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"excluded_edge_count": 0, "bucket_count": 23, "graph_edge_count": 4, "created_at": "2026-04-15T04:45:47.250871+00:00" } } ], "test_cases": [ { "case_id": "mash_target_discovery", "label": "MASH Target Discovery", "description": "MASH + fibrosis, human evidence preferred. Runs abstract-first slice and target discovery.", "task_mode": "target_discovery", "query": { "disease": [ "MASH" ], "mechanism": [ "fibrosis" ], "humans_only": true, "top_k": 25, "enable_llm_rerank": true, "llm_rerank_top_n": 25, "llm_rerank_batch_size": 8 }, "m3": { "top_n": 25, "max_workers": 2 }, "task_input": { "disease": [ "MASH" ], "limit": 25 }, "tags": [ "abstract_first", "target_discovery", "mash", "fibrosis" ], "launch_command": "python scripts/run_workbench_test_case.py --case-id mash_target_discovery --config \"/Volumes/Yulong/数据集/DoAtlas/configs/workbench_test_cases.json\" --rebuild-workbench --overwrite" }, { "case_id": "mash_target_ranking", "label": "MASH Target Ranking", "description": "MASH + fibrosis, same retrieval slice but evaluates ranking output.", "task_mode": "target_ranking", "query": { "disease": [ "MASH" ], "mechanism": [ "fibrosis" ], "humans_only": true, "top_k": 25, "enable_llm_rerank": true, "llm_rerank_top_n": 25, "llm_rerank_batch_size": 8 }, "m3": { "top_n": 25, "max_workers": 2 }, "task_input": { "disease": [ "MASH" ], "limit": 25 }, "tags": [ "abstract_first", "target_ranking", "mash", "fibrosis" ], "launch_command": "python scripts/run_workbench_test_case.py --case-id mash_target_ranking --config \"/Volumes/Yulong/数据集/DoAtlas/configs/workbench_test_cases.json\" --rebuild-workbench --overwrite" }, { "case_id": "obesity_semaglutide_review", "label": "Obesity Semaglutide Review", "description": "Obesity + semaglutide retrieval, then evidence review over the resulting slice.", "task_mode": "evidence_review", "query": { "disease": [ "obesity" ], "drug": [ "semaglutide" ], "top_k": 25, "enable_llm_rerank": true, "llm_rerank_top_n": 25, "llm_rerank_batch_size": 8 }, "m3": { "top_n": 25, "max_workers": 2 }, "task_input": { "disease": [ "obesity" ], "drug": [ "semaglutide" ], "limit": 25 }, "tags": [ "abstract_first", "evidence_review", "obesity", "semaglutide" ], "launch_command": "python scripts/run_workbench_test_case.py --case-id obesity_semaglutide_review --config \"/Volumes/Yulong/数据集/DoAtlas/configs/workbench_test_cases.json\" --rebuild-workbench --overwrite" }, { "case_id": "mash_vitamin_d_fulltext_review", "label": "MASH Vitamin D Fulltext Review", "description": "Runs the MASH evidence review path and then triggers the full-text upgrade slice.", "task_mode": "evidence_review", "query": { "disease": [ "MASH" ], "mechanism": [ "fibrosis" ], "humans_only": true, "top_k": 25, "enable_llm_rerank": true, "llm_rerank_top_n": 25, "llm_rerank_batch_size": 8 }, "m3": { "top_n": 25, "max_workers": 2 }, "task_input": { "drug": [ "Vitamin D3" ], "limit": 25 }, "run_fulltext_upgrade": true, "tags": [ "abstract_first", "fulltext_upgrade", "mash", "vitamin_d3" ], "launch_command": "python scripts/run_workbench_test_case.py --case-id mash_vitamin_d_fulltext_review --config \"/Volumes/Yulong/数据集/DoAtlas/configs/workbench_test_cases.json\" --rebuild-workbench --overwrite" } ], "tasks": [ { "task_run_id": "TASK:bcf2ff8f78a7", "snapshot_id": "SNAP:018c5a655059", "task_mode": "target_discovery", "results_db": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/RSCHRUN_0b4e8f5da0d8/m10_tasks/task_runs/TASK:bcf2ff8f78a7.duckdb", "task_input": { "disease": [ "MASH", "metabolic dysfunction-associated steatohepatitis", "non-alcoholic steatohepatitis", "NASH" ], "drug": [], "target": [], "concept_id": [], "graph_edge_id": [], "bucket_id": [], "limit": 20 }, "task_plan": { "task_mode": "target_discovery", "steps": [ { "step": "resolve_filters", "details": { "disease": [ "MASH", "metabolic dysfunction-associated steatohepatitis", "non-alcoholic steatohepatitis", "NASH" ], "drug": [], "target": [], "concept_id": [], "graph_edge_id": [], "bucket_id": [], "limit": 20 } }, { "step": "scan_snapshot_buckets_for_target_entities" }, { "step": "fallback_to_drug_target_crosswalk_when_direct_target_edges_missing" }, { "step": "aggregate_evidence_by_target" }, { "step": "build_target_candidate_list_or_ranking" } ] }, "result_object_type": "target_candidate_list", "result_object_id": "TOBJ:75afbb1c7ba9", "result": { "object_type": "target_candidate_list", "list_id": "TCLIST:f59cafa53a32", "snapshot_id": "SNAP:018c5a655059", "disease": { "concept_id": "MASH", "label": "MASH" }, "items": [], "coverage": { "graph_edge_count_scanned": 0, "target_to_disease_graph_edge_count": 0, "direct_candidate_count": 0, "crosswalk_candidate_count": 0, "candidate_count": 0, "empty_reason": "no_target_to_disease_graph_edges_matched_current_snapshot" }, "resolved_filters": { "disease": [ "MASH", "mash", "metabolic dysfunction associated steatohepatitis", "metabolic dysfunction-associated steatohepatitis", "steatohepatitis", "nash", "nonalcoholic steatohepatitis", "non alcoholic steatohepatitis", "non-alcoholic steatohepatitis", "NASH" ] }, "follow_up_actions": [] }, "task_file": "artifacts/runs/adhoc_task_runs/RSCHRUN_0b4e8f5da0d8/m10_tasks/TASK:bcf2ff8f78a7.json", "task_file_name": "TASK:bcf2ff8f78a7.json", "task_file_relative": "../../runs/adhoc_task_runs/RSCHRUN_0b4e8f5da0d8/m10_tasks/TASK:bcf2ff8f78a7.json", "summary": { "object_type": "target_candidate_list", "snapshot_id": "SNAP:018c5a655059", "item_count": 0, "label": "MASH" } }, { "task_run_id": "TASK:a107d9851f8a", "snapshot_id": "SNAP:0a351f76970e", "task_mode": "target_discovery", "results_db": "/Volumes/Yulong/数据集/DoAtlas/artifacts/adhoc_task_runs/interactive_ADHOC_b70b23612c81/m10_tasks/task_runs/TASK:a107d9851f8a.duckdb", "task_input": { "disease": [ "MASH" ], "drug": [], "target": [], "concept_id": [], "graph_edge_id": [], "bucket_id": [], "limit": 20 }, "task_plan": { "task_mode": "target_discovery", "steps": [ { "step": "resolve_filters", "details": { "disease": [ "MASH" ], "drug": [], "target": [], "concept_id": [], "graph_edge_id": [], "bucket_id": [], "limit": 20 } }, { "step": "scan_snapshot_buckets_for_target_entities" }, { "step": "fallback_to_drug_target_crosswalk_when_direct_target_edges_missing" }, { "step": "aggregate_evidence_by_target" }, { "step": "build_target_candidate_list_or_ranking" } ] }, "result_object_type": "target_candidate_list", "result_object_id": "TOBJ:313b1870c50c", "result": { "object_type": "target_candidate_list", "list_id": "TCLIST:c30d8c0dd3f4", "snapshot_id": "SNAP:0a351f76970e", "disease": { "concept_id": "MASH", "label": "MASH" }, "items": [ { "target": { "concept_id": "TARGET:glp_1_receptor", "label": "GLP-1 receptor" }, "candidate_score": 0.7, "raw_candidate_score": 2.0, "evidence_tier": "crosswalk_derived", "preview_reasons": [ "drug_support", "no_direction_conflict", "mash patients", "agonist", "alias_group:2" ], "evidence_summary": { "supporting_bucket_count": 1, "supporting_edge_count": 1, "supporting_paper_count": 1, "record_status_counts": { "accepted": 0, "review_required": 1, "excluded": 0 }, "effect_status_counts": { "usable": 0, "missing": 1, "blocked": 0 }, "conflict_status": "none" }, "derivation_modes": [ "drug_target_crosswalk" ], "source_drugs": [ "DRUG:semaglutide" ], "evidence_link": { "graph_edge_ids": [], "bucket_ids": [ "BUCKET:96f36ae8f43b8bbd" ], "edge_ids": [ "AEV-39609545#4" ], "paper_ids": [ "PMID:39609545" ] }, "alias_concept_ids": [ "TARGET:glp_1_receptor", "TARGET:glucagon_like_peptide_1_receptor" ], "alias_labels": [ "GLP-1 receptor", "glucagon-like peptide 1 receptor" ], "alias_count": 2 }, { "target": { "concept_id": "TARGET:sodium_hydrogen_transporter", "label": "sodium-hydrogen transporter" }, "candidate_score": 0.7, "raw_candidate_score": 2.0, "evidence_tier": "crosswalk_derived", "preview_reasons": [ "drug_support", "no_direction_conflict", "mash patients", "inhibitor" ], "evidence_summary": { "supporting_bucket_count": 1, "supporting_edge_count": 1, "supporting_paper_count": 1, "record_status_counts": { "accepted": 0, "review_required": 1, "excluded": 0 }, "effect_status_counts": { "usable": 0, "missing": 1, "blocked": 0 }, "conflict_status": "none" }, "derivation_modes": [ "drug_target_crosswalk" ], "source_drugs": [ "DRUG:semaglutide" ], "evidence_link": { "graph_edge_ids": [], "bucket_ids": [ "BUCKET:96f36ae8f43b8bbd" ], "edge_ids": [ "AEV-39609545#4" ], "paper_ids": [ "PMID:39609545" ] }, "alias_concept_ids": [ "TARGET:sodium_hydrogen_transporter" ], "alias_labels": [ "sodium-hydrogen transporter" ], "alias_count": 1 }, { "target": { "concept_id": "TARGET:thyroid_hormone_receptor_beta", "label": "thyroid hormone receptor-beta" }, "candidate_score": 0.7, "raw_candidate_score": 2.0, "evidence_tier": "crosswalk_derived", "preview_reasons": [ "drug_support", "no_direction_conflict", "mash patients", "agonist" ], "evidence_summary": { "supporting_bucket_count": 1, "supporting_edge_count": 1, "supporting_paper_count": 1, "record_status_counts": { "accepted": 0, "review_required": 1, "excluded": 0 }, "effect_status_counts": { "usable": 0, "missing": 1, "blocked": 0 }, "conflict_status": "none" }, "derivation_modes": [ "drug_target_crosswalk" ], "source_drugs": [ "DRUG:resmetirom" ], "evidence_link": { "graph_edge_ids": [], "bucket_ids": [ "BUCKET:70179a91ccaeaf1e" ], "edge_ids": [ "AEV-39609545#6" ], "paper_ids": [ "PMID:39609545" ] }, "alias_concept_ids": [ "TARGET:thyroid_hormone_receptor_beta" ], "alias_labels": [ "thyroid hormone receptor-beta" ], "alias_count": 1 } ], "coverage": { "graph_edge_count_scanned": 0, "target_to_disease_graph_edge_count": 0, "direct_candidate_count": 0, "crosswalk_candidate_count": 3, "candidate_count": 3 }, "resolved_filters": { "disease": [ "MASH", "mash", "metabolic dysfunction associated steatohepatitis", "metabolic dysfunction-associated steatohepatitis", "steatohepatitis", "nash", "nonalcoholic steatohepatitis", "non alcoholic steatohepatitis" ] }, "follow_up_actions": [ { "action_type": "fulltext_upgrade", "priority": "high", "paper_ids": [ "PMID:39609545" ], "target_concept_id": "TARGET:glp_1_receptor", "evidence_tier": "crosswalk_derived", "reason_codes": [ "crosswalk_derived_target", "review_required_evidence_present", "missing_usable_effect" ], "reason": "Upgrade supporting papers to full-text extraction for higher-confidence target evidence." } ] }, "task_file": "artifacts/runs/adhoc_task_runs/interactive_ADHOC_b70b23612c81/m10_tasks/TASK:a107d9851f8a.json", "task_file_name": "TASK:a107d9851f8a.json", "task_file_relative": "../../runs/adhoc_task_runs/interactive_ADHOC_b70b23612c81/m10_tasks/TASK:a107d9851f8a.json", "summary": { "object_type": "target_candidate_list", "snapshot_id": "SNAP:0a351f76970e", "item_count": 3, "label": "MASH" } }, { "task_run_id": "TASK:488ea941657d", "snapshot_id": "SNAP:30e766921fb3", "task_mode": "target_discovery", "results_db": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m10_tasks/task_runs/TASK:488ea941657d.duckdb", "task_input": { "disease": [ "特发性肺纤维化", "Idiopathic Pulmonary Fibrosis", "IPF", "Cryptogenic Fibrosing Alveolitis" ], "drug": [], "target": [], "concept_id": [], "graph_edge_id": [], "bucket_id": [], "limit": 25, "paper_id": [], "edge_id": [], "candidate_targets": [], "ranking_profile": {}, "review_scope": {} }, "task_plan": { "task_mode": "target_discovery", "steps": [ { "step": "resolve_filters", "details": { "disease": [ "特发性肺纤维化", "Idiopathic Pulmonary Fibrosis", "IPF", "Cryptogenic Fibrosing Alveolitis" ], "drug": [], "target": [], "concept_id": [], "graph_edge_id": [], "bucket_id": [], "limit": 25, "paper_id": [], "edge_id": [], "candidate_targets": [], "ranking_profile": {}, "review_scope": {} } }, { "step": "scan_snapshot_buckets_for_target_entities" }, { "step": "fallback_to_drug_target_crosswalk_when_direct_target_edges_missing" }, { "step": "aggregate_evidence_by_target" }, { "step": "assemble_candidate_dossiers" }, { "step": "build_target_candidate_list_or_ranking" } ] }, "result_object_type": "target_candidate_list", "result_object_id": "TOBJ:b4c8a24dfc81", "result": { "object_type": "target_candidate_list", "list_id": "TCLIST:74533ad485e7", "snapshot_id": "SNAP:30e766921fb3", "disease": { "concept_id": "特发性肺纤维化", "label": "特发性肺纤维化" }, "items": [ { "target": { "concept_id": "TARGET:fgfr", "label": "FGFR" }, "candidate_score": 22.75, "raw_candidate_score": 65.0, "evidence_tier": "crosswalk_derived", "preview_reasons": [ "drug_to_outcome", "drug_support", "no_direction_conflict", "MED:outcome:abnormal_liver_function_tests", "MED:outcome:all_cause_mortality", "MED:outcome:annual_rate_of_decline_in_fvc" ], "evidence_summary": { "supporting_bucket_count": 10, "supporting_edge_count": 10, "supporting_paper_count": 2, "record_status_counts": { "accepted": 10, "review_required": 0, "excluded": 0 }, "effect_status_counts": { "usable": 10, "missing": 0, "blocked": 0 }, "conflict_status": "none", "review_queue_count": 0 }, "derivation_modes": [ "drug_target_crosswalk" ], "source_drugs": [ "DRUG:nintedanib" ], "evidence_link": { "graph_edge_ids": [], "bucket_ids": [ "BUCKET:076f76dd6b68de27", "BUCKET:57f0c69a22fda8da", "BUCKET:f6b2d9ad9a27f76b", "BUCKET:72d978dab750e796", "BUCKET:a702a467256c5011", "BUCKET:db337d27c4182659", "BUCKET:109c09576d1c270d", "BUCKET:8d9b38c931fa669e", "BUCKET:6dccf80dbaaed877", "BUCKET:efc79d5b93878c11" ], "edge_ids": [ "AEV-30176872#2", "AEV-30176872#3", "AEV-41026018#1", "AEV-41026018#2", "AEV-41026018#3", "AEV-41026018#4", "AEV-41026018#5", "AEV-41026018#6", "AEV-41026018#7", "AEV-41026018#8" ], "paper_ids": [ "PMID:30176872", "PMID:41026018" ] }, "alias_concept_ids": [ "TARGET:fgfr" ], "alias_labels": [ "FGFR" ], "alias_count": 1, "candidate_dossier_id": "DOSSIER:6454b7d259f8" }, { "target": { "concept_id": "TARGET:fibroblast_growth_factor_receptor", "label": "fibroblast growth factor receptor" }, "candidate_score": 22.75, "raw_candidate_score": 65.0, "evidence_tier": "crosswalk_derived", "preview_reasons": [ "drug_to_outcome", "drug_support", "no_direction_conflict", "MED:outcome:abnormal_liver_function_tests", "MED:outcome:all_cause_mortality", "MED:outcome:annual_rate_of_decline_in_fvc" ], "evidence_summary": { "supporting_bucket_count": 10, "supporting_edge_count": 10, "supporting_paper_count": 2, "record_status_counts": { "accepted": 10, "review_required": 0, "excluded": 0 }, "effect_status_counts": { "usable": 10, "missing": 0, "blocked": 0 }, "conflict_status": "none", "review_queue_count": 0 }, "derivation_modes": [ "drug_target_crosswalk" ], "source_drugs": [ "DRUG:nintedanib" ], "evidence_link": { "graph_edge_ids": [], "bucket_ids": [ "BUCKET:076f76dd6b68de27", "BUCKET:57f0c69a22fda8da", "BUCKET:f6b2d9ad9a27f76b", "BUCKET:72d978dab750e796", "BUCKET:a702a467256c5011", "BUCKET:db337d27c4182659", "BUCKET:109c09576d1c270d", "BUCKET:8d9b38c931fa669e", "BUCKET:6dccf80dbaaed877", "BUCKET:efc79d5b93878c11" ], "edge_ids": [ "AEV-30176872#2", "AEV-30176872#3", "AEV-41026018#1", "AEV-41026018#2", "AEV-41026018#3", "AEV-41026018#4", "AEV-41026018#5", "AEV-41026018#6", "AEV-41026018#7", "AEV-41026018#8" ], "paper_ids": [ "PMID:30176872", "PMID:41026018" ] }, "alias_concept_ids": [ "TARGET:fibroblast_growth_factor_receptor" ], "alias_labels": [ "fibroblast growth factor receptor" ], "alias_count": 1, "candidate_dossier_id": "DOSSIER:4c2d0f5a326c" }, { "target": { "concept_id": "TARGET:non_receptor_members_of_the_src_family", "label": "non-receptor members of the Src family" }, "candidate_score": 22.75, "raw_candidate_score": 65.0, "evidence_tier": "crosswalk_derived", "preview_reasons": [ "drug_to_outcome", "drug_support", "no_direction_conflict", "MED:outcome:abnormal_liver_function_tests", "MED:outcome:all_cause_mortality", "MED:outcome:annual_rate_of_decline_in_fvc" ], "evidence_summary": { "supporting_bucket_count": 10, "supporting_edge_count": 10, "supporting_paper_count": 2, "record_status_counts": { "accepted": 10, "review_required": 0, "excluded": 0 }, "effect_status_counts": { "usable": 10, "missing": 0, "blocked": 0 }, "conflict_status": "none", "review_queue_count": 0 }, "derivation_modes": [ "drug_target_crosswalk" ], "source_drugs": [ "DRUG:nintedanib" ], "evidence_link": { "graph_edge_ids": [], "bucket_ids": [ "BUCKET:076f76dd6b68de27", "BUCKET:57f0c69a22fda8da", "BUCKET:f6b2d9ad9a27f76b", "BUCKET:72d978dab750e796", "BUCKET:a702a467256c5011", "BUCKET:db337d27c4182659", "BUCKET:109c09576d1c270d", "BUCKET:8d9b38c931fa669e", "BUCKET:6dccf80dbaaed877", "BUCKET:efc79d5b93878c11" ], "edge_ids": [ "AEV-30176872#2", "AEV-30176872#3", "AEV-41026018#1", "AEV-41026018#2", "AEV-41026018#3", "AEV-41026018#4", "AEV-41026018#5", "AEV-41026018#6", "AEV-41026018#7", "AEV-41026018#8" ], "paper_ids": [ "PMID:30176872", "PMID:41026018" ] }, "alias_concept_ids": [ "TARGET:non_receptor_members_of_the_src_family" ], "alias_labels": [ "non-receptor members of the Src family" ], "alias_count": 1, "candidate_dossier_id": "DOSSIER:1fb096927e60" }, { "target": { "concept_id": "TARGET:pdgfr", "label": "PDGFR" }, "candidate_score": 22.75, "raw_candidate_score": 65.0, "evidence_tier": "crosswalk_derived", "preview_reasons": [ "drug_to_outcome", "drug_support", "no_direction_conflict", "MED:outcome:abnormal_liver_function_tests", "MED:outcome:all_cause_mortality", "MED:outcome:annual_rate_of_decline_in_fvc" ], "evidence_summary": { "supporting_bucket_count": 10, "supporting_edge_count": 10, "supporting_paper_count": 2, "record_status_counts": { "accepted": 10, "review_required": 0, "excluded": 0 }, "effect_status_counts": { "usable": 10, "missing": 0, "blocked": 0 }, "conflict_status": "none", "review_queue_count": 0 }, "derivation_modes": [ "drug_target_crosswalk" ], "source_drugs": [ "DRUG:nintedanib" ], "evidence_link": { "graph_edge_ids": [], "bucket_ids": [ "BUCKET:076f76dd6b68de27", "BUCKET:57f0c69a22fda8da", "BUCKET:f6b2d9ad9a27f76b", "BUCKET:72d978dab750e796", "BUCKET:a702a467256c5011", "BUCKET:db337d27c4182659", "BUCKET:109c09576d1c270d", "BUCKET:8d9b38c931fa669e", "BUCKET:6dccf80dbaaed877", "BUCKET:efc79d5b93878c11" ], "edge_ids": [ "AEV-30176872#2", "AEV-30176872#3", "AEV-41026018#1", "AEV-41026018#2", "AEV-41026018#3", "AEV-41026018#4", "AEV-41026018#5", "AEV-41026018#6", "AEV-41026018#7", "AEV-41026018#8" ], "paper_ids": [ "PMID:30176872", "PMID:41026018" ] }, "alias_concept_ids": [ "TARGET:pdgfr" ], "alias_labels": [ "PDGFR" ], "alias_count": 1, "candidate_dossier_id": "DOSSIER:39f5ea4c0aff" }, { "target": { "concept_id": "TARGET:platelet_derived_growth_factor_receptor", "label": "platelet-derived growth factor receptor" }, "candidate_score": 22.75, "raw_candidate_score": 65.0, "evidence_tier": "crosswalk_derived", "preview_reasons": [ "drug_to_outcome", "drug_support", "no_direction_conflict", "MED:outcome:abnormal_liver_function_tests", "MED:outcome:all_cause_mortality", "MED:outcome:annual_rate_of_decline_in_fvc" ], "evidence_summary": { "supporting_bucket_count": 10, "supporting_edge_count": 10, "supporting_paper_count": 2, 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Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Observational", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "NFS reduction", "c_raw": null, "y_raw": "histologic fibrosis improvement", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nfs reduction", "c_norm_text": null, "y_norm_text": "histologic fibrosis improvement", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.201, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-14T13:10:16.942674+00:00", "quality_decision_id": "QDEC:aee2a8cfcc91c0c5", "quality_run_id": "QRUN:e6a686cd0592ed26", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": true, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-14T13:10:42.594550+00:00" }, "PMID:30270688::AEV-30270688#1": { "norm_edge_pk": "NORM:RAW:0dbd64830ca0", "raw_edge_pk": "RAW:0dbd64830ca0", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#1", "edge_order": 1, "paper_dir": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. 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No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. 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No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "Vitamin D3", "c_raw": "Placebo", "y_raw": "NAFLD activity score", "z_raw_json": [ "NASH", "hypovitaminosis D" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "nafld activity score", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-14T13:10:16.942674+00:00", "quality_decision_id": "QDEC:f90ab2fac4cb977c", "quality_run_id": "QRUN:e6a686cd0592ed26", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": true, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-14T13:10:42.594550+00:00" } }, "edges_by_edge_id": { "AEV-30253043#1": [ { "norm_edge_pk": "NORM:RAW:d4ddab90be66", "raw_edge_pk": "RAW:d4ddab90be66", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#1", "edge_order": 1, "paper_dir": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. 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Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. 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Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. 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Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Observational", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "FIB-4 index reduction", "c_raw": null, "y_raw": "histologic fibrosis improvement", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "fib-4 index reduction", "c_norm_text": null, "y_norm_text": "histologic fibrosis improvement", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.036, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-14T13:10:16.942674+00:00", "quality_decision_id": "QDEC:089fab0cf08b626b", "quality_run_id": "QRUN:e6a686cd0592ed26", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": true, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-14T13:10:42.594550+00:00" } ], "AEV-30253043#6": [ { "norm_edge_pk": "NORM:RAW:48673993502c", "raw_edge_pk": "RAW:48673993502c", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#6", "edge_order": 6, "paper_dir": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Observational", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "NFS reduction", "c_raw": null, "y_raw": "histologic fibrosis improvement", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nfs reduction", "c_norm_text": null, "y_norm_text": "histologic fibrosis improvement", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.201, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-14T13:10:16.942674+00:00", "quality_decision_id": "QDEC:aee2a8cfcc91c0c5", "quality_run_id": "QRUN:e6a686cd0592ed26", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": true, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-14T13:10:42.594550+00:00" } ], "AEV-30270688#1": [ { "norm_edge_pk": "NORM:RAW:0dbd64830ca0", "raw_edge_pk": "RAW:0dbd64830ca0", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#1", "edge_order": 1, "paper_dir": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "Vitamin D3", "c_raw": "Placebo", "y_raw": "Alanine aminotransferase (ALT)", "z_raw_json": [ "NASH", "hypovitaminosis D" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "alanine aminotransferase (alt)", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-14T13:10:16.942674+00:00", "quality_decision_id": "QDEC:8b20d905780e3dcd", "quality_run_id": "QRUN:e6a686cd0592ed26", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-14T13:10:42.594550+00:00" } ], "AEV-30270688#2": [ { "norm_edge_pk": "NORM:RAW:d94d4083b798", "raw_edge_pk": "RAW:d94d4083b798", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#2", "edge_order": 2, "paper_dir": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. 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Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Randomized Controlled Trial", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "Obeticholic acid", "c_raw": "placebo", "y_raw": "NFS", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "obeticholic acid", "c_norm_text": "placebo", "y_norm_text": "nfs", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.05, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-14T13:10:16.942674+00:00", "quality_decision_id": "QDEC:177b1cd74a4f511c", "quality_run_id": "QRUN:bb4863860e0ef848", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "missing_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-14T14:54:35.030215+00:00" } ], "AEV-30253043#4": [ { "norm_edge_pk": "NORM:RAW:53255ac19a5f", "raw_edge_pk": "RAW:53255ac19a5f", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#4", "edge_order": 4, "paper_dir": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Observational", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "APRI score reduction", "c_raw": null, "y_raw": "histologic fibrosis improvement", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "apri score reduction", "c_norm_text": null, "y_norm_text": "histologic fibrosis improvement", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.015, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-14T13:10:16.942674+00:00", "quality_decision_id": "QDEC:ddb4462d616c7793", "quality_run_id": "QRUN:bb4863860e0ef848", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-14T14:54:35.030215+00:00" } ], "AEV-30253043#5": [ { "norm_edge_pk": "NORM:RAW:f8b4f3d17787", "raw_edge_pk": "RAW:f8b4f3d17787", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#5", "edge_order": 5, "paper_dir": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Observational", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "FIB-4 index reduction", "c_raw": null, "y_raw": "histologic fibrosis improvement", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "fib-4 index reduction", "c_norm_text": null, "y_norm_text": "histologic fibrosis improvement", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.036, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-14T13:10:16.942674+00:00", "quality_decision_id": "QDEC:fe5399bfa045d858", "quality_run_id": "QRUN:bb4863860e0ef848", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": true, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-14T14:54:35.030215+00:00" } ], "AEV-30253043#6": [ { "norm_edge_pk": "NORM:RAW:48673993502c", "raw_edge_pk": "RAW:48673993502c", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#6", "edge_order": 6, "paper_dir": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. 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No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "Vitamin D3", "c_raw": "Placebo", "y_raw": "Alanine aminotransferase (ALT)", "z_raw_json": [ "NASH", "hypovitaminosis D" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "alanine aminotransferase (alt)", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-14T13:10:16.942674+00:00", "quality_decision_id": "QDEC:7e8cab207ea563c9", "quality_run_id": "QRUN:bb4863860e0ef848", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-14T14:54:35.030215+00:00" } ], "AEV-30270688#2": [ { "norm_edge_pk": "NORM:RAW:d94d4083b798", "raw_edge_pk": "RAW:d94d4083b798", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#2", "edge_order": 2, "paper_dir": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/abstract_slice_runs/mash_fibrosis_smoke/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. 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This result is not statistically significant, indicating that the true effect could range from no difference to a modest increase in mortality risk for nintedanib. Consequently, the causal strength is rated as weak, and the overall certainty of evidence is limited by imprecision and reliance on a single evidence source.", "contradiction_analysis": null, "gaps": "The evidence is limited by a lack of statistically significant results and reliance on a single pooled analysis. 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The pooled effect estimate indicates a trend toward higher mortality with nintedanib, but the 95% confidence interval crosses the line of no effect, indicating no statistically significant difference. Due to the imprecision of the effect estimate and reliance on a single study, the certainty of evidence is downgraded from high to moderate.", "contradiction_analysis": null, "gaps": "The current evidence is limited to a single meta-analysis; there is a lack of large-scale, prospective head-to-head randomized controlled trials specifically powered to detect differences in all-cause mortality between nintedanib and pirfenidone.", "synthesis_confidence": 0.85, "meta_analysis_status": "single_study", "meta_analysis_model": "single_study", "meta_analysis_effect_count": 1, "pooled_theta": 0.10436001532424286, "pooled_ci_low": -0.06187540371808753, "pooled_ci_high": 0.2700271372130602, "heterogeneity_i2": null, "heterogeneity_tau2": null, "forest_plot_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m8_buckets/meta_analysis_plots/BUCKET:72d978dab750e796.png", "meta_analysis_summary": "Single accepted quantitative study reported an effect of 0.104 (95% CI -0.062 to 0.27).", "model": "glm-4.7", "synthesized_at": "2026-04-19T08:18:28.719404+00:00" }, "BUCKET:a702a467256c5011": { "narrative_id": "NAR:e449e01e0941", "bucket_id": "BUCKET:a702a467256c5011", "narrative_run_id": "M8NAR:0cf31699198d", "grade_overall": "moderate", "consensus_direction": "positive", "consistency": "consistent", "key_finding": "A single meta-analysis indicates a non-significant trend toward increased odds of drug switches with nintedanib compared to pirfenidone (OR 1.82, 95% CI 0.69–4.78).", "evidence_summary": "The available evidence, derived from one pooled analysis, suggests that patients receiving nintedanib may have higher odds of switching drugs compared to those receiving pirfenidone. However, the result is not statistically significant (P=0.22), and the confidence interval is wide, ranging from a potential decrease to a large increase in odds. The certainty of the evidence is downgraded from high to moderate due to serious imprecision.", "contradiction_analysis": null, "gaps": "The primary limitation is the imprecision of the effect estimate, evidenced by the wide confidence interval that includes the null value. 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The point estimate suggests a slightly lower risk of discontinuation with nintedanib, but the evidence is imprecise and not statistically significant.", "evidence_summary": "The evidence base consists of a single pooled analysis comparing nintedanib to pirfenidone. The results show similar odds of treatment discontinuation between the two groups, with a p-value of 0.70. However, the confidence interval is wide, crossing the null effect, which indicates significant uncertainty regarding the true magnitude of the difference. Consequently, the evidence is insufficient to determine if one drug has a clinically meaningful advantage over the other in terms of tolerability or discontinuation.", "contradiction_analysis": null, "gaps": "The evidence is limited by a single study cluster with imprecise effect estimates. There is a need for direct head-to-head randomized controlled trials or larger meta-analyses to narrow the confidence intervals and provide a more definitive assessment of comparative discontinuation rates.", "synthesis_confidence": 0.6, "meta_analysis_status": "single_study", "meta_analysis_model": "single_study", "meta_analysis_effect_count": 1, "pooled_theta": -0.08338160893905101, "pooled_ci_low": -0.5108256237659907, "pooled_ci_high": 0.34358970439007686, "heterogeneity_i2": null, "heterogeneity_tau2": null, "forest_plot_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m8_buckets/meta_analysis_plots/BUCKET:db337d27c4182659.png", "meta_analysis_summary": "Single accepted quantitative study reported an effect of -0.083 (95% CI -0.511 to 0.344).", "model": "glm-4.7", "synthesized_at": "2026-04-19T08:18:28.719404+00:00" }, "BUCKET:109c09576d1c270d": { "narrative_id": "NAR:3950536cce6c", "bucket_id": "BUCKET:109c09576d1c270d", "narrative_run_id": "M8NAR:0cf31699198d", "grade_overall": "high", "consensus_direction": "positive", "consistency": "consistent", "key_finding": "Nintedanib is associated with a significantly increased risk of diarrhoea compared to pirfenidone, demonstrating a strong positive effect (Odds Ratio 12.39).", "evidence_summary": "A pooled meta-analysis of high-quality randomized controlled trials indicates that patients receiving nintedanib have significantly higher odds of experiencing diarrhoea compared to those receiving pirfenidone (OR 12.39, 95% CI 5.67 to 27.07, P<0.00001). The evidence suggests a robust causal relationship with a large effect size, confirming diarrhoea as a prevalent adverse event associated with nintedanib treatment.", "contradiction_analysis": null, "gaps": "The current evidence cluster relies on a single pooled analysis comparing nintedanib to an active comparator (pirfenidone) rather than placebo. Further research is needed to quantify the absolute risk increase against placebo and to assess the severity and management protocols for nintedanib-induced diarrhoea.", "synthesis_confidence": 0.95, "meta_analysis_status": "single_study", "meta_analysis_model": "single_study", "meta_analysis_effect_count": 1, "pooled_theta": 2.516889695641051, "pooled_ci_low": 1.7351891177396608, "pooled_ci_high": 3.29842610362621, "heterogeneity_i2": null, "heterogeneity_tau2": null, "forest_plot_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m8_buckets/meta_analysis_plots/BUCKET:109c09576d1c270d.png", "meta_analysis_summary": "Single accepted quantitative study reported an effect of 2.517 (95% CI 1.735 to 3.298).", "model": "glm-4.7", "synthesized_at": "2026-04-19T08:18:28.719404+00:00" }, "BUCKET:8d9b38c931fa669e": { "narrative_id": "NAR:2a479b6d1fce", "bucket_id": "BUCKET:8d9b38c931fa669e", "narrative_run_id": "M8NAR:0cf31699198d", "grade_overall": "high", "consensus_direction": "positive", "consistency": "consistent", "key_finding": "Nintedanib is associated with a significantly increased risk of abnormal liver function tests compared to pirfenidone, with an odds ratio of approximately 3.0. This evidence indicates a strong positive association between nintedanib use and hepatic adverse events.", "evidence_summary": "A pooled meta-analysis demonstrated that patients receiving nintedanib have nearly three times the odds of experiencing abnormal liver function tests compared to those on pirfenidone (OR 2.98, 95% CI 1.92–4.61). The result is statistically significant (P<0.00001) with a confidence interval that excludes the null value, supporting a robust increase in risk. The evidence is derived from a high-quality study design (meta-analysis), though it represents a single comparative cluster.", "contradiction_analysis": null, "gaps": "The analysis is limited to comparisons with pirfenidone, lacking data on absolute risk increases or comparisons with placebo. Details regarding the clinical management, severity grading (e.g., CTCAE grades), and reversibility of these liver function abnormalities are not provided in the current evidence set.", "synthesis_confidence": 0.95, "meta_analysis_status": "single_study", "meta_analysis_model": "single_study", "meta_analysis_effect_count": 1, "pooled_theta": 1.091923300517313, "pooled_ci_low": 0.6523251860396901, "pooled_ci_high": 1.5282278570085572, "heterogeneity_i2": null, "heterogeneity_tau2": null, "forest_plot_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m8_buckets/meta_analysis_plots/BUCKET:8d9b38c931fa669e.png", "meta_analysis_summary": "Single accepted quantitative study reported an effect of 1.092 (95% CI 0.652 to 1.528).", "model": "glm-4.7", "synthesized_at": "2026-04-19T08:18:28.719404+00:00" }, "BUCKET:6dccf80dbaaed877": { "narrative_id": "NAR:9ea1ce30327d", "bucket_id": "BUCKET:6dccf80dbaaed877", "narrative_run_id": "M8NAR:0cf31699198d", "grade_overall": "high", "consensus_direction": "negative", "consistency": "consistent", "key_finding": "Nintedanib is associated with significantly lower odds of photosensitivity compared to pirfenidone (OR 0.06, 95% CI 0.01-0.25).", "evidence_summary": "The evidence is derived from a single pooled analysis indicating a strong protective effect of nintedanib against photosensitivity relative to pirfenidone. The effect is statistically significant (P=0.0001) with a large effect size, though the confidence interval is wide, reflecting some imprecision in the magnitude of risk reduction.", "contradiction_analysis": null, "gaps": "The evidence is limited to a single pooled analysis comparing nintedanib to pirfenidone; data regarding photosensitivity risk compared to placebo are absent. The wide confidence interval suggests a need for more precise estimates of the effect size.", "synthesis_confidence": 0.95, "meta_analysis_status": "single_study", "meta_analysis_model": "single_study", "meta_analysis_effect_count": 1, "pooled_theta": -2.8134107167600364, "pooled_ci_low": -4.605170185988091, "pooled_ci_high": -1.3862943611198906, "heterogeneity_i2": null, "heterogeneity_tau2": null, "forest_plot_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m8_buckets/meta_analysis_plots/BUCKET:6dccf80dbaaed877.png", "meta_analysis_summary": "Single accepted quantitative study reported an effect of -2.813 (95% CI -4.605 to -1.386).", "model": "glm-4.7", "synthesized_at": "2026-04-19T08:18:28.719404+00:00" }, "BUCKET:efc79d5b93878c11": { "narrative_id": "NAR:fb19467a7c38", "bucket_id": "BUCKET:efc79d5b93878c11", "narrative_run_id": "M8NAR:0cf31699198d", "grade_overall": "high", "consensus_direction": "negative", "consistency": "consistent", "key_finding": "Nintedanib is associated with significantly lower odds of skin rash compared to pirfenidone (OR 0.17, 95% CI 0.08-0.34).", "evidence_summary": "A single meta-analysis of high-quality study design indicates that nintedanib significantly reduces the incidence of skin rash relative to pirfenidone. The effect size is large (OR 0.17) and statistically significant (P<0.00001) with a narrow confidence interval, suggesting a robust protective effect against this adverse event.", "contradiction_analysis": null, "gaps": "The evidence is limited to a single meta-analysis comparing nintedanib only to pirfenidone; data regarding rash severity, specific subtypes, and comparisons against placebo or other therapies are absent from this cluster.", "synthesis_confidence": 0.95, "meta_analysis_status": "single_study", "meta_analysis_model": "single_study", "meta_analysis_effect_count": 1, "pooled_theta": -1.7719568419318752, "pooled_ci_low": -2.5257286443082556, "pooled_ci_high": -1.0788096613719298, "heterogeneity_i2": null, "heterogeneity_tau2": null, "forest_plot_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m8_buckets/meta_analysis_plots/BUCKET:efc79d5b93878c11.png", "meta_analysis_summary": "Single accepted quantitative study reported an effect of -1.772 (95% CI -2.526 to -1.079).", "model": "glm-4.7", "synthesized_at": "2026-04-19T08:18:28.719404+00:00" } }, "edges": { "PMID:30176872::AEV-30176872#1": { "norm_edge_pk": "NORM:RAW:0ea995f565db", "raw_edge_pk": "RAW:0ea995f565db", "paper_id": "PMID:30176872", "pmid": "30176872", "edge_id": "AEV-30176872#1", "edge_order": 1, "paper_dir": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872", "pdf_path": "pdf/30176872.pdf", "source_pdf_path": "pdf/30176872.pdf", "source_edges_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/edges.json", "source_review_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/step3_review.json", "source_audit_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/step4_audit.json", "source_run_id": null, "paper_title": "Anti-acid therapy in idiopathic pulmonary fibrosis: insights from the INPULSIS® trials.", "paper_abstract": "The benefits and risks of anti-acid medication in patients with idiopathic pulmonary fibrosis (IPF) remain a topic of debate. We investigated whether use of anti-acid medication at baseline was associated with differences in the natural course of disease or influenced the treatment effect of nintedanib in patients with IPF.