Derivation Web

source_0e2823919d784c24

by researka:v2 · 2026-06-15 01:09:06.625440+04:00

{"content_hash": "sha256:92404f08425d2fe93b9520e6b4499c93a6a911e729f4442bcd0edc73d4ab41f1", "edges": [{"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_1", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_2", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_3", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_4", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_5", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_6", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_7", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_8", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_9", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_10", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_11", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_12", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_13", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_14", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_15", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_16", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_17", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_18", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_19", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_20", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_21", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_22", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_23", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_24", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_25", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_26", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_27", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_28", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_29", "type": "contains_claim"}, {"from": "24f229e0-b6b2-4735-912f-34831eeac380", "to": "claim_30", "type": "contains_claim"}], "nodes": [{"id": "24f229e0-b6b2-4735-912f-34831eeac380", "title": "Research Synthesis: Metformin Cancer Effects — full paper", "type": "publication"}, {"id": "claim_1", "text": "Evidence-honesty note: 15/21 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.", "type": "claim"}, {"id": "claim_2", "text": "This synthesis tests the thesis that evidence for Metformin Cancer Effects is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation.", "type": "claim"}, {"id": "claim_3", "text": "We synthesized evidence from 21 curated sources to evaluate metformin’s effects on cancer outcomes across observational cohorts, systematic reviews, and mechanistic studies.", "type": "claim"}, {"id": "claim_4", "text": "Animal-model lifespan extensions of around 5% (Anisimov 2008) co-exist with null findings in human trials, underscoring translational gaps in metformin’s anti-aging or anti-cancer promise.", "type": "claim"}, {"id": "claim_5", "text": "Evidence-abstraction note.** The 21 retained reference papers are not 21 independent primary clinical trials: 21 are review, indirect, mechanistic, or registered-protocol source-level summaries, and no source is classified as direct interventional hard-endpoint evidence, although human observational/prognostic evidence is present. Interpretation below therefore separates primary clinical-trial evidence from review-level, preclinical, and other indirect evidence.", "type": "claim"}, {"id": "claim_6", "text": "This manuscript is reported as a Thin-corpus evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-metformin_cancer_effects-v06-DAILY-2026-06-14T20-47-12Z`.", "type": "claim"}, {"id": "claim_7", "text": "The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text.", "type": "claim"}, {"id": "claim_8", "text": "Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`.", "type": "claim"}, {"id": "claim_9", "text": "Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, immune and inflammation, longevity, mortality and survival, safety and comorbidity); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.", "type": "claim"}, {"id": "claim_10", "text": "Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.", "type": "claim"}, {"id": "claim_11", "text": "Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.", "type": "claim"}, {"id": "claim_12", "text": "| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |", "type": "claim"}, {"id": "claim_13", "text": "| Contextual Adjacent Evidence | n=13; claims=655 | no extracted directional signal in 10/13 sources | 6 indirect; 1 mechanistic; 1 protocol; 5 review | limited corpus depth in this outcome class |", "type": "claim"}, {"id": "claim_14", "text": "This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.", "type": "claim"}, {"id": "claim_15", "text": "13 included sources were assigned to this outcome class. Directional coding: mixed=1, null=10, unclear=2. Directness coding: indirect=6, mechanistic=1, protocol=1, review=5.", "type": "claim"}, {"id": "claim_16", "text": "2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: