regex_v1", + "review_required": True, + }, + } diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/text_clean.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/text_clean.py" new file mode 100644 index 0000000..38bb52f --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/text_clean.py" @@ -0,0 +1,140 @@ +"""Rule-based medical text cleaning operator. + +Removes web noise, headers/footers, links/images, LaTeX artifacts and short +fragments while protecting markdown/Chinese structural headings. Cleaning regexes +are ported from the team's previously validated `pathology_text_clean` operator. +""" +from __future__ import annotations + +import re +from typing import Any + +from medigraph.operators.base import BaseOperator, OperatorMeta + + +class TextCleanOperator(BaseOperator): + _ZH_HEADING_RE = re.compile( + r"^(?:第[一二三四五六七八九十百千\d]+[章节篇卷]|[一二三四五六七八九十百千]+[、])" + ) + + HEADER_FOOTER_PATTERNS = [ + r"Page\s+\d+\s+of\s+\d+", + r"第\s*\d+\s*页\s*[，,/]\s*共\s*\d+\s*页", + r"©\s*\d{4}.*?(?:All rights reserved|版权所有)", + r"Downloaded from.*?(?:\n|$)", + ] + WEB_NOISE_PATTERNS = [ + r"Home\s*[>»›]\s*.*?[>»›]", + r"Click here to.*?(?:\n|$)", + r"Show Image", + r"Read more\.{0,3}", + r"Related (?:articles?|topics?|links?).*?(?:\n|$)", + r"Share (?:on|this|via).*?(?:\n|$)", + r"Advertisement", + r"cookie(?:s)?\s*(?:policy|notice)", + ] + METADATA_FOOTNOTE_PATTERNS = [ + r"^数据来源[：:].+$", + r"^参考(?:文献|书目|资料)[：:].+$", + r"^来源[：:].+$", + r"^出版社[：:].+$", + ] + + def __init__(self, min_line_length: int = 8, min_paragraph_length: int = 30): + self.min_line_length = min_line_length + self.min_paragraph_length = min_paragraph_length + self.meta = OperatorMeta( + name="text_clean", + description=( + "清洗医疗/病理原始文本：去除网页噪声、页眉页脚、Markdown 链接与图片、" + "LaTeX 公式残留和无意义短碎片，保护标题结构。输入 {text}, 输出 {text}。" + ), + input_schema={"type": "object", "properties": {"text": {"type": "string"}}, "required": ["text"]}, + output_schema={"type": "object", "properties": {"text": {"type": "string"}}}, + ) + + # ------------------------------------------------------------------ # + def run(self, inputs: dict, **kwargs) -> dict: + text = inputs.get("text", "") or "" + if not text.strip(): + return {"text": ""} + text = self._remove_line_patterns(text, self.HEADER_FOOTER_PATTERNS) + text = self._remove_line_patterns(text, self.WEB_NOISE_PATTERNS) + text = self._remove_metadata_footnotes(text) + text = self._clean_links(text) + text = self._clean_latex(text) + text = self._remove_short_fragments(text) + text = self._normalize_whitespace(text) + return {"text": text.strip()} + + # ------------------------------------------------------------------ # + def _is_zh_heading(self, line: str) -> bool: + return bool(self._ZH_HEADING_RE.match(line.strip())) + + def _remove_line_patterns(self, text: str, patterns: list[str]) -> str: + out = [] + for line in text.split("\n"): + if line.lstrip().startswith("#"): # protect markdown headings + out.append(line) + continue + for pat in patterns: + line = re.sub(pat, "", line, flags=re.IGNORECASE) + out.append(line) + return "\n".join(out) + + def _remove_metadata_footnotes(self, text: str) -> str: + out = [] + for line in text.split("\n"): + stripped = line.strip() + if any(re.match(p, stripped, flags=re.IGNORECASE) for p in self.METADATA_FOOTNOTE_PATTERNS): + continue + out.append(line) + return "\n".join(out) + + def _clean_links(self, text: str) -> str: + text = re.sub(r"!\[([^\]]*)\]\([^)]*\)", "", text) # images + text = re.sub(r"\[([^\]]+)\]\([^)]+\)", r"\1", text) # links -> label + text = re.sub(r"https?://\S+", "", text) # bare URLs + text = re.sub( + r"^(?![ \t]*#)[^\n]*\.(?:jpg|png|jpeg|gif|tif)\)?\s*$", + "", text, flags=re.MULTILINE | re.IGNORECASE, + ) + return text + + def _clean_latex(self, text: str) -> str: + def simplify(m): + inner = m.group(1).strip() + inner = re.sub(r"\\(?:mathrm|text|mathbf|textbf)\{([^}]+)\}", r"\1", inner) + inner = re.sub(r"[\^_]\{([^}]+)\}", r"\1", inner) + inner = re.sub(r"\\[a-zA-Z]+", "", inner) + return inner.strip("{}").strip() + + text = re.sub(r"\$\$[\s\S]*?\$\$", "", text) + text = re.sub(r"\$([^$\n]+)\$", simplify, text) + return text.replace("$", "") + + def _remove_short_fragments(self, text: str) -> str: + out = [] + for line in text.split("\n"): + stripped = line.strip() + if not stripped: + out.append(line) + continue + if stripped.startswith(("#", "|", "【")) or self._is_zh_heading(stripped): + out.append(line) + continue + if stripped.startswith(("-", "*", "•")) and len(stripped) > 5: + out.append(line) + continue + if re.match(r"^\d+[\.、\）\)]\s", stripped): + out.append(line) + continue + if len(stripped) < self.min_line_length and not stripped.endswith(("。", ".", "：", ":")): + continue + out.append(line) + return "\n".join(out) + + def _normalize_whitespace(self, text: str) -> str: + text = re.sub(r"[ \t]+$", "", text, flags=re.MULTILINE) + text = re.sub(r"\n{3,}", "\n\n", text) + return text.strip("\n") + "\n" diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/triple_validator.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/triple_validator.py" new file mode 100644 index 0000000..e35c139 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/operators/triple_validator.py" @@ -0,0 +1,191 @@ +"""Triple generation & validation operator. + +Validates candidate relation triples against the ontology and quality rules: + 1. Schema legality: relation's (head_type, tail_type) must match the ontology. + 2. Dedup + normalization: collapse case/whitespace duplicates. + 3. Confidence threshold filtering. + 4. Conflict detection: mutually exclusive relations on the same entity pair. +Each rejected triple carries an explicit reason (explainability / result quality). +An optional LLM adjudication path can rescue borderline-confidence triples. +""" +from __future__ import annotations + +from typing import Any + +from medigraph.operators.base import BaseOperator, OperatorMeta +from medigraph.schema.ontology import check_relation_constraint, is_valid_relation +from medigraph.schema.normalize import canonical_key, is_valid_entity_name + +# Relations that cannot both hold for the same (head, tail) pair. +_CONFLICTS = {("positive_marker", "negative_marker")} +_REVERSED_CONFLICTS = {("recommend_drug", "contraindication")} + + +class TripleValidatorOperator(BaseOperator): + def __init__(self, llm: Any | None = None, min_confidence: float = 0.5, + adjudicate_band: float = 0.2): + self.llm = llm + self.min_confidence = min_confidence + # Borderline triples in [min_conf - band, min_conf) are sent to the LLM + # for a keep/drop decision (with reason) instead of being auto-rejected. + self.adjudicate_band = adjudicate_band + self.meta = OperatorMeta( + name="triple_validator", + version="2.0.0", + description=( + "对候选三元组做校验与治理：schema 合法性、去重归一、置信度过滤、冲突检测，" + "输出通过的三元组与每条拒因。输入 {triples, min_confidence?}, 输出 {valid:[...], rejected:[...]}。" + ), + input_schema={ + "type": "object", + "properties": {"triples": {"type": "array"}, "min_confidence": {"type": "number"}}, + "required": ["triples"], + }, + output_schema={ + "type": "object", + "properties": {"valid": {"type": "array"}, "rejected": {"type": "array"}}, + }, + ) + + def run(self, inputs: dict, **kwargs) -> dict: + triples = inputs.get("triples", []) or [] + min_conf = float(inputs.get("min_confidence") or self.min_confidence) + + valid: list[dict] = [] + rejected: list[dict] = [] + seen: dict[str, dict] = {} + pair_relations: dict[tuple, set] = {} + + # Higher-confidence claims win deterministic conflict resolution. + ordered = sorted( + (item for item in triples if isinstance(item, dict)), + key=lambda item: -self._as_float(item.get("confidence", 0.0)), + ) + for t in ordered: + if not isinstance(t, dict): + continue + head = str(t.get("head", "")).strip() + tail = str(t.get("tail", "")).strip() + rel = str(t.get("relation", "")).strip() + ht = str(t.get("head_type", "")).strip() + tt = str(t.get("tail_type", "")).strip() + conf = self._as_float(t.get("confidence", 0.0)) + + if not head or not tail or not rel: + self._reject(rejected, t, "missing head/tail/relation") + continue + if not is_valid_entity_name(head) or not is_valid_entity_name(tail): + self._reject(rejected, t, "invalid or placeholder entity name") + continue + if not is_valid_relation(rel): + self._reject(rejected, t, f"unknown relation '{rel}'") + continue + if not check_relation_constraint(rel, ht, tt): + self._reject(rejected, t, f"schema violation: {ht}-{rel}->{tt}") + continue + if conf < min_conf: + # LLM adjudication for borderline triples (plan 4.4 rule 4). + if ( + self.llm is not None + and conf >= min_conf - self.adjudicate_band + and self._adjudicate(t, inputs.get("text", "")) + ): + conf = min_conf # rescued; promote to threshold + t["adjudicated"] = True + else: + self._reject(rejected, t, f"low confidence {conf:.2f} < {min_conf:.2f}") + continue + + key = f"{ht}:{canonical_key(head)}|{rel}|{tt}:{canonical_key(tail)}" + if key in seen: + # keep the higher-confidence duplicate + if conf > seen[key]["confidence"]: + seen[key]["confidence"] = round(conf, 3) + continue + + # conflict detection on the (head, tail) pair + pair = (canonical_key(head), canonical_key(tail)) + rels = pair_relations.setdefault(pair, set()) + conflict = next( + (r for r in rels if (r, rel) in _CONFLICTS or (rel, r) in _CONFLICTS), + None, + ) + if conflict: + self._reject(rejected, t, f"conflicts with existing relation '{conflict}'") + continue + reverse_rels = pair_relations.get((pair[1], pair[0]), set()) + reverse_conflict = next( + ( + other + for other in reverse_rels + if (rel, other) in _REVERSED_CONFLICTS or (other, rel) in _REVERSED_CONFLICTS + ), + None, + ) + if reverse_conflict: + self._reject(rejected, t, f"conflicts with reverse relation '{reverse_conflict}'") + continue + rels.add(rel) + + norm = { + "head": head, + "head_type": ht, + "relation": rel, + "tail": tail, + "tail_type": tt, + "confidence": round(conf, 3), + } + # Retain extraction evidence and routing provenance instead of + # discarding it at the validation boundary. + for field in ( + "extractor", + "model_version", + "evidence_method", + "evidence", + "cascade_sources", + "cmeie_relation", + "cmeie_predicate", + "adjudicated", + "head_canonical_id", + "tail_canonical_id", + ): + if field in t: + norm[field] = t[field] + seen[key] = norm + valid.append(norm) + + return { + "valid": valid, + "rejected": rejected, + "stats": { + "candidates": len(ordered), + "valid": len(valid), + "rejected": len(rejected), + "pass_rate": round(len(valid) / len(ordered), 4) if ordered else 0.0, + }, + } + + def _adjudicate(self, triple: dict, context: str = "") -> bool: + """Ask the LLM whether a borderline triple should be kept. Returns bool.""" + ctx = f"\n参考文本片段：\n{context[:800]}\n" if context else "" + prompt = ( + "判断下面这条医学知识三元组是否成立、是否应保留进知识图谱。" + f"{ctx}\n三元组：{triple.get('head')} -[{triple.get('relation')}]-> {triple.get('tail')}\n" + '只输出 JSON：{"keep": true/false, "reason": "简要理由"}' + ) + try: + res = self.llm.chat_json(prompt, default={"keep": False}) + return bool(isinstance(res, dict) and res.get("keep")) + except Exception: # noqa: BLE001 - adjudication is best-effort + return False + + @staticmethod + def _as_float(v: Any) -> float: + try: + return float(v) + except (TypeError, ValueError): + return 0.0 + + @staticmethod + def _reject(bucket: list, triple: dict, reason: str) -> None: + bucket.append({"triple": triple, "reason": reason}) diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/schema/__init__.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/schema/__init__.py" new file mode 100644 index 0000000..e69de29 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/schema/cmeie_schema.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/schema/cmeie_schema.py" new file mode 100644 index 0000000..6a21b23 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/schema/cmeie_schema.py" @@ -0,0 +1,121 @@ +"""Complete CMeIE-V2 schema adapter. + +The project graph keeps a compact clinical ontology for user-facing QA. This +adapter preserves all 53 official schema rows (44 predicate labels) for strict +benchmark evaluation, avoiding the misleading practice of scoring only an easy +relation subset while calling it "full CMeIE". +""" +from __future__ import annotations + +import json +from pathlib import Path + +CMEIE_ENTITY_TYPES: dict[str, str] = { + "疾病": "Disease", + "症状": "Symptom", + "检查": "Examination", + "药物": "Drug", + "部位": "Body", + "手术治疗": "Procedure", + "其他治疗": "Procedure", + "流行病学": "Epidemiology", + "社会学": "SocialFactor", + "预后": "Prognosis", + "其他": "Other", +} + +CMEIE_PREDICATE_KEYS: dict[str, str] = { + "预防": "prevention", + "阶段": "stage", + "就诊科室": "department", + "同义词": "synonym", + "辅助治疗": "adjuvant_therapy", + "化疗": "chemotherapy", + "放射治疗": "radiotherapy", + "手术治疗": "surgical_treatment", + "实验室检查": "laboratory_examination", + "影像学检查": "imaging_examination", + "辅助检查": "auxiliary_examination", + "组织学检查": "histological_examination", + "内窥镜检查": "endoscopic_examination", + "筛查": "screening", + "多发群体": "susceptible_population", + "发病率": "incidence", + "发病年龄": "onset_age", + "多发地区": "high_incidence_area", + "发病性别倾向": "sex_tendency", + "死亡率": "mortality", + "多发季节": "seasonality", + "传播途径": "transmission_route", + "并发症": "complication", + "病理分型": "pathological_classification", + "相关（导致）": "related_cause", + "鉴别诊断": "differential_diagnosis", + "相关（转化）": "related_transformation", + "相关（症状）": "related_symptom", + "临床表现": "clinical_manifestation", + "治疗后症状": "post_treatment_symptom", + "侵及周围组织转移的症状": "invasion_symptom", + "病因": "etiology", + "高危因素": "high_risk_factor", + "风险评估因素": "risk_assessment_factor", + "病史": "medical_history", + "遗传因素": "genetic_factor", + "发病机制": "pathogenesis", + "病理生理": "pathophysiology", + "药物治疗": "drug_treatment", + "发病部位": "onset_site", + "转移部位": "metastatic_site", + "外侵部位": "invasion_site", + "预后状况": "prognosis_status", + "预后生存率": "prognosis_survival_rate", +} + + +def predicate_key(predicate: str) -> str: + key = CMEIE_PREDICATE_KEYS.get(predicate) + return f"cmeie:{key}" if key else "" + + +#: cmeie: -> Chinese predicate, for displaying edges that only carry the raw +#: schema key (as graph_scaled.json's does -- it stores the full 53-row CMeIE +#: predicate space, not the compact CM3KG-style relation set that ships a +#: `relation_zh` on each edge). Built once at import time from the same table +#: `predicate_key()` uses, so the two directions can never drift apart. +CMEIE_KEY_TO_PREDICATE: dict[str, str] = { + f"cmeie:{key}": predicate for predicate, key in CMEIE_PREDICATE_KEYS.items() +} + + +def predicate_zh(relation: str) -> str: + """Best-effort Chinese label for a relation key. + + Handles both relation vocabularies used across the two graph artefacts: + CM3KG-style bare keys (resolved via `medigraph.schema.ontology.RELATION_TYPES` + by the caller) and CMeIE-style `cmeie:xxx` keys (resolved here). Falls back to + the raw key so a caller can always safely display *something*. + """ + return CMEIE_KEY_TO_PREDICATE.get(relation, relation) + + +def load_schema(path: str | Path) -> list[dict]: + """Load the official schema file, tolerating its leading comment line.""" + text = Path(path).read_text(encoding="utf-8") + if text.lstrip().startswith("#"): + text = "\n".join(text.splitlines()[1:]) + rows = json.loads(text) + result = [] + for row in rows: + object_type = row.get("object_type", "") + if isinstance(object_type, dict): + object_type = object_type.get("@value", "") + result.append( + { + "subject_type": str(row.get("subject_type", "")), + "predicate": str(row.get("predicate", "")), + "predicate_key": predicate_key(str(row.get("predicate", ""))), + "object_type": str(object_type), + "direction": int(row.get("direction", 1)), + } + ) + return result diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/schema/normalize.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/schema/normalize.py" new file mode 100644 index 0000000..9f24b3c --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/schema/normalize.py" @@ -0,0 +1,110 @@ +"""Entity normalization & alignment helpers. + +Improves graph quality by: + 1. canonical_key(): a case/space/punct-insensitive key so "Pheochromocytoma", + "pheochromocytoma" and "Pheochromocytoma " collapse to one node. + 2. ALIASES: a small medical synonym map for cross-surface alignment + (e.g. 阿斯匹林/阿司匹林 -> 阿司匹林; CgA -> chromogranin). + 3. is_structural_noise(): rejects document-structure phrases that pathology web + pages leak (section titles like "Radiology images", "Gross description"). + 4. is_valid_entity_name(): rejects placeholders / table markers such as "|" + or a standalone Roman numeral "Ⅰ" before they enter demos. + +This is intentionally lightweight (no external KB); it removes the bulk of the +observed noise. Full ontology linking (e.g. CMeKG) is a documented next step. +""" +from __future__ import annotations + +import re + +# Known surface-form aliases -> canonical display name (extend as needed). +ALIASES: dict[str, str] = { + "阿斯匹林": "阿司匹林", + "乙酰水杨酸": "阿司匹林", + "cga": "chromogranin", + "chromogranin a": "chromogranin", + "syn": "synaptophysin", + "二甲双胍片": "二甲双胍", +} + +# Document-structure / navigation phrases that are not medical entities. These are +# section headings common in pathologyoutlines-style pages. Matching is on the +# canonical (lowercased) form. +_NOISE_PHRASES = { + "definition", "general", "essential features", "terminology", "icd coding", + "epidemiology", "sites", "pathophysiology", "etiology", "clinical features", + "diagnosis", "laboratory", "radiology", "radiology description", + "radiology images", "prognostic factors", "case reports", "treatment", + "clinical images", "gross description", "gross images", + "frozen section description", "frozen section images", + "microscopic histologic description", "microscopic histologic images", + "virtual slides", "cytology images", "cytology", "positive stains", + "negative stains", "electron microscopy", "electron microscopy description", + "electron microscopy images", "molecular cytogenetics", + "molecular cytogenetics description", "sample pathology report", + "differential diagnosis", "additional references", "board review", + "images hosted on other servers", "contributed by", "table", +} + + +def _strip_punct(text: str) -> str: + return re.sub(r"[^\w一-鿿]+", " ", text).strip() + + +def canonical_key(name: str) -> str: + """Identity key for dedup: lowercase, punctuation->space, spaces removed.""" + base = _strip_punct(name).lower() + return base.replace(" ", "") + + +def canonical_name(name: str) -> str: + """Normalized display name: trim, collapse spaces, apply alias map.""" + cleaned = re.sub(r"\s+", " ", name).strip() + alias = ALIASES.get(cleaned.lower()) + return alias if alias else cleaned + + +def is_structural_noise(name: str) -> bool: + """True if `name` looks like a section heading / navigation, not an entity.""" + canon = _strip_punct(name).lower() + if not canon: + return True + if canon in _NOISE_PHRASES: + return True + # very short all-caps section-ish tokens or pure numbers + if canon.isdigit(): + return True + return False + + +_STANDALONE_ROMAN = { + "Ⅰ", "Ⅱ", "Ⅲ", "Ⅳ", "Ⅴ", "Ⅵ", "Ⅶ", "Ⅷ", "Ⅸ", "Ⅹ", "Ⅺ", "Ⅻ", + "I", "II", "III", "IV", "V", "VI", "VII", "VIII", "IX", "X", +} +_PLACEHOLDER_TOKENS = { + "|", "/", "\\", "-", "—", "–", "_", "+", "*", "?", "？", ".", "。", + "无", "未知", "其他", "其它", "NA", "N/A", "null", "None", +} + + +def is_valid_entity_name(name: str) -> bool: + """False for tokens that should never be treated as medical entities. + + CM3KG occasionally contains table markers such as a standalone Roman numeral + "Ⅰ". Real concepts like "硝苯地平缓释片Ⅰ" or "ApoA-Ⅰ" are kept because the + marker is part of a longer medical term. + """ + cleaned = canonical_name(str(name or "")) + if not cleaned: + return False + if is_structural_noise(cleaned): + return False + if cleaned in _PLACEHOLDER_TOKENS or cleaned.upper() in _PLACEHOLDER_TOKENS: + return False + if cleaned in _STANDALONE_ROMAN or cleaned.upper() in _STANDALONE_ROMAN: + return False + if re.fullmatch(r"[\W_]+", cleaned, flags=re.UNICODE): + return False + if len(cleaned) == 1 and not re.search(r"[\u4e00-\u9fffA-Za-z0-9]", cleaned): + return False + return True diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/schema/ontology.