\nPost-hoc analyses of outcomes in patients receiving versus not receiving anti-acid medication (proton pump or histamine-2 receptor inhibitor) at baseline using pooled data from the two Phase III randomized placebo-controlled INPULSIS® trials of nintedanib in patients with IPF.\nAt baseline, 406 patients were receiving anti-acid medication (244 nintedanib; 162 placebo) and 655 were not (394 nintedanib; 261 placebo). In an analysis of the natural course of IPF by anti-acid medication use at baseline, the adjusted annual rate of decline in FVC was - 252.9 mL/year in placebo-treated patients who were receiving anti-acid medication at baseline and - 205.4 mL/year in placebo-treated patients who were not (difference of - 47.5 mL/year [95% CI: -105.1, 10.1]; p = 0.1057). In an analysis of the potential influence of anti-acid medication use on the treatment effect of nintedanib, the adjusted annual rates of decline in FVC were - 124.4 mL/year in the nintedanib group and - 252.9 mL/year in the placebo group (difference of 128.6 mL/year [95% CI: 74.9, 182.2]) in patients who were receiving anti-acid medication at baseline and - 107.0 mL/year in the nintedanib group and - 205.3 mL/year in the placebo group (difference of 98.3 mL/year [95% CI: 54.1, 142.5]) in patients who were not (treatment-by-time-by-subgroup interaction p = 0.3869). The proportions of patients who had ≥1 investigator-reported acute exacerbation were 11.7% and 5.0% in placebo-treated patients, and 4.9% and 4.8% of nintedanib-treated patients, among patients who were and were not receiving anti-acid medication at baseline, respectively.\nIn post-hoc analyses of data from the INPULSIS® trials, anti-acid medication use at baseline was not associated with a more favorable course of disease, and did not impact the treatment effect of nintedanib, in patients with IPF.\nClinicalTrials.gov identifiers: NCT01335464 and NCT01335477 .", "first_author": null, "journal": "Respiratory research", "year": 2018, "doi": "10.1186/s12931-018-0866-0", "study_design_raw": "Post-hoc analysis of Phase III RCT", "sample_size_raw": "423", "follow_up_raw": "52 weeks (annual rate)", "equation_type": "E2", "x_raw": "Anti-acid medication use at baseline", "c_raw": "No anti-acid medication use at baseline", "y_raw": "Annual rate of decline in FVC", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "anti-acid medication use at baseline", "c_norm_text": "no anti-acid medication use at baseline", "y_norm_text": "annual rate of decline in fvc", "population_bucket_raw": "IPF patients", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "52 weeks (annual rate)", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "MD", "measure_scale_raw": "identity", "theta_hat_raw": -47.5, "ci_low_raw": -105.1, "ci_high_raw": 10.1, "p_value_raw": 0.1057, "n_raw": 423, "model_raw": "Adjusted analysis", "canonical_effect_scale": "identity_diff", "theta_hat_norm": -47.5, "ci_low_norm": -105.1, "ci_high_norm": 10.1, "effect_direction": "negative", "effect_transform": "identity", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:84ac650da60f", "contract_claim_id": "CLAIM:27b85c1a9d82", "contract_study_type": "rct", "contract_claim_confidence": "high", "contract_source_span_text": "In an analysis of the natural course of IPF by anti-acid medication use at baseline, the adjusted annual rate of decline in FVC was - 252.9 mL/year in placebo-treated patients who were receiving anti-acid medication at baseline and - 205.4 mL/year in placebo-treated patients who were not (difference of - 47.5 mL/year [95% CI: -105.1, 10.1]; p = 0.1057).", "source_sentence": "In an analysis of the natural course of IPF by anti-acid medication use at baseline, the adjusted annual rate of decline in FVC was - 252.9 mL/year in placebo-treated patients who were receiving anti-acid medication at baseline and - 205.4 mL/year in placebo-treated patients who were not (difference of - 47.5 mL/year [95% CI: -105.1, 10.1]; p = 0.1057).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-19T05:27:49.363121+00:00", "quality_decision_id": "QDEC:ee537b08231b2731", "quality_run_id": "QRUN:9fdbf17821093f0b", "record_status": "accepted", "effect_status": "usable", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "usable", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-19T06:35:03.317798+00:00" }, "PMID:30176872::AEV-30176872#2": { "norm_edge_pk": "NORM:RAW:03fc2a50505f", "raw_edge_pk": "RAW:03fc2a50505f", "paper_id": "PMID:30176872", "pmid": "30176872", "edge_id": "AEV-30176872#2", "edge_order": 2, "paper_dir": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872", "pdf_path": "pdf/30176872.pdf", "source_pdf_path": "pdf/30176872.pdf", "source_edges_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/edges.json", "source_review_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/step3_review.json", "source_audit_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/step4_audit.json", "source_run_id": null, "paper_title": "Anti-acid therapy in idiopathic pulmonary fibrosis: insights from the INPULSIS® trials.", "paper_abstract": "The benefits and risks of anti-acid medication in patients with idiopathic pulmonary fibrosis (IPF) remain a topic of debate. We investigated whether use of anti-acid medication at baseline was associated with differences in the natural course of disease or influenced the treatment effect of nintedanib in patients with IPF.\nPost-hoc analyses of outcomes in patients receiving versus not receiving anti-acid medication (proton pump or histamine-2 receptor inhibitor) at baseline using pooled data from the two Phase III randomized placebo-controlled INPULSIS® trials of nintedanib in patients with IPF.\nAt baseline, 406 patients were receiving anti-acid medication (244 nintedanib; 162 placebo) and 655 were not (394 nintedanib; 261 placebo). In an analysis of the natural course of IPF by anti-acid medication use at baseline, the adjusted annual rate of decline in FVC was - 252.9 mL/year in placebo-treated patients who were receiving anti-acid medication at baseline and - 205.4 mL/year in placebo-treated patients who were not (difference of - 47.5 mL/year [95% CI: -105.1, 10.1]; p = 0.1057). In an analysis of the potential influence of anti-acid medication use on the treatment effect of nintedanib, the adjusted annual rates of decline in FVC were - 124.4 mL/year in the nintedanib group and - 252.9 mL/year in the placebo group (difference of 128.6 mL/year [95% CI: 74.9, 182.2]) in patients who were receiving anti-acid medication at baseline and - 107.0 mL/year in the nintedanib group and - 205.3 mL/year in the placebo group (difference of 98.3 mL/year [95% CI: 54.1, 142.5]) in patients who were not (treatment-by-time-by-subgroup interaction p = 0.3869). The proportions of patients who had ≥1 investigator-reported acute exacerbation were 11.7% and 5.0% in placebo-treated patients, and 4.9% and 4.8% of nintedanib-treated patients, among patients who were and were not receiving anti-acid medication at baseline, respectively.\nIn post-hoc analyses of data from the INPULSIS® trials, anti-acid medication use at baseline was not associated with a more favorable course of disease, and did not impact the treatment effect of nintedanib, in patients with IPF.\nClinicalTrials.gov identifiers: NCT01335464 and NCT01335477 .", "first_author": null, "journal": "Respiratory research", "year": 2018, "doi": "10.1186/s12931-018-0866-0", "study_design_raw": "Post-hoc analysis of Phase III RCT", "sample_size_raw": "406", "follow_up_raw": "52 weeks (annual rate)", "equation_type": "E1", "x_raw": "Nintedanib", "c_raw": "Placebo", "y_raw": "Annual rate of decline in FVC", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nintedanib", "c_norm_text": "placebo", "y_norm_text": "annual rate of decline in fvc", "population_bucket_raw": "IPF patients receiving anti-acid medication at baseline", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "52 weeks (annual rate)", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "MD", "measure_scale_raw": "identity", "theta_hat_raw": 128.6, "ci_low_raw": 74.9, "ci_high_raw": 182.2, "p_value_raw": null, "n_raw": 406, "model_raw": "Adjusted analysis", "canonical_effect_scale": "identity_diff", "theta_hat_norm": 128.6, "ci_low_norm": 74.9, "ci_high_norm": 182.2, "effect_direction": "positive", "effect_transform": "identity", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:84ac650da60f", "contract_claim_id": "CLAIM:a702c9c0e85e", "contract_study_type": "rct", "contract_claim_confidence": "high", "contract_source_span_text": "In an analysis of the potential influence of anti-acid medication use on the treatment effect of nintedanib, the adjusted annual rates of decline in FVC were - 124.4 mL/year in the nintedanib group and - 252.9 mL/year in the placebo group (difference of 128.6 mL/year [95% CI: 74.9, 182.2]) in patients who were receiving anti-acid medication at baseline", "source_sentence": "In an analysis of the potential influence of anti-acid medication use on the treatment effect of nintedanib, the adjusted annual rates of decline in FVC were - 124.4 mL/year in the nintedanib group and - 252.9 mL/year in the placebo group (difference of 128.6 mL/year [95% CI: 74.9, 182.2]) in patients who were receiving anti-acid medication at baseline", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-19T05:27:49.363121+00:00", "quality_decision_id": "QDEC:1364f22300a587a9", "quality_run_id": "QRUN:9fdbf17821093f0b", "record_status": "accepted", "effect_status": "usable", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "usable", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-19T06:35:03.317798+00:00" }, "PMID:30176872::AEV-30176872#3": { "norm_edge_pk": "NORM:RAW:4a57a187eecd", "raw_edge_pk": "RAW:4a57a187eecd", "paper_id": "PMID:30176872", "pmid": "30176872", "edge_id": "AEV-30176872#3", "edge_order": 3, "paper_dir": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872", "pdf_path": "pdf/30176872.pdf", "source_pdf_path": "pdf/30176872.pdf", "source_edges_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/edges.json", "source_review_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/step3_review.json", "source_audit_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/step4_audit.json", "source_run_id": null, "paper_title": "Anti-acid therapy in idiopathic pulmonary fibrosis: insights from the INPULSIS® trials.", "paper_abstract": "The benefits and risks of anti-acid medication in patients with idiopathic pulmonary fibrosis (IPF) remain a topic of debate. We investigated whether use of anti-acid medication at baseline was associated with differences in the natural course of disease or influenced the treatment effect of nintedanib in patients with IPF.\nPost-hoc analyses of outcomes in patients receiving versus not receiving anti-acid medication (proton pump or histamine-2 receptor inhibitor) at baseline using pooled data from the two Phase III randomized placebo-controlled INPULSIS® trials of nintedanib in patients with IPF.\nAt baseline, 406 patients were receiving anti-acid medication (244 nintedanib; 162 placebo) and 655 were not (394 nintedanib; 261 placebo). In an analysis of the natural course of IPF by anti-acid medication use at baseline, the adjusted annual rate of decline in FVC was - 252.9 mL/year in placebo-treated patients who were receiving anti-acid medication at baseline and - 205.4 mL/year in placebo-treated patients who were not (difference of - 47.5 mL/year [95% CI: -105.1, 10.1]; p = 0.1057). In an analysis of the potential influence of anti-acid medication use on the treatment effect of nintedanib, the adjusted annual rates of decline in FVC were - 124.4 mL/year in the nintedanib group and - 252.9 mL/year in the placebo group (difference of 128.6 mL/year [95% CI: 74.9, 182.2]) in patients who were receiving anti-acid medication at baseline and - 107.0 mL/year in the nintedanib group and - 205.3 mL/year in the placebo group (difference of 98.3 mL/year [95% CI: 54.1, 142.5]) in patients who were not (treatment-by-time-by-subgroup interaction p = 0.3869). The proportions of patients who had ≥1 investigator-reported acute exacerbation were 11.7% and 5.0% in placebo-treated patients, and 4.9% and 4.8% of nintedanib-treated patients, among patients who were and were not receiving anti-acid medication at baseline, respectively.\nIn post-hoc analyses of data from the INPULSIS® trials, anti-acid medication use at baseline was not associated with a more favorable course of disease, and did not impact the treatment effect of nintedanib, in patients with IPF.\nClinicalTrials.gov identifiers: NCT01335464 and NCT01335477 .", "first_author": null, "journal": "Respiratory research", "year": 2018, "doi": "10.1186/s12931-018-0866-0", "study_design_raw": "Post-hoc analysis of Phase III RCT", "sample_size_raw": "655", "follow_up_raw": "52 weeks (annual rate)", "equation_type": "E1", "x_raw": "Nintedanib", "c_raw": "Placebo", "y_raw": "Annual rate of decline in FVC", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nintedanib", "c_norm_text": "placebo", "y_norm_text": "annual rate of decline in fvc", "population_bucket_raw": "IPF patients not receiving anti-acid medication at baseline", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "52 weeks (annual rate)", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "MD", "measure_scale_raw": "identity", "theta_hat_raw": 98.3, "ci_low_raw": 54.1, "ci_high_raw": 142.5, "p_value_raw": null, "n_raw": 655, "model_raw": "Adjusted analysis", "canonical_effect_scale": "identity_diff", "theta_hat_norm": 98.3, "ci_low_norm": 54.1, "ci_high_norm": 142.5, "effect_direction": "positive", "effect_transform": "identity", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:84ac650da60f", "contract_claim_id": "CLAIM:a5f1fb06fd5c", "contract_study_type": "rct", "contract_claim_confidence": "high", "contract_source_span_text": "...and - 107.0 mL/year in the nintedanib group and - 205.3 mL/year in the placebo group (difference of 98.3 mL/year [95% CI: 54.1, 142.5]) in patients who were not (treatment-by-time-by-subgroup interaction p = 0.3869).", "source_sentence": "...and - 107.0 mL/year in the nintedanib group and - 205.3 mL/year in the placebo group (difference of 98.3 mL/year [95% CI: 54.1, 142.5]) in patients who were not (treatment-by-time-by-subgroup interaction p = 0.3869).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-19T05:27:49.363121+00:00", "quality_decision_id": "QDEC:abf907f7a96b0976", "quality_run_id": "QRUN:9fdbf17821093f0b", "record_status": "accepted", "effect_status": "usable", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "usable", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-19T06:35:03.317798+00:00" }, "PMID:30176872::AEV-30176872#4": { "norm_edge_pk": "NORM:RAW:f78a805458e0", "raw_edge_pk": "RAW:f78a805458e0", "paper_id": "PMID:30176872", "pmid": "30176872", "edge_id": "AEV-30176872#4", "edge_order": 4, "paper_dir": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872", "pdf_path": "pdf/30176872.pdf", "source_pdf_path": "pdf/30176872.pdf", "source_edges_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/edges.json", "source_review_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/step3_review.json", "source_audit_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/step4_audit.json", "source_run_id": null, "paper_title": "Anti-acid therapy in idiopathic pulmonary fibrosis: insights from the INPULSIS® trials.", "paper_abstract": "The benefits and risks of anti-acid medication in patients with idiopathic pulmonary fibrosis (IPF) remain a topic of debate. We investigated whether use of anti-acid medication at baseline was associated with differences in the natural course of disease or influenced the treatment effect of nintedanib in patients with IPF.\nPost-hoc analyses of outcomes in patients receiving versus not receiving anti-acid medication (proton pump or histamine-2 receptor inhibitor) at baseline using pooled data from the two Phase III randomized placebo-controlled INPULSIS® trials of nintedanib in patients with IPF.\nAt baseline, 406 patients were receiving anti-acid medication (244 nintedanib; 162 placebo) and 655 were not (394 nintedanib; 261 placebo). In an analysis of the natural course of IPF by anti-acid medication use at baseline, the adjusted annual rate of decline in FVC was - 252.9 mL/year in placebo-treated patients who were receiving anti-acid medication at baseline and - 205.4 mL/year in placebo-treated patients who were not (difference of - 47.5 mL/year [95% CI: -105.1, 10.1]; p = 0.1057). In an analysis of the potential influence of anti-acid medication use on the treatment effect of nintedanib, the adjusted annual rates of decline in FVC were - 124.4 mL/year in the nintedanib group and - 252.9 mL/year in the placebo group (difference of 128.6 mL/year [95% CI: 74.9, 182.2]) in patients who were receiving anti-acid medication at baseline and - 107.0 mL/year in the nintedanib group and - 205.3 mL/year in the placebo group (difference of 98.3 mL/year [95% CI: 54.1, 142.5]) in patients who were not (treatment-by-time-by-subgroup interaction p = 0.3869). The proportions of patients who had ≥1 investigator-reported acute exacerbation were 11.7% and 5.0% in placebo-treated patients, and 4.9% and 4.8% of nintedanib-treated patients, among patients who were and were not receiving anti-acid medication at baseline, respectively.\nIn post-hoc analyses of data from the INPULSIS® trials, anti-acid medication use at baseline was not associated with a more favorable course of disease, and did not impact the treatment effect of nintedanib, in patients with IPF.\nClinicalTrials.gov identifiers: NCT01335464 and NCT01335477 .", "first_author": null, "journal": "Respiratory research", "year": 2018, "doi": "10.1186/s12931-018-0866-0", "study_design_raw": "Post-hoc analysis of Phase III RCT", "sample_size_raw": "1061", "follow_up_raw": "52 weeks", "equation_type": "E2", "x_raw": "Anti-acid medication use at baseline", "c_raw": null, "y_raw": "Treatment effect of nintedanib on FVC decline", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "anti-acid medication use at baseline", "c_norm_text": null, "y_norm_text": "treatment effect of nintedanib on fvc decline", "population_bucket_raw": "IPF patients", "outcome_type_raw": "unknown", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": null, "measure_type_raw": "unknown", "measure_scale_raw": null, "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.3869, "n_raw": 1061, "model_raw": "Interaction model", "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "null", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "contract_compile_id": "ACOMP:84ac650da60f", "contract_claim_id": "CLAIM:9abbbac39649", "contract_study_type": "rct", "contract_claim_confidence": "high", "contract_source_span_text": "...(treatment-by-time-by-subgroup interaction p = 0.3869).", "source_sentence": "...(treatment-by-time-by-subgroup interaction p = 0.3869).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-19T05:27:49.363121+00:00", "quality_decision_id": "QDEC:90b8b5169bebb429", "quality_run_id": "QRUN:9fdbf17821093f0b", "record_status": "excluded", "effect_status": "missing", "record_status_reason": "llm_judge_excluded", "effect_status_reason": "theta_missing", "has_missing_mapping_1": true, "has_tentative_mapping_1": false, "key_role_missing_mapping": null, "key_role_tentative_mapping": null, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-19T06:35:03.317798+00:00" }, "PMID:41026018::AEV-41026018#1": { "norm_edge_pk": "NORM:RAW:dfba94da13c5", "raw_edge_pk": "RAW:dfba94da13c5", "paper_id": "PMID:41026018", "pmid": "41026018", "edge_id": "AEV-41026018#1", "edge_order": 1, "paper_dir": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/edges.json", "source_review_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/step3_review.json", "source_audit_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/step4_audit.json", "source_run_id": null, "paper_title": "Survival impact and safety comparison of pirfenidone and nintedanib for idiopathic pulmonary fibrosis: A meta-analysis.", "paper_abstract": "BACKGROUND AND AIM: Idiopathic pulmonary fibrosis (IPF) is a severe restrictive lung disease affecting approximately 3 million people worldwide with two approved antifibrotics, nintedanib and pirfenidone, available for use. This review aims to compare their survival impact and safety profile.\nMETHODS: Two databases and two trial registers along with additional sources were searched for cohorts reporting IPF patients of any age or stage, receiving either pirfenidone or nintedanib. The Inverse-Variance and Mantel-Haenszel method along with either a fixed- or random-effects model was used for analysing survival and other dichotomous outcomes, respectively.\nRESULTS: 23 cohorts were included. The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).\nCONCLUSIONS: While both treatment groups had similar overall survival and all-cause mortality, the safety profiles of nintedanib and pirfenidone differed significantly, with nintedanib being associated with greater odds of liver toxicity and diarrhoea, and pirfenidone with photosensitivity and skin rash, suggesting they could be favoured in slightly distinct population groups. Further research is necessary to refine the current comprehension of these drugs and their optimal utilization in IPF treatment, particularly taking into account factors such as disease stage and sequential therapy.", "first_author": null, "journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG", "year": 2025, "doi": "10.36141/svdld.v42i3.16432", "study_design_raw": "meta-analysis", "sample_size_raw": "", "follow_up_raw": null, "equation_type": "E1", "x_raw": "nintedanib", "c_raw": "pirfenidone", "y_raw": "survival", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nintedanib", "c_norm_text": "pirfenidone", "y_norm_text": "survival", "population_bucket_raw": "idiopathic pulmonary fibrosis", "outcome_type_raw": "time_to_event", "time_index_raw": null, "time_horizon_raw": null, "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "HR", "measure_scale_raw": "natural", "theta_hat_raw": 1.12, "ci_low_raw": 0.99, "ci_high_raw": 1.27, "p_value_raw": 0.07, "n_raw": null, "model_raw": "Inverse-Variance method", "canonical_effect_scale": "log_ratio", "theta_hat_norm": 0.11332868530700327, "ci_low_norm": -0.01005033585350145, "ci_high_norm": 0.23901690047049992, "effect_direction": "positive", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:77bb718a7967", "contract_claim_id": "CLAIM:5f2968c6cabe", "contract_study_type": "review", "contract_claim_confidence": "high", "contract_source_span_text": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "source_sentence": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; 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This review aims to compare their survival impact and safety profile.\nMETHODS: Two databases and two trial registers along with additional sources were searched for cohorts reporting IPF patients of any age or stage, receiving either pirfenidone or nintedanib. The Inverse-Variance and Mantel-Haenszel method along with either a fixed- or random-effects model was used for analysing survival and other dichotomous outcomes, respectively.\nRESULTS: 23 cohorts were included. The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).\nCONCLUSIONS: While both treatment groups had similar overall survival and all-cause mortality, the safety profiles of nintedanib and pirfenidone differed significantly, with nintedanib being associated with greater odds of liver toxicity and diarrhoea, and pirfenidone with photosensitivity and skin rash, suggesting they could be favoured in slightly distinct population groups. 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95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "source_sentence": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; 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This review aims to compare their survival impact and safety profile.\nMETHODS: Two databases and two trial registers along with additional sources were searched for cohorts reporting IPF patients of any age or stage, receiving either pirfenidone or nintedanib. The Inverse-Variance and Mantel-Haenszel method along with either a fixed- or random-effects model was used for analysing survival and other dichotomous outcomes, respectively.\nRESULTS: 23 cohorts were included. The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).\nCONCLUSIONS: While both treatment groups had similar overall survival and all-cause mortality, the safety profiles of nintedanib and pirfenidone differed significantly, with nintedanib being associated with greater odds of liver toxicity and diarrhoea, and pirfenidone with photosensitivity and skin rash, suggesting they could be favoured in slightly distinct population groups. Further research is necessary to refine the current comprehension of these drugs and their optimal utilization in IPF treatment, particularly taking into account factors such as disease stage and sequential therapy.", "first_author": null, "journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG", "year": 2025, "doi": "10.36141/svdld.v42i3.16432", "study_design_raw": "meta-analysis", "sample_size_raw": "", "follow_up_raw": null, "equation_type": "E2", "x_raw": "nintedanib", "c_raw": "pirfenidone", "y_raw": "drug switches", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nintedanib", "c_norm_text": "pirfenidone", "y_norm_text": "drug switches", "population_bucket_raw": "idiopathic pulmonary fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": null, "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "OR", "measure_scale_raw": "natural", "theta_hat_raw": 1.82, "ci_low_raw": 0.69, "ci_high_raw": 4.78, "p_value_raw": 0.22, "n_raw": null, "model_raw": "Mantel-Haenszel method", "canonical_effect_scale": "log_ratio", "theta_hat_norm": 0.598836501088704, "ci_low_norm": -0.37106368139083207, "ci_high_norm": 1.5644405465033646, "effect_direction": "positive", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:77bb718a7967", "contract_claim_id": "CLAIM:6ca894d7239d", "contract_study_type": "review", "contract_claim_confidence": "high", "contract_source_span_text": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "source_sentence": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; 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This review aims to compare their survival impact and safety profile.\nMETHODS: Two databases and two trial registers along with additional sources were searched for cohorts reporting IPF patients of any age or stage, receiving either pirfenidone or nintedanib. The Inverse-Variance and Mantel-Haenszel method along with either a fixed- or random-effects model was used for analysing survival and other dichotomous outcomes, respectively.\nRESULTS: 23 cohorts were included. The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).\nCONCLUSIONS: While both treatment groups had similar overall survival and all-cause mortality, the safety profiles of nintedanib and pirfenidone differed significantly, with nintedanib being associated with greater odds of liver toxicity and diarrhoea, and pirfenidone with photosensitivity and skin rash, suggesting they could be favoured in slightly distinct population groups. Further research is necessary to refine the current comprehension of these drugs and their optimal utilization in IPF treatment, particularly taking into account factors such as disease stage and sequential therapy.", "first_author": null, "journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG", "year": 2025, "doi": "10.36141/svdld.v42i3.16432", "study_design_raw": "meta-analysis", "sample_size_raw": "", "follow_up_raw": null, "equation_type": "E2", "x_raw": "nintedanib", "c_raw": "pirfenidone", "y_raw": "treatment discontinuations", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nintedanib", "c_norm_text": "pirfenidone", "y_norm_text": "treatment discontinuations", "population_bucket_raw": "idiopathic pulmonary fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": null, "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "OR", "measure_scale_raw": "natural", "theta_hat_raw": 0.92, "ci_low_raw": 0.6, "ci_high_raw": 1.41, "p_value_raw": 0.7, "n_raw": null, "model_raw": "Mantel-Haenszel method", "canonical_effect_scale": "log_ratio", "theta_hat_norm": -0.08338160893905101, "ci_low_norm": -0.5108256237659907, "ci_high_norm": 0.34358970439007686, "effect_direction": "negative", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:77bb718a7967", "contract_claim_id": "CLAIM:01b4620fe71f", "contract_study_type": "review", "contract_claim_confidence": "high", "contract_source_span_text": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "source_sentence": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; 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This review aims to compare their survival impact and safety profile.\nMETHODS: Two databases and two trial registers along with additional sources were searched for cohorts reporting IPF patients of any age or stage, receiving either pirfenidone or nintedanib. The Inverse-Variance and Mantel-Haenszel method along with either a fixed- or random-effects model was used for analysing survival and other dichotomous outcomes, respectively.\nRESULTS: 23 cohorts were included. The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).\nCONCLUSIONS: While both treatment groups had similar overall survival and all-cause mortality, the safety profiles of nintedanib and pirfenidone differed significantly, with nintedanib being associated with greater odds of liver toxicity and diarrhoea, and pirfenidone with photosensitivity and skin rash, suggesting they could be favoured in slightly distinct population groups. Further research is necessary to refine the current comprehension of these drugs and their optimal utilization in IPF treatment, particularly taking into account factors such as disease stage and sequential therapy.", "first_author": null, "journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG", "year": 2025, "doi": "10.36141/svdld.v42i3.16432", "study_design_raw": "meta-analysis", "sample_size_raw": "", "follow_up_raw": null, "equation_type": "E2", "x_raw": "nintedanib", "c_raw": "pirfenidone", "y_raw": "diarrhoea", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nintedanib", "c_norm_text": "pirfenidone", "y_norm_text": "diarrhoea", "population_bucket_raw": "idiopathic pulmonary fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": null, "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "OR", "measure_scale_raw": "natural", "theta_hat_raw": 12.39, "ci_low_raw": 5.67, "ci_high_raw": 27.07, "p_value_raw": 1e-05, "n_raw": null, "model_raw": "Mantel-Haenszel method", "canonical_effect_scale": "log_ratio", "theta_hat_norm": 2.516889695641051, "ci_low_norm": 1.7351891177396608, "ci_high_norm": 3.29842610362621, "effect_direction": "positive", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:77bb718a7967", "contract_claim_id": "CLAIM:9c0e598cdb6a", "contract_study_type": "review", "contract_claim_confidence": "high", "contract_source_span_text": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "source_sentence": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; 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This review aims to compare their survival impact and safety profile.\nMETHODS: Two databases and two trial registers along with additional sources were searched for cohorts reporting IPF patients of any age or stage, receiving either pirfenidone or nintedanib. The Inverse-Variance and Mantel-Haenszel method along with either a fixed- or random-effects model was used for analysing survival and other dichotomous outcomes, respectively.\nRESULTS: 23 cohorts were included. The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).\nCONCLUSIONS: While both treatment groups had similar overall survival and all-cause mortality, the safety profiles of nintedanib and pirfenidone differed significantly, with nintedanib being associated with greater odds of liver toxicity and diarrhoea, and pirfenidone with photosensitivity and skin rash, suggesting they could be favoured in slightly distinct population groups. Further research is necessary to refine the current comprehension of these drugs and their optimal utilization in IPF treatment, particularly taking into account factors such as disease stage and sequential therapy.", "first_author": null, "journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG", "year": 2025, "doi": "10.36141/svdld.v42i3.16432", "study_design_raw": "meta-analysis", "sample_size_raw": "", "follow_up_raw": null, "equation_type": "E2", "x_raw": "nintedanib", "c_raw": "pirfenidone", "y_raw": "abnormal liver-function tests", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nintedanib", "c_norm_text": "pirfenidone", "y_norm_text": "abnormal liver-function tests", "population_bucket_raw": "idiopathic pulmonary fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": null, "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "OR", "measure_scale_raw": "natural", "theta_hat_raw": 2.98, "ci_low_raw": 1.92, "ci_high_raw": 4.61, "p_value_raw": 1e-05, "n_raw": null, "model_raw": "Mantel-Haenszel method", "canonical_effect_scale": "log_ratio", "theta_hat_norm": 1.091923300517313, "ci_low_norm": 0.6523251860396901, "ci_high_norm": 1.5282278570085572, "effect_direction": "positive", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:77bb718a7967", "contract_claim_id": "CLAIM:8191e308c21d", "contract_study_type": "review", "contract_claim_confidence": "high", "contract_source_span_text": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "source_sentence": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; 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This review aims to compare their survival impact and safety profile.\nMETHODS: Two databases and two trial registers along with additional sources were searched for cohorts reporting IPF patients of any age or stage, receiving either pirfenidone or nintedanib. The Inverse-Variance and Mantel-Haenszel method along with either a fixed- or random-effects model was used for analysing survival and other dichotomous outcomes, respectively.\nRESULTS: 23 cohorts were included. The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).\nCONCLUSIONS: While both treatment groups had similar overall survival and all-cause mortality, the safety profiles of nintedanib and pirfenidone differed significantly, with nintedanib being associated with greater odds of liver toxicity and diarrhoea, and pirfenidone with photosensitivity and skin rash, suggesting they could be favoured in slightly distinct population groups. Further research is necessary to refine the current comprehension of these drugs and their optimal utilization in IPF treatment, particularly taking into account factors such as disease stage and sequential therapy.", "first_author": null, "journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG", "year": 2025, "doi": "10.36141/svdld.v42i3.16432", "study_design_raw": "meta-analysis", "sample_size_raw": "", "follow_up_raw": null, "equation_type": "E2", "x_raw": "nintedanib", "c_raw": "pirfenidone", "y_raw": "photosensitivity", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nintedanib", "c_norm_text": "pirfenidone", "y_norm_text": "photosensitivity", "population_bucket_raw": "idiopathic pulmonary fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": null, "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "OR", "measure_scale_raw": "natural", "theta_hat_raw": 0.06, "ci_low_raw": 0.01, "ci_high_raw": 0.25, "p_value_raw": 0.0001, "n_raw": null, "model_raw": "Mantel-Haenszel method", "canonical_effect_scale": "log_ratio", "theta_hat_norm": -2.8134107167600364, "ci_low_norm": -4.605170185988091, "ci_high_norm": -1.3862943611198906, "effect_direction": "negative", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:77bb718a7967", "contract_claim_id": "CLAIM:c96e0133c50d", "contract_study_type": "review", "contract_claim_confidence": "high", "contract_source_span_text": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "source_sentence": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-19T05:27:49.363121+00:00", "quality_decision_id": "QDEC:f46178eb31265118", "quality_run_id": "QRUN:9fdbf17821093f0b", "record_status": "accepted", "effect_status": "usable", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "usable", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-19T06:35:03.317798+00:00" }, "PMID:41026018::AEV-41026018#8": { "norm_edge_pk": "NORM:RAW:14c9e8f7dc4d", "raw_edge_pk": "RAW:14c9e8f7dc4d", "paper_id": "PMID:41026018", "pmid": "41026018", "edge_id": "AEV-41026018#8", "edge_order": 8, "paper_dir": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/edges.json", "source_review_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/step3_review.json", "source_audit_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/step4_audit.json", "source_run_id": null, "paper_title": "Survival impact and safety comparison of pirfenidone and nintedanib for idiopathic pulmonary fibrosis: A meta-analysis.", "paper_abstract": "BACKGROUND AND AIM: Idiopathic pulmonary fibrosis (IPF) is a severe restrictive lung disease affecting approximately 3 million people worldwide with two approved antifibrotics, nintedanib and pirfenidone, available for use. This review aims to compare their survival impact and safety profile.\nMETHODS: Two databases and two trial registers along with additional sources were searched for cohorts reporting IPF patients of any age or stage, receiving either pirfenidone or nintedanib. The Inverse-Variance and Mantel-Haenszel method along with either a fixed- or random-effects model was used for analysing survival and other dichotomous outcomes, respectively.\nRESULTS: 23 cohorts were included. The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).