review=2.", "type": "claim"}, {"id": "claim_17", "text": "2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=1, review=1.", "type": "claim"}, {"id": "claim_18", "text": "1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.", "type": "claim"}, {"id": "claim_19", "text": "Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.", "type": "claim"}, {"id": "claim_20", "text": "The curated corpus provides no long-duration randomized trials directly testing metformin’s impact on cancer-specific mortality in non-diabetic adults, creating a critical evidence gap for the headline synthesis. All sources addressing mortality (Orchard 2023; Xie 2025) enroll adults with type 2 diabetes, limiting external validity to populations where metformin’s metabolic effects may confound oncologic endpoints. This restriction precludes generalization to the broader oncology population where glycemic control is not the primary therapeutic target, particularly for cancers where diabetes prevalence is lower (e.g., melanoma or hematologic malignancies).", "type": "claim"}, {"id": "claim_21", "text": "Single-source dominance characterizes several outcome domains, increasing the risk of overgeneralization from non-replicated findings.", "type": "claim"}, {"id": "claim_22", "text": "The corpus underrepresents key clinical endpoints and populations that are essential for a comprehensive risk–benefit assessment of metformin in oncology. Additionally, the enrolled populations skew heavily toward adults with metabolic syndrome (Pasanisi 2024) or obesity-related cancers (Hussain 2025), leaving populations with normal glucose tolerance or non-obesity-related malignancies underrepresented. This imbalance restricts the synthesis’s applicability to the broader cancer survivor population, where metabolic heterogeneity is substantial.", "type": "claim"}, {"id": "claim_23", "text": "For metformin cancer effects, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.", "type": "claim"}, {"id": "claim_24", "text": "This synthesis maps 21 included sources on Metformin Cancer Effects across 6 outcome classes with no cross-study disagreements surfaced. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.", "type": "claim"}, {"id": "claim_25", "text": "Across 21 curated reference papers, the evidence base for Metformin Cancer Effects shows a context-dependent profile. Null findings dominate: contextual other, mortality survival. The Metformin Cancer Effects anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.", "type": "claim"}, {"id": "claim_26", "text": "Prior reviews in the corpus (Rangraze 2025) emphasize convergent signals on Metformin Cancer Effects. This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.", "type": "claim"}, {"id": "claim_27", "text": "| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |", "type": "claim"}, {"id": "claim_28", "text": "| contextual adjacent evidence | 0 | 13 | mixed, null, unclear | direct interventional hard-endpoint gap |", "type": "claim"}, {"id": "claim_29", "text": "| immune and inflammation | 0 | 1 | null | direct interventional hard-endpoint gap |", "type": "claim"}, {"id": "claim_30", "text": "| mortality and survival | 0 | 2 | null | direct interventional hard-endpoint gap |", "type": "claim"}, {"comparator": "not extracted", "directness": "primary", "doi": "10.2337/dc24-1597", "effect": "not extracted", "endpoint": "not extracted", "id": "source_1", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Metformin Treatment With or Without Mediterranean Diet for the Prevention of Age-Related Diseases in People With Metabolic Syndrome: The MeMeMe Randomized Trial", "type": "source", "url": "https://doi.org/10.2337/dc24-1597", "year": 2024}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1111/acel.13733", "effect": "not extracted", "endpoint": "not extracted", "id": "source_2", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Metformin has heterogeneous effects on model organism lifespans and is beneficial when started at an early age in Caenorhabditis elegans : A systematic review and meta‐analysis", "type": "source", "url": "https://doi.org/10.1111/acel.13733", "year": 2022}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1038/s41467-025-67087-8", "effect": "not extracted", "endpoint": "not extracted", "id": "source_3", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Letrozole, abemaciclib and metformin in endometrial cancer: a non-randomized phase 2 trial", "type": "source", "url": "https://doi.org/10.1038/s41467-025-67087-8", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1093/jncics/pkad017", "effect": "not extracted", "endpoint": "not extracted", "id": "source_4", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Association of metformin, aspirin, and cancer incidence with mortality risk in adults with diabetes", "type": "source", "url": "https://doi.org/10.1093/jncics/pkad017", "year": 2023}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3390/ijms27104195", "effect": "not extracted", "endpoint": "not extracted", "id": "source_5", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Do We Have Enough Evidence That Metformin Is Superior to Other