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/schema/ontology.py" new file mode 100644 index 0000000..9f4a50d --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/schema/ontology.py" @@ -0,0 +1,132 @@ +"""Medical knowledge-graph ontology (entity types, relation types, constraints). + +Designed for general clinical text and extended with pathology-specific types so +it works on both the Chinese pathology textbooks and the English +pathologyoutlines-style data in this repo. Extraction is LLM-driven, so the +schema is bilingual-friendly: type names are Chinese (display) with English keys. +""" +from __future__ import annotations + +from dataclasses import dataclass + +# Entity types: key -> Chinese display name. +ENTITY_TYPES: dict[str, str] = { + "Disease": "疾病", + "Symptom": "症状", + "Drug": "药物", + "Examination": "检查", + "Procedure": "手术", + "Body": "身体部位", + "Department": "科室", + # Pathology-specific extensions + "Tumor": "肿瘤", + "Biomarker": "标志物", + "Gene": "基因", + "Morphology": "形态学特征", + # Public benchmark / open-schema extensions + "Epidemiology": "流行病学", + "SocialFactor": "社会因素", + "Prognosis": "预后", + "Other": "其他医学概念", + "Class": "类别", + "TestValue": "检查值", + "Frequency": "频率", + "Level": "程度", + "Reason": "原因", + "Duration": "持续时间", + "Amount": "用量", + "Method": "用药方法", + "Pathogenesis": "发病机制", +} + +# Relation types: key -> Chinese display name. +RELATION_TYPES: dict[str, str] = { + "has_symptom": "有症状", + "recommend_drug": "推荐药物", + "need_examination": "需做检查", + "complication": "并发", + "contraindication": "禁忌", + "treated_in_department": "就诊于", + "positive_marker": "阳性标志物", + "negative_marker": "阴性标志物", + "associated_gene": "关联基因", + "has_morphology": "形态学表现", + "located_in": "位于", + "subtype_of": "亚型", + "treated_by_procedure": "手术/操作治疗", + "adverse_reaction": "药物不良反应", +} + +# Allowed (head_type, tail_type) pairs per relation. Used by triple_validator to +# reject schema-illegal triples (e.g. a "recommend_drug" whose tail is not a Drug). +# Disease and Tumor are treated as interchangeable "lesion" heads for convenience. +_LESION = {"Disease", "Tumor"} +RELATION_CONSTRAINTS: dict[str, tuple[set[str], set[str]]] = { + "has_symptom": (_LESION, {"Symptom"}), + "recommend_drug": (_LESION, {"Drug"}), + "need_examination": (_LESION, {"Examination"}), + "complication": (_LESION, _LESION), + "contraindication": ({"Drug"}, _LESION | {"Symptom"}), + "treated_in_department": (_LESION, {"Department"}), + "positive_marker": (_LESION, {"Biomarker"}), + "negative_marker": (_LESION, {"Biomarker"}), + "associated_gene": (_LESION, {"Gene"}), + "has_morphology": (_LESION, {"Morphology"}), + "located_in": (_LESION | {"Symptom"}, {"Body"}), + "subtype_of": (_LESION, _LESION), + "treated_by_procedure": (_LESION, {"Procedure"}), + "adverse_reaction": ({"Drug"}, {"Symptom", "Disease"}), +} + + +@dataclass(frozen=True) +class Entity: + name: str + type: str + + def key(self) -> str: + """Normalized identity key for dedup (case/space-insensitive).""" + return f"{self.type}::{self.name.strip().lower()}" + + +@dataclass(frozen=True) +class Triple: + head: str + head_type: str + relation: str + tail: str + tail_type: str + confidence: float = 1.0 + source: str = "" + + def key(self) -> str: + return f"{self.head_type}:{self.head.lower()}|{self.relation}|{self.tail_type}:{self.tail.lower()}" + + +def is_valid_entity_type(t: str) -> bool: + return t in ENTITY_TYPES + + +def is_valid_relation(r: str) -> bool: + return r in RELATION_TYPES + + +def check_relation_constraint(relation: str, head_type: str, tail_type: str) -> bool: + """Return True if (head_type, tail_type) is allowed for `relation`.""" + if relation not in RELATION_CONSTRAINTS: + return False + head_ok, tail_ok = RELATION_CONSTRAINTS[relation] + return head_type in head_ok and tail_type in tail_ok + + +def ontology_prompt_block() -> str: + """Human/LLM-readable ontology description injected into extraction prompts.""" + ents = "\n".join(f" - {k} ({v})" for k, v in ENTITY_TYPES.items()) + rels_lines = [] + for k, v in RELATION_TYPES.items(): + head_ok, tail_ok = RELATION_CONSTRAINTS[k] + rels_lines.append( + f" - {k} ({v}): {'/'.join(sorted(head_ok))} -> {'/'.join(sorted(tail_ok))}" + ) + rels = "\n".join(rels_lines) + return f"实体类型 (entity types):\n{ents}\n\n关系类型 (relation types, 含两端类型约束):\n{rels}" diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/schema/relation_mapping.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/schema/relation_mapping.py" new file mode 100644 index 0000000..8e4ca42 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/schema/relation_mapping.py" @@ -0,0 +1,100 @@ +"""Relation mapping between the full CMeIE schema and the demo clinical ontology. + +The trained neural GPLinker is evaluated on the complete CMeIE predicate space +(``cmeie:*``). The user-facing graph/QA/BI layer intentionally keeps a smaller +clinical ontology such as ``has_symptom`` and ``recommend_drug`` so prompts, +GraphRAG intents and dashboards stay readable. This module bridges the two +without hiding provenance: mapped triples keep their original CMeIE predicate. +""" +from __future__ import annotations + +from medigraph.schema.ontology import check_relation_constraint +from medigraph.schema.normalize import canonical_key + + +CMEIE_TO_CLINICAL_RELATION: dict[str, str] = { + "cmeie:clinical_manifestation": "has_symptom", + "cmeie:related_symptom": "has_symptom", + "cmeie:post_treatment_symptom": "has_symptom", + "cmeie:invasion_symptom": "has_symptom", + "cmeie:drug_treatment": "recommend_drug", + "cmeie:laboratory_examination": "need_examination", + "cmeie:imaging_examination": "need_examination", + "cmeie:auxiliary_examination": "need_examination", + "cmeie:histological_examination": "need_examination", + "cmeie:endoscopic_examination": "need_examination", + "cmeie:screening": "need_examination", + "cmeie:complication": "complication", + "cmeie:department": "treated_in_department", + "cmeie:onset_site": "located_in", + "cmeie:metastatic_site": "located_in", + "cmeie:invasion_site": "located_in", + "cmeie:surgical_treatment": "treated_by_procedure", +} + + +def entity_type_lookup(*entity_lists: list[dict]) -> dict[str, str]: + """Build a canonical surface -> type lookup from one or more entity lists.""" + lookup: dict[str, str] = {} + for entities in entity_lists: + for item in entities or []: + if not isinstance(item, dict): + continue + name = str(item.get("name", "")).strip() + etype = str(item.get("type", "")).strip() + if name and etype: + lookup.setdefault(canonical_key(name), etype) + return lookup + + +def map_cmeie_triple_to_clinical(triple: dict, type_lookup: dict[str, str] | None = None) -> dict | None: + """Return a clinical-ontology triple, or ``None`` when no safe mapping exists.""" + relation = str(triple.get("relation", "")).strip() + mapped = CMEIE_TO_CLINICAL_RELATION.get(relation) + if not mapped: + return None + + head = str(triple.get("head", "")).strip() + tail = str(triple.get("tail", "")).strip() + if not head or not tail: + return None + type_lookup = type_lookup or {} + head_type = str(triple.get("head_type", "")).strip() or type_lookup.get(canonical_key(head), "") + tail_type = str(triple.get("tail_type", "")).strip() or type_lookup.get(canonical_key(tail), "") + if not check_relation_constraint(mapped, head_type, tail_type): + return None + + out = dict(triple) + out["relation"] = mapped + out["head_type"] = head_type + out["tail_type"] = tail_type + out["cmeie_relation"] = relation + if triple.get("predicate"): + out["cmeie_predicate"] = triple.get("predicate") + out["evidence_method"] = out.get("evidence_method", "neural_cmeie_mapped") + return out + + +def map_cmeie_triples_to_clinical( + triples: list[dict], + *entity_lists: list[dict], +) -> list[dict]: + """Map a list of CMeIE triples and deduplicate by clinical triple key.""" + lookup = entity_type_lookup(*entity_lists) + merged: dict[tuple[str, str, str], dict] = {} + for triple in triples or []: + mapped = map_cmeie_triple_to_clinical(triple, lookup) + if mapped is None: + continue + key = ( + canonical_key(str(mapped.get("head", ""))), + str(mapped.get("relation", "")), + canonical_key(str(mapped.get("tail", ""))), + ) + old = merged.get(key) + if old is None or float(mapped.get("confidence", 0.0)) > float(old.get("confidence", 0.0)): + merged[key] = mapped + return sorted( + merged.values(), + key=lambda item: (-float(item.get("confidence", 0.0)), item.get("head", ""), item.get("relation", "")), + ) diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/utils/__init__.