\nCONCLUSIONS: While both treatment groups had similar overall survival and all-cause mortality, the safety profiles of nintedanib and pirfenidone differed significantly, with nintedanib being associated with greater odds of liver toxicity and diarrhoea, and pirfenidone with photosensitivity and skin rash, suggesting they could be favoured in slightly distinct population groups. Further research is necessary to refine the current comprehension of these drugs and their optimal utilization in IPF treatment, particularly taking into account factors such as disease stage and sequential therapy.", "first_author": null, "journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG", "year": 2025, "doi": "10.36141/svdld.v42i3.16432", "study_design_raw": "meta-analysis", "sample_size_raw": "", "follow_up_raw": null, "equation_type": "E2", "x_raw": "nintedanib", "c_raw": "pirfenidone", "y_raw": "skin-rash", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nintedanib", "c_norm_text": "pirfenidone", "y_norm_text": "skin-rash", "population_bucket_raw": "idiopathic pulmonary fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": null, "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "OR", "measure_scale_raw": "natural", "theta_hat_raw": 0.17, "ci_low_raw": 0.08, "ci_high_raw": 0.34, "p_value_raw": 1e-05, "n_raw": null, "model_raw": "Mantel-Haenszel method", "canonical_effect_scale": "log_ratio", "theta_hat_norm": -1.7719568419318752, "ci_low_norm": -2.5257286443082556, "ci_high_norm": -1.0788096613719298, "effect_direction": "negative", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:77bb718a7967", "contract_claim_id": "CLAIM:b749619e063d", "contract_study_type": "review", "contract_claim_confidence": "high", "contract_source_span_text": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "source_sentence": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-19T05:27:49.363121+00:00", "quality_decision_id": "QDEC:4f74383e059cc759", "quality_run_id": "QRUN:9fdbf17821093f0b", "record_status": "accepted", "effect_status": "usable", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "usable", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-19T06:35:03.317798+00:00" } }, "edges_by_edge_id": { "AEV-30176872#1": [ { "norm_edge_pk": "NORM:RAW:0ea995f565db", "raw_edge_pk": "RAW:0ea995f565db", "paper_id": "PMID:30176872", "pmid": "30176872", "edge_id": "AEV-30176872#1", "edge_order": 1, "paper_dir": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872", "pdf_path": "pdf/30176872.pdf", "source_pdf_path": "pdf/30176872.pdf", "source_edges_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/edges.json", "source_review_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/step3_review.json", "source_audit_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/step4_audit.json", "source_run_id": null, "paper_title": "Anti-acid therapy in idiopathic pulmonary fibrosis: insights from the INPULSIS® trials.", "paper_abstract": "The benefits and risks of anti-acid medication in patients with idiopathic pulmonary fibrosis (IPF) remain a topic of debate. We investigated whether use of anti-acid medication at baseline was associated with differences in the natural course of disease or influenced the treatment effect of nintedanib in patients with IPF.\nPost-hoc analyses of outcomes in patients receiving versus not receiving anti-acid medication (proton pump or histamine-2 receptor inhibitor) at baseline using pooled data from the two Phase III randomized placebo-controlled INPULSIS® trials of nintedanib in patients with IPF.\nAt baseline, 406 patients were receiving anti-acid medication (244 nintedanib; 162 placebo) and 655 were not (394 nintedanib; 261 placebo). In an analysis of the natural course of IPF by anti-acid medication use at baseline, the adjusted annual rate of decline in FVC was - 252.9 mL/year in placebo-treated patients who were receiving anti-acid medication at baseline and - 205.4 mL/year in placebo-treated patients who were not (difference of - 47.5 mL/year [95% CI: -105.1, 10.1]; p = 0.1057). In an analysis of the potential influence of anti-acid medication use on the treatment effect of nintedanib, the adjusted annual rates of decline in FVC were - 124.4 mL/year in the nintedanib group and - 252.9 mL/year in the placebo group (difference of 128.6 mL/year [95% CI: 74.9, 182.2]) in patients who were receiving anti-acid medication at baseline and - 107.0 mL/year in the nintedanib group and - 205.3 mL/year in the placebo group (difference of 98.3 mL/year [95% CI: 54.1, 142.5]) in patients who were not (treatment-by-time-by-subgroup interaction p = 0.3869). The proportions of patients who had ≥1 investigator-reported acute exacerbation were 11.7% and 5.0% in placebo-treated patients, and 4.9% and 4.8% of nintedanib-treated patients, among patients who were and were not receiving anti-acid medication at baseline, respectively.\nIn post-hoc analyses of data from the INPULSIS® trials, anti-acid medication use at baseline was not associated with a more favorable course of disease, and did not impact the treatment effect of nintedanib, in patients with IPF.\nClinicalTrials.gov identifiers: NCT01335464 and NCT01335477 .", "first_author": null, "journal": "Respiratory research", "year": 2018, "doi": "10.1186/s12931-018-0866-0", "study_design_raw": "Post-hoc analysis of Phase III RCT", "sample_size_raw": "423", "follow_up_raw": "52 weeks (annual rate)", "equation_type": "E2", "x_raw": "Anti-acid medication use at baseline", "c_raw": "No anti-acid medication use at baseline", "y_raw": "Annual rate of decline in FVC", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "anti-acid medication use at baseline", "c_norm_text": "no anti-acid medication use at baseline", "y_norm_text": "annual rate of decline in fvc", "population_bucket_raw": "IPF patients", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "52 weeks (annual rate)", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "MD", "measure_scale_raw": "identity", "theta_hat_raw": -47.5, "ci_low_raw": -105.1, "ci_high_raw": 10.1, "p_value_raw": 0.1057, "n_raw": 423, "model_raw": "Adjusted analysis", "canonical_effect_scale": "identity_diff", "theta_hat_norm": -47.5, "ci_low_norm": -105.1, "ci_high_norm": 10.1, "effect_direction": "negative", "effect_transform": "identity", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:84ac650da60f", "contract_claim_id": "CLAIM:27b85c1a9d82", "contract_study_type": "rct", "contract_claim_confidence": "high", "contract_source_span_text": "In an analysis of the natural course of IPF by anti-acid medication use at baseline, the adjusted annual rate of decline in FVC was - 252.9 mL/year in placebo-treated patients who were receiving anti-acid medication at baseline and - 205.4 mL/year in placebo-treated patients who were not (difference of - 47.5 mL/year [95% CI: -105.1, 10.1]; p = 0.1057).", "source_sentence": "In an analysis of the natural course of IPF by anti-acid medication use at baseline, the adjusted annual rate of decline in FVC was - 252.9 mL/year in placebo-treated patients who were receiving anti-acid medication at baseline and - 205.4 mL/year in placebo-treated patients who were not (difference of - 47.5 mL/year [95% CI: -105.1, 10.1]; p = 0.1057).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-19T05:27:49.363121+00:00", "quality_decision_id": "QDEC:ee537b08231b2731", "quality_run_id": "QRUN:9fdbf17821093f0b", "record_status": "accepted", "effect_status": "usable", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "usable", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-19T06:35:03.317798+00:00" } ], "AEV-30176872#2": [ { "norm_edge_pk": "NORM:RAW:03fc2a50505f", "raw_edge_pk": "RAW:03fc2a50505f", "paper_id": "PMID:30176872", "pmid": "30176872", "edge_id": "AEV-30176872#2", "edge_order": 2, "paper_dir": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872", "pdf_path": "pdf/30176872.pdf", "source_pdf_path": "pdf/30176872.pdf", "source_edges_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/edges.json", "source_review_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/step3_review.json", "source_audit_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/step4_audit.json", "source_run_id": null, "paper_title": "Anti-acid therapy in idiopathic pulmonary fibrosis: insights from the INPULSIS® trials.", "paper_abstract": "The benefits and risks of anti-acid medication in patients with idiopathic pulmonary fibrosis (IPF) remain a topic of debate. We investigated whether use of anti-acid medication at baseline was associated with differences in the natural course of disease or influenced the treatment effect of nintedanib in patients with IPF.\nPost-hoc analyses of outcomes in patients receiving versus not receiving anti-acid medication (proton pump or histamine-2 receptor inhibitor) at baseline using pooled data from the two Phase III randomized placebo-controlled INPULSIS® trials of nintedanib in patients with IPF.\nAt baseline, 406 patients were receiving anti-acid medication (244 nintedanib; 162 placebo) and 655 were not (394 nintedanib; 261 placebo). In an analysis of the natural course of IPF by anti-acid medication use at baseline, the adjusted annual rate of decline in FVC was - 252.9 mL/year in placebo-treated patients who were receiving anti-acid medication at baseline and - 205.4 mL/year in placebo-treated patients who were not (difference of - 47.5 mL/year [95% CI: -105.1, 10.1]; p = 0.1057). In an analysis of the potential influence of anti-acid medication use on the treatment effect of nintedanib, the adjusted annual rates of decline in FVC were - 124.4 mL/year in the nintedanib group and - 252.9 mL/year in the placebo group (difference of 128.6 mL/year [95% CI: 74.9, 182.2]) in patients who were receiving anti-acid medication at baseline and - 107.0 mL/year in the nintedanib group and - 205.3 mL/year in the placebo group (difference of 98.3 mL/year [95% CI: 54.1, 142.5]) in patients who were not (treatment-by-time-by-subgroup interaction p = 0.3869). The proportions of patients who had ≥1 investigator-reported acute exacerbation were 11.7% and 5.0% in placebo-treated patients, and 4.9% and 4.8% of nintedanib-treated patients, among patients who were and were not receiving anti-acid medication at baseline, respectively.\nIn post-hoc analyses of data from the INPULSIS® trials, anti-acid medication use at baseline was not associated with a more favorable course of disease, and did not impact the treatment effect of nintedanib, in patients with IPF.\nClinicalTrials.gov identifiers: NCT01335464 and NCT01335477 .", "first_author": null, "journal": "Respiratory research", "year": 2018, "doi": "10.1186/s12931-018-0866-0", "study_design_raw": "Post-hoc analysis of Phase III RCT", "sample_size_raw": "406", "follow_up_raw": "52 weeks (annual rate)", "equation_type": "E1", "x_raw": "Nintedanib", "c_raw": "Placebo", "y_raw": "Annual rate of decline in FVC", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nintedanib", "c_norm_text": "placebo", "y_norm_text": "annual rate of decline in fvc", "population_bucket_raw": "IPF patients receiving anti-acid medication at baseline", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "52 weeks (annual rate)", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "MD", "measure_scale_raw": "identity", "theta_hat_raw": 128.6, "ci_low_raw": 74.9, "ci_high_raw": 182.2, "p_value_raw": null, "n_raw": 406, "model_raw": "Adjusted analysis", "canonical_effect_scale": "identity_diff", "theta_hat_norm": 128.6, "ci_low_norm": 74.9, "ci_high_norm": 182.2, "effect_direction": "positive", "effect_transform": "identity", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:84ac650da60f", "contract_claim_id": "CLAIM:a702c9c0e85e", "contract_study_type": "rct", "contract_claim_confidence": "high", "contract_source_span_text": "In an analysis of the potential influence of anti-acid medication use on the treatment effect of nintedanib, the adjusted annual rates of decline in FVC were - 124.4 mL/year in the nintedanib group and - 252.9 mL/year in the placebo group (difference of 128.6 mL/year [95% CI: 74.9, 182.2]) in patients who were receiving anti-acid medication at baseline", "source_sentence": "In an analysis of the potential influence of anti-acid medication use on the treatment effect of nintedanib, the adjusted annual rates of decline in FVC were - 124.4 mL/year in the nintedanib group and - 252.9 mL/year in the placebo group (difference of 128.6 mL/year [95% CI: 74.9, 182.2]) in patients who were receiving anti-acid medication at baseline", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-19T05:27:49.363121+00:00", "quality_decision_id": "QDEC:1364f22300a587a9", "quality_run_id": "QRUN:9fdbf17821093f0b", "record_status": "accepted", "effect_status": "usable", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "usable", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-19T06:35:03.317798+00:00" } ], "AEV-30176872#3": [ { "norm_edge_pk": "NORM:RAW:4a57a187eecd", "raw_edge_pk": "RAW:4a57a187eecd", "paper_id": "PMID:30176872", "pmid": "30176872", "edge_id": "AEV-30176872#3", "edge_order": 3, "paper_dir": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872", "pdf_path": "pdf/30176872.pdf", "source_pdf_path": "pdf/30176872.pdf", "source_edges_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/edges.json", "source_review_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/step3_review.json", "source_audit_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/step4_audit.json", "source_run_id": null, "paper_title": "Anti-acid therapy in idiopathic pulmonary fibrosis: insights from the INPULSIS® trials.", "paper_abstract": "The benefits and risks of anti-acid medication in patients with idiopathic pulmonary fibrosis (IPF) remain a topic of debate. We investigated whether use of anti-acid medication at baseline was associated with differences in the natural course of disease or influenced the treatment effect of nintedanib in patients with IPF.\nPost-hoc analyses of outcomes in patients receiving versus not receiving anti-acid medication (proton pump or histamine-2 receptor inhibitor) at baseline using pooled data from the two Phase III randomized placebo-controlled INPULSIS® trials of nintedanib in patients with IPF.\nAt baseline, 406 patients were receiving anti-acid medication (244 nintedanib; 162 placebo) and 655 were not (394 nintedanib; 261 placebo). In an analysis of the natural course of IPF by anti-acid medication use at baseline, the adjusted annual rate of decline in FVC was - 252.9 mL/year in placebo-treated patients who were receiving anti-acid medication at baseline and - 205.4 mL/year in placebo-treated patients who were not (difference of - 47.5 mL/year [95% CI: -105.1, 10.1]; p = 0.1057). In an analysis of the potential influence of anti-acid medication use on the treatment effect of nintedanib, the adjusted annual rates of decline in FVC were - 124.4 mL/year in the nintedanib group and - 252.9 mL/year in the placebo group (difference of 128.6 mL/year [95% CI: 74.9, 182.2]) in patients who were receiving anti-acid medication at baseline and - 107.0 mL/year in the nintedanib group and - 205.3 mL/year in the placebo group (difference of 98.3 mL/year [95% CI: 54.1, 142.5]) in patients who were not (treatment-by-time-by-subgroup interaction p = 0.3869). The proportions of patients who had ≥1 investigator-reported acute exacerbation were 11.7% and 5.0% in placebo-treated patients, and 4.9% and 4.8% of nintedanib-treated patients, among patients who were and were not receiving anti-acid medication at baseline, respectively.\nIn post-hoc analyses of data from the INPULSIS® trials, anti-acid medication use at baseline was not associated with a more favorable course of disease, and did not impact the treatment effect of nintedanib, in patients with IPF.\nClinicalTrials.gov identifiers: NCT01335464 and NCT01335477 .", "first_author": null, "journal": "Respiratory research", "year": 2018, "doi": "10.1186/s12931-018-0866-0", "study_design_raw": "Post-hoc analysis of Phase III RCT", "sample_size_raw": "655", "follow_up_raw": "52 weeks (annual rate)", "equation_type": "E1", "x_raw": "Nintedanib", "c_raw": "Placebo", "y_raw": "Annual rate of decline in FVC", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nintedanib", "c_norm_text": "placebo", "y_norm_text": "annual rate of decline in fvc", "population_bucket_raw": "IPF patients not receiving anti-acid medication at baseline", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "52 weeks (annual rate)", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "MD", "measure_scale_raw": "identity", "theta_hat_raw": 98.3, "ci_low_raw": 54.1, "ci_high_raw": 142.5, "p_value_raw": null, "n_raw": 655, "model_raw": "Adjusted analysis", "canonical_effect_scale": "identity_diff", "theta_hat_norm": 98.3, "ci_low_norm": 54.1, "ci_high_norm": 142.5, "effect_direction": "positive", "effect_transform": "identity", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:84ac650da60f", "contract_claim_id": "CLAIM:a5f1fb06fd5c", "contract_study_type": "rct", "contract_claim_confidence": "high", "contract_source_span_text": "...and - 107.0 mL/year in the nintedanib group and - 205.3 mL/year in the placebo group (difference of 98.3 mL/year [95% CI: 54.1, 142.5]) in patients who were not (treatment-by-time-by-subgroup interaction p = 0.3869).", "source_sentence": "...and - 107.0 mL/year in the nintedanib group and - 205.3 mL/year in the placebo group (difference of 98.3 mL/year [95% CI: 54.1, 142.5]) in patients who were not (treatment-by-time-by-subgroup interaction p = 0.3869).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-19T05:27:49.363121+00:00", "quality_decision_id": "QDEC:abf907f7a96b0976", "quality_run_id": "QRUN:9fdbf17821093f0b", "record_status": "accepted", "effect_status": "usable", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "usable", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-19T06:35:03.317798+00:00" } ], "AEV-30176872#4": [ { "norm_edge_pk": "NORM:RAW:f78a805458e0", "raw_edge_pk": "RAW:f78a805458e0", "paper_id": "PMID:30176872", "pmid": "30176872", "edge_id": "AEV-30176872#4", "edge_order": 4, "paper_dir": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872", "pdf_path": "pdf/30176872.pdf", "source_pdf_path": "pdf/30176872.pdf", "source_edges_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/edges.json", "source_review_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/step3_review.json", "source_audit_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/30/30176872/step4_audit.json", "source_run_id": null, "paper_title": "Anti-acid therapy in idiopathic pulmonary fibrosis: insights from the INPULSIS® trials.", "paper_abstract": "The benefits and risks of anti-acid medication in patients with idiopathic pulmonary fibrosis (IPF) remain a topic of debate. We investigated whether use of anti-acid medication at baseline was associated with differences in the natural course of disease or influenced the treatment effect of nintedanib in patients with IPF.\nPost-hoc analyses of outcomes in patients receiving versus not receiving anti-acid medication (proton pump or histamine-2 receptor inhibitor) at baseline using pooled data from the two Phase III randomized placebo-controlled INPULSIS® trials of nintedanib in patients with IPF.\nAt baseline, 406 patients were receiving anti-acid medication (244 nintedanib; 162 placebo) and 655 were not (394 nintedanib; 261 placebo). In an analysis of the natural course of IPF by anti-acid medication use at baseline, the adjusted annual rate of decline in FVC was - 252.9 mL/year in placebo-treated patients who were receiving anti-acid medication at baseline and - 205.4 mL/year in placebo-treated patients who were not (difference of - 47.5 mL/year [95% CI: -105.1, 10.1]; p = 0.1057). In an analysis of the potential influence of anti-acid medication use on the treatment effect of nintedanib, the adjusted annual rates of decline in FVC were - 124.4 mL/year in the nintedanib group and - 252.9 mL/year in the placebo group (difference of 128.6 mL/year [95% CI: 74.9, 182.2]) in patients who were receiving anti-acid medication at baseline and - 107.0 mL/year in the nintedanib group and - 205.3 mL/year in the placebo group (difference of 98.3 mL/year [95% CI: 54.1, 142.5]) in patients who were not (treatment-by-time-by-subgroup interaction p = 0.3869). The proportions of patients who had ≥1 investigator-reported acute exacerbation were 11.7% and 5.0% in placebo-treated patients, and 4.9% and 4.8% of nintedanib-treated patients, among patients who were and were not receiving anti-acid medication at baseline, respectively.\nIn post-hoc analyses of data from the INPULSIS® trials, anti-acid medication use at baseline was not associated with a more favorable course of disease, and did not impact the treatment effect of nintedanib, in patients with IPF.\nClinicalTrials.gov identifiers: NCT01335464 and NCT01335477 .", "first_author": null, "journal": "Respiratory research", "year": 2018, "doi": "10.1186/s12931-018-0866-0", "study_design_raw": "Post-hoc analysis of Phase III RCT", "sample_size_raw": "1061", "follow_up_raw": "52 weeks", "equation_type": "E2", "x_raw": "Anti-acid medication use at baseline", "c_raw": null, "y_raw": "Treatment effect of nintedanib on FVC decline", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "anti-acid medication use at baseline", "c_norm_text": null, "y_norm_text": "treatment effect of nintedanib on fvc decline", "population_bucket_raw": "IPF patients", "outcome_type_raw": "unknown", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": null, "measure_type_raw": "unknown", "measure_scale_raw": null, "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.3869, "n_raw": 1061, "model_raw": "Interaction model", "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "null", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "contract_compile_id": "ACOMP:84ac650da60f", "contract_claim_id": "CLAIM:9abbbac39649", "contract_study_type": "rct", "contract_claim_confidence": "high", "contract_source_span_text": "...(treatment-by-time-by-subgroup interaction p = 0.3869).", "source_sentence": "...(treatment-by-time-by-subgroup interaction p = 0.3869).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-19T05:27:49.363121+00:00", "quality_decision_id": "QDEC:90b8b5169bebb429", "quality_run_id": "QRUN:9fdbf17821093f0b", "record_status": "excluded", "effect_status": "missing", "record_status_reason": "llm_judge_excluded", "effect_status_reason": "theta_missing", "has_missing_mapping_1": true, "has_tentative_mapping_1": false, "key_role_missing_mapping": null, "key_role_tentative_mapping": null, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-19T06:35:03.317798+00:00" } ], "AEV-41026018#1": [ { "norm_edge_pk": "NORM:RAW:dfba94da13c5", "raw_edge_pk": "RAW:dfba94da13c5", "paper_id": "PMID:41026018", "pmid": "41026018", "edge_id": "AEV-41026018#1", "edge_order": 1, "paper_dir": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/edges.json", "source_review_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/step3_review.json", "source_audit_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/step4_audit.json", "source_run_id": null, "paper_title": "Survival impact and safety comparison of pirfenidone and nintedanib for idiopathic pulmonary fibrosis: A meta-analysis.", "paper_abstract": "BACKGROUND AND AIM: Idiopathic pulmonary fibrosis (IPF) is a severe restrictive lung disease affecting approximately 3 million people worldwide with two approved antifibrotics, nintedanib and pirfenidone, available for use. This review aims to compare their survival impact and safety profile.\nMETHODS: Two databases and two trial registers along with additional sources were searched for cohorts reporting IPF patients of any age or stage, receiving either pirfenidone or nintedanib. The Inverse-Variance and Mantel-Haenszel method along with either a fixed- or random-effects model was used for analysing survival and other dichotomous outcomes, respectively.\nRESULTS: 23 cohorts were included. The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).\nCONCLUSIONS: While both treatment groups had similar overall survival and all-cause mortality, the safety profiles of nintedanib and pirfenidone differed significantly, with nintedanib being associated with greater odds of liver toxicity and diarrhoea, and pirfenidone with photosensitivity and skin rash, suggesting they could be favoured in slightly distinct population groups. Further research is necessary to refine the current comprehension of these drugs and their optimal utilization in IPF treatment, particularly taking into account factors such as disease stage and sequential therapy.", "first_author": null, "journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG", "year": 2025, "doi": "10.36141/svdld.v42i3.16432", "study_design_raw": "meta-analysis", "sample_size_raw": "", "follow_up_raw": null, "equation_type": "E1", "x_raw": "nintedanib", "c_raw": "pirfenidone", "y_raw": "survival", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nintedanib", "c_norm_text": "pirfenidone", "y_norm_text": "survival", "population_bucket_raw": "idiopathic pulmonary fibrosis", "outcome_type_raw": "time_to_event", "time_index_raw": null, "time_horizon_raw": null, "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "HR", "measure_scale_raw": "natural", "theta_hat_raw": 1.12, "ci_low_raw": 0.99, "ci_high_raw": 1.27, "p_value_raw": 0.07, "n_raw": null, "model_raw": "Inverse-Variance method", "canonical_effect_scale": "log_ratio", "theta_hat_norm": 0.11332868530700327, "ci_low_norm": -0.01005033585350145, "ci_high_norm": 0.23901690047049992, "effect_direction": "positive", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:77bb718a7967", "contract_claim_id": "CLAIM:5f2968c6cabe", "contract_study_type": "review", "contract_claim_confidence": "high", "contract_source_span_text": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "source_sentence": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-19T05:27:49.363121+00:00", "quality_decision_id": "QDEC:dfb854ead7600aa4", "quality_run_id": "QRUN:9fdbf17821093f0b", "record_status": "accepted", "effect_status": "usable", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "usable", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-19T06:35:03.317798+00:00" } ], "AEV-41026018#2": [ { "norm_edge_pk": "NORM:RAW:db0f1cf19e03", "raw_edge_pk": "RAW:db0f1cf19e03", "paper_id": "PMID:41026018", "pmid": "41026018", "edge_id": "AEV-41026018#2", "edge_order": 2, "paper_dir": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/edges.json", "source_review_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/step3_review.json", "source_audit_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/step4_audit.json", "source_run_id": null, "paper_title": "Survival impact and safety comparison of pirfenidone and nintedanib for idiopathic pulmonary fibrosis: A meta-analysis.", "paper_abstract": "BACKGROUND AND AIM: Idiopathic pulmonary fibrosis (IPF) is a severe restrictive lung disease affecting approximately 3 million people worldwide with two approved antifibrotics, nintedanib and pirfenidone, available for use. This review aims to compare their survival impact and safety profile.\nMETHODS: Two databases and two trial registers along with additional sources were searched for cohorts reporting IPF patients of any age or stage, receiving either pirfenidone or nintedanib. The Inverse-Variance and Mantel-Haenszel method along with either a fixed- or random-effects model was used for analysing survival and other dichotomous outcomes, respectively.\nRESULTS: 23 cohorts were included. The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).\nCONCLUSIONS: While both treatment groups had similar overall survival and all-cause mortality, the safety profiles of nintedanib and pirfenidone differed significantly, with nintedanib being associated with greater odds of liver toxicity and diarrhoea, and pirfenidone with photosensitivity and skin rash, suggesting they could be favoured in slightly distinct population groups. Further research is necessary to refine the current comprehension of these drugs and their optimal utilization in IPF treatment, particularly taking into account factors such as disease stage and sequential therapy.", "first_author": null, "journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG", "year": 2025, "doi": "10.36141/svdld.v42i3.16432", "study_design_raw": "meta-analysis", "sample_size_raw": "", "follow_up_raw": null, "equation_type": "E2", "x_raw": "nintedanib", "c_raw": "pirfenidone", "y_raw": "all-cause mortality", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nintedanib", "c_norm_text": "pirfenidone", "y_norm_text": "all-cause mortality", "population_bucket_raw": "idiopathic pulmonary fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": null, "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "OR", "measure_scale_raw": "natural", "theta_hat_raw": 1.11, "ci_low_raw": 0.94, "ci_high_raw": 1.31, "p_value_raw": 0.22, "n_raw": null, "model_raw": "Mantel-Haenszel method", "canonical_effect_scale": "log_ratio", "theta_hat_norm": 0.10436001532424286, "ci_low_norm": -0.06187540371808753, "ci_high_norm": 0.2700271372130602, "effect_direction": "positive", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:77bb718a7967", "contract_claim_id": "CLAIM:3ca50ea238d5", "contract_study_type": "review", "contract_claim_confidence": "high", "contract_source_span_text": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "source_sentence": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-19T05:27:49.363121+00:00", "quality_decision_id": "QDEC:aca1adc6cca3c789", "quality_run_id": "QRUN:9fdbf17821093f0b", "record_status": "accepted", "effect_status": "usable", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "usable", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-19T06:35:03.317798+00:00" } ], "AEV-41026018#3": [ { "norm_edge_pk": "NORM:RAW:27bee41f9919", "raw_edge_pk": "RAW:27bee41f9919", "paper_id": "PMID:41026018", "pmid": "41026018", "edge_id": "AEV-41026018#3", "edge_order": 3, "paper_dir": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/edges.json", "source_review_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/step3_review.json", "source_audit_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/step4_audit.json", "source_run_id": null, "paper_title": "Survival impact and safety comparison of pirfenidone and nintedanib for idiopathic pulmonary fibrosis: A meta-analysis.", "paper_abstract": "BACKGROUND AND AIM: Idiopathic pulmonary fibrosis (IPF) is a severe restrictive lung disease affecting approximately 3 million people worldwide with two approved antifibrotics, nintedanib and pirfenidone, available for use. This review aims to compare their survival impact and safety profile.\nMETHODS: Two databases and two trial registers along with additional sources were searched for cohorts reporting IPF patients of any age or stage, receiving either pirfenidone or nintedanib. The Inverse-Variance and Mantel-Haenszel method along with either a fixed- or random-effects model was used for analysing survival and other dichotomous outcomes, respectively.\nRESULTS: 23 cohorts were included. The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).\nCONCLUSIONS: While both treatment groups had similar overall survival and all-cause mortality, the safety profiles of nintedanib and pirfenidone differed significantly, with nintedanib being associated with greater odds of liver toxicity and diarrhoea, and pirfenidone with photosensitivity and skin rash, suggesting they could be favoured in slightly distinct population groups. Further research is necessary to refine the current comprehension of these drugs and their optimal utilization in IPF treatment, particularly taking into account factors such as disease stage and sequential therapy.", "first_author": null, "journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG", "year": 2025, "doi": "10.36141/svdld.v42i3.16432", "study_design_raw": "meta-analysis", "sample_size_raw": "", "follow_up_raw": null, "equation_type": "E2", "x_raw": "nintedanib", "c_raw": "pirfenidone", "y_raw": "drug switches", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nintedanib", "c_norm_text": "pirfenidone", "y_norm_text": "drug switches", "population_bucket_raw": "idiopathic pulmonary fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": null, "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "OR", "measure_scale_raw": "natural", "theta_hat_raw": 1.82, "ci_low_raw": 0.69, "ci_high_raw": 4.78, "p_value_raw": 0.22, "n_raw": null, "model_raw": "Mantel-Haenszel method", "canonical_effect_scale": "log_ratio", "theta_hat_norm": 0.598836501088704, "ci_low_norm": -0.37106368139083207, "ci_high_norm": 1.5644405465033646, "effect_direction": "positive", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:77bb718a7967", "contract_claim_id": "CLAIM:6ca894d7239d", "contract_study_type": "review", "contract_claim_confidence": "high", "contract_source_span_text": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "source_sentence": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-19T05:27:49.363121+00:00", "quality_decision_id": "QDEC:e91740ecc8ae8a86", "quality_run_id": "QRUN:9fdbf17821093f0b", "record_status": "accepted", "effect_status": "usable", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "usable", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-19T06:35:03.317798+00:00" } ], "AEV-41026018#4": [ { "norm_edge_pk": "NORM:RAW:72e1463640c6", "raw_edge_pk": "RAW:72e1463640c6", "paper_id": "PMID:41026018", "pmid": "41026018", "edge_id": "AEV-41026018#4", "edge_order": 4, "paper_dir": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/edges.json", "source_review_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/step3_review.json", "source_audit_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/step4_audit.json", "source_run_id": null, "paper_title": "Survival impact and safety comparison of pirfenidone and nintedanib for idiopathic pulmonary fibrosis: A meta-analysis.", "paper_abstract": "BACKGROUND AND AIM: Idiopathic pulmonary fibrosis (IPF) is a severe restrictive lung disease affecting approximately 3 million people worldwide with two approved antifibrotics, nintedanib and pirfenidone, available for use. This review aims to compare their survival impact and safety profile.\nMETHODS: Two databases and two trial registers along with additional sources were searched for cohorts reporting IPF patients of any age or stage, receiving either pirfenidone or nintedanib. The Inverse-Variance and Mantel-Haenszel method along with either a fixed- or random-effects model was used for analysing survival and other dichotomous outcomes, respectively.\nRESULTS: 23 cohorts were included. The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).\nCONCLUSIONS: While both treatment groups had similar overall survival and all-cause mortality, the safety profiles of nintedanib and pirfenidone differed significantly, with nintedanib being associated with greater odds of liver toxicity and diarrhoea, and pirfenidone with photosensitivity and skin rash, suggesting they could be favoured in slightly distinct population groups. Further research is necessary to refine the current comprehension of these drugs and their optimal utilization in IPF treatment, particularly taking into account factors such as disease stage and sequential therapy.", "first_author": null, "journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG", "year": 2025, "doi": "10.36141/svdld.v42i3.16432", "study_design_raw": "meta-analysis", "sample_size_raw": "", "follow_up_raw": null, "equation_type": "E2", "x_raw": "nintedanib", "c_raw": "pirfenidone", "y_raw": "treatment discontinuations", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nintedanib", "c_norm_text": "pirfenidone", "y_norm_text": "treatment discontinuations", "population_bucket_raw": "idiopathic pulmonary fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": null, "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "OR", "measure_scale_raw": "natural", "theta_hat_raw": 0.92, "ci_low_raw": 0.6, "ci_high_raw": 1.41, "p_value_raw": 0.7, "n_raw": null, "model_raw": "Mantel-Haenszel method", "canonical_effect_scale": "log_ratio", "theta_hat_norm": -0.08338160893905101, "ci_low_norm": -0.5108256237659907, "ci_high_norm": 0.34358970439007686, "effect_direction": "negative", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:77bb718a7967", "contract_claim_id": "CLAIM:01b4620fe71f", "contract_study_type": "review", "contract_claim_confidence": "high", "contract_source_span_text": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "source_sentence": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-19T05:27:49.363121+00:00", "quality_decision_id": "QDEC:0f0496505622ae95", "quality_run_id": "QRUN:9fdbf17821093f0b", "record_status": "accepted", "effect_status": "usable", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "usable", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-19T06:35:03.317798+00:00" } ], "AEV-41026018#5": [ { "norm_edge_pk": "NORM:RAW:9d1d76d71ff3", "raw_edge_pk": "RAW:9d1d76d71ff3", "paper_id": "PMID:41026018", "pmid": "41026018", "edge_id": "AEV-41026018#5", "edge_order": 5, "paper_dir": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/edges.json", "source_review_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/step3_review.json", "source_audit_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/step4_audit.json", "source_run_id": null, "paper_title": "Survival impact and safety comparison of pirfenidone and nintedanib for idiopathic pulmonary fibrosis: A meta-analysis.", "paper_abstract": "BACKGROUND AND AIM: Idiopathic pulmonary fibrosis (IPF) is a severe restrictive lung disease affecting approximately 3 million people worldwide with two approved antifibrotics, nintedanib and pirfenidone, available for use. This review aims to compare their survival impact and safety profile.\nMETHODS: Two databases and two trial registers along with additional sources were searched for cohorts reporting IPF patients of any age or stage, receiving either pirfenidone or nintedanib. The Inverse-Variance and Mantel-Haenszel method along with either a fixed- or random-effects model was used for analysing survival and other dichotomous outcomes, respectively.\nRESULTS: 23 cohorts were included. The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).\nCONCLUSIONS: While both treatment groups had similar overall survival and all-cause mortality, the safety profiles of nintedanib and pirfenidone differed significantly, with nintedanib being associated with greater odds of liver toxicity and diarrhoea, and pirfenidone with photosensitivity and skin rash, suggesting they could be favoured in slightly distinct population groups. Further research is necessary to refine the current comprehension of these drugs and their optimal utilization in IPF treatment, particularly taking into account factors such as disease stage and sequential therapy.", "first_author": null, "journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG", "year": 2025, "doi": "10.36141/svdld.v42i3.16432", "study_design_raw": "meta-analysis", "sample_size_raw": "", "follow_up_raw": null, "equation_type": "E2", "x_raw": "nintedanib", "c_raw": "pirfenidone", "y_raw": "diarrhoea", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nintedanib", "c_norm_text": "pirfenidone", "y_norm_text": "diarrhoea", "population_bucket_raw": "idiopathic pulmonary fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": null, "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "OR", "measure_scale_raw": "natural", "theta_hat_raw": 12.39, "ci_low_raw": 5.67, "ci_high_raw": 27.07, "p_value_raw": 1e-05, "n_raw": null, "model_raw": "Mantel-Haenszel method", "canonical_effect_scale": "log_ratio", "theta_hat_norm": 2.516889695641051, "ci_low_norm": 1.7351891177396608, "ci_high_norm": 3.29842610362621, "effect_direction": "positive", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:77bb718a7967", "contract_claim_id": "CLAIM:9c0e598cdb6a", "contract_study_type": "review", "contract_claim_confidence": "high", "contract_source_span_text": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "source_sentence": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-19T05:27:49.363121+00:00", "quality_decision_id": "QDEC:4c29201ae8e8f507", "quality_run_id": "QRUN:9fdbf17821093f0b", "record_status": "accepted", "effect_status": "usable", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "usable", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-19T06:35:03.317798+00:00" } ], "AEV-41026018#6": [ { "norm_edge_pk": "NORM:RAW:8f951c742825", "raw_edge_pk": "RAW:8f951c742825", "paper_id": "PMID:41026018", "pmid": "41026018", "edge_id": "AEV-41026018#6", "edge_order": 6, "paper_dir": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/edges.json", "source_review_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/step3_review.json", "source_audit_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/step4_audit.json", "source_run_id": null, "paper_title": "Survival impact and safety comparison of pirfenidone and nintedanib for idiopathic pulmonary fibrosis: A meta-analysis.", "paper_abstract": "BACKGROUND AND AIM: Idiopathic pulmonary fibrosis (IPF) is a severe restrictive lung disease affecting approximately 3 million people worldwide with two approved antifibrotics, nintedanib and pirfenidone, available for use. This review aims to compare their survival impact and safety profile.