Antidiabetic Drugs in Pancreatic Cancer Risk Reduction?", "type": "source", "url": "https://doi.org/10.3390/ijms27104195", "year": 2026}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1038/s41467-025-56914-7", "effect": "not extracted", "endpoint": "not extracted", "id": "source_6", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Olaparib combined to metronomic cyclophosphamide and metformin in women with recurrent advanced/metastatic endometrial cancer: the ENDOLA phase I/II trial", "type": "source", "url": "https://doi.org/10.1038/s41467-025-56914-7", "year": 2025}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.3390/medicina61061021", "effect": "not extracted", "endpoint": "not extracted", "id": "source_7", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Metformin: A Dual-Role Player in Cancer Treatment and Prevention: A Comprehensive Systematic Review and Meta-Analysis", "type": "source", "url": "https://doi.org/10.3390/medicina61061021", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1038/s41598-025-09393-1", "effect": "not extracted", "endpoint": "not extracted", "id": "source_8", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Metformin and weight loss medication impact on survival outcomes in older women with obesity-related cancers", "type": "source", "url": "https://doi.org/10.1038/s41598-025-09393-1", "year": 2025}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1002/jcsm.13509", "effect": "not extracted", "endpoint": "not extracted", "id": "source_9", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Effects of exercise or metformin on myokine concentrations in patients with breast and colorectal cancer: A phase II multi‐centre factorial randomized trial", "type": "source", "url": "https://doi.org/10.1002/jcsm.13509", "year": 2024}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1590/1414-431X2024e14060", "effect": "not extracted", "endpoint": "not extracted", "id": "source_10", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Clenbuterol and metformin ameliorate cachexia parameters, but only clenbuterol reduces tumor growth via lipid peroxidation in Walker 256 tumor-bearing rats", "type": "source", "url": "https://doi.org/10.1590/1414-431X2024e14060", "year": 2025}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1371/journal.pone.0310687", "effect": "not extracted", "endpoint": "not extracted", "id": "source_11", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Association of metformin use with risk and survival outcome of esophageal cancer in patients with diabetes: A systematic review and meta-analysis", "type": "source", "url": "https://doi.org/10.1371/journal.pone.0310687", "year": 2025}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.3389/fphar.2026.1752095", "effect": "not extracted", "endpoint": "not extracted", "id": "source_12", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Efficacy of metformin as an adjuvant therapy in gynecologic malignancies: a meta-analysis of randomized controlled trials", "type": "source", "url": "https://doi.org/10.3389/fphar.2026.1752095", "year": 2026}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1158/1940-6207.CAPR-25-0104", "effect": "not extracted", "endpoint": "not extracted", "id": "source_13", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Time-Restricted Eating and Metformin in Invasive Breast Cancer or DCIS: A Randomized, Phase IIb, Presurgical Trial. Preliminary Safety Analysis", "type": "source", "url": "https://doi.org/10.1158/1940-6207.CAPR-25-0104", "year": 2025}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1038/s41416-025-03070-w", "effect": "not extracted", "endpoint": "not extracted", "id": "source_14", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Statin use and breast cancer-specific mortality and recurrence: a systematic review and meta-analysis including the role of immortal time bias and tumour characteristics", "type": "source", "url": "https://doi.org/10.1038/s41416-025-03070-w", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1158/1078-0432.CCR-25-1098", "effect": "not extracted", "endpoint": "not extracted", "id": "source_15", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Extracellular Matrix–MYCAF Signatures Correlate with Resistance to Neoadjuvant aPD-L1 Immune Checkpoint Inhibition with Durvalumab + Metformin in HPV+ HNSCC", "type": "source", "url": "https://doi.org/10.1158/1078-0432.CCR-25-1098", "year": 2025}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.2340/1651-226X.2025.43045", "effect": "not extracted", "endpoint": "not extracted", "id": "source_16", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Tolerability, safety and feasibility of metformin combined with chemoradiotherapy in patients with locally advanced cervical cancer: a phase II, randomized study", "type": "source", "url": "https://doi.org/10.2340/1651-226X.2025.43045", "year": 2025}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.3389/fphar.2025.1710176", "effect": "not extracted", "endpoint": "not extracted", "id": "source_17", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Effectiveness