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/utils/__init__.py" new file mode 100644 index 0000000..e69de29 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/utils/console.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/utils/console.py" new file mode 100644 index 0000000..b8550e3 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/utils/console.py" @@ -0,0 +1,15 @@ +"""Console helpers. Force UTF-8 stdout/stderr so Chinese output does not crash on +the default Windows GBK code page.""" +from __future__ import annotations + +import sys + + +def enable_utf8() -> None: + for stream in (sys.stdout, sys.stderr): + reconfigure = getattr(stream, "reconfigure", None) + if callable(reconfigure): + try: + reconfigure(encoding="utf-8") + except Exception: # noqa: BLE001 + pass diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/utils/io.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/utils/io.py" new file mode 100644 index 0000000..f6d4cec --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/medigraph/utils/io.py" @@ -0,0 +1,42 @@ +"""Small IO helpers: read markdown/txt documents, write jsonl.""" +from __future__ import annotations + +import json +from pathlib import Path +from typing import Iterable + + +def read_text(path: str | Path) -> str: + p = Path(path) + return p.read_text(encoding="utf-8-sig").replace("\r\n", "\n") + + +def iter_documents(input_dir: str | Path, exts: tuple[str, ...] = (".md", ".txt", ".markdown")) -> list[dict]: + """Return [{fileName, filePath, text}] for every document under input_dir.""" + root = Path(input_dir) + docs: list[dict] = [] + if not root.exists(): + return docs + for p in sorted(root.rglob("*")): + if p.is_file() and p.suffix.lower() in exts: + try: + docs.append({"fileName": p.name, "filePath": str(p), "text": read_text(p)}) + except Exception as exc: # noqa: BLE001 + print(f"[io] skip {p}: {exc}") + return docs + + +def write_jsonl(records: Iterable[dict], path: str | Path) -> str: + p = Path(path) + p.parent.mkdir(parents=True, exist_ok=True) + with p.open("w", encoding="utf-8") as f: + for r in records: + f.write(json.dumps(r, ensure_ascii=False) + "\n") + return str(p) + + +def write_json(obj, path: str | Path) -> str: + p = Path(path) + p.parent.mkdir(parents=True, exist_ok=True) + p.write_text(json.dumps(obj, ensure_ascii=False, indent=2), encoding="utf-8") + return str(p) diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/outputs/analytics.db" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/outputs/analytics.db" new file mode 100644 index 0000000000000000000000000000000000000000..de44108c6420a73e62a67d84c3c1efc8979b8b70 GIT binary patch literal 2514944 zcmeFad3+RA+BV$PNvE@RgT%zdkc3S@NJuB0G--$wL_m~H77s}i#nV!!&s+G&l*Or8hIR%?GRUc^27@8YU@%U{|JVPS@Q={? 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"a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/requirements.txt" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/requirements.txt" new file mode 100644 index 0000000..163892b --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/requirements.txt" @@ -0,0 +1,53 @@ +# MediGraph-Agent core dependencies (local-first, API-driven) +openai>=1.30.0 # OpenAI-compatible client for SiliconFlow / DashScope +python-dotenv>=1.0.0 # load .env config +pydantic>=2.5.0 # operator metadata / schema models +networkx>=3.0 # default local knowledge-graph backend +numpy>=1.26 # cosine search for the local vector store (hybrid GraphRAG) +pyvis>=0.3.2 # interactive HTML graph visualization +tqdm>=4.66.0 # progress bars +tenacity>=8.2.0 # retry for LLM calls +pypdf>=4.0.0 # PDF ingestion in document_loader (DOCX uses stdlib ZIP/XML) +sqlglot>=25.0.0 # SQL AST read-only guard + SQLite/PostgreSQL transpile + +# Nexent integration (MCP tools) -- needed only to run mcp_server/server.py +fastmcp>=0.2.0 + +# Platform integration (DataMate REST client, A2A server) -- integration/ +requests>=2.31.0 # DataMate REST client +fastapi>=0.110.0 # A2A server + HTTP service layer +uvicorn>=0.27.0 # A2A server + HTTP service layer + +# HTTP service layer (service/) -- observability and SSE streaming +prometheus-client>=0.20.0 # /metrics exposition +python-json-logger>=3.0.0 # structured JSON logs +sse-starlette>=2.0.0 # SSE response helpers + +# Optional storage backends (ANALYTICS_BACKEND=postgres / CACHE_ENABLED=true). +# The offline SQLite path never needs these; tests skip when the servers are absent. +psycopg[binary,pool]>=3.1.0 # PostgreSQL driver + connection pool +pgvector>=0.2.0 # vector type adapter for the HNSW ANN store +redis>=5.0.0 # result cache client + +# Optional-but-shipped neural GPLinker L1. If absent, auto mode falls back to +# the deterministic lexicon path and/or LLM. +torch>=2.2.0 +transformers>=4.40.0 + +# Optional Neo4j backend -- needed only when GRAPH_BACKEND=neo4j +neo4j>=5.14.0 + +# Optional: Ragas evaluation of GraphRAG answer quality +# (benchmarks/eval_ragas_kg_qa.py). Not needed for any offline/CI path. +# Ragas 0.4.x's llms/base.py unconditionally imports +# langchain_community.chat_models.vertexai, which recent langchain-community +# releases no longer ship (split into langchain-google-vertexai); the eval +# script stubs that one module before importing ragas so the rest of the +# (used) API works. If a future ragas release fixes this, the stub in +# eval_ragas_kg_qa.py can be deleted -- it is a no-op once the import succeeds +# on its own. +ragas>=0.4.0 +langchain-openai>=1.0.0 + +# Testing +pytest>=7.4.0 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/check_demo_services.ps1" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/check_demo_services.ps1" new file mode 100644 index 0000000..0db79e9 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/check_demo_services.ps1" @@ -0,0 +1,31 @@ +$ports = 8011, 18088, 8100 + +Write-Host "Listening ports:" +$listeners = Get-NetTCPConnection -State Listen -ErrorAction SilentlyContinue | + Where-Object { $ports -contains $_.LocalPort } | + Select-Object LocalAddress, LocalPort, OwningProcess +if ($listeners) { + $listeners | Format-Table -AutoSize +} else { + Write-Host " none (demo services are stopped)" +} + +Write-Host "Fine-tuned model API:" +try { + $models = Invoke-RestMethod -Uri "http://localhost:18088/v1/models" -TimeoutSec 3 + Write-Host " healthy - model:" $models.data[0].id +} catch { + Write-Host " stopped/unreachable" +} + +Write-Host "A2A collaborator:" +try { + $card = Invoke-RestMethod -Uri "http://localhost:8100/.well-known/agent.json" -TimeoutSec 3 + Write-Host " healthy - agent:" $card.name +} catch { + Write-Host " stopped/unreachable" +} + +Write-Host "Nexent MCP URL (from Docker): http://host.docker.internal:8011/sse" +Write-Host "Fine-tuned model URL (from Docker): http://host.docker.internal:18088/v1/" +Write-Host "A2A Agent Card URL (from Docker): http://host.docker.internal:8100/.well-known/agent.json" diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/docker_down.ps1" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/docker_down.ps1" new file mode 100644 index 0000000..b95b935 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/docker_down.ps1" @@ -0,0 +1,14 @@ +$ErrorActionPreference = "Stop" +$projectRoot = Split-Path -Parent $PSScriptRoot +Set-Location -LiteralPath $projectRoot + +if (-not (Get-Command docker -ErrorAction SilentlyContinue)) { + throw "Docker CLI was not found." +} + +& docker compose down +if ($LASTEXITCODE -ne 0) { + throw "docker compose down failed." +} + +Write-Host "MediGraph MCP and A2A containers stopped." diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/docker_up.ps1" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/docker_up.ps1" new file mode 100644 index 0000000..32347bb --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/docker_up.ps1" @@ -0,0 +1,95 @@ +param( + [switch]$Neural, + [switch]$NoBuild +) + +$ErrorActionPreference = "Stop" +$projectRoot = Split-Path -Parent $PSScriptRoot +Set-Location -LiteralPath $projectRoot + +if (-not (Get-Command docker -ErrorAction SilentlyContinue)) { + throw "Docker CLI was not found. Install and start Docker Desktop first." +} + +docker info *> $null +if ($LASTEXITCODE -ne 0) { + throw "Docker daemon is unavailable. Start Docker Desktop and retry." +} + +if ($Neural) { + $env:MEDIGRAPH_INSTALL_NEURAL = "true" + Write-Host "Neural image requested: torch/transformers will be installed." + Write-Host "The first build is large; model files remain bind-mounted from data/." +} + +$arguments = @("compose", "up", "-d") +if (-not $NoBuild) { + $arguments += "--build" +} + +Write-Host "Starting MediGraph MCP and A2A..." +& docker @arguments +if ($LASTEXITCODE -ne 0) { + throw "docker compose up failed. Check whether ports 8011 or 8100 are occupied." +} + +function Get-PublishedPort([string]$Service, [int]$ContainerPort) { + $mapping = [string](& docker compose port $Service $ContainerPort | + Select-Object -First 1) + $match = [regex]::Match($mapping.Trim(), ":(\d+)$") + if (-not $match.Success) { + throw "Cannot resolve the published port for $Service/$ContainerPort." + } + return [int]$match.Groups[1].Value +} + +$mcpPort = Get-PublishedPort "mcp" 8011 +$a2aPort = Get-PublishedPort "a2a" 8100 + +function Test-TcpPort([int]$Port) { + $client = [System.Net.Sockets.TcpClient]::new() + try { + $task = $client.ConnectAsync("127.0.0.1", $Port) + if (-not $task.Wait(1000)) { + return $false + } + return $client.Connected + } catch { + return $false + } finally { + $client.Dispose() + } +} + +$deadline = (Get-Date).AddMinutes(2) +$mcpReady = $false +$a2aReady = $false +while ((Get-Date) -lt $deadline) { + $mcpReady = Test-TcpPort $mcpPort + try { + $card = Invoke-RestMethod ` + -Uri "http://127.0.0.1:$a2aPort/.well-known/agent.json" ` + -TimeoutSec 2 + $a2aReady = [bool]$card.name + } catch { + $a2aReady = $false + } + if ($mcpReady -and $a2aReady) { + break + } + Start-Sleep -Seconds 2 +} + +& docker compose ps + +if (-not ($mcpReady -and $a2aReady)) { + & docker compose logs --tail 80 + throw "Services did not become ready within 2 minutes." +} + +Write-Host "" +Write-Host "MediGraph Docker services are ready." +Write-Host "MCP (host): http://127.0.0.1:$mcpPort/sse" +Write-Host "MCP (Nexent): http://host.docker.internal:$mcpPort/sse" +Write-Host "A2A card: http://127.0.0.1:$a2aPort/.well-known/agent.json" +Write-Host "Stop: powershell -ExecutionPolicy Bypass -File scripts/docker_down.ps1" diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/download_encoder.