\nMETHODS: Two databases and two trial registers along with additional sources were searched for cohorts reporting IPF patients of any age or stage, receiving either pirfenidone or nintedanib. The Inverse-Variance and Mantel-Haenszel method along with either a fixed- or random-effects model was used for analysing survival and other dichotomous outcomes, respectively.\nRESULTS: 23 cohorts were included. The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).\nCONCLUSIONS: While both treatment groups had similar overall survival and all-cause mortality, the safety profiles of nintedanib and pirfenidone differed significantly, with nintedanib being associated with greater odds of liver toxicity and diarrhoea, and pirfenidone with photosensitivity and skin rash, suggesting they could be favoured in slightly distinct population groups. Further research is necessary to refine the current comprehension of these drugs and their optimal utilization in IPF treatment, particularly taking into account factors such as disease stage and sequential therapy.", "first_author": null, "journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG", "year": 2025, "doi": "10.36141/svdld.v42i3.16432", "study_design_raw": "meta-analysis", "sample_size_raw": "", "follow_up_raw": null, "equation_type": "E2", "x_raw": "nintedanib", "c_raw": "pirfenidone", "y_raw": "abnormal liver-function tests", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nintedanib", "c_norm_text": "pirfenidone", "y_norm_text": "abnormal liver-function tests", "population_bucket_raw": "idiopathic pulmonary fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": null, "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "OR", "measure_scale_raw": "natural", "theta_hat_raw": 2.98, "ci_low_raw": 1.92, "ci_high_raw": 4.61, "p_value_raw": 1e-05, "n_raw": null, "model_raw": "Mantel-Haenszel method", "canonical_effect_scale": "log_ratio", "theta_hat_norm": 1.091923300517313, "ci_low_norm": 0.6523251860396901, "ci_high_norm": 1.5282278570085572, "effect_direction": "positive", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:77bb718a7967", "contract_claim_id": "CLAIM:8191e308c21d", "contract_study_type": "review", "contract_claim_confidence": "high", "contract_source_span_text": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "source_sentence": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-19T05:27:49.363121+00:00", "quality_decision_id": "QDEC:056e4ba828bbda18", "quality_run_id": "QRUN:9fdbf17821093f0b", "record_status": "accepted", "effect_status": "usable", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "usable", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-19T06:35:03.317798+00:00" } ], "AEV-41026018#7": [ { "norm_edge_pk": "NORM:RAW:98f65e111800", "raw_edge_pk": "RAW:98f65e111800", "paper_id": "PMID:41026018", "pmid": "41026018", "edge_id": "AEV-41026018#7", "edge_order": 7, "paper_dir": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/edges.json", "source_review_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/step3_review.json", "source_audit_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/step4_audit.json", "source_run_id": null, "paper_title": "Survival impact and safety comparison of pirfenidone and nintedanib for idiopathic pulmonary fibrosis: A meta-analysis.", "paper_abstract": "BACKGROUND AND AIM: Idiopathic pulmonary fibrosis (IPF) is a severe restrictive lung disease affecting approximately 3 million people worldwide with two approved antifibrotics, nintedanib and pirfenidone, available for use. This review aims to compare their survival impact and safety profile.\nMETHODS: Two databases and two trial registers along with additional sources were searched for cohorts reporting IPF patients of any age or stage, receiving either pirfenidone or nintedanib. The Inverse-Variance and Mantel-Haenszel method along with either a fixed- or random-effects model was used for analysing survival and other dichotomous outcomes, respectively.\nRESULTS: 23 cohorts were included. The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).\nCONCLUSIONS: While both treatment groups had similar overall survival and all-cause mortality, the safety profiles of nintedanib and pirfenidone differed significantly, with nintedanib being associated with greater odds of liver toxicity and diarrhoea, and pirfenidone with photosensitivity and skin rash, suggesting they could be favoured in slightly distinct population groups. Further research is necessary to refine the current comprehension of these drugs and their optimal utilization in IPF treatment, particularly taking into account factors such as disease stage and sequential therapy.", "first_author": null, "journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG", "year": 2025, "doi": "10.36141/svdld.v42i3.16432", "study_design_raw": "meta-analysis", "sample_size_raw": "", "follow_up_raw": null, "equation_type": "E2", "x_raw": "nintedanib", "c_raw": "pirfenidone", "y_raw": "photosensitivity", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nintedanib", "c_norm_text": "pirfenidone", "y_norm_text": "photosensitivity", "population_bucket_raw": "idiopathic pulmonary fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": null, "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "OR", "measure_scale_raw": "natural", "theta_hat_raw": 0.06, "ci_low_raw": 0.01, "ci_high_raw": 0.25, "p_value_raw": 0.0001, "n_raw": null, "model_raw": "Mantel-Haenszel method", "canonical_effect_scale": "log_ratio", "theta_hat_norm": -2.8134107167600364, "ci_low_norm": -4.605170185988091, "ci_high_norm": -1.3862943611198906, "effect_direction": "negative", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:77bb718a7967", "contract_claim_id": "CLAIM:c96e0133c50d", "contract_study_type": "review", "contract_claim_confidence": "high", "contract_source_span_text": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "source_sentence": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-19T05:27:49.363121+00:00", "quality_decision_id": "QDEC:f46178eb31265118", "quality_run_id": "QRUN:9fdbf17821093f0b", "record_status": "accepted", "effect_status": "usable", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "usable", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-19T06:35:03.317798+00:00" } ], "AEV-41026018#8": [ { "norm_edge_pk": "NORM:RAW:14c9e8f7dc4d", "raw_edge_pk": "RAW:14c9e8f7dc4d", "paper_id": "PMID:41026018", "pmid": "41026018", "edge_id": "AEV-41026018#8", "edge_order": 8, "paper_dir": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/edges.json", "source_review_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/step3_review.json", "source_audit_path": "/Volumes/Yulong/数据集/DoAtlas/artifacts/runs/adhoc_task_runs/请帮我创建一个特发性肺纤维化候选靶点研究任务_并说明你会重点看哪些证据__local_fallback/m3a_extract/41/41026018/step4_audit.json", "source_run_id": null, "paper_title": "Survival impact and safety comparison of pirfenidone and nintedanib for idiopathic pulmonary fibrosis: A meta-analysis.", "paper_abstract": "BACKGROUND AND AIM: Idiopathic pulmonary fibrosis (IPF) is a severe restrictive lung disease affecting approximately 3 million people worldwide with two approved antifibrotics, nintedanib and pirfenidone, available for use. This review aims to compare their survival impact and safety profile.\nMETHODS: Two databases and two trial registers along with additional sources were searched for cohorts reporting IPF patients of any age or stage, receiving either pirfenidone or nintedanib. The Inverse-Variance and Mantel-Haenszel method along with either a fixed- or random-effects model was used for analysing survival and other dichotomous outcomes, respectively.\nRESULTS: 23 cohorts were included. The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).\nCONCLUSIONS: While both treatment groups had similar overall survival and all-cause mortality, the safety profiles of nintedanib and pirfenidone differed significantly, with nintedanib being associated with greater odds of liver toxicity and diarrhoea, and pirfenidone with photosensitivity and skin rash, suggesting they could be favoured in slightly distinct population groups. Further research is necessary to refine the current comprehension of these drugs and their optimal utilization in IPF treatment, particularly taking into account factors such as disease stage and sequential therapy.", "first_author": null, "journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG", "year": 2025, "doi": "10.36141/svdld.v42i3.16432", "study_design_raw": "meta-analysis", "sample_size_raw": "", "follow_up_raw": null, "equation_type": "E2", "x_raw": "nintedanib", "c_raw": "pirfenidone", "y_raw": "skin-rash", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nintedanib", "c_norm_text": "pirfenidone", "y_norm_text": "skin-rash", "population_bucket_raw": "idiopathic pulmonary fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": null, "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "OR", "measure_scale_raw": "natural", "theta_hat_raw": 0.17, "ci_low_raw": 0.08, "ci_high_raw": 0.34, "p_value_raw": 1e-05, "n_raw": null, "model_raw": "Mantel-Haenszel method", "canonical_effect_scale": "log_ratio", "theta_hat_norm": -1.7719568419318752, "ci_low_norm": -2.5257286443082556, "ci_high_norm": -1.0788096613719298, "effect_direction": "negative", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "contract_compile_id": "ACOMP:77bb718a7967", "contract_claim_id": "CLAIM:b749619e063d", "contract_study_type": "review", "contract_claim_confidence": "high", "contract_source_span_text": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of photosensitivity (OR=0.06; 95%-CI:0.01-0.25; P=0.0001), and skin-rash (OR=0.17; 95%-CI:0.08-0.34; P<0.00001).", "source_sentence": "The pooled analysis showed that compared to pirfenidone, nintedanib group had similar survival (HR=1.12; 95%-CI:0.99-1.27; P=0.07), all-cause mortality (OR=1.11; 95%-CI:0.94-1.31; P=0.22), drug switches (OR=1.82; 95%-CI:0.69-4.78; P=0.22), and treatment discontinuations (OR=0.92; 95%-CI:0.60-1.41; P=0.70), higher odds of diarrhoea (OR=12.39; 95%-CI: 5.67-27.07; P<0.00001) and abnormal liver-function tests (OR=2.98; 95%-CI:1.92-4.61; P<0.00001), and lower odds of 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The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "7", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "vitamin D3", "c_raw": "placebo", "y_raw": "hepatic steatosis", "z_raw_json": [ "histologically determined NASH", "elevated ALT at baseline", "decreased 25-OH vitamin D level at baseline" ], 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Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. 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Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. 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No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. 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Histologic analyses of liver biopsies collected at baseline were performed by a blinded pathologist. Information collected at baseline and at each examination included frequency and duration of aspirin and nonsteroidal anti-inflammatory drug (NSAID) use. Using multivariable-adjusted logistic regression, we estimated the association of aspirin use with prevalent steatohepatitis (NASH) and fibrosis. Using multivariable-adjusted Cox proportional hazards modeling, we estimated the association between aspirin use and risk for fibrosis progression.\nAt enrollment, 151 subjects used aspirin daily. Compared with non-regular use, daily aspirin use was associated with significantly lower odds of NASH (adjusted odds ratio, 0.68; 95% CI, 0.37-0.89) and fibrosis (adjusted odds ratio, 0.54; 95% CI, 0.31-0.82). Among individuals with baseline F0-F2 fibrosis (n = 317), 86 developed advanced fibrosis over 3692 person-years. 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Conversely, use of nonaspirin NSAIDs was not associated with risk for advanced fibrosis (aHR, 0.93; 95% CI, 0.81-1.05).\nIn a prospective study of patients with biopsy-proven NAFLD, daily aspirin use was associated with less severe histologic features of NAFLD and NASH, and lower risk for progression to advanced fibrosis with time.", "first_author": null, "journal": "Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association", "year": 2019, "doi": "10.1016/j.cgh.2019.04.061", "study_design_raw": "prospective cohort study", "sample_size_raw": "317", "follow_up_raw": "3692 person-years", "equation_type": "E3", "x_raw": "Non-aspirin NSAIDs", "c_raw": null, "y_raw": "advanced fibrosis", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "non-aspirin nsaids", "c_norm_text": null, "y_norm_text": "advanced fibrosis", "population_bucket_raw": "adults with biopsy-confirmed NAFLD", "outcome_type_raw": "time_to_event", "time_index_raw": null, "time_horizon_raw": "3692 person-years", "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "HR", "measure_scale_raw": "natural", "theta_hat_raw": 0.93, "ci_low_raw": 0.81, "ci_high_raw": 1.05, "p_value_raw": null, "n_raw": 317, "model_raw": "multivariable-adjusted Cox proportional hazards modeling", "canonical_effect_scale": "log_ratio", "theta_hat_norm": -0.07257069283483537, "ci_low_norm": -0.21072103131565253, "ci_high_norm": 0.04879016416943205, "effect_direction": "negative", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "source_sentence": "Conversely, use of nonaspirin NSAIDs was not associated with risk for advanced fibrosis (aHR, 0.93; 95% CI, 0.81-1.05).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T10:33:18.981000+00:00", "quality_decision_id": "QDEC:5662b8c5625af72f", "quality_run_id": "QRUN:5c1b506bb7e585b1", "record_status": "accepted", "effect_status": "usable", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "usable", "has_missing_mapping_1": true, "has_tentative_mapping_1": false, "key_role_missing_mapping": null, "key_role_tentative_mapping": null, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T11:29:05.738989+00:00" }, "PMID:32794259::AEV-32794259#1": { "norm_edge_pk": "NORM:RAW:d0239fab1da5", "raw_edge_pk": "RAW:d0239fab1da5", "paper_id": "PMID:32794259", "pmid": "32794259", "edge_id": "AEV-32794259#1", "edge_order": 1, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/32/32794259", "pdf_path": "pdf/32794259.pdf", "source_pdf_path": "pdf/32794259.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/32/32794259/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/32/32794259/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/32/32794259/step4_audit.json", "source_run_id": null, "paper_title": "The Commensal Microbe Veillonella as a Marker for Response to an FGF19 Analog in NASH.", "paper_abstract": "The composition of the human gut microbiota is linked to health and disease, and knowledge of the impact of therapeutics on the microbiota is essential to decipher their biological roles and to gain new mechanistic insights. 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Here we report the effect of aldafermin, an analog of the gut hormone FGF19, versus placebo on the gut microbiota in a prospective, phase 2 study in patients with NASH.\nA total of 176 patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) (nonalcoholic fatty liver disease activity score ≥ 4), fibrosis (F1-F3 by NASH Clinical Research Network criteria), and elevated liver fat content (≥ 8% by magnetic resonance imaging-proton density fat fraction) received 0.3 mg (n = 23), 1 mg (n = 49), 3 mg (n = 49), and 6 mg (n = 28) aldafermin or placebo (n = 27) for 12 weeks. Stool samples were collected on day 1 and week 12 and profiled using 16S ribosomal RNA gene sequencing; 122 patients had paired stool microbiome profiles at both day 1 and week 12. Overall, the state of the gut microbial community was distinctly stable in patients treated with aldafermin, with all major phyla and genera unaltered during therapy. Patients treated with aldafermin showed a significant, dose-dependent enrichment in the rare genus Veillonella, a commensal microbe known to have lactate-degrading and performance-enhancing properties, which correlated with changes in serum bile acid profile.\nVeillonella may be a bile acid-sensitive bacteria whose enrichment is enabled by aldafermin-mediated suppression of bile acid synthesis and, in particular, decreases in toxic bile acids. This study provides an integrated analysis of gut microbiome, serum bile acid metabolome, imaging, and histological measurements in clinical trials testing aldafermin for NASH. Our results provide a better understanding of the intricacies of microbiome-host interactions (clinicaltrials.gov trial No. NCT02443116).", "first_author": null, "journal": "Hepatology (Baltimore, Md.)", "year": 2021, "doi": "10.1002/hep.31523", "study_design_raw": "prospective, phase 2 study", "sample_size_raw": "122", "follow_up_raw": "12 weeks", "equation_type": "E3", "x_raw": "Veillonella abundance", "c_raw": null, "y_raw": "Serum bile acid profile", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "veillonella abundance", "c_norm_text": null, "y_norm_text": "serum bile acid profile", "population_bucket_raw": "Patients with NASH treated with aldafermin", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "12 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 122, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unclear", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "source_sentence": "Patients treated with aldafermin showed a significant, dose-dependent enrichment in the rare genus Veillonella, a commensal microbe known to have lactate-degrading and performance-enhancing properties, which correlated with changes in serum bile acid profile.", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T10:33:18.981000+00:00", "quality_decision_id": "QDEC:40d5a40f8b61d32f", "quality_run_id": "QRUN:5c1b506bb7e585b1", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "missing_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": true, "has_tentative_mapping_1": true, "key_role_missing_mapping": true, "key_role_tentative_mapping": true, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T11:29:05.738989+00:00" }, "PMID:38856224::AEV-38856224#1": { "norm_edge_pk": "NORM:RAW:970c362cd81a", "raw_edge_pk": "RAW:970c362cd81a", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#1", "edge_order": 1, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "190", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "Tirzepatide (5 mg)", "c_raw": "Placebo", "y_raw": "Resolution of MASH without worsening of fibrosis", "z_raw_json": [ "biopsy-confirmed MASH", "stage F2 or F3 fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide (5 mg)", "c_norm_text": "placebo", "y_norm_text": "resolution of mash without worsening of fibrosis", "population_bucket_raw": "Participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": 34.0, "ci_low_raw": 17.0, "ci_high_raw": 50.0, "p_value_raw": 0.001, "n_raw": 190, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "positive", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "source_sentence": "The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50)...", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": true, "normalization_status": "partial", "normalization_issues_json": [ "unsupported_measure_type" ], "compiled_at": "2026-04-17T10:33:18.981000+00:00", "quality_decision_id": "QDEC:38781c2b8a5f7001", "quality_run_id": "QRUN:5c1b506bb7e585b1", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "effect_parse_failed", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T11:29:05.738989+00:00" }, "PMID:38856224::AEV-38856224#2": { "norm_edge_pk": "NORM:RAW:25f7e46c568f", "raw_edge_pk": "RAW:25f7e46c568f", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#2", "edge_order": 2, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "190", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "Tirzepatide (10 mg)", "c_raw": "Placebo", "y_raw": "Resolution of MASH without worsening of fibrosis", "z_raw_json": [ "biopsy-confirmed MASH", "stage F2 or F3 fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide (10 mg)", "c_norm_text": "placebo", "y_norm_text": "resolution of mash without worsening of fibrosis", "population_bucket_raw": "Participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": 46.0, "ci_low_raw": 29.0, "ci_high_raw": 62.0, "p_value_raw": 0.001, "n_raw": 190, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "positive", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "source_sentence": "...56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62)...", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": true, "normalization_status": "partial", "normalization_issues_json": [ "unsupported_measure_type" ], "compiled_at": "2026-04-17T10:33:18.981000+00:00", "quality_decision_id": "QDEC:f4cc7a819c51ded8", "quality_run_id": "QRUN:5c1b506bb7e585b1", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "missing_key_role_mapping", "effect_status_reason": "effect_parse_failed", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T11:29:05.738989+00:00" }, "PMID:38856224::AEV-38856224#3": { "norm_edge_pk": "NORM:RAW:193dfe5be595", "raw_edge_pk": "RAW:193dfe5be595", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#3", "edge_order": 3, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. 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The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. 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The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. 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The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. 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The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. 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Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. 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Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Post hoc analysis", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E6", "x_raw": "APRI reduction (week 72)", "c_raw": null, "y_raw": "Histologic fibrosis improvement (week 72)", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "apri reduction (week 72)", "c_norm_text": null, "y_norm_text": "histologic fibrosis improvement (week 72)", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.012, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "negative", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "source_sentence": "Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T10:33:18.981000+00:00", "quality_decision_id": "QDEC:38b6746e633f88f9", "quality_run_id": "QRUN:5c1b506bb7e585b1", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": true, "has_tentative_mapping_1": true, "key_role_missing_mapping": true, "key_role_tentative_mapping": true, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T11:29:05.738989+00:00" } ], "AEV-30270688#1": [ { "norm_edge_pk": "NORM:RAW:0dbd64830ca0", "raw_edge_pk": "RAW:0dbd64830ca0", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#1", "edge_order": 1, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "Vitamin D3", "c_raw": "Placebo", "y_raw": "Alanine aminotransferase", "z_raw_json": [ "hypovitaminosis D" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "alanine aminotransferase", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "negative", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "source_sentence": "In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase.", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T10:33:18.981000+00:00", "quality_decision_id": "QDEC:5e7e55d996e939cd", "quality_run_id": "QRUN:5c1b506bb7e585b1", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T11:29:05.738989+00:00" } ], "AEV-30270688#2": [ { "norm_edge_pk": "NORM:RAW:d94d4083b798", "raw_edge_pk": "RAW:d94d4083b798", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#2", "edge_order": 2, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. 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Histologic analyses of liver biopsies collected at baseline were performed by a blinded pathologist. Information collected at baseline and at each examination included frequency and duration of aspirin and nonsteroidal anti-inflammatory drug (NSAID) use. Using multivariable-adjusted logistic regression, we estimated the association of aspirin use with prevalent steatohepatitis (NASH) and fibrosis. Using multivariable-adjusted Cox proportional hazards modeling, we estimated the association between aspirin use and risk for fibrosis progression.\nAt enrollment, 151 subjects used aspirin daily. Compared with non-regular use, daily aspirin use was associated with significantly lower odds of NASH (adjusted odds ratio, 0.68; 95% CI, 0.37-0.89) and fibrosis (adjusted odds ratio, 0.54; 95% CI, 0.31-0.82). Among individuals with baseline F0-F2 fibrosis (n = 317), 86 developed advanced fibrosis over 3692 person-years. 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Conversely, use of nonaspirin NSAIDs was not associated with risk for advanced fibrosis (aHR, 0.93; 95% CI, 0.81-1.05).\nIn a prospective study of patients with biopsy-proven NAFLD, daily aspirin use was associated with less severe histologic features of NAFLD and NASH, and lower risk for progression to advanced fibrosis with time.", "first_author": null, "journal": "Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association", "year": 2019, "doi": "10.1016/j.cgh.2019.04.061", "study_design_raw": "prospective cohort study", "sample_size_raw": "361", "follow_up_raw": null, "equation_type": "E2", "x_raw": "Aspirin", "c_raw": "non-regular use", "y_raw": "fibrosis", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "aspirin", "c_norm_text": "non-regular use", "y_norm_text": "fibrosis", "population_bucket_raw": "adults with biopsy-confirmed NAFLD", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": null, "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "OR", "measure_scale_raw": "natural", "theta_hat_raw": 0.54, "ci_low_raw": 0.31, "ci_high_raw": 0.82, "p_value_raw": null, "n_raw": 361, "model_raw": "multivariable-adjusted logistic regression", "canonical_effect_scale": "log_ratio", "theta_hat_norm": -0.616186139423817, "ci_low_norm": -1.171182981502945, "ci_high_norm": -0.19845093872383832, "effect_direction": "negative", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "source_sentence": "Compared with non-regular use, daily aspirin use was associated with significantly lower odds of NASH (adjusted odds ratio, 0.68; 95% CI, 0.37-0.89) and fibrosis (adjusted odds ratio, 0.54; 95% CI, 0.31-0.82).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T10:33:18.981000+00:00", "quality_decision_id": "QDEC:25cce01495d2f6ae", "quality_run_id": "QRUN:5c1b506bb7e585b1", "record_status": "accepted", "effect_status": "usable", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "usable", "has_missing_mapping_1": true, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T11:29:05.738989+00:00" } ], "AEV-31077838#3": [ { "norm_edge_pk": "NORM:RAW:1ee5dd8cf329", "raw_edge_pk": "RAW:1ee5dd8cf329", "paper_id": "PMID:31077838", "pmid": "31077838", "edge_id": "AEV-31077838#3", "edge_order": 3, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/31/31077838", "pdf_path": "pdf/31077838.pdf", "source_pdf_path": "pdf/31077838.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/31/31077838/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/31/31077838/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/31/31077838/step4_audit.json", "source_run_id": null, "paper_title": "Daily Aspirin Use Associated With Reduced Risk For Fibrosis Progression In Patients With Nonalcoholic Fatty Liver Disease.", "paper_abstract": "There are few data from prospective studies on the effects of aspirin on fibrosis in patients with nonalcoholic fatty liver disease (NAFLD).\nWe performed a prospective cohort study of 361 adults with biopsy-confirmed NAFLD, from 2006 through 2015, examined every 3-12 months for incident advanced fibrosis defined using serial measurements of validated indices (the Fibrosis-4, NAFLD fibrosis score, and aspartate aminotransferase to platelet ratio indices). Histologic analyses of liver biopsies collected at baseline were performed by a blinded pathologist. Information collected at baseline and at each examination included frequency and duration of aspirin and nonsteroidal anti-inflammatory drug (NSAID) use. Using multivariable-adjusted logistic regression, we estimated the association of aspirin use with prevalent steatohepatitis (NASH) and fibrosis. Using multivariable-adjusted Cox proportional hazards modeling, we estimated the association between aspirin use and risk for fibrosis progression.\nAt enrollment, 151 subjects used aspirin daily. Compared with non-regular use, daily aspirin use was associated with significantly lower odds of NASH (adjusted odds ratio, 0.68; 95% CI, 0.37-0.89) and fibrosis (adjusted odds ratio, 0.54; 95% CI, 0.31-0.82). Among individuals with baseline F0-F2 fibrosis (n = 317), 86 developed advanced fibrosis over 3692 person-years. Daily aspirin users had significantly lower risk for developing incident advanced fibrosis vs non-regular users (adjusted hazard ratio [aHR], 0.63; 95% CI, 0.43-0.85). This relationship appeared to be duration dependent (adjusted P trend=.026), with the greatest benefit found with at least 4 years or more of aspirin use (aHR, 0.50; 95% CI, 0.35-0.73). Conversely, use of nonaspirin NSAIDs was not associated with risk for advanced fibrosis (aHR, 0.93; 95% CI, 0.81-1.05).\nIn a prospective study of patients with biopsy-proven NAFLD, daily aspirin use was associated with less severe histologic features of NAFLD and NASH, and lower risk for progression to advanced fibrosis with time.", "first_author": null, "journal": "Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association", "year": 2019, "doi": "10.1016/j.cgh.2019.04.061", "study_design_raw": "prospective cohort study", "sample_size_raw": "317", "follow_up_raw": "3692 person-years", "equation_type": "E3", "x_raw": "Aspirin", "c_raw": "non-regular use", "y_raw": "advanced fibrosis", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "aspirin", "c_norm_text": "non-regular use", "y_norm_text": "advanced fibrosis", "population_bucket_raw": "adults with biopsy-confirmed NAFLD", "outcome_type_raw": "time_to_event", "time_index_raw": null, "time_horizon_raw": "3692 person-years", "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "HR", "measure_scale_raw": "natural", "theta_hat_raw": 0.63, "ci_low_raw": 0.43, "ci_high_raw": 0.85, "p_value_raw": null, "n_raw": 317, "model_raw": "multivariable-adjusted Cox proportional hazards modeling", "canonical_effect_scale": "log_ratio", "theta_hat_norm": -0.4620354595965587, "ci_low_norm": -0.843970070294529, "ci_high_norm": -0.16251892949777494, "effect_direction": "negative", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "source_sentence": "Daily aspirin users had significantly lower risk for developing incident advanced fibrosis vs non-regular users (adjusted hazard ratio [aHR], 0.63; 95% CI, 0.43-0.85).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T10:33:18.981000+00:00", "quality_decision_id": "QDEC:f11f243ae5d63c67", "quality_run_id": "QRUN:5c1b506bb7e585b1", "record_status": "accepted", "effect_status": "usable", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "usable", "has_missing_mapping_1": true, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T11:29:05.738989+00:00" } ], "AEV-31077838#4": [ { "norm_edge_pk": "NORM:RAW:b599fb3dc9c1", "raw_edge_pk": "RAW:b599fb3dc9c1", "paper_id": "PMID:31077838", "pmid": "31077838", "edge_id": "AEV-31077838#4", "edge_order": 4, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/31/31077838", "pdf_path": "pdf/31077838.pdf", "source_pdf_path": "pdf/31077838.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/31/31077838/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/31/31077838/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/31/31077838/step4_audit.json", "source_run_id": null, "paper_title": "Daily Aspirin Use Associated With Reduced Risk For Fibrosis Progression In Patients With Nonalcoholic Fatty Liver Disease.", "paper_abstract": "There are few data from prospective studies on the effects of aspirin on fibrosis in patients with nonalcoholic fatty liver disease (NAFLD).\nWe performed a prospective cohort study of 361 adults with biopsy-confirmed NAFLD, from 2006 through 2015, examined every 3-12 months for incident advanced fibrosis defined using serial measurements of validated indices (the Fibrosis-4, NAFLD fibrosis score, and aspartate aminotransferase to platelet ratio indices). Histologic analyses of liver biopsies collected at baseline were performed by a blinded pathologist. Information collected at baseline and at each examination included frequency and duration of aspirin and nonsteroidal anti-inflammatory drug (NSAID) use. Using multivariable-adjusted logistic regression, we estimated the association of aspirin use with prevalent steatohepatitis (NASH) and fibrosis. Using multivariable-adjusted Cox proportional hazards modeling, we estimated the association between aspirin use and risk for fibrosis progression.\nAt enrollment, 151 subjects used aspirin daily. Compared with non-regular use, daily aspirin use was associated with significantly lower odds of NASH (adjusted odds ratio, 0.68; 95% CI, 0.37-0.89) and fibrosis (adjusted odds ratio, 0.54; 95% CI, 0.31-0.82). Among individuals with baseline F0-F2 fibrosis (n = 317), 86 developed advanced fibrosis over 3692 person-years. Daily aspirin users had significantly lower risk for developing incident advanced fibrosis vs non-regular users (adjusted hazard ratio [aHR], 0.63; 95% CI, 0.43-0.85). This relationship appeared to be duration dependent (adjusted P trend=.026), with the greatest benefit found with at least 4 years or more of aspirin use (aHR, 0.50; 95% CI, 0.35-0.73). Conversely, use of nonaspirin NSAIDs was not associated with risk for advanced fibrosis (aHR, 0.93; 95% CI, 0.81-1.05).\nIn a prospective study of patients with biopsy-proven NAFLD, daily aspirin use was associated with less severe histologic features of NAFLD and NASH, and lower risk for progression to advanced fibrosis with time.", "first_author": null, "journal": "Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association", "year": 2019, "doi": "10.1016/j.cgh.2019.04.061", "study_design_raw": "prospective cohort study", "sample_size_raw": "317", "follow_up_raw": "3692 person-years", "equation_type": "E3", "x_raw": "Aspirin use (>= 4 years)", "c_raw": null, "y_raw": "advanced fibrosis", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "aspirin use (>= 4 years)", "c_norm_text": null, "y_norm_text": "advanced fibrosis", "population_bucket_raw": "adults with biopsy-confirmed NAFLD", "outcome_type_raw": "time_to_event", "time_index_raw": null, "time_horizon_raw": "3692 person-years", "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "HR", "measure_scale_raw": "natural", "theta_hat_raw": 0.5, "ci_low_raw": 0.35, "ci_high_raw": 0.73, "p_value_raw": 0.026, "n_raw": 317, "model_raw": "multivariable-adjusted Cox proportional hazards modeling", "canonical_effect_scale": "log_ratio", "theta_hat_norm": -0.6931471805599453, "ci_low_norm": -1.0498221244986778, "ci_high_norm": -0.31471074483970024, "effect_direction": "negative", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "source_sentence": "This relationship appeared to be duration dependent (adjusted P trend=.026), with the greatest benefit found with at least 4 years or more of aspirin use (aHR, 0.50; 95% CI, 0.35-0.73).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T10:33:18.981000+00:00", "quality_decision_id": "QDEC:3194a0cabf35d483", "quality_run_id": "QRUN:5c1b506bb7e585b1", "record_status": "accepted", "effect_status": "usable", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "usable", "has_missing_mapping_1": true, "has_tentative_mapping_1": false, "key_role_missing_mapping": null, "key_role_tentative_mapping": null, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T11:29:05.738989+00:00" } ], "AEV-31077838#5": [ { "norm_edge_pk": "NORM:RAW:20987b906078", "raw_edge_pk": "RAW:20987b906078", "paper_id": "PMID:31077838", "pmid": "31077838", "edge_id": "AEV-31077838#5", "edge_order": 5, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/31/31077838", "pdf_path": "pdf/31077838.pdf", "source_pdf_path": "pdf/31077838.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/31/31077838/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/31/31077838/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/31/31077838/step4_audit.json", "source_run_id": null, "paper_title": "Daily Aspirin Use Associated With Reduced Risk For Fibrosis Progression In Patients With Nonalcoholic Fatty Liver Disease.", "paper_abstract": "There are few data from prospective studies on the effects of aspirin on fibrosis in patients with nonalcoholic fatty liver disease (NAFLD).\nWe performed a prospective cohort study of 361 adults with biopsy-confirmed NAFLD, from 2006 through 2015, examined every 3-12 months for incident advanced fibrosis defined using serial measurements of validated indices (the Fibrosis-4, NAFLD fibrosis score, and aspartate aminotransferase to platelet ratio indices). Histologic analyses of liver biopsies collected at baseline were performed by a blinded pathologist. Information collected at baseline and at each examination included frequency and duration of aspirin and nonsteroidal anti-inflammatory drug (NSAID) use. Using multivariable-adjusted logistic regression, we estimated the association of aspirin use with prevalent steatohepatitis (NASH) and fibrosis. Using multivariable-adjusted Cox proportional hazards modeling, we estimated the association between aspirin use and risk for fibrosis progression.\nAt enrollment, 151 subjects used aspirin daily. Compared with non-regular use, daily aspirin use was associated with significantly lower odds of NASH (adjusted odds ratio, 0.68; 95% CI, 0.37-0.89) and fibrosis (adjusted odds ratio, 0.54; 95% CI, 0.31-0.82). Among individuals with baseline F0-F2 fibrosis (n = 317), 86 developed advanced fibrosis over 3692 person-years. Daily aspirin users had significantly lower risk for developing incident advanced fibrosis vs non-regular users (adjusted hazard ratio [aHR], 0.63; 95% CI, 0.43-0.85). This relationship appeared to be duration dependent (adjusted P trend=.026), with the greatest benefit found with at least 4 years or more of aspirin use (aHR, 0.50; 95% CI, 0.35-0.73). Conversely, use of nonaspirin NSAIDs was not associated with risk for advanced fibrosis (aHR, 0.93; 95% CI, 0.81-1.05).