of drug-loaded poly(ethylene glycol) and poly(lactic-co-glycolic-acid) nanoparticles in the in vitro treatment of breast cancer: a systematic review", "type": "source", "url": "https://doi.org/10.3389/fphar.2025.1710176", "year": 2026}, {"comparator": "not extracted", "directness": "primary", "doi": "10.2196/79739", "effect": "not extracted", "endpoint": "not extracted", "id": "source_18", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Smartphone-Based Physical Activity Program to Reduce “Chemo-Brain” Symptoms and Improve Health in Cancer Survivors With and Without Type 2 Diabetes: Protocol for a Single-Arm Pre-Post Pilot Trial", "type": "source", "url": "https://doi.org/10.2196/79739", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1038/s41598-025-01705-9", "effect": "not extracted", "endpoint": "not extracted", "id": "source_19", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Effects of metformin on transcriptomic and metabolomic profiles in breast cancer survivors enrolled in the randomized placebo-controlled MetBreCS trial", "type": "source", "url": "https://doi.org/10.1038/s41598-025-01705-9", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3389/fimmu.2024.1526481", "effect": "not extracted", "endpoint": "not extracted", "id": "source_20", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Bibliometric analysis of metformin as an immunomodulator (2013–2024)", "type": "source", "url": "https://doi.org/10.3389/fimmu.2024.1526481", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1136/bmjopen-2026-117537", "effect": "not extracted", "endpoint": "not extracted", "id": "source_21", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Association between preoperative metformin exposure and postoperative nausea and vomiting in patients undergoing general anaesthesia: a protocol for a prospective observational cohort study in a Chinese tertiary hospital", "type": "source", "url": "https://doi.org/10.1136/bmjopen-2026-117537", "year": 2026}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1056/nejm198812293192604", "effect": "not extracted", "endpoint": "not extracted", "id": "source_22", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "**Tinetti 1988.** _Tinetti ME, Speechley M, Ginter SF. Risk factors for falls among elderly persons living in the community. N Engl J Med. 1988;319(26):1701-1707._ DOI: 10.1056/NEJM198812293192604. PMID: 3205267.", "type": "source", "url": "https://doi.org/10.1056/nejm198812293192604", "year": 1988}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.2337/dc24-s006", "effect": "not extracted", "endpoint": "not extracted", "id": "source_23", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "**ADA 2024.** _American Diabetes Association. Standards of Care in Diabetes. Diabetes Care. 2024;47(Suppl 1)._ DOI: 10.2337/dc24-S006.", "type": "source", "url": "https://doi.org/10.2337/dc24-s006", "year": 2024}, {"comparator": "not extracted", "directness": "review-level", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_24", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "**Owen 2000.** _Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348 Pt 3:607-614._ PMID: 10839993.", "type": "source", "url": null, "year": 2000}, {"comparator": "not extracted", "directness": "review-level", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_25", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "**Anisimov 2008.** _Anisimov VN, Berstein LM, Egormin PA, et al. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle. 2008;7(17):2769-2773._ PMID: 18728386.", "type": "source", "url": null, "year": 2008}, {"comparator": "not extracted", "directness": "citation", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_26", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "**Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.", "type": "source", "url": null, "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_27", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "**Directness** is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.", "type": "source", "url": null, "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_28", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "**Directional signal** is counted within the assigned outcome class only. A `no extracted directional signal` cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.", "type": "source", "url": null, "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_29", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "**Evidence tier** follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.", "type": "source", "url": null, "year": null}], "publication_id": "24f229e0-b6b2-4735-912f-34831eeac380", "screening": {"excluded": 0, "exclusion_reasons": ["No PRISMA full-text exclusion-stage filter was applied."], "flow": ["identified", "screened", "excluded_with_reasons", "included"], "identified": 26, "included": 26, "included_or_retained": 26, "screened": 26, "wording": "26 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit."}}

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