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/download_encoder.py" new file mode 100644 index 0000000..0e4fd2a --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/download_encoder.py" @@ -0,0 +1,64 @@ +"""Fetch a HuggingFace encoder to a local dir via hf-mirror (robust to SSL +interception in restricted networks). Used to obtain the Chinese encoder for +the neural extractor without relying on the hub client. + + python scripts/download_encoder.py --repo hfl/chinese-roberta-wwm-ext +""" +from __future__ import annotations + +import argparse +import ssl +import sys +import urllib.request +from pathlib import Path + +FILES = [ + "config.json", "vocab.txt", "tokenizer_config.json", + "special_tokens_map.json", "tokenizer.json", "added_tokens.json", + "pytorch_model.bin", +] +REQUIRED = {"config.json", "vocab.txt", "pytorch_model.bin"} + + +def fetch(url: str, dest: Path) -> bool: + ctx = ssl.create_default_context() + ctx.check_hostname = False + ctx.verify_mode = ssl.CERT_NONE + req = urllib.request.Request(url, headers={"User-Agent": "curl/8"}) + try: + with urllib.request.urlopen(req, context=ctx, timeout=120) as resp: + data = resp.read() + dest.write_bytes(data) + print(f" OK {dest.name} ({len(data)/1e6:.1f} MB)", flush=True) + return True + except Exception as exc: # noqa: BLE001 + print(f" skip {dest.name}: {type(exc).__name__} {str(exc)[:80]}", flush=True) + return False + + +def main(): + ap = argparse.ArgumentParser() + ap.add_argument("--repo", default="hfl/chinese-roberta-wwm-ext") + ap.add_argument("--endpoint", default="https://hf-mirror.com") + ap.add_argument("--out", default="") + args = ap.parse_args() + out = Path(args.out) if args.out else ( + Path(__file__).resolve().parent.parent / "data" / "models" / "encoder" + / args.repo.split("/")[-1]) + out.mkdir(parents=True, exist_ok=True) + got = set() + for name in FILES: + url = f"{args.endpoint}/{args.repo}/resolve/main/{name}" + if fetch(url, out / name): + got.add(name) + elif (out / name).exists() and (out / name).stat().st_size == 0: + (out / name).unlink() + missing = REQUIRED - got + if missing: + print(f"FAILED: missing required files {missing}") + sys.exit(1) + print(f"encoder ready at {out}") + + +if __name__ == "__main__": + main() diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/start_a2a.ps1" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/start_a2a.ps1" new file mode 100644 index 0000000..eb5c5fd --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/start_a2a.ps1" @@ -0,0 +1,32 @@ +$ErrorActionPreference = "Stop" + +$projectRoot = Split-Path -Parent $PSScriptRoot +$venvPython = Join-Path $projectRoot ".venv-neural\Scripts\python.exe" +$python = if ($env:MEDIGRAPH_PYTHON) { + $env:MEDIGRAPH_PYTHON +} elseif (Test-Path -LiteralPath $venvPython) { + $venvPython +} else { + "C:\Python314\python.exe" +} +$port = 8100 + +if (-not (Test-Path -LiteralPath $python)) { + throw "Python not found: $python" +} +$listener = Get-NetTCPConnection -State Listen -LocalPort $port -ErrorAction SilentlyContinue +if ($listener) { + $process = Get-CimInstance Win32_Process -Filter "ProcessId=$($listener.OwningProcess)" -ErrorAction SilentlyContinue + if ($process -and $process.CommandLine -like "*integration\a2a\a2a_server.py*") { + Write-Host "MediGraph A2A agent is already running at http://localhost:$port/.well-known/agent.json (PID $($process.ProcessId))." + Write-Host "Nothing else needs to be started." + exit 0 + } + throw "Port $port is occupied by another process (PID $($listener.OwningProcess))." +} + +Set-Location -LiteralPath $projectRoot +Write-Host "MediGraph A2A agent starting at http://localhost:$port/.well-known/agent.json" +Write-Host "Python: $python" +Write-Host "Keep this terminal open. Press Ctrl+C to stop." +& $python -X utf8 integration\a2a\a2a_server.py diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/start_finetuned_model.ps1" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/start_finetuned_model.ps1" new file mode 100644 index 0000000..e8f54e1 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/start_finetuned_model.ps1" @@ -0,0 +1,46 @@ +$ErrorActionPreference = "Stop" + +$projectRoot = Split-Path -Parent $PSScriptRoot + +# Python with torch/transformers/peft. Override via MEDIGRAPH_TUNE_PYTHON. +$python = $env:MEDIGRAPH_TUNE_PYTHON +if (-not $python) { + $condaPython = Join-Path $env:USERPROFILE ".conda\envs\meditune\python.exe" + if (Test-Path -LiteralPath $condaPython) { $python = $condaPython } else { $python = "python" } +} + +# Local Qwen3.5-0.8B base weights (e.g. modelscope cache). Override via ORCHESTRATOR_BASE_MODEL. +$baseModel = $env:ORCHESTRATOR_BASE_MODEL +if (-not $baseModel) { + $baseModel = Join-Path $env:USERPROFILE ".cache\modelscope\hub\models\Qwen\Qwen3___5-0___8B" +} +$adapter = Join-Path $projectRoot "finetune\outputs\qwen3p5-0p8b-orchestrator" +$port = 18088 + +if (-not (Get-Command $python -ErrorAction SilentlyContinue)) { + throw "Python interpreter not found: $python (set MEDIGRAPH_TUNE_PYTHON)" +} +foreach ($path in @($baseModel, $adapter)) { + if (-not (Test-Path -LiteralPath $path)) { + throw "Required path not found: $path" + } +} +$listener = Get-NetTCPConnection -State Listen -LocalPort $port -ErrorAction SilentlyContinue +if ($listener) { + $process = Get-CimInstance Win32_Process -Filter "ProcessId=$($listener.OwningProcess)" -ErrorAction SilentlyContinue + if ($process -and $process.CommandLine -like "*finetune\openai_compatible_server.py*") { + Write-Host "Fine-tuned model API is already running at http://localhost:$port/v1/ (PID $($process.ProcessId))." + Write-Host "Nothing else needs to be started." + exit 0 + } + throw "Port $port is occupied by another process (PID $($listener.OwningProcess))." +} + +Set-Location -LiteralPath $projectRoot +Write-Host "Fine-tuned Qwen3.5-0.8B API starting at http://localhost:$port/v1/" +Write-Host "First load can take about 1-2 minutes. Keep this terminal open; Ctrl+C stops it." +& $python finetune\openai_compatible_server.py ` + --host 0.0.0.0 ` + --port $port ` + --base $baseModel ` + --adapter $adapter diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/start_mcp.ps1" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/start_mcp.ps1" new file mode 100644 index 0000000..540eb85 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/start_mcp.ps1" @@ -0,0 +1,37 @@ +$ErrorActionPreference = "Stop" + +$projectRoot = Split-Path -Parent $PSScriptRoot +$venvPython = Join-Path $projectRoot ".venv-neural\Scripts\python.exe" +$python = if ($env:MEDIGRAPH_PYTHON) { + $env:MEDIGRAPH_PYTHON +} elseif (Test-Path -LiteralPath $venvPython) { + $venvPython +} else { + "C:\Python314\python.exe" +} +$port = 8011 + +if (-not (Test-Path -LiteralPath $python)) { + throw "Python not found: $python" +} +$listener = Get-NetTCPConnection -State Listen -LocalPort $port -ErrorAction SilentlyContinue +if ($listener) { + $process = Get-CimInstance Win32_Process -Filter "ProcessId=$($listener.OwningProcess)" -ErrorAction SilentlyContinue + if ($process -and $process.CommandLine -like "*mcp_server\server.py*") { + Write-Host "MediGraph MCP is already running at http://localhost:$port/sse (PID $($process.ProcessId))." + Write-Host "Nothing else needs to be started." + exit 0 + } + throw "Port $port is occupied by another process (PID $($listener.OwningProcess))." +} + +$env:MEDIGRAPH_MCP_HOST = "0.0.0.0" +$env:MEDIGRAPH_MCP_PORT = "$port" +$env:FINETUNED_ORCHESTRATOR_URL = "http://127.0.0.1:18088/v1/chat/completions" +$env:FINETUNED_ORCHESTRATOR_MODEL = "qwen3p5-0p8b-orchestrator" + +Set-Location -LiteralPath $projectRoot +Write-Host "MediGraph MCP starting at http://localhost:$port/sse" +Write-Host "Python: $python" +Write-Host "Keep this terminal open. Press Ctrl+C to stop." +& $python -X utf8 mcp_server\server.py diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/stop_demo_services.ps1" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/stop_demo_services.ps1" new file mode 100644 index 0000000..a0a377a --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/mcp\346\234\215\345\212\241/scripts/stop_demo_services.ps1" @@ -0,0 +1,18 @@ +$targets = @( + @{ Port = 8011; Pattern = "mcp_server\server.py" }, + @{ Port = 18088; Pattern = "finetune\openai_compatible_server.py" }, + @{ Port = 8100; Pattern = "integration\a2a\a2a_server.py" } +) + +foreach ($target in $targets) { + $listeners = Get-NetTCPConnection -State Listen -LocalPort $target.Port -ErrorAction SilentlyContinue + foreach ($listener in $listeners) { + $process = Get-CimInstance Win32_Process -Filter "ProcessId=$($listener.OwningProcess)" -ErrorAction SilentlyContinue + if ($process -and $process.CommandLine -like "*$($target.Pattern)*") { + Stop-Process -Id $process.ProcessId -Force + Write-Host "Stopped port $($target.Port), PID $($process.ProcessId)" + } elseif ($process) { + Write-Warning "Skipped PID $($process.ProcessId): command line did not match $($target.Pattern)" + } + } +} diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/skills/build_skill_zip.