\nIn a prospective study of patients with biopsy-proven NAFLD, daily aspirin use was associated with less severe histologic features of NAFLD and NASH, and lower risk for progression to advanced fibrosis with time.", "first_author": null, "journal": "Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association", "year": 2019, "doi": "10.1016/j.cgh.2019.04.061", "study_design_raw": "prospective cohort study", "sample_size_raw": "317", "follow_up_raw": "3692 person-years", "equation_type": "E3", "x_raw": "Non-aspirin NSAIDs", "c_raw": null, "y_raw": "advanced fibrosis", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "non-aspirin nsaids", "c_norm_text": null, "y_norm_text": "advanced fibrosis", "population_bucket_raw": "adults with biopsy-confirmed NAFLD", "outcome_type_raw": "time_to_event", "time_index_raw": null, "time_horizon_raw": "3692 person-years", "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "HR", "measure_scale_raw": "natural", "theta_hat_raw": 0.93, "ci_low_raw": 0.81, "ci_high_raw": 1.05, "p_value_raw": null, "n_raw": 317, "model_raw": "multivariable-adjusted Cox proportional hazards modeling", "canonical_effect_scale": "log_ratio", "theta_hat_norm": -0.07257069283483537, "ci_low_norm": -0.21072103131565253, "ci_high_norm": 0.04879016416943205, "effect_direction": "negative", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "source_sentence": "Conversely, use of nonaspirin NSAIDs was not associated with risk for advanced fibrosis (aHR, 0.93; 95% CI, 0.81-1.05).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T10:33:18.981000+00:00", "quality_decision_id": "QDEC:5662b8c5625af72f", "quality_run_id": "QRUN:5c1b506bb7e585b1", "record_status": "accepted", "effect_status": "usable", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "usable", "has_missing_mapping_1": true, "has_tentative_mapping_1": false, "key_role_missing_mapping": null, "key_role_tentative_mapping": null, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T11:29:05.738989+00:00" } ], "AEV-32794259#1": [ { "norm_edge_pk": "NORM:RAW:d0239fab1da5", "raw_edge_pk": "RAW:d0239fab1da5", "paper_id": "PMID:32794259", "pmid": "32794259", "edge_id": "AEV-32794259#1", "edge_order": 1, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/32/32794259", "pdf_path": "pdf/32794259.pdf", "source_pdf_path": "pdf/32794259.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/32/32794259/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/32/32794259/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/32/32794259/step4_audit.json", "source_run_id": null, "paper_title": "The Commensal Microbe Veillonella as a Marker for Response to an FGF19 Analog in NASH.", "paper_abstract": "The composition of the human gut microbiota is linked to health and disease, and knowledge of the impact of therapeutics on the microbiota is essential to decipher their biological roles and to gain new mechanistic insights. 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Here we report the effect of aldafermin, an analog of the gut hormone FGF19, versus placebo on the gut microbiota in a prospective, phase 2 study in patients with NASH.\nA total of 176 patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) (nonalcoholic fatty liver disease activity score ≥ 4), fibrosis (F1-F3 by NASH Clinical Research Network criteria), and elevated liver fat content (≥ 8% by magnetic resonance imaging-proton density fat fraction) received 0.3 mg (n = 23), 1 mg (n = 49), 3 mg (n = 49), and 6 mg (n = 28) aldafermin or placebo (n = 27) for 12 weeks. Stool samples were collected on day 1 and week 12 and profiled using 16S ribosomal RNA gene sequencing; 122 patients had paired stool microbiome profiles at both day 1 and week 12. Overall, the state of the gut microbial community was distinctly stable in patients treated with aldafermin, with all major phyla and genera unaltered during therapy. 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Our results provide a better understanding of the intricacies of microbiome-host interactions (clinicaltrials.gov trial No. NCT02443116).", "first_author": null, "journal": "Hepatology (Baltimore, Md.)", "year": 2021, "doi": "10.1002/hep.31523", "study_design_raw": "prospective, phase 2 study", "sample_size_raw": "122", "follow_up_raw": "12 weeks", "equation_type": "E3", "x_raw": "Veillonella abundance", "c_raw": null, "y_raw": "Serum bile acid profile", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "veillonella abundance", "c_norm_text": null, "y_norm_text": "serum bile acid profile", "population_bucket_raw": "Patients with NASH treated with aldafermin", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "12 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 122, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unclear", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "source_sentence": "Patients treated with aldafermin showed a significant, dose-dependent enrichment in the rare genus Veillonella, a commensal microbe known to have lactate-degrading and performance-enhancing properties, which correlated with changes in serum bile acid profile.", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T10:33:18.981000+00:00", "quality_decision_id": "QDEC:40d5a40f8b61d32f", "quality_run_id": "QRUN:5c1b506bb7e585b1", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "missing_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": true, "has_tentative_mapping_1": true, "key_role_missing_mapping": true, "key_role_tentative_mapping": true, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T11:29:05.738989+00:00" } ], "AEV-38856224#1": [ { "norm_edge_pk": "NORM:RAW:970c362cd81a", "raw_edge_pk": "RAW:970c362cd81a", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#1", "edge_order": 1, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "190", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "Tirzepatide (5 mg)", "c_raw": "Placebo", "y_raw": "Resolution of MASH without worsening of fibrosis", "z_raw_json": [ "biopsy-confirmed MASH", "stage F2 or F3 fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide (5 mg)", "c_norm_text": "placebo", "y_norm_text": "resolution of mash without worsening of fibrosis", "population_bucket_raw": "Participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": 34.0, "ci_low_raw": 17.0, "ci_high_raw": 50.0, "p_value_raw": 0.001, "n_raw": 190, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "positive", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "source_sentence": "The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50)...", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": true, "normalization_status": "partial", "normalization_issues_json": [ "unsupported_measure_type" ], "compiled_at": "2026-04-17T10:33:18.981000+00:00", "quality_decision_id": "QDEC:38781c2b8a5f7001", "quality_run_id": "QRUN:5c1b506bb7e585b1", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "effect_parse_failed", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T11:29:05.738989+00:00" } ], "AEV-38856224#2": [ { "norm_edge_pk": "NORM:RAW:25f7e46c568f", "raw_edge_pk": "RAW:25f7e46c568f", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#2", "edge_order": 2, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "190", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "Tirzepatide (10 mg)", "c_raw": "Placebo", "y_raw": "Resolution of MASH without worsening of fibrosis", "z_raw_json": [ "biopsy-confirmed MASH", "stage F2 or F3 fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide (10 mg)", "c_norm_text": "placebo", "y_norm_text": "resolution of mash without worsening of fibrosis", "population_bucket_raw": "Participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": 46.0, "ci_low_raw": 29.0, "ci_high_raw": 62.0, "p_value_raw": 0.001, "n_raw": 190, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "positive", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "source_sentence": "...56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62)...", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": true, "normalization_status": "partial", "normalization_issues_json": [ "unsupported_measure_type" ], "compiled_at": "2026-04-17T10:33:18.981000+00:00", "quality_decision_id": "QDEC:f4cc7a819c51ded8", "quality_run_id": "QRUN:5c1b506bb7e585b1", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "missing_key_role_mapping", "effect_status_reason": "effect_parse_failed", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T11:29:05.738989+00:00" } ], "AEV-38856224#3": [ { "norm_edge_pk": "NORM:RAW:193dfe5be595", "raw_edge_pk": "RAW:193dfe5be595", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#3", "edge_order": 3, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "190", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "Tirzepatide (15 mg)", "c_raw": "Placebo", "y_raw": "Resolution of MASH without worsening of fibrosis", "z_raw_json": [ "biopsy-confirmed MASH", "stage F2 or F3 fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide (15 mg)", "c_norm_text": "placebo", "y_norm_text": "resolution of mash without worsening of fibrosis", "population_bucket_raw": "Participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": 53.0, "ci_low_raw": 37.0, "ci_high_raw": 69.0, "p_value_raw": 0.001, "n_raw": 190, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "positive", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "source_sentence": "...62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": true, "normalization_status": "partial", "normalization_issues_json": [ "unsupported_measure_type" ], "compiled_at": "2026-04-17T10:33:18.981000+00:00", "quality_decision_id": "QDEC:829e5238a0431656", "quality_run_id": "QRUN:5c1b506bb7e585b1", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "effect_parse_failed", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T11:29:05.738989+00:00" } ], "AEV-38856224#4": [ { "norm_edge_pk": "NORM:RAW:f938e9b64d2b", "raw_edge_pk": "RAW:f938e9b64d2b", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#4", "edge_order": 4, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_discovery/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. 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The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. 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The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. 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The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. 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Polyphenols exert antioxidant action and inhibit NADPH oxidase in humans.\nTo analyse the effect of cocoa polyphenols on NADPH oxidase isoform 2 (NOX2) activation, oxidative stress and hepatocyte apoptosis in a population affected by NASH.\nIn a cross-sectional study comparing 19 NASH and 19 controls, oxidative stress, as assessed by serum NOX2 activity and F2-isoprostanes, and hepatocyte apoptosis, as assessed by serum cytokeratin-18 (CK-18) levels, were measured. Furthermore, the 19 NASH patients were randomly allocated in a crossover design to 40 g/day of dark chocolate (>85% cocoa) or 40 g/day of milk chocolate (<35% cocoa), for 2 weeks. sNOX2-dp, serum isoprostanes and CK-18 were assessed at baseline and after 2 weeks of chocolate intake.\nCompared to controls, NASH patients had higher sNOX2-dp, serum isoprostanes and CK-18 levels. A significant difference for treatments was found in subjects with respect to sNOX2-dp, serum isoprostanes and serum CK-18. The pairwise comparisons showed that, compared to baseline, after 14 days of dark chocolate intake, a significant reduction in sNOX2-dp serum isoprostanes and CK-18 M30 was found. No change was observed after milk chocolate ingestion. A simple linear regression analysis showed that ∆ of sNOX2-dp was associated with ∆ of serum isoprostanes.\nCocoa polyphenols exert an antioxidant activity via NOX2 down-regulation in NASH patients.", "first_author": null, "journal": "Alimentary pharmacology & therapeutics", "year": 2016, "doi": "10.1111/apt.13687", "study_design_raw": "simple linear regression analysis", "sample_size_raw": "19", "follow_up_raw": null, "equation_type": "E6", "x_raw": "∆sNOX2-dp", "c_raw": null, "y_raw": "∆serum isoprostanes", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "∆snox2-dp", "c_norm_text": null, "y_norm_text": "∆serum isoprostanes", "population_bucket_raw": "NASH patients", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": null, "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "beta", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 19, "model_raw": "simple linear regression", "canonical_effect_scale": "identity_diff", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "positive", "effect_transform": "identity", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "contract_compile_id": null, "contract_claim_id": null, "contract_study_type": null, "contract_claim_confidence": null, "contract_source_span_text": null, "source_sentence": "A simple linear regression analysis showed that ∆ of sNOX2-dp was associated with ∆ of serum isoprostanes.", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T15:22:19.851290+00:00", "quality_decision_id": "QDEC:39fc7d2d49bb15a9", "quality_run_id": "QRUN:361a396c811807a9", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "missing_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": true, "has_tentative_mapping_1": false, "key_role_missing_mapping": null, "key_role_tentative_mapping": null, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T16:08:48.682014+00:00" }, "PMID:30253043::AEV-30253043#1": { "norm_edge_pk": "NORM:RAW:d4ddab90be66", "raw_edge_pk": "RAW:d4ddab90be66", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#1", "edge_order": 1, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Phase 2b randomized controlled trial", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "Obeticholic acid (OCA)", "c_raw": "placebo", "y_raw": "APRI score reduction", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "obeticholic acid (oca)", "c_norm_text": "placebo", "y_norm_text": "apri score reduction", "population_bucket_raw": "patients with non-alcoholic steatohepatitis (NASH)", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": null, "measure_type_raw": "unknown", "measure_scale_raw": null, "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.0001, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "negative", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "contract_compile_id": null, "contract_claim_id": null, "contract_study_type": null, "contract_claim_confidence": null, "contract_source_span_text": null, "source_sentence": "Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T15:22:19.851290+00:00", "quality_decision_id": "QDEC:b1b00ef9d5a890d1", "quality_run_id": "QRUN:361a396c811807a9", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": true, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T16:08:48.682014+00:00" }, "PMID:30253043::AEV-30253043#2": { "norm_edge_pk": "NORM:RAW:da5299a111ed", "raw_edge_pk": "RAW:da5299a111ed", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#2", "edge_order": 2, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. 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Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Phase 2b randomized controlled trial", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "Obeticholic acid (OCA)", "c_raw": "placebo", "y_raw": "FIB-4 index reduction", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "obeticholic acid (oca)", "c_norm_text": "placebo", "y_norm_text": "fib-4 index reduction", "population_bucket_raw": "patients with non-alcoholic steatohepatitis (NASH)", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": null, "measure_type_raw": "unknown", "measure_scale_raw": null, "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.0001, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "negative", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "contract_compile_id": null, "contract_claim_id": null, "contract_study_type": null, "contract_claim_confidence": null, "contract_source_span_text": null, "source_sentence": "Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T15:22:19.851290+00:00", "quality_decision_id": "QDEC:c2d6d092f10cf731", "quality_run_id": "QRUN:361a396c811807a9", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": true, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": true, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T16:08:48.682014+00:00" }, "PMID:30253043::AEV-30253043#3": { "norm_edge_pk": "NORM:RAW:b1fede64de54", "raw_edge_pk": "RAW:b1fede64de54", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#3", "edge_order": 3, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. 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Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Phase 2b randomized controlled trial", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "Obeticholic acid (OCA)", "c_raw": "placebo", "y_raw": "NFS reduction", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "obeticholic acid (oca)", "c_norm_text": "placebo", "y_norm_text": "nfs reduction", "population_bucket_raw": "patients with non-alcoholic steatohepatitis (NASH)", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": null, "measure_type_raw": "unknown", "measure_scale_raw": null, "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.05, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "negative", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "contract_compile_id": null, "contract_claim_id": null, "contract_study_type": null, "contract_claim_confidence": null, "contract_source_span_text": null, "source_sentence": "Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T15:22:19.851290+00:00", "quality_decision_id": "QDEC:2f857b815dadef7c", "quality_run_id": "QRUN:361a396c811807a9", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": true, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T16:08:48.682014+00:00" }, "PMID:30253043::AEV-30253043#4": { "norm_edge_pk": "NORM:RAW:53255ac19a5f", "raw_edge_pk": "RAW:53255ac19a5f", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#4", "edge_order": 4, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Post-hoc analysis of Phase 2b randomized controlled trial", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "APRI reduction at week 24", "c_raw": null, "y_raw": "≥1-stage improvement in histologic fibrosis at week 72", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "apri reduction at week 24", "c_norm_text": null, "y_norm_text": "≥1-stage improvement in histologic fibrosis at week 72", "population_bucket_raw": "patients with non-alcoholic steatohepatitis (NASH)", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.015, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "positive", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "contract_compile_id": null, "contract_claim_id": null, "contract_study_type": null, "contract_claim_confidence": null, "contract_source_span_text": null, "source_sentence": "Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72.", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T15:22:19.851290+00:00", "quality_decision_id": "QDEC:20f181de1a845dd6", "quality_run_id": "QRUN:361a396c811807a9", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": true, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T16:08:48.682014+00:00" }, "PMID:30253043::AEV-30253043#5": { "norm_edge_pk": "NORM:RAW:f8b4f3d17787", "raw_edge_pk": "RAW:f8b4f3d17787", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#5", "edge_order": 5, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Post-hoc analysis of Phase 2b randomized controlled trial", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "FIB-4 reduction at week 24", "c_raw": null, "y_raw": "≥1-stage improvement in histologic fibrosis at week 72", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "fib-4 reduction at week 24", "c_norm_text": null, "y_norm_text": "≥1-stage improvement in histologic fibrosis at week 72", "population_bucket_raw": "patients with non-alcoholic steatohepatitis (NASH)", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.036, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "positive", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "contract_compile_id": null, "contract_claim_id": null, "contract_study_type": null, "contract_claim_confidence": null, "contract_source_span_text": null, "source_sentence": "Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72.", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T15:22:19.851290+00:00", "quality_decision_id": "QDEC:235c8eb57d989373", "quality_run_id": "QRUN:361a396c811807a9", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": true, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T16:08:48.682014+00:00" }, "PMID:30253043::AEV-30253043#6": { "norm_edge_pk": "NORM:RAW:48673993502c", "raw_edge_pk": "RAW:48673993502c", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#6", "edge_order": 6, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Post-hoc analysis of Phase 2b randomized controlled trial", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "NFS reduction at week 24", "c_raw": null, "y_raw": "≥1-stage improvement in histologic fibrosis at week 72", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nfs reduction at week 24", "c_norm_text": null, "y_norm_text": "≥1-stage improvement in histologic fibrosis at week 72", "population_bucket_raw": "patients with non-alcoholic steatohepatitis (NASH)", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.201, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "positive", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "contract_compile_id": null, "contract_claim_id": null, "contract_study_type": null, "contract_claim_confidence": null, "contract_source_span_text": null, "source_sentence": "Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72.", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T15:22:19.851290+00:00", "quality_decision_id": "QDEC:db843644bd23428e", "quality_run_id": "QRUN:361a396c811807a9", "record_status": "excluded", "effect_status": "missing", "record_status_reason": "llm_judge_excluded", "effect_status_reason": "theta_missing", "has_missing_mapping_1": true, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T16:08:48.682014+00:00" }, "PMID:30253043::AEV-30253043#7": { "norm_edge_pk": "NORM:RAW:288057a150d5", "raw_edge_pk": "RAW:288057a150d5", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#7", "edge_order": 7, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Post-hoc analysis of Phase 2b randomized controlled trial", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "APRI reduction at week 72", "c_raw": null, "y_raw": "fibrosis improvement at week 72", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "apri reduction at week 72", "c_norm_text": null, "y_norm_text": "fibrosis improvement at week 72", "population_bucket_raw": "patients with non-alcoholic steatohepatitis (NASH)", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.012, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "positive", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "contract_compile_id": null, "contract_claim_id": null, "contract_study_type": null, "contract_claim_confidence": null, "contract_source_span_text": null, "source_sentence": "Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012).", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T15:22:19.851290+00:00", "quality_decision_id": "QDEC:b213658b160c297a", "quality_run_id": "QRUN:361a396c811807a9", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": true, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T16:08:48.682014+00:00" }, "PMID:30270688::AEV-30270688#1": { "norm_edge_pk": "NORM:RAW:0dbd64830ca0", "raw_edge_pk": "RAW:0dbd64830ca0", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#1", "edge_order": 1, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. 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A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. 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Polyphenols exert antioxidant action and inhibit NADPH oxidase in humans.\nTo analyse the effect of cocoa polyphenols on NADPH oxidase isoform 2 (NOX2) activation, oxidative stress and hepatocyte apoptosis in a population affected by NASH.\nIn a cross-sectional study comparing 19 NASH and 19 controls, oxidative stress, as assessed by serum NOX2 activity and F2-isoprostanes, and hepatocyte apoptosis, as assessed by serum cytokeratin-18 (CK-18) levels, were measured. Furthermore, the 19 NASH patients were randomly allocated in a crossover design to 40 g/day of dark chocolate (>85% cocoa) or 40 g/day of milk chocolate (<35% cocoa), for 2 weeks. sNOX2-dp, serum isoprostanes and CK-18 were assessed at baseline and after 2 weeks of chocolate intake.\nCompared to controls, NASH patients had higher sNOX2-dp, serum isoprostanes and CK-18 levels. A significant difference for treatments was found in subjects with respect to sNOX2-dp, serum isoprostanes and serum CK-18. The pairwise comparisons showed that, compared to baseline, after 14 days of dark chocolate intake, a significant reduction in sNOX2-dp serum isoprostanes and CK-18 M30 was found. No change was observed after milk chocolate ingestion. A simple linear regression analysis showed that ∆ of sNOX2-dp was associated with ∆ of serum isoprostanes.\nCocoa polyphenols exert an antioxidant activity via NOX2 down-regulation in NASH patients.", "first_author": null, "journal": "Alimentary pharmacology & therapeutics", "year": 2016, "doi": "10.1111/apt.13687", "study_design_raw": "crossover randomized controlled trial", "sample_size_raw": "19", "follow_up_raw": "2 weeks", "equation_type": "E1", "x_raw": "Milk chocolate", "c_raw": "Baseline", "y_raw": "sNOX2-dp, serum isoprostanes, CK-18", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "milk chocolate", "c_norm_text": "baseline", "y_norm_text": "snox2-dp, serum isoprostanes, ck-18", "population_bucket_raw": "NASH patients", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "2 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 19, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "null", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "contract_compile_id": null, "contract_claim_id": null, "contract_study_type": null, "contract_claim_confidence": null, "contract_source_span_text": null, "source_sentence": "No change was observed after milk chocolate ingestion.", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T15:22:19.851290+00:00", "quality_decision_id": "QDEC:b9b7dae3e53dbda2", "quality_run_id": "QRUN:361a396c811807a9", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "missing_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": true, "has_tentative_mapping_1": false, "key_role_missing_mapping": null, "key_role_tentative_mapping": null, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T16:08:48.682014+00:00" } ], "AEV-27265388#5": [ { "norm_edge_pk": "NORM:RAW:f8f7635dbe62", "raw_edge_pk": "RAW:f8f7635dbe62", "paper_id": "PMID:27265388", "pmid": "27265388", "edge_id": "AEV-27265388#5", "edge_order": 5, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/27/27265388", "pdf_path": "pdf/27265388.pdf", "source_pdf_path": "pdf/27265388.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/27/27265388/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/27/27265388/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/27/27265388/step4_audit.json", "source_run_id": null, "paper_title": "Effects of dark chocolate on NOX-2-generated oxidative stress in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is considered a pathogenetic mechanism determining fibrosis and disease progression in non-alcoholic steatohepatitis (NASH). Polyphenols exert antioxidant action and inhibit NADPH oxidase in humans.\nTo analyse the effect of cocoa polyphenols on NADPH oxidase isoform 2 (NOX2) activation, oxidative stress and hepatocyte apoptosis in a population affected by NASH.\nIn a cross-sectional study comparing 19 NASH and 19 controls, oxidative stress, as assessed by serum NOX2 activity and F2-isoprostanes, and hepatocyte apoptosis, as assessed by serum cytokeratin-18 (CK-18) levels, were measured. Furthermore, the 19 NASH patients were randomly allocated in a crossover design to 40 g/day of dark chocolate (>85% cocoa) or 40 g/day of milk chocolate (<35% cocoa), for 2 weeks. sNOX2-dp, serum isoprostanes and CK-18 were assessed at baseline and after 2 weeks of chocolate intake.\nCompared to controls, NASH patients had higher sNOX2-dp, serum isoprostanes and CK-18 levels. A significant difference for treatments was found in subjects with respect to sNOX2-dp, serum isoprostanes and serum CK-18. The pairwise comparisons showed that, compared to baseline, after 14 days of dark chocolate intake, a significant reduction in sNOX2-dp serum isoprostanes and CK-18 M30 was found. No change was observed after milk chocolate ingestion. A simple linear regression analysis showed that ∆ of sNOX2-dp was associated with ∆ of serum isoprostanes.\nCocoa polyphenols exert an antioxidant activity via NOX2 down-regulation in NASH patients.", "first_author": null, "journal": "Alimentary pharmacology & therapeutics", "year": 2016, "doi": "10.1111/apt.13687", "study_design_raw": "cross-sectional study", "sample_size_raw": "38", "follow_up_raw": null, "equation_type": "E1", "x_raw": "NASH", "c_raw": "Controls", "y_raw": "sNOX2-dp, serum isoprostanes, CK-18", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nash", "c_norm_text": "controls", "y_norm_text": "snox2-dp, serum isoprostanes, ck-18", "population_bucket_raw": "Humans", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": null, "tau_aligned_raw": null, "measure_family_raw": null, "measure_type_raw": "unknown", "measure_scale_raw": null, "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 38, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "positive", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "contract_compile_id": null, "contract_claim_id": null, "contract_study_type": null, "contract_claim_confidence": null, "contract_source_span_text": null, "source_sentence": "Compared to controls, NASH patients had higher sNOX2-dp, serum isoprostanes and CK-18 levels.", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T15:22:19.851290+00:00", "quality_decision_id": "QDEC:4cffc10a049a4d29", "quality_run_id": "QRUN:361a396c811807a9", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": true, "has_tentative_mapping_1": false, "key_role_missing_mapping": null, "key_role_tentative_mapping": null, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T16:08:48.682014+00:00" } ], "AEV-27265388#6": [ { "norm_edge_pk": "NORM:RAW:a7e04d094620", "raw_edge_pk": "RAW:a7e04d094620", "paper_id": "PMID:27265388", "pmid": "27265388", "edge_id": "AEV-27265388#6", "edge_order": 6, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/27/27265388", "pdf_path": "pdf/27265388.pdf", "source_pdf_path": "pdf/27265388.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/27/27265388/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/27/27265388/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/27/27265388/step4_audit.json", "source_run_id": null, "paper_title": "Effects of dark chocolate on NOX-2-generated oxidative stress in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is considered a pathogenetic mechanism determining fibrosis and disease progression in non-alcoholic steatohepatitis (NASH). Polyphenols exert antioxidant action and inhibit NADPH oxidase in humans.\nTo analyse the effect of cocoa polyphenols on NADPH oxidase isoform 2 (NOX2) activation, oxidative stress and hepatocyte apoptosis in a population affected by NASH.\nIn a cross-sectional study comparing 19 NASH and 19 controls, oxidative stress, as assessed by serum NOX2 activity and F2-isoprostanes, and hepatocyte apoptosis, as assessed by serum cytokeratin-18 (CK-18) levels, were measured. Furthermore, the 19 NASH patients were randomly allocated in a crossover design to 40 g/day of dark chocolate (>85% cocoa) or 40 g/day of milk chocolate (<35% cocoa), for 2 weeks. sNOX2-dp, serum isoprostanes and CK-18 were assessed at baseline and after 2 weeks of chocolate intake.\nCompared to controls, NASH patients had higher sNOX2-dp, serum isoprostanes and CK-18 levels. A significant difference for treatments was found in subjects with respect to sNOX2-dp, serum isoprostanes and serum CK-18. The pairwise comparisons showed that, compared to baseline, after 14 days of dark chocolate intake, a significant reduction in sNOX2-dp serum isoprostanes and CK-18 M30 was found. No change was observed after milk chocolate ingestion. A simple linear regression analysis showed that ∆ of sNOX2-dp was associated with ∆ of serum isoprostanes.\nCocoa polyphenols exert an antioxidant activity via NOX2 down-regulation in NASH patients.", "first_author": null, "journal": "Alimentary pharmacology & therapeutics", "year": 2016, "doi": "10.1111/apt.13687", "study_design_raw": "simple linear regression analysis", "sample_size_raw": "19", "follow_up_raw": null, "equation_type": "E6", "x_raw": "∆sNOX2-dp", "c_raw": null, "y_raw": "∆serum isoprostanes", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "∆snox2-dp", "c_norm_text": null, "y_norm_text": "∆serum isoprostanes", "population_bucket_raw": "NASH patients", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": null, "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "beta", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 19, "model_raw": "simple linear regression", "canonical_effect_scale": "identity_diff", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "positive", "effect_transform": "identity", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "contract_compile_id": null, "contract_claim_id": null, "contract_study_type": null, "contract_claim_confidence": null, "contract_source_span_text": null, "source_sentence": "A simple linear regression analysis showed that ∆ of sNOX2-dp was associated with ∆ of serum isoprostanes.", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T15:22:19.851290+00:00", "quality_decision_id": "QDEC:39fc7d2d49bb15a9", "quality_run_id": "QRUN:361a396c811807a9", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "missing_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": true, "has_tentative_mapping_1": false, "key_role_missing_mapping": null, "key_role_tentative_mapping": null, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T16:08:48.682014+00:00" } ], "AEV-30253043#1": [ { "norm_edge_pk": "NORM:RAW:d4ddab90be66", "raw_edge_pk": "RAW:d4ddab90be66", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#1", "edge_order": 1, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. 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Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. 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Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. 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No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "Vitamin D3", "c_raw": "Placebo", "y_raw": "Alanine aminotransferase (ALT)", "z_raw_json": [ "hypovitaminosis D", "histology-proven NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "alanine aminotransferase (alt)", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "negative", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "contract_compile_id": null, "contract_claim_id": null, "contract_study_type": null, "contract_claim_confidence": null, "contract_source_span_text": null, "source_sentence": "In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase.", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T15:22:19.851290+00:00", "quality_decision_id": "QDEC:80c282900278a891", "quality_run_id": "QRUN:361a396c811807a9", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T16:08:48.682014+00:00" } ], "AEV-30270688#2": [ { "norm_edge_pk": "NORM:RAW:d94d4083b798", "raw_edge_pk": "RAW:d94d4083b798", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#2", "edge_order": 2, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "Vitamin D3", "c_raw": "Placebo", "y_raw": "Cytokeratin-18 fragments", "z_raw_json": [ "hypovitaminosis D", "histology-proven NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "cytokeratin-18 fragments", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "negative", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "contract_compile_id": null, "contract_claim_id": null, "contract_study_type": null, "contract_claim_confidence": null, "contract_source_span_text": null, "source_sentence": "A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo.", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T15:22:19.851290+00:00", "quality_decision_id": "QDEC:ba449eac040682d1", "quality_run_id": "QRUN:361a396c811807a9", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T16:08:48.682014+00:00" } ], "AEV-30270688#3": [ { "norm_edge_pk": "NORM:RAW:24912f6772ad", "raw_edge_pk": "RAW:24912f6772ad", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#3", "edge_order": 3, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "Vitamin D3", "c_raw": "Placebo", "y_raw": "Serum 25-OH vitamin D levels", "z_raw_json": [ "hypovitaminosis D", "histology-proven NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "serum 25-oh vitamin d levels", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "positive", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "contract_compile_id": null, "contract_claim_id": null, "contract_study_type": null, "contract_claim_confidence": null, "contract_source_span_text": null, "source_sentence": "Serum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance.", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T15:22:19.851290+00:00", "quality_decision_id": "QDEC:67b42db84fdce125", "quality_run_id": "QRUN:361a396c811807a9", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T16:08:48.682014+00:00" } ], "AEV-30270688#4": [ { "norm_edge_pk": "NORM:RAW:d0ad9261f54e", "raw_edge_pk": "RAW:d0ad9261f54e", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#4", "edge_order": 4, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "Vitamin D3", "c_raw": "Placebo", "y_raw": "Hepatic steatosis", "z_raw_json": [ "hypovitaminosis D", "histology-proven NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "hepatic steatosis", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": null, "measure_type_raw": "unknown", "measure_scale_raw": null, "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "negative", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "contract_compile_id": null, "contract_claim_id": null, "contract_study_type": null, "contract_claim_confidence": null, "contract_source_span_text": null, "source_sentence": "...together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T15:22:19.851290+00:00", "quality_decision_id": "QDEC:d5841500947d77fe", "quality_run_id": "QRUN:361a396c811807a9", "record_status": "excluded", "effect_status": "missing", "record_status_reason": "llm_judge_excluded", "effect_status_reason": "theta_missing", "has_missing_mapping_1": true, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T16:08:48.682014+00:00" } ], "AEV-30270688#5": [ { "norm_edge_pk": "NORM:RAW:5560147697d6", "raw_edge_pk": "RAW:5560147697d6", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#5", "edge_order": 5, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "Vitamin D3", "c_raw": "Placebo", "y_raw": "Tolerability", "z_raw_json": [ "hypovitaminosis D", "histology-proven NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "tolerability", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "positive", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "contract_compile_id": null, "contract_claim_id": null, "contract_study_type": null, "contract_claim_confidence": null, "contract_source_span_text": null, "source_sentence": "Treatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated...", "grounding_run_id": null, "grounding_confidence": null, "grounding_claims_json": null, "reflection_run_id": null, "reflected_fields_json": null, "reflection_confidence": null, "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-17T15:22:19.851290+00:00", "quality_decision_id": "QDEC:c21da6591f21053f", "quality_run_id": "QRUN:361a396c811807a9", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "llm_judge_accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-17T16:08:48.682014+00:00" } ], "AEV-32794259#1": [ { "norm_edge_pk": "NORM:RAW:d0239fab1da5", "raw_edge_pk": "RAW:d0239fab1da5", "paper_id": "PMID:32794259", "pmid": "32794259", "edge_id": "AEV-32794259#1", "edge_order": 1, "paper_dir": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/32/32794259", "pdf_path": "pdf/32794259.pdf", "source_pdf_path": "pdf/32794259.pdf", "source_edges_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/32/32794259/edges.json", "source_review_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/32/32794259/step3_review.json", "source_audit_path": "artifacts/runs/regression_fullperf_manual_20260417/mash_target_ranking/m3a_extract/32/32794259/step4_audit.json", "source_run_id": null, "paper_title": "The Commensal Microbe Veillonella as a Marker for Response to an FGF19 Analog in NASH.", "paper_abstract": "The composition of the human gut microbiota is linked to health and disease, and knowledge of the impact of therapeutics on the microbiota is essential to decipher their biological roles and to gain new mechanistic insights. 