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/skills/build_skill_zip.py" new file mode 100644 index 0000000..b6a0552 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/skills/build_skill_zip.py" @@ -0,0 +1,38 @@ +"""Package the medical-kg-report skill into an uploadable zip for Nexent. + +Matches the official skill layout (files nested under the skill folder name): + medical-kg-report/SKILL.md + medical-kg-report/scripts/*.py +Output: nexent_skill/dist/medical-kg-report.zip + +Usage: + python nexent_skill/build_skill_zip.py +Then in Nexent: 构建技能 -> 上传技能文件 -> 选择该 zip。 +""" +from __future__ import annotations + +import zipfile +from pathlib import Path + +HERE = Path(__file__).resolve().parent +SKILL = "medical-kg-report" +SRC = HERE / SKILL +DIST = HERE / "dist" + + +def main() -> None: + if not SRC.exists(): + raise FileNotFoundError(SRC) + DIST.mkdir(exist_ok=True) + zip_path = DIST / f"{SKILL}.zip" + with zipfile.ZipFile(zip_path, "w", zipfile.ZIP_DEFLATED) as zf: + for f in sorted(SRC.rglob("*")): + if f.is_file() and "__pycache__" not in f.parts: + # archive name keeps the skill folder as the top-level entry + zf.write(f, arcname=str(Path(SKILL) / f.relative_to(SRC))) + print(f"packaged -> {zip_path}") + print("Upload via Nexent: 构建技能 -> 上传技能文件") + + +if __name__ == "__main__": + main() diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/skills/medical-kg-report.zip" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/skills/medical-kg-report.zip" new file mode 100644 index 0000000000000000000000000000000000000000..f2dc7ea9501a1944fc1823f9a0555316f3868dc7 GIT binary patch literal 4776 zcmb7|cQhR8x`)RwdW{;QL>)vYL=w@X8$=1Cj6Ui_2%?V?y^9h(S|+-Q8eK*RBJ2=G zH`rQ67j2yEd)B?@th@HPYu)er<6ZB!zV-b1{MP$Ibcsor0000vpp;|^S{19r<_-b? 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Outputs JSON. + +```python +result = run_skill_script( + "medical-kg-report", + "scripts/extract_triples.py", + params='--text "高血压常用药物包括硝苯地平，可并发冠心病。" --api-key "$KEY" --model "Qwen/Qwen3.5-35B-A3B"' +) +return result +``` + +## Usage rules +- For a report from an existing graph, use `render_report.py` (fast, no API). +- To turn free text into triples, use `extract_triples.py`. +- Return the raw JSON result from the script directly; do not reformat. + +## Storage +- Default output directory: `/mnt/nexent`. Override with `--output`/`--working-dir`. diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/skills/medical-kg-report\346\272\220\347\240\201/scripts/extract_triples.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/skills/medical-kg-report\346\272\220\347\240\201/scripts/extract_triples.py" new file mode 100644 index 0000000..c859200 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/skills/medical-kg-report\346\272\220\347\240\201/scripts/extract_triples.py" @@ -0,0 +1,67 @@ +#!/usr/bin/env python3 +"""Extract ontology-constrained medical relation triples from text via an +OpenAI-compatible API. Uses only `openai` (available in the Nexent runtime). +Prints the result as JSON to stdout. +""" +import argparse +import json +import os +import re + +RELATIONS = ("has_symptom", "recommend_drug", "need_examination", "complication", + "contraindication", "treated_in_department", "positive_marker", + "negative_marker", "associated_gene", "has_morphology", "located_in", "subtype_of") + +_SYSTEM = "你是严谨的医学关系抽取引擎，只输出 JSON，不要任何解释。" +_PROMPT = """从医学文本中抽取实体间关系三元组。relation 只能取：{rels}。 +输出 JSON 对象：{{"triples":[{{"head":"","head_type":"","relation":"","tail":"","tail_type":"","confidence":0.0}}]}} + +文本： +\"\"\" +{text} +\"\"\" +""" + + +def _extract_json(text: str): + if not text: + return {} + m = re.search(r"```(?:json)?\s*(.+?)```", text, flags=re.DOTALL) + if m: + text = m.group(1) + text = text.strip() + try: + return json.loads(text) + except json.JSONDecodeError: + a, b = text.find("{"), text.rfind("}") + if a != -1 and b > a: + try: + return json.loads(text[a:b + 1]) + except json.JSONDecodeError: + return {} + return {} + + +def main() -> None: + ap = argparse.ArgumentParser() + ap.add_argument("--text", required=True) + ap.add_argument("--api-key", default=os.getenv("SILICONFLOW_API_KEY", os.getenv("OPENAI_API_KEY", ""))) + ap.add_argument("--api-base", default=os.getenv("SILICONFLOW_BASE_URL", "https://api.siliconflow.cn/v1")) + ap.add_argument("--model", default=os.getenv("LLM_MODEL", "Qwen/Qwen3.5-35B-A3B")) + args = ap.parse_args() + + from openai import OpenAI + client = OpenAI(api_key=args.api_key or "EMPTY", base_url=args.api_base, timeout=120) + resp = client.chat.completions.create( + model=args.model, temperature=0.2, + messages=[{"role": "system", "content": _SYSTEM}, + {"role": "user", "content": _PROMPT.format(rels="/".join(RELATIONS), text=args.text[:4000])}], + ) + data = _extract_json(resp.choices[0].message.content or "") + triples = [t for t in (data.get("triples", []) if isinstance(data, dict) else []) + if isinstance(t, dict) and t.get("relation") in RELATIONS and t.get("head") and t.get("tail")] + print(json.dumps({"status": "success", "count": len(triples), "triples": triples}, ensure_ascii=False)) + + +if __name__ == "__main__": + main() diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/skills/medical-kg-report\346\272\220\347\240\201/scripts/render_report.py" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/skills/medical-kg-report\346\272\220\347\240\201/scripts/render_report.py" new file mode 100644 index 0000000..766a03b --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/skills/medical-kg-report\346\272\220\347\240\201/scripts/render_report.py" @@ -0,0 +1,87 @@ +#!/usr/bin/env python3 +"""Render a medical knowledge graph (graph.json) into a self-contained HTML report. + +Pure standard library (no third-party deps) so it runs inside the Nexent skill +runtime. Reads MediGraph's exported graph.json ({nodes:[{id,type}], edges:[...]}). +""" +import argparse +import html +import json +import os +from collections import Counter +from pathlib import Path + +DEFAULT_OUTPUT_DIR = "/mnt/nexent" +ENTITY_ZH = { + "Disease": "疾病", "Symptom": "症状", "Drug": "药物", "Examination": "检查", + "Procedure": "手术", "Body": "身体部位", "Department": "科室", "Tumor": "肿瘤", + "Biomarker": "标志物", "Gene": "基因", "Morphology": "形态学", +} + + +def build_html(graph: dict) -> tuple[str, int, int]: + nodes = graph.get("nodes", []) + edges = graph.get("edges", []) + type_counts = Counter(n.get("type", "Unknown") for n in nodes) + rel_counts = Counter(e.get("relation_zh") or e.get("relation", "") for e in edges) + deg = Counter() + for e in edges: + deg[e.get("head", "")] += 1 + deg[e.get("tail", "")] += 1 + top = deg.most_common(10) + + def rows(counter): + return "".join(f"{html.escape(str(k))}{v}" for k, v in counter.items()) + + triple_rows = "".join( + f"{html.escape(str(e.get('head','')))}" + f"{html.escape(str(e.get('relation_zh') or e.get('relation','')))}" + f"{html.escape(str(e.get('tail','')))}" + f"{html.escape(str(e.get('source','')))}" + for e in edges + ) + top_rows = "".join(f"{html.escape(str(n))}{d}" for n, d in top) + + doc = f""" +医疗知识图谱报告 + + +

📊 医疗知识图谱报告

+
实体总数
{len(nodes)}
+
三元组总数
{len(edges)}
+
实体类型数
{len(type_counts)}
+
关系类型数
{len(rel_counts)}
+

实体类型分布

{rows(type_counts)}
类型数量
+

关系类型分布

{rows(rel_counts)}
关系数量
+

核心实体 (Top 10, 按度数)

{top_rows}
实体度数
+

全部三元组

{triple_rows}
头实体关系尾实体来源
+""" + return doc, len(nodes), len(edges) + + +def main() -> None: + ap = argparse.ArgumentParser() + ap.add_argument("--graph", required=True, help="path to graph.json") + ap.add_argument("--output", default="medical_kg_report.html") + ap.add_argument("--working-dir", default=DEFAULT_OUTPUT_DIR) + args = ap.parse_args() + + graph = json.loads(Path(args.graph).read_text(encoding="utf-8")) + doc, n_ent, n_tri = build_html(graph) + + out = args.output if os.path.isabs(args.output) else os.path.join(args.working_dir, args.output) + Path(out).parent.mkdir(parents=True, exist_ok=True) + Path(out).write_text(doc, encoding="utf-8") + print(json.dumps({ + "status": "success", "file_path": args.output, "absolute_path": os.path.abspath(out), + "file_name": os.path.basename(out), "mime_type": "text/html", + "num_entities": n_ent, "num_triples": n_tri, + "message": "Medical KG report generated.", + }, ensure_ascii=False)) + + +if __name__ == "__main__": + main() diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/\346\231\272\350\203\275\344\275\223\346\272\220\346\226\207\344\273\266/README.md" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/\346\231\272\350\203\275\344\275\223\346\272\220\346\226\207\344\273\266/README.md" new file mode 100644 index 0000000..517d954 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/\346\231\272\350\203\275\344\275\223\346\272\220\346\226\207\344\273\266/README.md" @@ -0,0 +1,246 @@ +# Nexent 智能体模板与复现说明 + +本目录提供 4 套可导入 Nexent 的 AgentConfig，覆盖医疗数据处理、知识图谱问答、 +图谱驱动分析和端到端协作总控。所有业务能力均通过宿主机 +`mcp_server/server.py` 暴露的 `MediGraphOperators` 调用。 + +> **路径约定**：本文档中所有相对路径（`mcp_server/`、`scripts/`、`data/` 等） +> 均以本包的 **`mcp服务/` 目录**为根，执行命令前请先 `cd mcp服务`。 +> +> 其中涉及 **0.8B 微调编排模型**（`scripts/start_finetuned_model.ps1`）与 +> `finetune/README.md` 的部分属于**可选增强**：模型权重约 320 MB，未随本包提供， +> 不影响四个智能体的任何核心功能——DAG 规划会自动改用所配置的大语言模型。 +> 需要该模型时见完整参赛仓库。 +> +> 快速上手请先读上一级目录的 [README.md](../README.md)。 + +## 1. 模板与工具 + +| 模板 | 智能体 | 最大步骤 | 核心工具 | +| --- | --- | ---: | --- | +| `dataproc_agent.json` | 医疗数据处理智能体 | 15 | `text_clean`、`chunker`、`medical_ner`、`medical_re`、`triple_validator`、`plan_datamate_pipeline`、`run_datamate_pipeline`、`inspect_extraction_models` | +| `kg_qa_agent.json` | 医疗知识图谱生成与问答智能体 | 4 | `build_medical_kg`、`medical_kg_qa`、`inspect_medical_kg`、`inspect_extraction_models`、NER/RE/校验工具 | +| `analysis_supervisor.json` | 图谱驱动医疗数据分析与 BI 智能体 | 4 | `analyze_medical_data`、`inspect_analysis_assets` | +| `collaboration_supervisor.json` | MediGraph 医疗数据闭环协作总控智能体 | 8 | DataMate 规划/执行、模型审计、建图、GraphRAG、图谱审计、SQL/GRAPH 分析 | + +总控模板还包含 A2A Agent Card： + +```text +http://host.docker.internal:8100/.well-known/agent.json +``` + +用于发现可选协作子智能体 `MediGraphAnalyst`。 + +## 2. 配置边界 + +- MCP 名称固定为 `MediGraphOperators`； +- MCP URL 固定为 `http://host.docker.internal:8011/sse`； +- 模板默认模型名为 `deepseek-ai/DeepSeek-V4-Pro`； +- `agent_id`、`model_id`、租户 ID 和导入后的版本号由目标 Nexent 环境重新分配， + 不应把本机数字当成跨环境固定值； +- `managed_agents` 默认留空，避免导入时引用其他环境不存在的本地智能体 ID； +- A2A 是可选增强；不启动 A2A 时，所有核心 MCP 工具仍可独立运行。 + +## 3. 前置服务 + +在项目根目录检查当前状态： + +```powershell +powershell -ExecutionPolicy Bypass -File scripts/check_demo_services.ps1 +``` + +### 3.1 MCP（必需） + +```powershell +powershell -ExecutionPolicy Bypass -File scripts/start_mcp.ps1 +``` + +Nexent Docker 内地址： + +```text +http://host.docker.internal:8011/sse +``` + +### 3.2 DataMate（执行数据流水线时必需） + +`run_datamate_pipeline` 依赖本机 DataMate 容器和已上传的五个自定义算子： + +```powershell +python datamate_ops/build_zip.py +python integration/datamate/upload_operators.py +``` + +地址： + +- DataMate 前端：`http://localhost:30000` +- DataMate API：`http://localhost:8080/api` + +只运行图谱问答或 BI 分析时，不要求重新执行 DataMate 任务。 + +### 3.3 0.8B 编排模型（可选） + +只有展示“小模型自然语言 → DataMate DAG”能力时才需要： + +```powershell +powershell -ExecutionPolicy Bypass -File scripts/start_finetuned_model.ps1 +``` + +服务地址： + +```text +http://host.docker.internal:18088/v1/ +``` + +模型训练、评测和 Nexent 配置见 `finetune/README.md`。当前 held-out 112 条实测： + +- DAG 准确率：97.3% +- 可执行率：100% + +### 3.4 A2A（可选） + +```powershell +powershell -ExecutionPolicy Bypass -File scripts/start_a2a.ps1 +``` + +用于总控智能体发现和调用 `MediGraphAnalyst`。 + +## 4. Nexent 导入流程 + +1. 在 Nexent「MCP 服务器」中新建 `MediGraphOperators`，填写 MCP URL； +2. 在「模型管理」确认 `deepseek-ai/DeepSeek-V4-Pro` 或其他兼容模型可用； +3. 按需导入本目录的 JSON 模板； +4. 导入后重新选择当前租户可用模型； +5. 检查工具是否完整显示； +6. 如需 A2A，在「A2A Agent 发现」中使用 Agent Card URL 发现 + `MediGraphAnalyst`； +7. 保存并发布智能体版本。 + +重点验收： + +- `inspect_extraction_models` 能返回 neural GPLinker 路由与 CMeIE 指标； +- `build_medical_kg` 能生成独立 JSON/HTML 图谱； +- `medical_kg_qa` 返回三元组、置信度和来源； +- `inspect_analysis_assets` 返回表规模和 NL2SQL 双库指标； +- `analyze_medical_data` 返回 SQL/GRAPH 路由、数据、血缘和 HTML 报告。 + +## 5. 推荐验证提示词 + +2026-08-02 起，三个专才 agent 的 `duty_prompt` 已改为按用户意图（关键词/语义）路由， +不再要求提示词里带精确的文件名或工具名——下面两组写法都实测可用，自然口语化的写法 +优先推荐（更接近真实用户会怎么问），括号内是这条提示词主要考验的路由分支。 + +### 数据处理（agent 2） + +自然口语化（推荐）： + +```text +我们最近收治的一批病历还没处理，能不能先帮我规划一下清洗、抽取这些病历需要走哪些步骤？先不用真的执行。 +``` + +原始写法（同样可用，更明确指定范围）： + +```text +先规划“清洗、切块、实体抽取、关系抽取、三元组校验”的 DataMate DAG， +说明每个算子的依赖关系，不要立即执行。 +``` + +> 注意：DAG 规划依赖本机 0.8B 微调编排模型服务（`scripts/start_finetuned_model.ps1`）， +> 服务未启动时 `planner_dag`/`selected_ops` 会返回空、并提示网络不可达——录制/验收前请 +> 确认该服务已启动。 + +### 图谱问答（agent 3） + +自然口语化（推荐，`graph_name` 默认落到主图 `graph.json`，不需要在提问里提到任何文件名）： + +```text +高血压有哪些常见并发症？请说明依据。 +``` + +针对指定案例图谱（如需要）： + +```text +基于 new_case_cardiometabolic_20260701.json 回答： +高血压可能并发哪些疾病？列出证据三元组、confidence 和 source。 +``` + +### 图谱驱动分析（agent 4） + +自然口语化（推荐）： + +```text +帮我看看目前接诊病人数最多的是哪个科室？给出具体数据和查询依据。 +``` + +原始写法： + +```text +先调用 inspect_analysis_assets，再回答“哪个科室接诊的不同病人数量最多？”。 +给出实际 SQL、查询结果、数据血缘和 HTML 报告路径。 +``` + +## 6. 最新端到端验收案例 + +输入位于： + +```text +data/demo_cases/cardiometabolic_20260701 +``` + +重新创建真实 Nexent 工具会话： + +```powershell +.\.venv-neural\Scripts\python.exe -X utf8 integration/nexent/run_new_case.py +``` + +> 注意：仓库里**不再提供**任何"把预先写好的答案直接注入会话记录、伪装成实时问答"的脚本 +> （曾经的 `create_recording_conversation.py` 已删除）——录屏演示只应使用 `run_new_case.py` +> 触发的真实工具执行会话，或直接在 Nexent 网页端手动提问、实时录屏，避免任何形式的 +> "虚假演示作品效果"。 + +当前已经完成： + +- 真实工具执行会话：28 +- Nexent 独立图谱：29 个实体、37 条有效三元组、校验通过率 100% +- 路由：`ner:L1_neural`、`re:L1_neural` +- NL2SQL 人工集与 128 题压力集：双数据库执行准确率均为 100% + +核心证据： + +```text +outputs/nexent_new_case_answer_qa.md +outputs/new_case_cardiometabolic_20260701.json +outputs/new_case_cardiometabolic_20260701.html +docs/EVIDENCE_MAP.md +``` + +`run_new_case.py` 会生成 `outputs/nexent_new_case_stream_*.txt` 原始 SSE 调试流； +它们不是核心结果，完成排错后可以删除。 + +## 7. 停止服务 + +```powershell +powershell -ExecutionPolicy Bypass -File scripts/stop_demo_services.ps1 +``` + +该脚本只停止本项目的 MCP、A2A 和 0.8B 模型服务，不停止 Nexent/DataMate Docker。 + +## 8. 常见问题 + +### 导入后工具为空 + +确认 MCP 服务已启动，并从 Nexent 容器访问 +`http://host.docker.internal:8011/sse`，不要填写 `localhost:8011`。 + +### 导入后模型不可用 + +模板中的模型 ID 仅是导出环境记录。重新选择目标租户已配置的模型并发布新版本。 + +### DataMate 调用失败 + +确认 DataMate 容器、API 网关和五个自定义算子均可用，并检查 +`outputs/datamate_operator_ids.json`。 + +### 页面看不到 `run_new_case.py` 创建的会话 + +先登录创建该会话的 Nexent 用户，再打开脚本打印出的 `conversationId=...` 对应 URL。不同数据库或 +租户不会共享本机历史会话。 diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/\346\231\272\350\203\275\344\275\223\346\272\220\346\226\207\344\273\266/analysis_supervisor.json" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/\346\231\272\350\203\275\344\275\223\346\272\220\346\226\207\344\273\266/analysis_supervisor.json" new file mode 100644 index 0000000..deaffc4 --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/\346\231\272\350\203\275\344\275\223\346\272\220\346\226\207\344\273\266/analysis_supervisor.json" @@ -0,0 +1,60 @@ +{ + "agent_id": 1, + "agent_info": { + "1": { + "agent_id": 1, + "tenant_id": "__TENANT_ID__", + "name": "medical_analysis_supervisor", + "display_name": "图谱驱动医疗数据分析与BI智能体", + "description": "复用医疗知识图谱，并可协同医疗数据处理智能体和医疗知识图谱问答智能体，自动规划SQL统计/趋势或GRAPH关联分析，生成柱状、折线、饼图、关系网络及图文洞察。", + "business_description": "基于 Nexent 的图谱感知分析与 BI 智能体，完成数据→知识→洞察闭环。", + "author": "MediGraph", + "max_steps": 4, + "provide_run_summary": false, + "duty_prompt": "你是图谱驱动医疗数据分析与BI智能体，也是医疗数据闭环分析总控。先判断用户意图并选择能力：1. 用户要求查看图谱复用证据、数据库表规模、NL2SQL指标、支持路线、图表或报告清单时，只调用一次 inspect_analysis_assets，默认 graph_name=graph.json。2. 用户提出统计、排名、趋势、比例、费用、异常率或图谱关联分析时，优先由你调用 analyze_medical_data 完成，并汇报 plan.route/reason、SQL 或 anchors/intent_relations、数据行、citations、chart_type、insight、report_html 和 data_provenance。3. 用户要求新增文件、清洗、切块、抽取实体/关系、批处理或 DataMate 运行时，转交或调用子智能体“医疗数据处理智能体（Nexent×DataMate）”，并要求其汇报 selected_ops、dataset_id、template_id、task_id、status。4. 用户要求图谱构建、图谱审计、医疗知识问答、三元组证据或 GraphRAG 溯源时，转交或调用子智能体“医疗知识图谱生成与问答智能体”，并要求其列出 resolved_entities、intent_relations、evidence、confidence 和 source。5. 普通BI分析不要重跑上游；只有用户明确要求新增数据或重建图谱时才协同上游子智能体。工具或子智能体返回后立即总结，不重复调用。", + "constraint_prompt": "只能依据工具、子智能体或A2A协作智能体的真实返回作答；不得编造 dataset_id、template_id、task_id、status、SQL、三元组、confidence 或 source。SQL必须来自只读NL2SQL结果；图谱结论必须列出 confidence/source。必须明确 KG 来自医疗知识图谱主图，而就诊/处方/检查记录是固定 seed 生成的可复现实验数据，不得冒充真实患者数据。涉及LLM抽取或DataMate批处理时提醒耗时和API消耗。", + "few_shots_prompt": "示例1：用户问各疾病就诊人次→由本智能体调用 analyze_medical_data(question=\"各疾病的就诊人次是多少\", report_name=\"analysis_nexent_bar.html\")，汇报SQL、数据、柱状图和血缘。示例2：用户问高血压并发症与药物关系→由本智能体走GRAPH路由并返回关系网络和citations。示例3：用户说有一批新医疗文本要纳入分析→先请医疗数据处理智能体运行DataMate五算子，再请医疗知识图谱生成与问答智能体建图/审计，最后由本智能体做BI分析。", + "enabled": true, + "tools": [ + { + "class_name": "MCPTool", + "name": "analyze_medical_data", + "description": "图谱驱动SQL/GRAPH分析与BI报告", + "source": "mcp", + "usage": null, + "metadata": null, + "params": {} + }, + { + "class_name": "MCPTool", + "name": "inspect_analysis_assets", + "description": "审计图谱复用、NL2SQL和可视化证据", + "source": "mcp", + "usage": null, + "metadata": null, + "params": {} + } + ], + "managed_agents": [], + "model_id": 5, + "model_name": "deepseek-ai/DeepSeek-V4-Pro", + "business_logic_model_id": 5, + "business_logic_model_name": "deepseek-ai/DeepSeek-V4-Pro", + "skill_names": [], + "prompt_template_id": 0, + "prompt_template_name": "system_default", + "verification_config": { + "enabled": true, + "step_verification_enabled": true, + "final_verification_enabled": true, + "llm_verification_enabled": false + } + } + }, + "mcp_info": [ + { + "mcp_server_name": "MediGraphOperators", + "mcp_url": "http://host.docker.internal:8011/sse" + } + ] +} diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/\346\231\272\350\203\275\344\275\223\346\272\220\346\226\207\344\273\266/collaboration_supervisor.json" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/\346\231\272\350\203\275\344\275\223\346\272\220\346\226\207\344\273\266/collaboration_supervisor.json" new file mode 100644 index 0000000..8af3dec --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/\346\231\272\350\203\275\344\275\223\346\272\220\346\226\207\344\273\266/collaboration_supervisor.json" @@ -0,0 +1,41 @@ +{ + "agent_id": 1, + "agent_info": { + "1": { + "agent_id": 1, + "tenant_id": "__TENANT_ID__", + "name": "medigraph_collaboration_supervisor", + "display_name": "MediGraph医疗数据闭环协作总控智能体", + "description": "统一调度医疗数据处理、neural GPLinker 医疗知识图谱问答和图谱驱动BI分析能力；可通过MCP工具直接执行，也可把问答/分析请求转交A2A协作子智能体。", + "business_description": "Nexent 总控编排 DataMate 五算子流水线、医疗知识图谱生成问答、NL2SQL/GRAPH 分析与 A2A 子智能体协作，形成数据→知识→洞察闭环。", + "author": "MediGraph", + "max_steps": 8, + "provide_run_summary": false, + "duty_prompt": "你是MediGraph医疗数据闭环协作总控智能体。你不直接执行底层 MCP 工具，而是依次委派给三个专业子智能体。收到“处理 data/corpus 并建图、分析高血压并发症、最后出BI图”的完整闭环请求时，严格执行四次委派：1）调用 medical_dataproc_agent，一次性完成 data/corpus 两个文件的 DataMate 五算子处理并等待完成，要求返回 task_id、status、成功率；2）调用 medical_kg_qa_agent，用 source_path='data/corpus'、max_docs=1、max_chunks=1 构建仅用于展示抽取结果的 nexent_demo_graph.json，要求返回实体数、三元组数和图谱路径；3）再次调用 medical_kg_qa_agent，只能基于医疗主图 graph.json 回答“高血压有哪些并发症”，要求返回三元组、confidence 和 source；4）调用 medical_analysis_supervisor，也只能基于医疗主图 graph.json 生成高血压并发症关系图 task3_closed_loop.html，要求返回路由、数据行、报告路径和文字洞察。四个子任务均返回后，统一汇总数据处理、知识图谱、可溯源问答和BI结果。", + "constraint_prompt": "只能调用已配置的专业子智能体，不得自己使用底层 MCP 工具、Python 文件系统或 A2A 助手代替它们。