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Patients treated with aldafermin showed a significant, dose-dependent enrichment in the rare genus Veillonella, a commensal microbe known to have lactate-degrading and performance-enhancing properties, which correlated with changes in serum bile acid profile.\nVeillonella may be a bile acid-sensitive bacteria whose enrichment is enabled by aldafermin-mediated suppression of bile acid synthesis and, in particular, decreases in toxic bile acids. This study provides an integrated analysis of gut microbiome, serum bile acid metabolome, imaging, and histological measurements in clinical trials testing aldafermin for NASH. 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"paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. 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No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "Vitamin D3", "c_raw": "placebo", "y_raw": "Hepatic steatosis", "z_raw_json": [ "histologically determined NASH", "elevated ALT", "decreased 25-OH vitamin D level" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "hepatic steatosis", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:17:28.718733+00:00", "quality_decision_id": "QDEC:62d82699fde1b391", "quality_run_id": "QRUN:b1e32987214671e9", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:17:36.207111+00:00" }, "PMID:30270688::AEV-30270688#4": { "norm_edge_pk": "NORM:RAW:d0ad9261f54e", "raw_edge_pk": "RAW:d0ad9261f54e", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#4", "edge_order": 4, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "Vitamin D3", "c_raw": "placebo", "y_raw": "Fibrosis Score", "z_raw_json": [ "histologically determined NASH", "elevated ALT", "decreased 25-OH vitamin D level" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "fibrosis score", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:17:28.718733+00:00", "quality_decision_id": "QDEC:9b0b42ba4e8cd6fc", "quality_run_id": "QRUN:b1e32987214671e9", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:17:36.207111+00:00" }, "PMID:38856224::AEV-38856224#1": { "norm_edge_pk": "NORM:RAW:970c362cd81a", "raw_edge_pk": "RAW:970c362cd81a", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#1", "edge_order": 1, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "157", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "Tirzepatide", "c_raw": "Placebo", "y_raw": "Resolution of MASH without worsening of fibrosis", "z_raw_json": [ "MASH", "moderate or severe fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "resolution of mash without worsening of fibrosis", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 157, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:17:28.718733+00:00", "quality_decision_id": "QDEC:9077a036813f9ef4", "quality_run_id": "QRUN:b1e32987214671e9", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:17:36.207111+00:00" }, "PMID:38856224::AEV-38856224#2": { "norm_edge_pk": "NORM:RAW:25f7e46c568f", "raw_edge_pk": "RAW:25f7e46c568f", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#2", "edge_order": 2, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "157", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "Tirzepatide", "c_raw": "Placebo", "y_raw": "Improvement of at least one fibrosis stage without worsening of MASH", "z_raw_json": [ "MASH", "moderate or severe fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "improvement of at least one fibrosis stage without worsening of mash", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 157, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:17:28.718733+00:00", "quality_decision_id": "QDEC:d0dd6dfb1a4ccadd", "quality_run_id": "QRUN:b1e32987214671e9", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": true, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:17:36.207111+00:00" }, "PMID:38856224::AEV-38856224#3": { "norm_edge_pk": "NORM:RAW:193dfe5be595", "raw_edge_pk": "RAW:193dfe5be595", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#3", "edge_order": 3, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. 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Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. 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Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Observational (Post hoc analysis)", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "FIB-4 index reduction", "c_raw": null, "y_raw": "histologic fibrosis improvement", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "fib-4 index reduction", "c_norm_text": null, "y_norm_text": "histologic fibrosis improvement", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.036, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:17:28.718733+00:00", "quality_decision_id": "QDEC:fb8ab0cc1d5d45b5", "quality_run_id": "QRUN:b1e32987214671e9", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": true, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:17:36.207111+00:00" } ], "AEV-30253043#6": [ { "norm_edge_pk": "NORM:RAW:48673993502c", "raw_edge_pk": "RAW:48673993502c", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#6", "edge_order": 6, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Observational (Post hoc analysis)", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "NFS reduction", "c_raw": null, "y_raw": "histologic fibrosis improvement", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nfs reduction", "c_norm_text": null, "y_norm_text": "histologic fibrosis improvement", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.201, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:17:28.718733+00:00", "quality_decision_id": "QDEC:43b4e4d837b1fdb2", "quality_run_id": "QRUN:b1e32987214671e9", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "missing_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:17:36.207111+00:00" } ], "AEV-30253043#7": [ { "norm_edge_pk": "NORM:RAW:288057a150d5", "raw_edge_pk": "RAW:288057a150d5", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#7", "edge_order": 7, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Observational (Post hoc analysis)", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "APRI score reduction", "c_raw": null, "y_raw": "histologic fibrosis improvement", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "apri score reduction", "c_norm_text": null, "y_norm_text": "histologic fibrosis improvement", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.012, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:17:28.718733+00:00", "quality_decision_id": "QDEC:827eccb06aab9de2", "quality_run_id": "QRUN:b1e32987214671e9", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:17:36.207111+00:00" } ], "AEV-30270688#1": [ { "norm_edge_pk": "NORM:RAW:0dbd64830ca0", "raw_edge_pk": "RAW:0dbd64830ca0", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#1", "edge_order": 1, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "Vitamin D3", "c_raw": "placebo", "y_raw": "Alanine aminotransferase (ALT)", "z_raw_json": [ "histologically determined NASH", "elevated ALT", "decreased 25-OH vitamin D level" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "alanine aminotransferase (alt)", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:17:28.718733+00:00", "quality_decision_id": "QDEC:c000ad11004a1497", "quality_run_id": "QRUN:b1e32987214671e9", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:17:36.207111+00:00" } ], "AEV-30270688#2": [ { "norm_edge_pk": "NORM:RAW:d94d4083b798", "raw_edge_pk": "RAW:d94d4083b798", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#2", "edge_order": 2, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "Vitamin D3", "c_raw": "placebo", "y_raw": "Cytokeratin-18 fragments", "z_raw_json": [ "histologically determined NASH", "elevated ALT", "decreased 25-OH vitamin D level" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "cytokeratin-18 fragments", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:17:28.718733+00:00", "quality_decision_id": "QDEC:916e5c51f3edc50f", "quality_run_id": "QRUN:b1e32987214671e9", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "missing_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:17:36.207111+00:00" } ], "AEV-30270688#3": [ { "norm_edge_pk": "NORM:RAW:24912f6772ad", "raw_edge_pk": "RAW:24912f6772ad", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#3", "edge_order": 3, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "Vitamin D3", "c_raw": "placebo", "y_raw": "Hepatic steatosis", "z_raw_json": [ "histologically determined NASH", "elevated ALT", "decreased 25-OH vitamin D level" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "hepatic steatosis", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:17:28.718733+00:00", "quality_decision_id": "QDEC:62d82699fde1b391", "quality_run_id": "QRUN:b1e32987214671e9", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:17:36.207111+00:00" } ], "AEV-30270688#4": [ { "norm_edge_pk": "NORM:RAW:d0ad9261f54e", "raw_edge_pk": "RAW:d0ad9261f54e", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#4", "edge_order": 4, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "Vitamin D3", "c_raw": "placebo", "y_raw": "Fibrosis Score", "z_raw_json": [ "histologically determined NASH", "elevated ALT", "decreased 25-OH vitamin D level" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "fibrosis score", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:17:28.718733+00:00", "quality_decision_id": "QDEC:9b0b42ba4e8cd6fc", "quality_run_id": "QRUN:b1e32987214671e9", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:17:36.207111+00:00" } ], "AEV-38856224#1": [ { "norm_edge_pk": "NORM:RAW:970c362cd81a", "raw_edge_pk": "RAW:970c362cd81a", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#1", "edge_order": 1, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "157", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "Tirzepatide", "c_raw": "Placebo", "y_raw": "Resolution of MASH without worsening of fibrosis", "z_raw_json": [ "MASH", "moderate or severe fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "resolution of mash without worsening of fibrosis", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 157, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:17:28.718733+00:00", "quality_decision_id": "QDEC:9077a036813f9ef4", "quality_run_id": "QRUN:b1e32987214671e9", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:17:36.207111+00:00" } ], "AEV-38856224#2": [ { "norm_edge_pk": "NORM:RAW:25f7e46c568f", "raw_edge_pk": "RAW:25f7e46c568f", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#2", "edge_order": 2, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "157", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "Tirzepatide", "c_raw": "Placebo", "y_raw": "Improvement of at least one fibrosis stage without worsening of MASH", "z_raw_json": [ "MASH", "moderate or severe fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "improvement of at least one fibrosis stage without worsening of mash", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 157, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:17:28.718733+00:00", "quality_decision_id": "QDEC:d0dd6dfb1a4ccadd", "quality_run_id": "QRUN:b1e32987214671e9", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": true, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:17:36.207111+00:00" } ], "AEV-38856224#3": [ { "norm_edge_pk": "NORM:RAW:193dfe5be595", "raw_edge_pk": "RAW:193dfe5be595", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#3", "edge_order": 3, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "", "follow_up_raw": "52 weeks", "equation_type": "E3", "x_raw": "Tirzepatide", "c_raw": null, "y_raw": "Gastrointestinal adverse events", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": null, "y_norm_text": "gastrointestinal adverse events", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "other", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": null, "measure_type_raw": "unknown", "measure_scale_raw": null, "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": 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"record_status_reason": "accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:17:36.207111+00:00" } ] }, "graph_edges": {}, "papers": { "PMID:30253043": { "paper_id": "PMID:30253043", "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "year": 2019, "doi": "10.1111/liv.13974", "source_pdf_path": "pdf/30253043.pdf", "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_a/m3a_extract/30/30253043" }, "PMID:30270688": { "paper_id": "PMID:30270688", "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, 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Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Randomized Controlled Trial", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "APRI score reduction", "c_raw": null, "y_raw": "histologic fibrosis improvement", "z_raw_json": [ "NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "apri score reduction", "c_norm_text": null, "y_norm_text": "histologic fibrosis improvement", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.015, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:20:57.057510+00:00", "quality_decision_id": "QDEC:c7f88657aa2bf5c6", "quality_run_id": "QRUN:d9c91bcdccce150d", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" }, "PMID:30253043::AEV-30253043#5": { "norm_edge_pk": "NORM:RAW:f8b4f3d17787", "raw_edge_pk": "RAW:f8b4f3d17787", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#5", "edge_order": 5, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Randomized Controlled Trial", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "FIB-4 index reduction", "c_raw": null, "y_raw": "histologic fibrosis improvement", "z_raw_json": [ "NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "fib-4 index reduction", "c_norm_text": null, "y_norm_text": "histologic fibrosis improvement", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.036, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:20:57.057510+00:00", "quality_decision_id": "QDEC:80d6a138cde74bd0", "quality_run_id": "QRUN:d9c91bcdccce150d", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": true, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" }, "PMID:30253043::AEV-30253043#6": { "norm_edge_pk": "NORM:RAW:48673993502c", "raw_edge_pk": "RAW:48673993502c", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#6", "edge_order": 6, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Randomized Controlled Trial", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "NFS reduction", "c_raw": null, "y_raw": "histologic fibrosis improvement", "z_raw_json": [ "NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nfs reduction", "c_norm_text": null, "y_norm_text": "histologic fibrosis improvement", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.201, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:20:57.057510+00:00", "quality_decision_id": "QDEC:275c909de07e38f5", "quality_run_id": "QRUN:d9c91bcdccce150d", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "missing_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" }, "PMID:30253043::AEV-30253043#7": { "norm_edge_pk": "NORM:RAW:288057a150d5", "raw_edge_pk": "RAW:288057a150d5", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#7", "edge_order": 7, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Randomized Controlled Trial", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "APRI score reduction", "c_raw": null, "y_raw": "histologic fibrosis improvement", "z_raw_json": [ "NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "apri score reduction", "c_norm_text": null, "y_norm_text": "histologic fibrosis improvement", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.012, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:20:57.057510+00:00", "quality_decision_id": "QDEC:62a9ad27667379c5", "quality_run_id": "QRUN:d9c91bcdccce150d", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" }, "PMID:30270688::AEV-30270688#1": { "norm_edge_pk": "NORM:RAW:0dbd64830ca0", "raw_edge_pk": "RAW:0dbd64830ca0", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#1", "edge_order": 1, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "vitamin D3", "c_raw": "placebo", "y_raw": "ALT levels", "z_raw_json": [ "hypovitaminosis D", "histology-proven NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "alt levels", "population_bucket_raw": "NASH patients", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:20:57.057510+00:00", "quality_decision_id": "QDEC:3f6f7242da5bce15", "quality_run_id": "QRUN:d9c91bcdccce150d", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" }, "PMID:30270688::AEV-30270688#2": { "norm_edge_pk": "NORM:RAW:d94d4083b798", "raw_edge_pk": "RAW:d94d4083b798", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#2", "edge_order": 2, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "vitamin D3", "c_raw": "placebo", "y_raw": "cytokeratin-18 fragments", "z_raw_json": [ "hypovitaminosis D", "histology-proven NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "cytokeratin-18 fragments", "population_bucket_raw": "NASH patients", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:20:57.057510+00:00", "quality_decision_id": "QDEC:cf3cddc2e36b66e4", "quality_run_id": "QRUN:d9c91bcdccce150d", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "missing_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" }, "PMID:30270688::AEV-30270688#3": { "norm_edge_pk": "NORM:RAW:24912f6772ad", "raw_edge_pk": "RAW:24912f6772ad", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#3", "edge_order": 3, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "vitamin D3", "c_raw": "placebo", "y_raw": "hepatic steatosis", "z_raw_json": [ "hypovitaminosis D", "histology-proven NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "hepatic steatosis", "population_bucket_raw": "NASH patients", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:20:57.057510+00:00", "quality_decision_id": "QDEC:5214942d02266783", "quality_run_id": "QRUN:d9c91bcdccce150d", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" }, "PMID:30270688::AEV-30270688#4": { "norm_edge_pk": "NORM:RAW:d0ad9261f54e", "raw_edge_pk": "RAW:d0ad9261f54e", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#4", "edge_order": 4, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "vitamin D3", "c_raw": "placebo", "y_raw": "Serum 25-OH vitamin D levels", "z_raw_json": [ "hypovitaminosis D", "histology-proven NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "serum 25-oh vitamin d levels", "population_bucket_raw": "NASH patients", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:20:57.057510+00:00", "quality_decision_id": "QDEC:3bff29a8caf1a056", "quality_run_id": "QRUN:d9c91bcdccce150d", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" }, "PMID:38856224::AEV-38856224#1": { "norm_edge_pk": "NORM:RAW:970c362cd81a", "raw_edge_pk": "RAW:970c362cd81a", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#1", "edge_order": 1, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "157", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "tirzepatide", "c_raw": "placebo", "y_raw": "resolution of MASH without worsening of fibrosis", "z_raw_json": [ "moderate or severe fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "resolution of mash without worsening of fibrosis", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 157, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:20:57.057510+00:00", "quality_decision_id": "QDEC:3f489673a1470c28", "quality_run_id": "QRUN:d9c91bcdccce150d", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" }, "PMID:38856224::AEV-38856224#2": { "norm_edge_pk": "NORM:RAW:25f7e46c568f", "raw_edge_pk": "RAW:25f7e46c568f", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#2", "edge_order": 2, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "157", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "tirzepatide", "c_raw": "placebo", "y_raw": "improvement of at least one fibrosis stage without worsening of MASH", "z_raw_json": [ "moderate or severe fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "improvement of at least one fibrosis stage without worsening of mash", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 157, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:20:57.057510+00:00", "quality_decision_id": "QDEC:58eadce83b094500", "quality_run_id": "QRUN:d9c91bcdccce150d", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": true, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" }, "PMID:38856224::AEV-38856224#3": { "norm_edge_pk": "NORM:RAW:193dfe5be595", "raw_edge_pk": "RAW:193dfe5be595", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#3", "edge_order": 3, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "tirzepatide", "c_raw": "placebo", "y_raw": "adverse events", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "adverse events", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "other", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": null, "measure_type_raw": "unknown", "measure_scale_raw": null, "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:20:57.057510+00:00", "quality_decision_id": "QDEC:77420eb8242e7b3b", "quality_run_id": "QRUN:d9c91bcdccce150d", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" } }, "edges_by_edge_id": { "AEV-30253043#1": [ { "norm_edge_pk": "NORM:RAW:d4ddab90be66", "raw_edge_pk": "RAW:d4ddab90be66", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#1", "edge_order": 1, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Randomized Controlled Trial", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "Obeticholic acid", "c_raw": "placebo", "y_raw": "APRI score", "z_raw_json": [ "NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "obeticholic acid", "c_norm_text": "placebo", "y_norm_text": "apri score", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.0001, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:20:57.057510+00:00", "quality_decision_id": "QDEC:ae2c56284a2b4c28", "quality_run_id": "QRUN:d9c91bcdccce150d", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" } ], "AEV-30253043#2": [ { "norm_edge_pk": "NORM:RAW:da5299a111ed", "raw_edge_pk": "RAW:da5299a111ed", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#2", "edge_order": 2, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. 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Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Randomized Controlled Trial", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "NFS reduction", "c_raw": null, "y_raw": "histologic fibrosis improvement", "z_raw_json": [ "NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nfs reduction", "c_norm_text": null, "y_norm_text": "histologic fibrosis improvement", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.201, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:20:57.057510+00:00", "quality_decision_id": "QDEC:275c909de07e38f5", "quality_run_id": "QRUN:d9c91bcdccce150d", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "missing_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" } ], "AEV-30253043#7": [ { "norm_edge_pk": "NORM:RAW:288057a150d5", "raw_edge_pk": "RAW:288057a150d5", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#7", "edge_order": 7, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Randomized Controlled Trial", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "APRI score reduction", "c_raw": null, "y_raw": "histologic fibrosis improvement", "z_raw_json": [ "NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "apri score reduction", "c_norm_text": null, "y_norm_text": "histologic fibrosis improvement", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.012, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:20:57.057510+00:00", "quality_decision_id": "QDEC:62a9ad27667379c5", "quality_run_id": "QRUN:d9c91bcdccce150d", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" } ], "AEV-30270688#1": [ { "norm_edge_pk": "NORM:RAW:0dbd64830ca0", "raw_edge_pk": "RAW:0dbd64830ca0", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#1", "edge_order": 1, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "vitamin D3", "c_raw": "placebo", "y_raw": "ALT levels", "z_raw_json": [ "hypovitaminosis D", "histology-proven NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "alt levels", "population_bucket_raw": "NASH patients", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:20:57.057510+00:00", "quality_decision_id": "QDEC:3f6f7242da5bce15", "quality_run_id": "QRUN:d9c91bcdccce150d", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" } ], "AEV-30270688#2": [ { "norm_edge_pk": "NORM:RAW:d94d4083b798", "raw_edge_pk": "RAW:d94d4083b798", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#2", "edge_order": 2, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "vitamin D3", "c_raw": "placebo", "y_raw": "cytokeratin-18 fragments", "z_raw_json": [ "hypovitaminosis D", "histology-proven NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "cytokeratin-18 fragments", "population_bucket_raw": "NASH patients", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:20:57.057510+00:00", "quality_decision_id": "QDEC:cf3cddc2e36b66e4", "quality_run_id": "QRUN:d9c91bcdccce150d", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "missing_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" } ], "AEV-30270688#3": [ { "norm_edge_pk": "NORM:RAW:24912f6772ad", "raw_edge_pk": "RAW:24912f6772ad", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#3", "edge_order": 3, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "vitamin D3", "c_raw": "placebo", "y_raw": "hepatic steatosis", "z_raw_json": [ "hypovitaminosis D", "histology-proven NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "hepatic steatosis", "population_bucket_raw": "NASH patients", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:20:57.057510+00:00", "quality_decision_id": "QDEC:5214942d02266783", "quality_run_id": "QRUN:d9c91bcdccce150d", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" } ], "AEV-30270688#4": [ { "norm_edge_pk": "NORM:RAW:d0ad9261f54e", "raw_edge_pk": "RAW:d0ad9261f54e", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#4", "edge_order": 4, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "vitamin D3", "c_raw": "placebo", "y_raw": "Serum 25-OH vitamin D levels", "z_raw_json": [ "hypovitaminosis D", "histology-proven NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "serum 25-oh vitamin d levels", "population_bucket_raw": "NASH patients", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:20:57.057510+00:00", "quality_decision_id": "QDEC:3bff29a8caf1a056", "quality_run_id": "QRUN:d9c91bcdccce150d", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" } ], "AEV-38856224#1": [ { "norm_edge_pk": "NORM:RAW:970c362cd81a", "raw_edge_pk": "RAW:970c362cd81a", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#1", "edge_order": 1, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "157", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "tirzepatide", "c_raw": "placebo", "y_raw": "resolution of MASH without worsening of fibrosis", "z_raw_json": [ "moderate or severe fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "resolution of mash without worsening of fibrosis", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 157, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:20:57.057510+00:00", "quality_decision_id": "QDEC:3f489673a1470c28", "quality_run_id": "QRUN:d9c91bcdccce150d", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" } ], "AEV-38856224#2": [ { "norm_edge_pk": "NORM:RAW:25f7e46c568f", "raw_edge_pk": "RAW:25f7e46c568f", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#2", "edge_order": 2, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "157", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "tirzepatide", "c_raw": "placebo", "y_raw": "improvement of at least one fibrosis stage without worsening of MASH", "z_raw_json": [ "moderate or severe fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "improvement of at least one fibrosis stage without worsening of mash", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 157, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T14:20:57.057510+00:00", "quality_decision_id": "QDEC:58eadce83b094500", "quality_run_id": "QRUN:d9c91bcdccce150d", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": true, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" } ], "AEV-38856224#3": [ { "norm_edge_pk": "NORM:RAW:193dfe5be595", "raw_edge_pk": "RAW:193dfe5be595", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#3", "edge_order": 3, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "tirzepatide", "c_raw": "placebo", "y_raw": "adverse events", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "adverse events", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "other", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": null, "measure_type_raw": "unknown", "measure_scale_raw": null, "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, 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"record_status_reason": "accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T14:21:13.602762+00:00" } ] }, "graph_edges": {}, "papers": { "PMID:30253043": { "paper_id": "PMID:30253043", "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "year": 2019, "doi": "10.1111/liv.13974", "source_pdf_path": "pdf/30253043.pdf", "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/review_fix_b/m3a_extract/30/30253043" }, "PMID:30270688": { "paper_id": "PMID:30270688", "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, 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"norm_edge_pk": "NORM:RAW:d4ddab90be66", "raw_edge_pk": "RAW:d4ddab90be66", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#1", "edge_order": 1, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. 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Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. 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Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Observational", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "Reduction in NFS", "c_raw": null, "y_raw": "Improvement in histologic fibrosis stage", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "reduction in nfs", "c_norm_text": null, "y_norm_text": "improvement in histologic fibrosis stage", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.201, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T09:18:41.521542+00:00", "quality_decision_id": "QDEC:a51ed6c3b5bd0821", "quality_run_id": "QRUN:ed979dd737f8cf46", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "missing_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T09:18:51.064126+00:00" }, "PMID:30270688::AEV-30270688#1": { "norm_edge_pk": "NORM:RAW:0dbd64830ca0", "raw_edge_pk": "RAW:0dbd64830ca0", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#1", "edge_order": 1, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "vitamin D3", "c_raw": "placebo", "y_raw": "alanine aminotransferase (ALT)", "z_raw_json": [ "histologically determined NASH", "elevated ALT", "decreased 25-OH vitamin D level" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "alanine aminotransferase (alt)", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T09:18:41.521542+00:00", "quality_decision_id": "QDEC:86bb3ecdc29ff736", "quality_run_id": "QRUN:ed979dd737f8cf46", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T09:18:51.064126+00:00" }, "PMID:30270688::AEV-30270688#2": { "norm_edge_pk": "NORM:RAW:d94d4083b798", "raw_edge_pk": "RAW:d94d4083b798", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#2", "edge_order": 2, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "vitamin D3", "c_raw": "placebo", "y_raw": "cytokeratin-18 fragments", "z_raw_json": [ "histologically determined NASH", "elevated ALT", "decreased 25-OH vitamin D level" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "cytokeratin-18 fragments", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T09:18:41.521542+00:00", "quality_decision_id": "QDEC:34bc985047062fb3", "quality_run_id": "QRUN:ed979dd737f8cf46", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "missing_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T09:18:51.064126+00:00" }, "PMID:30270688::AEV-30270688#3": { "norm_edge_pk": "NORM:RAW:24912f6772ad", "raw_edge_pk": "RAW:24912f6772ad", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#3", "edge_order": 3, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "vitamin D3", "c_raw": "placebo", "y_raw": "hepatic steatosis", "z_raw_json": [ "histologically determined NASH", "elevated ALT", "decreased 25-OH vitamin D level" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "hepatic steatosis", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T09:18:41.521542+00:00", "quality_decision_id": "QDEC:04c59242d336988b", "quality_run_id": "QRUN:ed979dd737f8cf46", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T09:18:51.064126+00:00" }, "PMID:30270688::AEV-30270688#4": { "norm_edge_pk": "NORM:RAW:d0ad9261f54e", "raw_edge_pk": "RAW:d0ad9261f54e", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#4", "edge_order": 4, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "vitamin D3", "c_raw": "placebo", "y_raw": "Serum 25-OH vitamin D levels", "z_raw_json": [ "histologically determined NASH", "elevated ALT", "decreased 25-OH vitamin D level" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "serum 25-oh vitamin d levels", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T09:18:41.521542+00:00", "quality_decision_id": "QDEC:aafa37764663c073", "quality_run_id": "QRUN:ed979dd737f8cf46", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T09:18:51.064126+00:00" }, "PMID:38856224::AEV-38856224#1": { "norm_edge_pk": "NORM:RAW:970c362cd81a", "raw_edge_pk": "RAW:970c362cd81a", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#1", "edge_order": 1, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "157", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "tirzepatide", "c_raw": "placebo", "y_raw": "resolution of MASH without worsening of fibrosis", "z_raw_json": [ "moderate or severe fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "resolution of mash without worsening of fibrosis", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 157, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T09:18:41.521542+00:00", "quality_decision_id": "QDEC:5d09a98df27d0290", "quality_run_id": "QRUN:ed979dd737f8cf46", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T09:18:51.064126+00:00" }, "PMID:38856224::AEV-38856224#2": { "norm_edge_pk": "NORM:RAW:25f7e46c568f", "raw_edge_pk": "RAW:25f7e46c568f", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#2", "edge_order": 2, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "157", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "tirzepatide", "c_raw": "placebo", "y_raw": "improvement of at least one fibrosis stage without worsening of MASH", "z_raw_json": [ "moderate or severe fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "improvement of at least one fibrosis stage without worsening of mash", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 157, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T09:18:41.521542+00:00", "quality_decision_id": "QDEC:1c9911ec2049470c", "quality_run_id": "QRUN:ed979dd737f8cf46", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": true, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T09:18:51.064126+00:00" }, "PMID:38856224::AEV-38856224#3": { "norm_edge_pk": "NORM:RAW:193dfe5be595", "raw_edge_pk": "RAW:193dfe5be595", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#3", "edge_order": 3, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "190", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "tirzepatide", "c_raw": "placebo", "y_raw": "adverse events", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "adverse events", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "other", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": null, "measure_type_raw": "unknown", "measure_scale_raw": null, "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 190, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T09:18:41.521542+00:00", "quality_decision_id": "QDEC:a0f01a1a1bf019dc", "quality_run_id": "QRUN:ed979dd737f8cf46", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T09:18:51.064126+00:00" } }, "edges_by_edge_id": { "AEV-30253043#1": [ { "norm_edge_pk": "NORM:RAW:d4ddab90be66", "raw_edge_pk": "RAW:d4ddab90be66", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#1", "edge_order": 1, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. 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Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Observational", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "Reduction in FIB-4", "c_raw": null, "y_raw": "Improvement in histologic fibrosis stage", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "reduction in fib-4", "c_norm_text": null, "y_norm_text": "improvement in histologic fibrosis stage", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.036, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T09:18:41.521542+00:00", "quality_decision_id": "QDEC:f43a04015fc9cc5c", "quality_run_id": "QRUN:ed979dd737f8cf46", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T09:18:51.064126+00:00" } ], "AEV-30253043#6": [ { "norm_edge_pk": "NORM:RAW:48673993502c", "raw_edge_pk": "RAW:48673993502c", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#6", "edge_order": 6, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Observational", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "Reduction in NFS", "c_raw": null, "y_raw": "Improvement in histologic fibrosis stage", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "reduction in nfs", "c_norm_text": null, "y_norm_text": "improvement in histologic fibrosis stage", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.201, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T09:18:41.521542+00:00", "quality_decision_id": "QDEC:a51ed6c3b5bd0821", "quality_run_id": "QRUN:ed979dd737f8cf46", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "missing_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T09:18:51.064126+00:00" } ], "AEV-30270688#1": [ { "norm_edge_pk": "NORM:RAW:0dbd64830ca0", "raw_edge_pk": "RAW:0dbd64830ca0", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#1", "edge_order": 1, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "vitamin D3", "c_raw": "placebo", "y_raw": "alanine aminotransferase (ALT)", "z_raw_json": [ "histologically determined NASH", "elevated ALT", "decreased 25-OH vitamin D level" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "alanine aminotransferase (alt)", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T09:18:41.521542+00:00", "quality_decision_id": "QDEC:86bb3ecdc29ff736", "quality_run_id": "QRUN:ed979dd737f8cf46", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T09:18:51.064126+00:00" } ], "AEV-30270688#2": [ { "norm_edge_pk": "NORM:RAW:d94d4083b798", "raw_edge_pk": "RAW:d94d4083b798", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#2", "edge_order": 2, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "vitamin D3", "c_raw": "placebo", "y_raw": "cytokeratin-18 fragments", "z_raw_json": [ "histologically determined NASH", "elevated ALT", "decreased 25-OH vitamin D level" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "cytokeratin-18 fragments", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T09:18:41.521542+00:00", "quality_decision_id": "QDEC:34bc985047062fb3", "quality_run_id": "QRUN:ed979dd737f8cf46", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "missing_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T09:18:51.064126+00:00" } ], "AEV-30270688#3": [ { "norm_edge_pk": "NORM:RAW:24912f6772ad", "raw_edge_pk": "RAW:24912f6772ad", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#3", "edge_order": 3, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "vitamin D3", "c_raw": "placebo", "y_raw": "hepatic steatosis", "z_raw_json": [ "histologically determined NASH", "elevated ALT", "decreased 25-OH vitamin D level" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "hepatic steatosis", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T09:18:41.521542+00:00", "quality_decision_id": "QDEC:04c59242d336988b", "quality_run_id": "QRUN:ed979dd737f8cf46", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T09:18:51.064126+00:00" } ], "AEV-30270688#4": [ { "norm_edge_pk": "NORM:RAW:d0ad9261f54e", "raw_edge_pk": "RAW:d0ad9261f54e", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#4", "edge_order": 4, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "vitamin D3", "c_raw": "placebo", "y_raw": "Serum 25-OH vitamin D levels", "z_raw_json": [ "histologically determined NASH", "elevated ALT", "decreased 25-OH vitamin D level" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "serum 25-oh vitamin d levels", "population_bucket_raw": "NASH patients with hypovitaminosis D", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T09:18:41.521542+00:00", "quality_decision_id": "QDEC:aafa37764663c073", "quality_run_id": "QRUN:ed979dd737f8cf46", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T09:18:51.064126+00:00" } ], "AEV-38856224#1": [ { "norm_edge_pk": "NORM:RAW:970c362cd81a", "raw_edge_pk": "RAW:970c362cd81a", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#1", "edge_order": 1, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "157", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "tirzepatide", "c_raw": "placebo", "y_raw": "resolution of MASH without worsening of fibrosis", "z_raw_json": [ "moderate or severe fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "resolution of mash without worsening of fibrosis", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 157, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T09:18:41.521542+00:00", "quality_decision_id": "QDEC:5d09a98df27d0290", "quality_run_id": "QRUN:ed979dd737f8cf46", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T09:18:51.064126+00:00" } ], "AEV-38856224#2": [ { "norm_edge_pk": "NORM:RAW:25f7e46c568f", "raw_edge_pk": "RAW:25f7e46c568f", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#2", "edge_order": 2, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "157", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "tirzepatide", "c_raw": "placebo", "y_raw": "improvement of at least one fibrosis stage without worsening of MASH", "z_raw_json": [ "moderate or severe fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "improvement of at least one fibrosis stage without worsening of mash", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 157, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T09:18:41.521542+00:00", "quality_decision_id": "QDEC:1c9911ec2049470c", "quality_run_id": "QRUN:ed979dd737f8cf46", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": true, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T09:18:51.064126+00:00" } ], "AEV-38856224#3": [ { "norm_edge_pk": "NORM:RAW:193dfe5be595", "raw_edge_pk": "RAW:193dfe5be595", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#3", "edge_order": 3, "paper_dir": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/runs/workbench_test_runs/mash_target_discovery/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "190", "follow_up_raw": "52 weeks", "equation_type": "E1", "x_raw": "tirzepatide", "c_raw": "placebo", "y_raw": "adverse events", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "adverse events", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "other", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": null, "measure_type_raw": "unknown", "measure_scale_raw": null, "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 190, "model_raw": null, 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Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. 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No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "Vitamin D3", "c_raw": "Placebo", "y_raw": "Hepatic steatosis", "z_raw_json": [ "hypovitaminosis D", "histology-proven NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "hepatic steatosis", "population_bucket_raw": "NASH patients", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T04:46:20.060514+00:00", "quality_decision_id": "QDEC:754e1ae595873914", "quality_run_id": "QRUN:82799bf033d4dd99", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T04:46:27.388033+00:00" }, "PMID:30270688::AEV-30270688#4": { "norm_edge_pk": "NORM:RAW:d0ad9261f54e", "raw_edge_pk": "RAW:d0ad9261f54e", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#4", "edge_order": 4, "paper_dir": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "Vitamin D3", "c_raw": "Placebo", "y_raw": "Safety/Tolerability", "z_raw_json": [ "hypovitaminosis D", "histology-proven NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "safety/tolerability", "population_bucket_raw": "NASH patients", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T04:46:20.060514+00:00", "quality_decision_id": "QDEC:ba4d3270e223a28b", "quality_run_id": "QRUN:82799bf033d4dd99", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T04:46:27.388033+00:00" }, "PMID:38856224::AEV-38856224#1": { "norm_edge_pk": "NORM:RAW:970c362cd81a", "raw_edge_pk": "RAW:970c362cd81a", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#1", "edge_order": 1, "paper_dir": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "157", "follow_up_raw": "52 weeks", "equation_type": "E3", "x_raw": "tirzepatide", "c_raw": "placebo", "y_raw": "resolution of MASH without worsening of fibrosis", "z_raw_json": [ "moderate or severe fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "resolution of mash without worsening of fibrosis", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 157, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T04:46:20.060514+00:00", "quality_decision_id": "QDEC:89bf49b5199a6908", "quality_run_id": "QRUN:82799bf033d4dd99", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T04:46:27.388033+00:00" }, "PMID:38856224::AEV-38856224#2": { "norm_edge_pk": "NORM:RAW:25f7e46c568f", "raw_edge_pk": "RAW:25f7e46c568f", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#2", "edge_order": 2, "paper_dir": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "157", "follow_up_raw": "52 weeks", "equation_type": "E3", "x_raw": "tirzepatide", "c_raw": "placebo", "y_raw": "improvement of at least one fibrosis stage without worsening of MASH", "z_raw_json": [ "moderate or severe fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "improvement of at least one fibrosis stage without worsening of mash", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 157, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T04:46:20.060514+00:00", "quality_decision_id": "QDEC:f37c4ddd076c1873", "quality_run_id": "QRUN:82799bf033d4dd99", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": true, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T04:46:27.388033+00:00" }, "PMID:38856224::AEV-38856224#3": { "norm_edge_pk": "NORM:RAW:193dfe5be595", "raw_edge_pk": "RAW:193dfe5be595", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#3", "edge_order": 3, "paper_dir": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. 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Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Observational Cohort", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "FIB-4 index reduction", "c_raw": null, "y_raw": "histologic fibrosis improvement", "z_raw_json": [ "NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "fib-4 index reduction", "c_norm_text": null, "y_norm_text": "histologic fibrosis improvement", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.036, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T04:46:20.060514+00:00", "quality_decision_id": "QDEC:93ce574283d3ad30", "quality_run_id": "QRUN:82799bf033d4dd99", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": true, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T04:46:27.388033+00:00" } ], "AEV-30253043#6": [ { "norm_edge_pk": "NORM:RAW:48673993502c", "raw_edge_pk": "RAW:48673993502c", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#6", "edge_order": 6, "paper_dir": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.", "first_author": null, "journal": "Liver international : official journal of the International Association for the Study of the Liver", "year": 2019, "doi": "10.1111/liv.13974", "study_design_raw": "Observational Cohort", "sample_size_raw": "", "follow_up_raw": "72 weeks", "equation_type": "E3", "x_raw": "NFS reduction", "c_raw": null, "y_raw": "histologic fibrosis improvement", "z_raw_json": [ "NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "nfs reduction", "c_norm_text": null, "y_norm_text": "histologic fibrosis improvement", "population_bucket_raw": "patients with non-alcoholic steatohepatitis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "72 weeks", "tau_aligned_raw": null, "measure_family_raw": "association", "measure_type_raw": "correlation", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.201, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.667, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T04:46:20.060514+00:00", "quality_decision_id": "QDEC:dae3d1926c9c25d8", "quality_run_id": "QRUN:82799bf033d4dd99", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "missing_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T04:46:27.388033+00:00" } ], "AEV-30253043#7": [ { "norm_edge_pk": "NORM:RAW:288057a150d5", "raw_edge_pk": "RAW:288057a150d5", "paper_id": "PMID:30253043", "pmid": "30253043", "edge_id": "AEV-30253043#7", "edge_order": 7, "paper_dir": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/30/30253043", "pdf_path": "pdf/30253043.pdf", "source_pdf_path": "pdf/30253043.pdf", "source_edges_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/30/30253043/edges.json", "source_review_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/30/30253043/step3_review.json", "source_audit_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/30/30253043/step4_audit.json", "source_run_id": null, "paper_title": "Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.", "paper_abstract": "Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement.\nIn the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks.\nIn patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)].\nReadily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. 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No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "Vitamin D3", "c_raw": "Placebo", "y_raw": "Alanine aminotransferase (ALT)", "z_raw_json": [ "hypovitaminosis D", "histology-proven NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "alanine aminotransferase (alt)", "population_bucket_raw": "NASH patients", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T04:46:20.060514+00:00", "quality_decision_id": "QDEC:3f6787bfb1aea589", "quality_run_id": "QRUN:82799bf033d4dd99", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T04:46:27.388033+00:00" } ], "AEV-30270688#2": [ { "norm_edge_pk": "NORM:RAW:d94d4083b798", "raw_edge_pk": "RAW:d94d4083b798", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#2", "edge_order": 2, "paper_dir": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. 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No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "Vitamin D3", "c_raw": "Placebo", "y_raw": "Hepatic steatosis", "z_raw_json": [ "hypovitaminosis D", "histology-proven NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "hepatic steatosis", "population_bucket_raw": "NASH patients", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T04:46:20.060514+00:00", "quality_decision_id": "QDEC:754e1ae595873914", "quality_run_id": "QRUN:82799bf033d4dd99", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T04:46:27.388033+00:00" } ], "AEV-30270688#4": [ { "norm_edge_pk": "NORM:RAW:d0ad9261f54e", "raw_edge_pk": "RAW:d0ad9261f54e", "paper_id": "PMID:30270688", "pmid": "30270688", "edge_id": "AEV-30270688#4", "edge_order": 4, "paper_dir": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/30/30270688", "pdf_path": "pdf/30270688.pdf", "source_pdf_path": "pdf/30270688.pdf", "source_edges_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/30/30270688/edges.json", "source_review_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/30/30270688/step3_review.json", "source_audit_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/30/30270688/step4_audit.json", "source_run_id": null, "paper_title": "Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.", "paper_abstract": "Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available.\nTreatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.", "first_author": null, "journal": "Scandinavian journal of gastroenterology", "year": 2018, "doi": "10.1080/00365521.2018.1501091", "study_design_raw": "double-blinded, randomized, placebo-controlled pilot study", "sample_size_raw": "", "follow_up_raw": "48 weeks", "equation_type": "E1", "x_raw": "Vitamin D3", "c_raw": "Placebo", "y_raw": "Safety/Tolerability", "z_raw_json": [ "hypovitaminosis D", "histology-proven NASH" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "vitamin d3", "c_norm_text": "placebo", "y_norm_text": "safety/tolerability", "population_bucket_raw": "NASH patients", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "48 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": null, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T04:46:20.060514+00:00", "quality_decision_id": "QDEC:ba4d3270e223a28b", "quality_run_id": "QRUN:82799bf033d4dd99", "record_status": "accepted", "effect_status": "missing", "record_status_reason": "accepted", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": false, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T04:46:27.388033+00:00" } ], "AEV-38856224#1": [ { "norm_edge_pk": "NORM:RAW:970c362cd81a", "raw_edge_pk": "RAW:970c362cd81a", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#1", "edge_order": 1, "paper_dir": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "157", "follow_up_raw": "52 weeks", "equation_type": "E3", "x_raw": "tirzepatide", "c_raw": "placebo", "y_raw": "resolution of MASH without worsening of fibrosis", "z_raw_json": [ "moderate or severe fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "resolution of mash without worsening of fibrosis", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 157, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T04:46:20.060514+00:00", "quality_decision_id": "QDEC:89bf49b5199a6908", "quality_run_id": "QRUN:82799bf033d4dd99", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T04:46:27.388033+00:00" } ], "AEV-38856224#2": [ { "norm_edge_pk": "NORM:RAW:25f7e46c568f", "raw_edge_pk": "RAW:25f7e46c568f", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#2", "edge_order": 2, "paper_dir": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "157", "follow_up_raw": "52 weeks", "equation_type": "E3", "x_raw": "tirzepatide", "c_raw": "placebo", "y_raw": "improvement of at least one fibrosis stage without worsening of MASH", "z_raw_json": [ "moderate or severe fibrosis" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "improvement of at least one fibrosis stage without worsening of mash", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 157, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T04:46:20.060514+00:00", "quality_decision_id": "QDEC:f37c4ddd076c1873", "quality_run_id": "QRUN:82799bf033d4dd99", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_key_role_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": true, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T04:46:27.388033+00:00" } ], "AEV-38856224#3": [ { "norm_edge_pk": "NORM:RAW:193dfe5be595", "raw_edge_pk": "RAW:193dfe5be595", "paper_id": "PMID:38856224", "pmid": "38856224", "edge_id": "AEV-38856224#3", "edge_order": 3, "paper_dir": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224/edges.json", "source_review_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224/step3_review.json", "source_audit_path": "artifacts/workbench_test_runs/mash_target_ranking/m3a_extract/38/38856224/step4_audit.json", "source_run_id": null, "paper_title": "Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis.", "paper_abstract": "BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.\nMETHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.\nRESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.\nCONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2401943", "study_design_raw": "phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "190", "follow_up_raw": "52 weeks", "equation_type": "E3", "x_raw": "tirzepatide", "c_raw": "placebo", "y_raw": "adverse events", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "tirzepatide", "c_norm_text": "placebo", "y_norm_text": "adverse events", "population_bucket_raw": "participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis", "outcome_type_raw": "other", "time_index_raw": null, "time_horizon_raw": "52 weeks", "tau_aligned_raw": null, "measure_family_raw": null, "measure_type_raw": "unknown", "measure_scale_raw": null, "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 190, "model_raw": null, 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No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients.\nHistologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score.\nSerum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. 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We therefore assessed the efficacy and safety of subcutaneous semaglutide as treatment for obesity in patients without diabetes.\nMETHODOLOGY: A comprehensive search of PubMed/MEDLINE, Cochrane and Google scholar was performed to identify trials on the efficacy and safety of subcutaneous semaglutide on patients with obesity without diabetes. Primary outcome was expressed as percent mean weight difference. Secondary outcomes including risk for gastrointestinal adverse events, discontinuation of treatment and serious adverse events were expressed as risk ratios. These were calculated using the random effects model.\nRESULTS: The study included 4 randomized controlled trials having a total of 3,613 individuals with obesity without diabetes. The mean difference for weight reduction was -11.85%, favoring semaglutide [95% confidence interval (CI) (-12.81,-10.90), p<0.00001]. Secondary outcomes showed that the risk of developing gastrointestinal adverse events was 1.59 times more likely with semaglutide (RR 1.59, 95%CI [1.34, 1.88], p<0.00001). Risk for discontinuation due to adverse events was twice as likely in the semaglutide group (RR 2.19, 95%CI [1.36,3.55], p=0.001) and the risk for serious adverse events was 1.6 times more likely for semaglutide (RR1.60, 95%CI [1.24, 2.07], p=0.0003). Serious events were mostly of gastrointestinal and hepatobiliary disorders such as acute pancreatitis and cholelithiasis.\nCONCLUSION: Among individuals with obesity without type 2 diabetes, subcutaneous semaglutide is effective for weight loss with an 11.85% reduction from baseline compared to placebo. This supports the use of semaglutide for weight management in obesity. 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Secondary outcomes showed that the risk of developing gastrointestinal adverse events was 1.59 times more likely with semaglutide (RR 1.59, 95%CI [1.34, 1.88], p<0.00001). Risk for discontinuation due to adverse events was twice as likely in the semaglutide group (RR 2.19, 95%CI [1.36,3.55], p=0.001) and the risk for serious adverse events was 1.6 times more likely for semaglutide (RR1.60, 95%CI [1.24, 2.07], p=0.0003). Serious events were mostly of gastrointestinal and hepatobiliary disorders such as acute pancreatitis and cholelithiasis.\nCONCLUSION: Among individuals with obesity without type 2 diabetes, subcutaneous semaglutide is effective for weight loss with an 11.85% reduction from baseline compared to placebo. This supports the use of semaglutide for weight management in obesity. 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Secondary outcomes showed that the risk of developing gastrointestinal adverse events was 1.59 times more likely with semaglutide (RR 1.59, 95%CI [1.34, 1.88], p<0.00001). Risk for discontinuation due to adverse events was twice as likely in the semaglutide group (RR 2.19, 95%CI [1.36,3.55], p=0.001) and the risk for serious adverse events was 1.6 times more likely for semaglutide (RR1.60, 95%CI [1.24, 2.07], p=0.0003). Serious events were mostly of gastrointestinal and hepatobiliary disorders such as acute pancreatitis and cholelithiasis.\nCONCLUSION: Among individuals with obesity without type 2 diabetes, subcutaneous semaglutide is effective for weight loss with an 11.85% reduction from baseline compared to placebo. This supports the use of semaglutide for weight management in obesity. 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We therefore assessed the efficacy and safety of subcutaneous semaglutide as treatment for obesity in patients without diabetes.\nMETHODOLOGY: A comprehensive search of PubMed/MEDLINE, Cochrane and Google scholar was performed to identify trials on the efficacy and safety of subcutaneous semaglutide on patients with obesity without diabetes. Primary outcome was expressed as percent mean weight difference. Secondary outcomes including risk for gastrointestinal adverse events, discontinuation of treatment and serious adverse events were expressed as risk ratios. These were calculated using the random effects model.\nRESULTS: The study included 4 randomized controlled trials having a total of 3,613 individuals with obesity without diabetes. The mean difference for weight reduction was -11.85%, favoring semaglutide [95% confidence interval (CI) (-12.81,-10.90), p<0.00001]. Secondary outcomes showed that the risk of developing gastrointestinal adverse events was 1.59 times more likely with semaglutide (RR 1.59, 95%CI [1.34, 1.88], p<0.00001). Risk for discontinuation due to adverse events was twice as likely in the semaglutide group (RR 2.19, 95%CI [1.36,3.55], p=0.001) and the risk for serious adverse events was 1.6 times more likely for semaglutide (RR1.60, 95%CI [1.24, 2.07], p=0.0003). Serious events were mostly of gastrointestinal and hepatobiliary disorders such as acute pancreatitis and cholelithiasis.\nCONCLUSION: Among individuals with obesity without type 2 diabetes, subcutaneous semaglutide is effective for weight loss with an 11.85% reduction from baseline compared to placebo. This supports the use of semaglutide for weight management in obesity. 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The effect of glucagon-like peptide-1 receptor agonists on outcomes in knee osteoarthritis among persons with obesity has not been well studied.\nMETHODS: We conducted a 68-week, double-blind, randomized, placebo-controlled trial at 61 sites in 11 countries. Participants with obesity (a body-mass index [BMI; the weight in kilograms divided by the square of the height in meters] of ≥30) and a clinical and radiologic diagnosis of moderate knee osteoarthritis with at least moderate pain were randomly assigned, in a 2:1 ratio, to receive once-weekly subcutaneous semaglutide (2.4 mg) or placebo, in addition to counseling on physical activity and a reduced-calorie diet. The primary end points were the percentage change in body weight and the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (on a scale of 0 to 100, with higher scores reflecting worse outcomes) from baseline to week 68. A key confirmatory secondary end point was the physical-function score on the 36-Item Short Form Health Survey (SF-36), version 2 (on a scale of 0 to 100, with higher scores indicating greater well-being).\nRESULTS: A total of 407 participants were enrolled. The mean age was 56 years, the mean BMI 40.3, and the mean WOMAC pain score 70.9. A total of 81.6% of the participants were women. The mean change in body weight from baseline to week 68 was -13.7% with semaglutide and -3.2% with placebo (P<0.001). The mean change in the WOMAC pain score at week 68 was -41.7 points with semaglutide and -27.5 points with placebo (P<0.001). Participants in the semaglutide group had a greater improvement in SF-36 physical-function score than those in the placebo group (mean change, 12.0 points vs. 6.5 points; P<0.001). The incidence of serious adverse events was similar in the two groups. 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A key confirmatory secondary end point was the physical-function score on the 36-Item Short Form Health Survey (SF-36), version 2 (on a scale of 0 to 100, with higher scores indicating greater well-being).\nRESULTS: A total of 407 participants were enrolled. The mean age was 56 years, the mean BMI 40.3, and the mean WOMAC pain score 70.9. A total of 81.6% of the participants were women. The mean change in body weight from baseline to week 68 was -13.7% with semaglutide and -3.2% with placebo (P<0.001). The mean change in the WOMAC pain score at week 68 was -41.7 points with semaglutide and -27.5 points with placebo (P<0.001). Participants in the semaglutide group had a greater improvement in SF-36 physical-function score than those in the placebo group (mean change, 12.0 points vs. 6.5 points; P<0.001). The incidence of serious adverse events was similar in the two groups. Adverse events that led to permanent discontinuation of the trial regimen occurred in 6.7% of the participants in the semaglutide group and in 3.0% in the placebo group, with gastrointestinal disorders being the most common reason for discontinuation.\nCONCLUSIONS: Among participants with obesity and knee osteoarthritis with moderate-to-severe pain, treatment with once-weekly injectable semaglutide resulted in significantly greater reductions in body weight and pain related to knee osteoarthritis than placebo. (Funded by Novo Nordisk; STEP 9 ClinicalTrials.gov number, NCT05064735.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2403664", "study_design_raw": "68-week, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "407", "follow_up_raw": "68 weeks", "equation_type": "E1", "x_raw": "semaglutide", "c_raw": "placebo", "y_raw": "WOMAC pain score", "z_raw_json": [ "physical activity counseling", "reduced-calorie diet" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "semaglutide", "c_norm_text": "placebo", "y_norm_text": "womac pain score", "population_bucket_raw": "persons with obesity and knee osteoarthritis", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "68 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": -41.7, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.001, "n_raw": 407, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "negative", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": true, "normalization_status": "partial", "normalization_issues_json": [ "unsupported_measure_type" ], "compiled_at": "2026-04-15T04:45:33.820737+00:00", "quality_decision_id": "QDEC:48e3197eebd3aebb", "quality_run_id": "QRUN:73c4e6df275bd5ab", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "effect_parse_failed", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T04:45:46.307583+00:00" }, "PMID:39476339::AEV-39476339#3": { "norm_edge_pk": "NORM:RAW:6ddfcf4ef201", "raw_edge_pk": "RAW:6ddfcf4ef201", "paper_id": "PMID:39476339", "pmid": "39476339", "edge_id": "AEV-39476339#3", "edge_order": 3, "paper_dir": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/39/39476339", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/39/39476339/edges.json", "source_review_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/39/39476339/step3_review.json", "source_audit_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/39/39476339/step4_audit.json", "source_run_id": null, "paper_title": "Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis.", "paper_abstract": "BACKGROUND: Weight reduction has been shown to alleviate symptoms of osteoarthritis of the knee, including pain. The effect of glucagon-like peptide-1 receptor agonists on outcomes in knee osteoarthritis among persons with obesity has not been well studied.\nMETHODS: We conducted a 68-week, double-blind, randomized, placebo-controlled trial at 61 sites in 11 countries. Participants with obesity (a body-mass index [BMI; the weight in kilograms divided by the square of the height in meters] of ≥30) and a clinical and radiologic diagnosis of moderate knee osteoarthritis with at least moderate pain were randomly assigned, in a 2:1 ratio, to receive once-weekly subcutaneous semaglutide (2.4 mg) or placebo, in addition to counseling on physical activity and a reduced-calorie diet. The primary end points were the percentage change in body weight and the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (on a scale of 0 to 100, with higher scores reflecting worse outcomes) from baseline to week 68. A key confirmatory secondary end point was the physical-function score on the 36-Item Short Form Health Survey (SF-36), version 2 (on a scale of 0 to 100, with higher scores indicating greater well-being).\nRESULTS: A total of 407 participants were enrolled. The mean age was 56 years, the mean BMI 40.3, and the mean WOMAC pain score 70.9. A total of 81.6% of the participants were women. The mean change in body weight from baseline to week 68 was -13.7% with semaglutide and -3.2% with placebo (P<0.001). The mean change in the WOMAC pain score at week 68 was -41.7 points with semaglutide and -27.5 points with placebo (P<0.001). Participants in the semaglutide group had a greater improvement in SF-36 physical-function score than those in the placebo group (mean change, 12.0 points vs. 6.5 points; P<0.001). The incidence of serious adverse events was similar in the two groups. Adverse events that led to permanent discontinuation of the trial regimen occurred in 6.7% of the participants in the semaglutide group and in 3.0% in the placebo group, with gastrointestinal disorders being the most common reason for discontinuation.\nCONCLUSIONS: Among participants with obesity and knee osteoarthritis with moderate-to-severe pain, treatment with once-weekly injectable semaglutide resulted in significantly greater reductions in body weight and pain related to knee osteoarthritis than placebo. 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A key confirmatory secondary end point was the physical-function score on the 36-Item Short Form Health Survey (SF-36), version 2 (on a scale of 0 to 100, with higher scores indicating greater well-being).\nRESULTS: A total of 407 participants were enrolled. The mean age was 56 years, the mean BMI 40.3, and the mean WOMAC pain score 70.9. A total of 81.6% of the participants were women. The mean change in body weight from baseline to week 68 was -13.7% with semaglutide and -3.2% with placebo (P<0.001). The mean change in the WOMAC pain score at week 68 was -41.7 points with semaglutide and -27.5 points with placebo (P<0.001). Participants in the semaglutide group had a greater improvement in SF-36 physical-function score than those in the placebo group (mean change, 12.0 points vs. 6.5 points; P<0.001). The incidence of serious adverse events was similar in the two groups. Adverse events that led to permanent discontinuation of the trial regimen occurred in 6.7% of the participants in the semaglutide group and in 3.0% in the placebo group, with gastrointestinal disorders being the most common reason for discontinuation.\nCONCLUSIONS: Among participants with obesity and knee osteoarthritis with moderate-to-severe pain, treatment with once-weekly injectable semaglutide resulted in significantly greater reductions in body weight and pain related to knee osteoarthritis than placebo. 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A key confirmatory secondary end point was the physical-function score on the 36-Item Short Form Health Survey (SF-36), version 2 (on a scale of 0 to 100, with higher scores indicating greater well-being).\nRESULTS: A total of 407 participants were enrolled. The mean age was 56 years, the mean BMI 40.3, and the mean WOMAC pain score 70.9. A total of 81.6% of the participants were women. The mean change in body weight from baseline to week 68 was -13.7% with semaglutide and -3.2% with placebo (P<0.001). The mean change in the WOMAC pain score at week 68 was -41.7 points with semaglutide and -27.5 points with placebo (P<0.001). Participants in the semaglutide group had a greater improvement in SF-36 physical-function score than those in the placebo group (mean change, 12.0 points vs. 6.5 points; P<0.001). The incidence of serious adverse events was similar in the two groups. Adverse events that led to permanent discontinuation of the trial regimen occurred in 6.7% of the participants in the semaglutide group and in 3.0% in the placebo group, with gastrointestinal disorders being the most common reason for discontinuation.\nCONCLUSIONS: Among participants with obesity and knee osteoarthritis with moderate-to-severe pain, treatment with once-weekly injectable semaglutide resulted in significantly greater reductions in body weight and pain related to knee osteoarthritis than placebo. (Funded by Novo Nordisk; STEP 9 ClinicalTrials.gov number, NCT05064735.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2403664", "study_design_raw": "68-week, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "407", "follow_up_raw": "68 weeks", "equation_type": "E1", "x_raw": "semaglutide", "c_raw": "placebo", "y_raw": "adverse events leading to discontinuation", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "semaglutide", "c_norm_text": "placebo", "y_norm_text": "adverse events leading to discontinuation", "population_bucket_raw": "persons with obesity and knee osteoarthritis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "68 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": 6.7, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 407, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "positive", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": true, "normalization_status": "partial", "normalization_issues_json": [ "unsupported_measure_type" ], "compiled_at": "2026-04-15T04:45:33.820737+00:00", "quality_decision_id": "QDEC:46f6db57d25e8b1e", "quality_run_id": "QRUN:73c4e6df275bd5ab", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "effect_parse_failed", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T04:45:46.307583+00:00" }, "PMID:40175094::AEV-40175094#1": { "norm_edge_pk": "NORM:RAW:5ca37de49776", "raw_edge_pk": "RAW:5ca37de49776", "paper_id": "PMID:40175094", "pmid": "40175094", "edge_id": "AEV-40175094#1", "edge_order": 1, "paper_dir": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/40/40175094", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/40/40175094/edges.json", "source_review_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/40/40175094/step3_review.json", "source_audit_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/40/40175094/step4_audit.json", "source_run_id": null, "paper_title": "Comparing the risk of gastroparesis following different modalities for treating obesity: semaglutide versus bupropion-naltrexone versus sleeve gastrectomy - a retrospective cohort study.", "paper_abstract": "OBJECTIVE: The use of glucagon-like peptide 1 receptor agonists has been associated with gastroparesis, but little is known about the risk of gastroparesis in those with obesity but without type 2 diabetes (T2D), and how that risk compares with other treatment modalities for obesity. This study aims to characterise the relationship between different treatment modalities for obesity and the risk of gastroparesis in a population without pre-existing T2D.\nMETHODS: A retrospective cohort study using Merative MarketScan Research Databases of individuals with obesity who underwent treatment with semaglutide, bupropion-naltrexone or sleeve gastrectomy from 1 January 2018 to 31 December 2022. The incidence of gastroparesis diagnosis was evaluated using International Classification of Diseases, Version 10 codes. The risk of gastroparesis was compared between three intervention groups using Cox proportional hazards regression models.\nRESULTS: Of the 55 460 individuals included, 36 990 (66.7%) were treated with semaglutide, 7369 (13.3%) with bupropion-naltrexone and 11 101 (13.7%) with sleeve gastrectomy. Gastroparesis rates among those treated with semaglutide versus bupropion-naltrexone versus sleeve gastrectomy were 6.5 per 1000 person-years (PY) vs 2.1 per 1000 PY vs 1.1 per 1000 PY, respectively. After adjusting for baseline characteristics, individuals treated with semaglutide had a higher risk of gastroparesis than those treated with bupropion-naltrexone (adjusted HR 3.33, 95% CI 2.27, 4.98) and sleeve gastrectomy (adjusted HR 6.14, 95% CI 3.94, 9.57).\nCONCLUSIONS: There is an increased incidence of gastroparesis among individuals with obesity without T2D who are using semaglutide as compared with bupropion-naltrexone and sleeve gastrectomy. 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This study aims to characterise the relationship between different treatment modalities for obesity and the risk of gastroparesis in a population without pre-existing T2D.\nMETHODS: A retrospective cohort study using Merative MarketScan Research Databases of individuals with obesity who underwent treatment with semaglutide, bupropion-naltrexone or sleeve gastrectomy from 1 January 2018 to 31 December 2022. The incidence of gastroparesis diagnosis was evaluated using International Classification of Diseases, Version 10 codes. The risk of gastroparesis was compared between three intervention groups using Cox proportional hazards regression models.