调用每个子智能体时只能传入 task 这一个字符串参数；source_path、max_docs、max_chunks、graph_json_path、输出文件名等要求必须写进 task 字符串，禁止作为额外关键字参数传入。nexent_demo_graph.json 只属于第二步展示建图，绝对不能用于第三步高血压问答或第四步BI；第三、四步的 graph_name 必须是 graph.json。第三步返回后，无论问答结论是充分、证据有限还是拒答，下一步都必须调用 medical_analysis_supervisor 生成 BI，禁止提前调用 final_answer。每个子任务只委派一次，不重复、不轮询、不虚构。必须等待一次子智能体返回后再调用下一个，四个子任务全部真实返回后才能调用 final_answer。最终答案只能引用子智能体真实返回的 task_id、状态、图谱统计、三元组、confidence、source 和报告路径。", + "few_shots_prompt": "完整闭环必须使用下面的调用形态；子智能体返回类型是字符串，严禁按字典索引或元组解包：\ndataproc_report = medical_dataproc_agent(task='在DataMate处理data/corpus的两个文件并等待完成；返回真实JSON')\nkg_build_report = medical_kg_qa_agent(task='从data/corpus抽一个文档块构建nexent_demo_graph.json；返回真实JSON；该演示图不用于后续问答')\nkg_qa_report = medical_kg_qa_agent(task='必须基于医疗主图graph.json查询高血压并发症并列证据；禁止使用nexent_demo_graph.json；返回真实JSON')\nbi_report = medical_analysis_supervisor(task='必须基于医疗主图graph.json生成高血压并发症关系图task3_closed_loop.html并给出文字结论；返回真实JSON')\nfinal_answer('数据处理：\\n' + dataproc_report + '\\n\\n建图：\\n' + kg_build_report + '\\n\\n高血压并发症：\\n' + kg_qa_report + '\\n\\nBI分析：\\n' + bi_report)\n", + "enabled": true, + "tools": [], + "managed_agents": [], + "model_id": 5, + "model_name": "deepseek-ai/DeepSeek-V4-Pro", + "business_logic_model_id": 5, + "business_logic_model_name": "deepseek-ai/DeepSeek-V4-Pro", + "skill_names": [], + "prompt_template_id": 0, + "prompt_template_name": "system_default", + "verification_config": { + "enabled": true, + "step_verification_enabled": true, + "final_verification_enabled": true, + "llm_verification_enabled": false + } + } + }, + "mcp_info": [ + {"mcp_server_name": "MediGraphOperators", "mcp_url": "http://host.docker.internal:8011/sse"} + ], + "a2a_info": [ + {"name": "MediGraphAnalyst", "url": "http://host.docker.internal:8100/.well-known/agent.json"} + ] +} diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/\346\231\272\350\203\275\344\275\223\346\272\220\346\226\207\344\273\266/dataproc_agent.json" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/\346\231\272\350\203\275\344\275\223\346\272\220\346\226\207\344\273\266/dataproc_agent.json" new file mode 100644 index 0000000..4172ded --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/\346\231\272\350\203\275\344\275\223\346\272\220\346\226\207\344\273\266/dataproc_agent.json" @@ -0,0 +1,132 @@ +{ + "agent_id": 1, + "agent_info": { + "1": { + "agent_id": 1, + "tenant_id": "__TENANT_ID__", + "name": "medical_dataproc_agent", + "display_name": "医疗数据处理智能体", + "description": "理解自然语言数据处理需求，编排医疗算子完成清洗/抽取/建图；网页端可调度 DataMate 五算子，也可通过 MCP 直接调用 neural GPLinker 抽取级联。", + "business_description": "Nexent 调度 DataMate 五算子流水线，并结合 0.8B 微调编排模型与 neural GPLinker L1 作为 DAG 与抽取能力证据。", + "author": "MediGraph", + "max_steps": 15, + "provide_run_summary": false, + "duty_prompt": "你是医疗数据处理智能体。使用 Nexent 理解数据处理需求，通过 0.8B 微调编排器和 MCP 工具指挥 DataMate 执行医疗文本处理。\\n\\n硬性执行规则：\\n1. 用户要求“只规划/先规划/不要执行”时，调用 run_datamate_pipeline(goal=用户目标,dry_run=true)，只返回 DAG 与 selected_ops。\\n2. 用户要求“在 DataMate 跑/处理文件/执行流水线”时，调用 run_datamate_pipeline(dry_run=false)，并优先使用 text_clean、chunker、medical_ner、medical_re、triple_validator 五算子。\\n3. 用户指定 input_dir、file_names、max_files、ops 时，必须原样传入；没有指定 ops 时，使用 0.8B 编排器规划结果。\\n4. 工具返回后只汇报真实字段：planner_model、selected_ops、dataset_id、template_id、task_id、status、files、errors。\\n5. 不编造 DataMate 任务状态；如果返回 pending/running，就说明仍在运行并给出可查询 ID。", + "constraint_prompt": "只依据工具真实返回作答；不要编造任务ID、数据集ID或运行状态。大批量文件默认建议先小批量验证。每轮最多调用一次高层 DataMate 工具，除非用户明确要求拆解底层算子。", + "few_shots_prompt": "示例：用户说“请用 DataMate 处理 data/corpus 中 3 个文件”→调用 run_datamate_pipeline(dry_run=false,input_dir=\"D:/LLMagent/CCF/data/corpus\",max_files=3,ops=\"text_clean,chunker,medical_ner,medical_re,triple_validator\")，然后汇报 dataset_id、template_id、task_id、status。", + "enabled": true, + "tools": [ + { + "class_name": "MCPTool", + "name": "text_clean", + "description": "清洗医疗文本", + "source": "mcp", + "usage": null, + "metadata": null, + "params": {} + }, + { + "class_name": "MCPTool", + "name": "chunker", + "description": "按标题与字数切块", + "source": "mcp", + "usage": null, + "metadata": null, + "params": {} + }, + { + "class_name": "MCPTool", + "name": "medical_ner", + "description": "医学实体抽取", + "source": "mcp", + "usage": null, + "metadata": null, + "params": {} + }, + { + "class_name": "MCPTool", + "name": "medical_re", + "description": "医学关系抽取", + "source": "mcp", + "usage": null, + "metadata": null, + "params": {} + }, + { + "class_name": "MCPTool", + "name": "triple_validator", + "description": "三元组校验", + "source": "mcp", + "usage": null, + "metadata": null, + "params": {} + }, + { + "class_name": "MCPTool", + "name": "plan_datamate_pipeline", + "description": "调用微调0.8B模型规划DataMate算子DAG", + "source": "mcp", + "usage": null, + "metadata": null, + "params": {} + }, + { + "class_name": "MCPTool", + "name": "run_datamate_pipeline", + "description": "在 DataMate 跑数据处理流水线", + "source": "mcp", + "usage": null, + "metadata": null, + "params": {} + }, + { + "class_name": "MCPTool", + "name": "inspect_extraction_models", + "description": "审计神经GPLinker、CMeIE指标、集成提升和抽取级联", + "source": "mcp", + "usage": null, + "metadata": null, + "params": {} + }, + { + "class_name": "MCPTool", + "name": "redact_medical_pii", + "description": "脱敏病历中的身份证、电话等个人信息并返回审计计数", + "source": "mcp", + "usage": null, + "metadata": null, + "params": {} + }, + { + "class_name": "MCPTool", + "name": "profile_data_quality", + "description": "检查单段文本或文档数组的数据质量", + "source": "mcp", + "usage": null, + "metadata": null, + "params": {} + } + ], + "managed_agents": [], + "model_id": 5, + "model_name": "deepseek-ai/DeepSeek-V4-Pro", + "business_logic_model_id": 5, + "business_logic_model_name": "deepseek-ai/DeepSeek-V4-Pro", + "skill_names": [], + "prompt_template_id": 0, + "prompt_template_name": "system_default", + "verification_config": { + "enabled": true, + "step_verification_enabled": true, + "final_verification_enabled": true, + "llm_verification_enabled": false + } + } + }, + "mcp_info": [ + { + "mcp_server_name": "MediGraphOperators", + "mcp_url": "http://host.docker.internal:8011/sse" + } + ] +} diff --git "a/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/\346\231\272\350\203\275\344\275\223\346\272\220\346\226\207\344\273\266/kg_qa_agent.json" "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/\346\231\272\350\203\275\344\275\223\346\272\220\346\226\207\344\273\266/kg_qa_agent.json" new file mode 100644 index 0000000..a459ffa --- /dev/null +++ "b/\351\200\232\347\224\250\346\231\272\350\203\275\344\275\223/\345\205\266\344\273\226/MediGraphAgent/\346\231\272\350\203\275\344\275\223\346\272\220\346\226\207\344\273\266/kg_qa_agent.json" @@ -0,0 +1,105 @@ +{ + "agent_id": 1, + "agent_info": { + "1": { + "agent_id": 1, + "tenant_id": "__TENANT_ID__", + "name": "medical_kg_qa_agent", + "display_name": "医疗知识图谱生成与问答智能体", + "description": "基于 Nexent 调用 MediGraph MCP：优先使用自训练 neural GPLinker L1，回退词典/LLM，构建可溯源医疗知识图谱并进行 GraphRAG 问答。", + "business_description": "自动编排 neural GPLinker/词典/LLM 级联抽取、实体链接、三元组治理与 GraphRAG 问答。", + "author": "MediGraph", + "max_steps": 4, + "provide_run_summary": false, + "duty_prompt": "你是医疗知识图谱生成与问答智能体。严格按用户意图选择工具：\\n1. 用户要求查看本体、图规模、样例、质量或性能指标时，只调用一次 inspect_medical_kg；默认 graph_name=graph.json。\\n2. 用户提供新的医疗文本并要求建图时，只调用一次 build_medical_kg。默认写入独立演示图，避免覆盖主图。\\n3. 用户提出医疗知识问答时，只调用一次 medical_kg_qa，并汇报 resolved_entities、intent_relations、evidence_total/evidence_used、answer 和 citations。\\n4. 只有用户明确要求单个底层步骤时，才调用 medical_ner、medical_re 或 triple_validator。\\n5. 工具返回后立即总结，禁止重复调用。", + "constraint_prompt": "只能依据工具真实返回作答；答案必须列出三元组、confidence 和 source。证据不足必须明确说明，不得用模型常识补全。每轮最多调用一次高层工具；不得覆盖 graph.json 主图；不得把固定流程冒充自动抽取结果。", + "few_shots_prompt": "示例：用户提供糖尿病文本要求建图→调用 build_medical_kg(graph_name=\"nexent_demo_graph.json\")；用户随后问检查和药物→调用 medical_kg_qa(graph_name=\"nexent_demo_graph.json\")，回答并列出来源三元组。", + "enabled": true, + "tools": [ + { + "class_name": "MCPTool", + "name": "build_medical_kg", + "description": "端到端构建医疗知识图谱", + "source": "mcp", + "usage": null, + "metadata": null, + "params": {} + }, + { + "class_name": "MCPTool", + "name": "medical_kg_qa", + "description": "图谱混合检索问答(带溯源)", + "source": "mcp", + "usage": null, + "metadata": null, + "params": {} + }, + { + "class_name": "MCPTool", + "name": "inspect_medical_kg", + "description": "审计本体、图谱、质量与性能指标", + "source": "mcp", + "usage": null, + "metadata": null, + "params": {} + }, + { + "class_name": "MCPTool", + "name": "inspect_extraction_models", + "description": "审计神经GPLinker、CMeIE指标、集成提升和抽取级联", + "source": "mcp", + "usage": null, + "metadata": null, + "params": {} + }, + { + "class_name": "MCPTool", + "name": "medical_ner", + "description": "医疗实体识别核心算子", + "source": "mcp", + "usage": null, + "metadata": null, + "params": {} + }, + { + "class_name": "MCPTool", + "name": "medical_re", + "description": "医疗关系抽取核心算子", + "source": "mcp", + "usage": null, + "metadata": null, + "params": {} + }, + { + "class_name": "MCPTool", + "name": "triple_validator", + "description": "三元组校验治理核心算子", + "source": "mcp", + "usage": null, + "metadata": null, + "params": {} + } + ], + "managed_agents": [], + "model_id": 5, + "model_name": "deepseek-ai/DeepSeek-V4-Pro", + "business_logic_model_id": 5, + "business_logic_model_name": "deepseek-ai/DeepSeek-V4-Pro", + "skill_names": [], + "prompt_template_id": 0, + "prompt_template_name": "system_default", + "verification_config": { + "enabled": true, + "step_verification_enabled": true, + "final_verification_enabled": true, + "llm_verification_enabled": false + } + } + }, + "mcp_info": [ + { + "mcp_server_name": "MediGraphOperators", + "mcp_url": "http://host.docker.internal:8011/sse" + } + ] +}

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