\nRESULTS: Of the 55 460 individuals included, 36 990 (66.7%) were treated with semaglutide, 7369 (13.3%) with bupropion-naltrexone and 11 101 (13.7%) with sleeve gastrectomy. Gastroparesis rates among those treated with semaglutide versus bupropion-naltrexone versus sleeve gastrectomy were 6.5 per 1000 person-years (PY) vs 2.1 per 1000 PY vs 1.1 per 1000 PY, respectively. After adjusting for baseline characteristics, individuals treated with semaglutide had a higher risk of gastroparesis than those treated with bupropion-naltrexone (adjusted HR 3.33, 95% CI 2.27, 4.98) and sleeve gastrectomy (adjusted HR 6.14, 95% CI 3.94, 9.57).\nCONCLUSIONS: There is an increased incidence of gastroparesis among individuals with obesity without T2D who are using semaglutide as compared with bupropion-naltrexone and sleeve gastrectomy. 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We therefore assessed the efficacy and safety of subcutaneous semaglutide as treatment for obesity in patients without diabetes.\nMETHODOLOGY: A comprehensive search of PubMed/MEDLINE, Cochrane and Google scholar was performed to identify trials on the efficacy and safety of subcutaneous semaglutide on patients with obesity without diabetes. Primary outcome was expressed as percent mean weight difference. Secondary outcomes including risk for gastrointestinal adverse events, discontinuation of treatment and serious adverse events were expressed as risk ratios. These were calculated using the random effects model.\nRESULTS: The study included 4 randomized controlled trials having a total of 3,613 individuals with obesity without diabetes. The mean difference for weight reduction was -11.85%, favoring semaglutide [95% confidence interval (CI) (-12.81,-10.90), p<0.00001]. Secondary outcomes showed that the risk of developing gastrointestinal adverse events was 1.59 times more likely with semaglutide (RR 1.59, 95%CI [1.34, 1.88], p<0.00001). Risk for discontinuation due to adverse events was twice as likely in the semaglutide group (RR 2.19, 95%CI [1.36,3.55], p=0.001) and the risk for serious adverse events was 1.6 times more likely for semaglutide (RR1.60, 95%CI [1.24, 2.07], p=0.0003). Serious events were mostly of gastrointestinal and hepatobiliary disorders such as acute pancreatitis and cholelithiasis.\nCONCLUSION: Among individuals with obesity without type 2 diabetes, subcutaneous semaglutide is effective for weight loss with an 11.85% reduction from baseline compared to placebo. This supports the use of semaglutide for weight management in obesity. 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We therefore assessed the efficacy and safety of subcutaneous semaglutide as treatment for obesity in patients without diabetes.\nMETHODOLOGY: A comprehensive search of PubMed/MEDLINE, Cochrane and Google scholar was performed to identify trials on the efficacy and safety of subcutaneous semaglutide on patients with obesity without diabetes. Primary outcome was expressed as percent mean weight difference. Secondary outcomes including risk for gastrointestinal adverse events, discontinuation of treatment and serious adverse events were expressed as risk ratios. These were calculated using the random effects model.\nRESULTS: The study included 4 randomized controlled trials having a total of 3,613 individuals with obesity without diabetes. The mean difference for weight reduction was -11.85%, favoring semaglutide [95% confidence interval (CI) (-12.81,-10.90), p<0.00001]. Secondary outcomes showed that the risk of developing gastrointestinal adverse events was 1.59 times more likely with semaglutide (RR 1.59, 95%CI [1.34, 1.88], p<0.00001). Risk for discontinuation due to adverse events was twice as likely in the semaglutide group (RR 2.19, 95%CI [1.36,3.55], p=0.001) and the risk for serious adverse events was 1.6 times more likely for semaglutide (RR1.60, 95%CI [1.24, 2.07], p=0.0003). Serious events were mostly of gastrointestinal and hepatobiliary disorders such as acute pancreatitis and cholelithiasis.\nCONCLUSION: Among individuals with obesity without type 2 diabetes, subcutaneous semaglutide is effective for weight loss with an 11.85% reduction from baseline compared to placebo. This supports the use of semaglutide for weight management in obesity. However, risk of gastrointestinal adverse events, discontinuation of treatment and serious adverse events were higher in the semaglutide group versus placebo.", "first_author": null, "journal": null, "year": 2022, "doi": "10.15605/jafes.037.02.14", "study_design_raw": "randomized controlled trials", "sample_size_raw": "3613", "follow_up_raw": null, "equation_type": "E1", "x_raw": "semaglutide", "c_raw": "placebo", "y_raw": "gastrointestinal adverse events", "z_raw_json": [ "obesity without diabetes" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "semaglutide", "c_norm_text": "placebo", "y_norm_text": "gastrointestinal adverse events", "population_bucket_raw": "patients with obesity without diabetes", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": null, "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "RR", "measure_scale_raw": "natural", "theta_hat_raw": 1.59, "ci_low_raw": 1.34, "ci_high_raw": 1.88, "p_value_raw": 1e-05, "n_raw": 3613, "model_raw": "random effects model", "canonical_effect_scale": "log_ratio", "theta_hat_norm": 0.4637340162321402, "ci_low_norm": 0.29266961396282004, "ci_high_norm": 0.6312717768418578, "effect_direction": "positive", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T04:45:33.820737+00:00", "quality_decision_id": "QDEC:49b15a2b9bd28d32", "quality_run_id": "QRUN:73c4e6df275bd5ab", "record_status": "review_required", "effect_status": "usable", "record_status_reason": "tentative_mapping", "effect_status_reason": "usable", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T04:45:46.307583+00:00" } ], "AEV-36578889#3": [ { "norm_edge_pk": "NORM:RAW:de37146f4c63", "raw_edge_pk": "RAW:de37146f4c63", "paper_id": "PMID:36578889", "pmid": "36578889", "edge_id": "AEV-36578889#3", "edge_order": 3, "paper_dir": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/36/36578889", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/36/36578889/edges.json", "source_review_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/36/36578889/step3_review.json", "source_audit_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/36/36578889/step4_audit.json", "source_run_id": null, "paper_title": "Efficacy and Safety of Semaglutide for Weight Loss in Obesity Without Diabetes: A Systematic Review and Meta-Analysis.", "paper_abstract": "BACKGROUND: The weight loss benefit of semaglutide in patients with diabetes is well-documented, but its clinical utility in treating obesity among patients without diabetes is less described. We therefore assessed the efficacy and safety of subcutaneous semaglutide as treatment for obesity in patients without diabetes.\nMETHODOLOGY: A comprehensive search of PubMed/MEDLINE, Cochrane and Google scholar was performed to identify trials on the efficacy and safety of subcutaneous semaglutide on patients with obesity without diabetes. Primary outcome was expressed as percent mean weight difference. Secondary outcomes including risk for gastrointestinal adverse events, discontinuation of treatment and serious adverse events were expressed as risk ratios. These were calculated using the random effects model.\nRESULTS: The study included 4 randomized controlled trials having a total of 3,613 individuals with obesity without diabetes. The mean difference for weight reduction was -11.85%, favoring semaglutide [95% confidence interval (CI) (-12.81,-10.90), p<0.00001]. Secondary outcomes showed that the risk of developing gastrointestinal adverse events was 1.59 times more likely with semaglutide (RR 1.59, 95%CI [1.34, 1.88], p<0.00001). Risk for discontinuation due to adverse events was twice as likely in the semaglutide group (RR 2.19, 95%CI [1.36,3.55], p=0.001) and the risk for serious adverse events was 1.6 times more likely for semaglutide (RR1.60, 95%CI [1.24, 2.07], p=0.0003). Serious events were mostly of gastrointestinal and hepatobiliary disorders such as acute pancreatitis and cholelithiasis.\nCONCLUSION: Among individuals with obesity without type 2 diabetes, subcutaneous semaglutide is effective for weight loss with an 11.85% reduction from baseline compared to placebo. This supports the use of semaglutide for weight management in obesity. 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We therefore assessed the efficacy and safety of subcutaneous semaglutide as treatment for obesity in patients without diabetes.\nMETHODOLOGY: A comprehensive search of PubMed/MEDLINE, Cochrane and Google scholar was performed to identify trials on the efficacy and safety of subcutaneous semaglutide on patients with obesity without diabetes. Primary outcome was expressed as percent mean weight difference. Secondary outcomes including risk for gastrointestinal adverse events, discontinuation of treatment and serious adverse events were expressed as risk ratios. These were calculated using the random effects model.\nRESULTS: The study included 4 randomized controlled trials having a total of 3,613 individuals with obesity without diabetes. The mean difference for weight reduction was -11.85%, favoring semaglutide [95% confidence interval (CI) (-12.81,-10.90), p<0.00001]. Secondary outcomes showed that the risk of developing gastrointestinal adverse events was 1.59 times more likely with semaglutide (RR 1.59, 95%CI [1.34, 1.88], p<0.00001). Risk for discontinuation due to adverse events was twice as likely in the semaglutide group (RR 2.19, 95%CI [1.36,3.55], p=0.001) and the risk for serious adverse events was 1.6 times more likely for semaglutide (RR1.60, 95%CI [1.24, 2.07], p=0.0003). Serious events were mostly of gastrointestinal and hepatobiliary disorders such as acute pancreatitis and cholelithiasis.\nCONCLUSION: Among individuals with obesity without type 2 diabetes, subcutaneous semaglutide is effective for weight loss with an 11.85% reduction from baseline compared to placebo. This supports the use of semaglutide for weight management in obesity. 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The effect of glucagon-like peptide-1 receptor agonists on outcomes in knee osteoarthritis among persons with obesity has not been well studied.\nMETHODS: We conducted a 68-week, double-blind, randomized, placebo-controlled trial at 61 sites in 11 countries. Participants with obesity (a body-mass index [BMI; the weight in kilograms divided by the square of the height in meters] of ≥30) and a clinical and radiologic diagnosis of moderate knee osteoarthritis with at least moderate pain were randomly assigned, in a 2:1 ratio, to receive once-weekly subcutaneous semaglutide (2.4 mg) or placebo, in addition to counseling on physical activity and a reduced-calorie diet. The primary end points were the percentage change in body weight and the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (on a scale of 0 to 100, with higher scores reflecting worse outcomes) from baseline to week 68. A key confirmatory secondary end point was the physical-function score on the 36-Item Short Form Health Survey (SF-36), version 2 (on a scale of 0 to 100, with higher scores indicating greater well-being).\nRESULTS: A total of 407 participants were enrolled. The mean age was 56 years, the mean BMI 40.3, and the mean WOMAC pain score 70.9. A total of 81.6% of the participants were women. The mean change in body weight from baseline to week 68 was -13.7% with semaglutide and -3.2% with placebo (P<0.001). The mean change in the WOMAC pain score at week 68 was -41.7 points with semaglutide and -27.5 points with placebo (P<0.001). Participants in the semaglutide group had a greater improvement in SF-36 physical-function score than those in the placebo group (mean change, 12.0 points vs. 6.5 points; P<0.001). The incidence of serious adverse events was similar in the two groups. Adverse events that led to permanent discontinuation of the trial regimen occurred in 6.7% of the participants in the semaglutide group and in 3.0% in the placebo group, with gastrointestinal disorders being the most common reason for discontinuation.\nCONCLUSIONS: Among participants with obesity and knee osteoarthritis with moderate-to-severe pain, treatment with once-weekly injectable semaglutide resulted in significantly greater reductions in body weight and pain related to knee osteoarthritis than placebo. 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A key confirmatory secondary end point was the physical-function score on the 36-Item Short Form Health Survey (SF-36), version 2 (on a scale of 0 to 100, with higher scores indicating greater well-being).\nRESULTS: A total of 407 participants were enrolled. The mean age was 56 years, the mean BMI 40.3, and the mean WOMAC pain score 70.9. A total of 81.6% of the participants were women. The mean change in body weight from baseline to week 68 was -13.7% with semaglutide and -3.2% with placebo (P<0.001). The mean change in the WOMAC pain score at week 68 was -41.7 points with semaglutide and -27.5 points with placebo (P<0.001). Participants in the semaglutide group had a greater improvement in SF-36 physical-function score than those in the placebo group (mean change, 12.0 points vs. 6.5 points; P<0.001). The incidence of serious adverse events was similar in the two groups. Adverse events that led to permanent discontinuation of the trial regimen occurred in 6.7% of the participants in the semaglutide group and in 3.0% in the placebo group, with gastrointestinal disorders being the most common reason for discontinuation.\nCONCLUSIONS: Among participants with obesity and knee osteoarthritis with moderate-to-severe pain, treatment with once-weekly injectable semaglutide resulted in significantly greater reductions in body weight and pain related to knee osteoarthritis than placebo. (Funded by Novo Nordisk; STEP 9 ClinicalTrials.gov number, NCT05064735.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2403664", "study_design_raw": "68-week, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "407", "follow_up_raw": "68 weeks", "equation_type": "E1", "x_raw": "semaglutide", "c_raw": "placebo", "y_raw": "WOMAC pain score", "z_raw_json": [ "physical activity counseling", "reduced-calorie diet" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "semaglutide", "c_norm_text": "placebo", "y_norm_text": "womac pain score", "population_bucket_raw": "persons with obesity and knee osteoarthritis", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "68 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": -41.7, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.001, "n_raw": 407, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "negative", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": true, "normalization_status": "partial", "normalization_issues_json": [ "unsupported_measure_type" ], "compiled_at": "2026-04-15T04:45:33.820737+00:00", "quality_decision_id": "QDEC:48e3197eebd3aebb", "quality_run_id": "QRUN:73c4e6df275bd5ab", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "effect_parse_failed", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T04:45:46.307583+00:00" } ], "AEV-39476339#3": [ { "norm_edge_pk": "NORM:RAW:6ddfcf4ef201", "raw_edge_pk": "RAW:6ddfcf4ef201", "paper_id": "PMID:39476339", "pmid": "39476339", "edge_id": "AEV-39476339#3", "edge_order": 3, "paper_dir": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/39/39476339", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/39/39476339/edges.json", "source_review_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/39/39476339/step3_review.json", "source_audit_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/39/39476339/step4_audit.json", "source_run_id": null, "paper_title": "Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis.", "paper_abstract": "BACKGROUND: Weight reduction has been shown to alleviate symptoms of osteoarthritis of the knee, including pain. The effect of glucagon-like peptide-1 receptor agonists on outcomes in knee osteoarthritis among persons with obesity has not been well studied.\nMETHODS: We conducted a 68-week, double-blind, randomized, placebo-controlled trial at 61 sites in 11 countries. Participants with obesity (a body-mass index [BMI; the weight in kilograms divided by the square of the height in meters] of ≥30) and a clinical and radiologic diagnosis of moderate knee osteoarthritis with at least moderate pain were randomly assigned, in a 2:1 ratio, to receive once-weekly subcutaneous semaglutide (2.4 mg) or placebo, in addition to counseling on physical activity and a reduced-calorie diet. The primary end points were the percentage change in body weight and the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (on a scale of 0 to 100, with higher scores reflecting worse outcomes) from baseline to week 68. A key confirmatory secondary end point was the physical-function score on the 36-Item Short Form Health Survey (SF-36), version 2 (on a scale of 0 to 100, with higher scores indicating greater well-being).\nRESULTS: A total of 407 participants were enrolled. The mean age was 56 years, the mean BMI 40.3, and the mean WOMAC pain score 70.9. A total of 81.6% of the participants were women. The mean change in body weight from baseline to week 68 was -13.7% with semaglutide and -3.2% with placebo (P<0.001). The mean change in the WOMAC pain score at week 68 was -41.7 points with semaglutide and -27.5 points with placebo (P<0.001). Participants in the semaglutide group had a greater improvement in SF-36 physical-function score than those in the placebo group (mean change, 12.0 points vs. 6.5 points; P<0.001). The incidence of serious adverse events was similar in the two groups. Adverse events that led to permanent discontinuation of the trial regimen occurred in 6.7% of the participants in the semaglutide group and in 3.0% in the placebo group, with gastrointestinal disorders being the most common reason for discontinuation.\nCONCLUSIONS: Among participants with obesity and knee osteoarthritis with moderate-to-severe pain, treatment with once-weekly injectable semaglutide resulted in significantly greater reductions in body weight and pain related to knee osteoarthritis than placebo. (Funded by Novo Nordisk; STEP 9 ClinicalTrials.gov number, NCT05064735.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2403664", "study_design_raw": "68-week, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "407", "follow_up_raw": "68 weeks", "equation_type": "E1", "x_raw": "semaglutide", "c_raw": "placebo", "y_raw": "SF-36 physical-function score", "z_raw_json": [ "physical activity counseling", "reduced-calorie diet" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "semaglutide", "c_norm_text": "placebo", "y_norm_text": "sf-36 physical-function score", "population_bucket_raw": "persons with obesity and knee osteoarthritis", "outcome_type_raw": "continuous", "time_index_raw": null, "time_horizon_raw": "68 weeks", "tau_aligned_raw": null, "measure_family_raw": "difference", "measure_type_raw": "mean_change", "measure_scale_raw": "identity", "theta_hat_raw": 12.0, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": 0.001, "n_raw": 407, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "positive", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": true, "normalization_status": "partial", "normalization_issues_json": [ "unsupported_measure_type" ], "compiled_at": "2026-04-15T04:45:33.820737+00:00", "quality_decision_id": "QDEC:0cdb6e522748cc17", "quality_run_id": "QRUN:73c4e6df275bd5ab", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "effect_parse_failed", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T04:45:46.307583+00:00" } ], "AEV-39476339#4": [ { "norm_edge_pk": "NORM:RAW:efd0e40e1f67", "raw_edge_pk": "RAW:efd0e40e1f67", "paper_id": "PMID:39476339", "pmid": "39476339", "edge_id": "AEV-39476339#4", "edge_order": 4, "paper_dir": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/39/39476339", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/39/39476339/edges.json", "source_review_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/39/39476339/step3_review.json", "source_audit_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/39/39476339/step4_audit.json", "source_run_id": null, "paper_title": "Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis.", "paper_abstract": "BACKGROUND: Weight reduction has been shown to alleviate symptoms of osteoarthritis of the knee, including pain. The effect of glucagon-like peptide-1 receptor agonists on outcomes in knee osteoarthritis among persons with obesity has not been well studied.\nMETHODS: We conducted a 68-week, double-blind, randomized, placebo-controlled trial at 61 sites in 11 countries. Participants with obesity (a body-mass index [BMI; the weight in kilograms divided by the square of the height in meters] of ≥30) and a clinical and radiologic diagnosis of moderate knee osteoarthritis with at least moderate pain were randomly assigned, in a 2:1 ratio, to receive once-weekly subcutaneous semaglutide (2.4 mg) or placebo, in addition to counseling on physical activity and a reduced-calorie diet. The primary end points were the percentage change in body weight and the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (on a scale of 0 to 100, with higher scores reflecting worse outcomes) from baseline to week 68. A key confirmatory secondary end point was the physical-function score on the 36-Item Short Form Health Survey (SF-36), version 2 (on a scale of 0 to 100, with higher scores indicating greater well-being).\nRESULTS: A total of 407 participants were enrolled. The mean age was 56 years, the mean BMI 40.3, and the mean WOMAC pain score 70.9. A total of 81.6% of the participants were women. The mean change in body weight from baseline to week 68 was -13.7% with semaglutide and -3.2% with placebo (P<0.001). The mean change in the WOMAC pain score at week 68 was -41.7 points with semaglutide and -27.5 points with placebo (P<0.001). Participants in the semaglutide group had a greater improvement in SF-36 physical-function score than those in the placebo group (mean change, 12.0 points vs. 6.5 points; P<0.001). The incidence of serious adverse events was similar in the two groups. Adverse events that led to permanent discontinuation of the trial regimen occurred in 6.7% of the participants in the semaglutide group and in 3.0% in the placebo group, with gastrointestinal disorders being the most common reason for discontinuation.\nCONCLUSIONS: Among participants with obesity and knee osteoarthritis with moderate-to-severe pain, treatment with once-weekly injectable semaglutide resulted in significantly greater reductions in body weight and pain related to knee osteoarthritis than placebo. (Funded by Novo Nordisk; STEP 9 ClinicalTrials.gov number, NCT05064735.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2403664", "study_design_raw": "68-week, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "407", "follow_up_raw": "68 weeks", "equation_type": "E1", "x_raw": "semaglutide", "c_raw": "placebo", "y_raw": "serious adverse events", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "semaglutide", "c_norm_text": "placebo", "y_norm_text": "serious adverse events", "population_bucket_raw": "persons with obesity and knee osteoarthritis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "68 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": null, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 407, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "unknown", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 0.833, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 2, "audit_checks_raw_json": [ "abstract_only_extraction", "effect_not_reported_in_abstract" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T04:45:33.820737+00:00", "quality_decision_id": "QDEC:346f298d519929df", "quality_run_id": "QRUN:73c4e6df275bd5ab", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "theta_missing", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 2, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T04:45:46.307583+00:00" } ], "AEV-39476339#5": [ { "norm_edge_pk": "NORM:RAW:ded656bd7bd1", "raw_edge_pk": "RAW:ded656bd7bd1", "paper_id": "PMID:39476339", "pmid": "39476339", "edge_id": "AEV-39476339#5", "edge_order": 5, "paper_dir": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/39/39476339", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/39/39476339/edges.json", "source_review_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/39/39476339/step3_review.json", "source_audit_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/39/39476339/step4_audit.json", "source_run_id": null, "paper_title": "Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis.", "paper_abstract": "BACKGROUND: Weight reduction has been shown to alleviate symptoms of osteoarthritis of the knee, including pain. The effect of glucagon-like peptide-1 receptor agonists on outcomes in knee osteoarthritis among persons with obesity has not been well studied.\nMETHODS: We conducted a 68-week, double-blind, randomized, placebo-controlled trial at 61 sites in 11 countries. Participants with obesity (a body-mass index [BMI; the weight in kilograms divided by the square of the height in meters] of ≥30) and a clinical and radiologic diagnosis of moderate knee osteoarthritis with at least moderate pain were randomly assigned, in a 2:1 ratio, to receive once-weekly subcutaneous semaglutide (2.4 mg) or placebo, in addition to counseling on physical activity and a reduced-calorie diet. The primary end points were the percentage change in body weight and the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (on a scale of 0 to 100, with higher scores reflecting worse outcomes) from baseline to week 68. A key confirmatory secondary end point was the physical-function score on the 36-Item Short Form Health Survey (SF-36), version 2 (on a scale of 0 to 100, with higher scores indicating greater well-being).\nRESULTS: A total of 407 participants were enrolled. The mean age was 56 years, the mean BMI 40.3, and the mean WOMAC pain score 70.9. A total of 81.6% of the participants were women. The mean change in body weight from baseline to week 68 was -13.7% with semaglutide and -3.2% with placebo (P<0.001). The mean change in the WOMAC pain score at week 68 was -41.7 points with semaglutide and -27.5 points with placebo (P<0.001). Participants in the semaglutide group had a greater improvement in SF-36 physical-function score than those in the placebo group (mean change, 12.0 points vs. 6.5 points; P<0.001). The incidence of serious adverse events was similar in the two groups. Adverse events that led to permanent discontinuation of the trial regimen occurred in 6.7% of the participants in the semaglutide group and in 3.0% in the placebo group, with gastrointestinal disorders being the most common reason for discontinuation.\nCONCLUSIONS: Among participants with obesity and knee osteoarthritis with moderate-to-severe pain, treatment with once-weekly injectable semaglutide resulted in significantly greater reductions in body weight and pain related to knee osteoarthritis than placebo. (Funded by Novo Nordisk; STEP 9 ClinicalTrials.gov number, NCT05064735.).", "first_author": null, "journal": null, "year": 2024, "doi": "10.1056/NEJMoa2403664", "study_design_raw": "68-week, double-blind, randomized, placebo-controlled trial", "sample_size_raw": "407", "follow_up_raw": "68 weeks", "equation_type": "E1", "x_raw": "semaglutide", "c_raw": "placebo", "y_raw": "adverse events leading to discontinuation", "z_raw_json": null, "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "semaglutide", "c_norm_text": "placebo", "y_norm_text": "adverse events leading to discontinuation", "population_bucket_raw": "persons with obesity and knee osteoarthritis", "outcome_type_raw": "binary", "time_index_raw": null, "time_horizon_raw": "68 weeks", "tau_aligned_raw": null, "measure_family_raw": "proportion", "measure_type_raw": "proportion", "measure_scale_raw": "natural", "theta_hat_raw": 6.7, "ci_low_raw": null, "ci_high_raw": null, "p_value_raw": null, "n_raw": 407, "model_raw": null, "canonical_effect_scale": "unsupported", "theta_hat_norm": null, "ci_low_norm": null, "ci_high_norm": null, "effect_direction": "positive", "effect_transform": "unsupported", "effect_transform_success": false, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": true, "normalization_status": "partial", "normalization_issues_json": [ "unsupported_measure_type" ], "compiled_at": "2026-04-15T04:45:33.820737+00:00", "quality_decision_id": "QDEC:46f6db57d25e8b1e", "quality_run_id": "QRUN:73c4e6df275bd5ab", "record_status": "review_required", "effect_status": "missing", "record_status_reason": "tentative_mapping", "effect_status_reason": "effect_parse_failed", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": false, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T04:45:46.307583+00:00" } ], "AEV-40175094#1": [ { "norm_edge_pk": "NORM:RAW:5ca37de49776", "raw_edge_pk": "RAW:5ca37de49776", "paper_id": "PMID:40175094", "pmid": "40175094", "edge_id": "AEV-40175094#1", "edge_order": 1, "paper_dir": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/40/40175094", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/40/40175094/edges.json", "source_review_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/40/40175094/step3_review.json", "source_audit_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/40/40175094/step4_audit.json", "source_run_id": null, "paper_title": "Comparing the risk of gastroparesis following different modalities for treating obesity: semaglutide versus bupropion-naltrexone versus sleeve gastrectomy - a retrospective cohort study.", "paper_abstract": "OBJECTIVE: The use of glucagon-like peptide 1 receptor agonists has been associated with gastroparesis, but little is known about the risk of gastroparesis in those with obesity but without type 2 diabetes (T2D), and how that risk compares with other treatment modalities for obesity. This study aims to characterise the relationship between different treatment modalities for obesity and the risk of gastroparesis in a population without pre-existing T2D.\nMETHODS: A retrospective cohort study using Merative MarketScan Research Databases of individuals with obesity who underwent treatment with semaglutide, bupropion-naltrexone or sleeve gastrectomy from 1 January 2018 to 31 December 2022. The incidence of gastroparesis diagnosis was evaluated using International Classification of Diseases, Version 10 codes. The risk of gastroparesis was compared between three intervention groups using Cox proportional hazards regression models.\nRESULTS: Of the 55 460 individuals included, 36 990 (66.7%) were treated with semaglutide, 7369 (13.3%) with bupropion-naltrexone and 11 101 (13.7%) with sleeve gastrectomy. Gastroparesis rates among those treated with semaglutide versus bupropion-naltrexone versus sleeve gastrectomy were 6.5 per 1000 person-years (PY) vs 2.1 per 1000 PY vs 1.1 per 1000 PY, respectively. After adjusting for baseline characteristics, individuals treated with semaglutide had a higher risk of gastroparesis than those treated with bupropion-naltrexone (adjusted HR 3.33, 95% CI 2.27, 4.98) and sleeve gastrectomy (adjusted HR 6.14, 95% CI 3.94, 9.57).\nCONCLUSIONS: There is an increased incidence of gastroparesis among individuals with obesity without T2D who are using semaglutide as compared with bupropion-naltrexone and sleeve gastrectomy. Understanding these potential side effects, though rare, may help guide personalised treatment regimens.", "first_author": null, "journal": null, "year": 2025, "doi": "10.1136/bmjgast-2024-001704", "study_design_raw": "retrospective cohort study", "sample_size_raw": "44359", "follow_up_raw": "1 January 2018 to 31 December 2022", "equation_type": "E6", "x_raw": "semaglutide", "c_raw": "bupropion-naltrexone", "y_raw": "gastroparesis", "z_raw_json": [ "baseline characteristics" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "semaglutide", "c_norm_text": "bupropion-naltrexone", "y_norm_text": "gastroparesis", "population_bucket_raw": "individuals with obesity without pre-existing type 2 diabetes", "outcome_type_raw": "time_to_event", "time_index_raw": null, "time_horizon_raw": "1 January 2018 to 31 December 2022", "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "HR", "measure_scale_raw": "natural", "theta_hat_raw": 3.33, "ci_low_raw": 2.27, "ci_high_raw": 4.98, "p_value_raw": null, "n_raw": 44359, "model_raw": "Cox proportional hazards regression models", "canonical_effect_scale": "log_ratio", "theta_hat_norm": 1.2029723039923526, "ci_low_norm": 0.8197798314933114, "ci_high_norm": 1.6054298910365616, "effect_direction": "positive", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T04:45:33.820737+00:00", "quality_decision_id": "QDEC:0ca98923fb18e59a", "quality_run_id": "QRUN:73c4e6df275bd5ab", "record_status": "review_required", "effect_status": "usable", "record_status_reason": "missing_key_role_mapping", "effect_status_reason": "usable", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T04:45:46.307583+00:00" } ], "AEV-40175094#2": [ { "norm_edge_pk": "NORM:RAW:17a2c036ca45", "raw_edge_pk": "RAW:17a2c036ca45", "paper_id": "PMID:40175094", "pmid": "40175094", "edge_id": "AEV-40175094#2", "edge_order": 2, "paper_dir": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/40/40175094", "pdf_path": null, "source_pdf_path": null, "source_edges_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/40/40175094/edges.json", "source_review_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/40/40175094/step3_review.json", "source_audit_path": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/40/40175094/step4_audit.json", "source_run_id": null, "paper_title": "Comparing the risk of gastroparesis following different modalities for treating obesity: semaglutide versus bupropion-naltrexone versus sleeve gastrectomy - a retrospective cohort study.", "paper_abstract": "OBJECTIVE: The use of glucagon-like peptide 1 receptor agonists has been associated with gastroparesis, but little is known about the risk of gastroparesis in those with obesity but without type 2 diabetes (T2D), and how that risk compares with other treatment modalities for obesity. This study aims to characterise the relationship between different treatment modalities for obesity and the risk of gastroparesis in a population without pre-existing T2D.\nMETHODS: A retrospective cohort study using Merative MarketScan Research Databases of individuals with obesity who underwent treatment with semaglutide, bupropion-naltrexone or sleeve gastrectomy from 1 January 2018 to 31 December 2022. The incidence of gastroparesis diagnosis was evaluated using International Classification of Diseases, Version 10 codes. The risk of gastroparesis was compared between three intervention groups using Cox proportional hazards regression models.\nRESULTS: Of the 55 460 individuals included, 36 990 (66.7%) were treated with semaglutide, 7369 (13.3%) with bupropion-naltrexone and 11 101 (13.7%) with sleeve gastrectomy. Gastroparesis rates among those treated with semaglutide versus bupropion-naltrexone versus sleeve gastrectomy were 6.5 per 1000 person-years (PY) vs 2.1 per 1000 PY vs 1.1 per 1000 PY, respectively. After adjusting for baseline characteristics, individuals treated with semaglutide had a higher risk of gastroparesis than those treated with bupropion-naltrexone (adjusted HR 3.33, 95% CI 2.27, 4.98) and sleeve gastrectomy (adjusted HR 6.14, 95% CI 3.94, 9.57).\nCONCLUSIONS: There is an increased incidence of gastroparesis among individuals with obesity without T2D who are using semaglutide as compared with bupropion-naltrexone and sleeve gastrectomy. Understanding these potential side effects, though rare, may help guide personalised treatment regimens.", "first_author": null, "journal": null, "year": 2025, "doi": "10.1136/bmjgast-2024-001704", "study_design_raw": "retrospective cohort study", "sample_size_raw": "48091", "follow_up_raw": "1 January 2018 to 31 December 2022", "equation_type": "E6", "x_raw": "semaglutide", "c_raw": "sleeve gastrectomy", "y_raw": "gastroparesis", "z_raw_json": [ "baseline characteristics" ], "m_raw_json": null, "x2_raw_json": null, "x_norm_text": "semaglutide", "c_norm_text": "sleeve gastrectomy", "y_norm_text": "gastroparesis", "population_bucket_raw": "individuals with obesity without pre-existing type 2 diabetes", "outcome_type_raw": "time_to_event", "time_index_raw": null, "time_horizon_raw": "1 January 2018 to 31 December 2022", "tau_aligned_raw": null, "measure_family_raw": "ratio", "measure_type_raw": "HR", "measure_scale_raw": "natural", "theta_hat_raw": 6.14, "ci_low_raw": 3.94, "ci_high_raw": 9.57, "p_value_raw": null, "n_raw": 48091, "model_raw": "Cox proportional hazards regression models", "canonical_effect_scale": "log_ratio", "theta_hat_norm": 1.814824742159051, "ci_low_norm": 1.3711807233098425, "ci_high_norm": 2.258633205464863, "effect_direction": "positive", "effect_transform": "log", "effect_transform_success": true, "review_exists": true, "audit_exists": true, "review_valid_raw": true, "review_semantically_valid_raw": true, "review_fill_rate_raw": 1.0, "mapping_statuses_raw_json": [ "missing", "missing", "missing", "missing" ], "has_missing_mapping": true, "has_tentative_mapping": false, "audit_error_count_raw": 0, "audit_warning_count_raw": 1, "audit_checks_raw_json": [ "abstract_only_extraction" ], "placeholder_flag": false, "core_role_missing_flag": false, "effect_parse_failed_flag": false, "normalization_status": "compiled", "normalization_issues_json": [], "compiled_at": "2026-04-15T04:45:33.820737+00:00", "quality_decision_id": "QDEC:bc0705a790d2bb00", "quality_run_id": "QRUN:73c4e6df275bd5ab", "record_status": "review_required", "effect_status": "usable", "record_status_reason": "missing_key_role_mapping", "effect_status_reason": "usable", "has_missing_mapping_1": false, "has_tentative_mapping_1": true, "key_role_missing_mapping": true, "key_role_tentative_mapping": false, "audit_error_count": 0, "audit_warning_count": 1, "effect_nullified_flag": false, "quality_policy_version": "m7_v1", "decided_at": "2026-04-15T04:45:46.307583+00:00" } ] }, "graph_edges": {}, "papers": { "PMID:34942372": { "paper_id": "PMID:34942372", "paper_title": "Semaglutide for the treatment of obesity.", "year": 2023, "doi": "10.1016/j.tcm.2021.12.008", "source_pdf_path": null, "paper_dir": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/34/34942372" }, "PMID:36578889": { "paper_id": "PMID:36578889", "paper_title": "Efficacy and Safety of Semaglutide for Weight Loss in Obesity Without Diabetes: A Systematic Review and Meta-Analysis.", "year": 2022, "doi": "10.15605/jafes.037.02.14", "source_pdf_path": null, "paper_dir": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/36/36578889" }, "PMID:38048584": { "paper_id": "PMID:38048584", "paper_title": "In patients with HFpEF and obesity, semaglutide increased weight loss and reduced symptoms and physical limitations at 52 wk.", "year": 2023, "doi": "10.7326/j23-0101", "source_pdf_path": null, "paper_dir": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/38/38048584" }, "PMID:39476339": { "paper_id": "PMID:39476339", "paper_title": "Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis.", "year": 2024, "doi": "10.1056/NEJMoa2403664", "source_pdf_path": null, "paper_dir": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/39/39476339" }, "PMID:40175094": { "paper_id": "PMID:40175094", "paper_title": "Comparing the risk of gastroparesis following different modalities for treating obesity: semaglutide versus bupropion-naltrexone versus sleeve gastrectomy - a retrospective cohort study.", "year": 2025, "doi": "10.1136/bmjgast-2024-001704", "source_pdf_path": null, "paper_dir": "artifacts/workbench_test_runs/obesity_semaglutide_review/m3a_extract/40/40175094" } } } } }