Derivation Web

source_2bd7ed7e985344ed

by researka:v2 · 2026-06-06 12:37:16.675820+04:00

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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. 11/12 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.", "type": "claim"}, {"id": "claim_2", "text": "The evidence profile contains 1 direct clinical source, 4 adjacent clinical sources, and no sources classified primarily as mechanistic or model-system evidence, with 13 cross-study disagreements across the evidence base.", "type": "claim"}, {"id": "claim_3", "text": "No single positive outcome class dominates the retained corpus; null signals cluster in the contextual adjacent evidence, cardiometabolic and frailty outcome classes, and negative signals cluster in the dosing and pharmacokinetics outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.", "type": "claim"}, {"id": "claim_4", "text": "The conclusion is that resveratrol biomarker effects should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.", "type": "claim"}, {"id": "claim_5", "text": "Aging is the dominant risk factor for the majority of chronic diseases that drive morbidity, mortality, and healthcare expenditure in industrialized nations. The question of whether pharmacological or nutraceutical interventions can slow the biological processes underlying aging — and thereby compress the period of disability at end of life — has moved to the center of translational geroscience. Healthspan, defined as the years lived free of major chronic disease and functional limitation, has become a co-primary target alongside lifespan itself, reflecting a recognition that mere longevity without quality of life holds limited clinical or societal value. Against this backdrop, a growing number of candidate molecules have been proposed as \"anti-aging\" agents, with Resveratrol receiving among the most sustained public and scientific attention over the past two decades. The urgency of this question appears to intensify as global populations age: by mid-century, the number of adults over 60 is projected to double, and the burden of multimorbidity, frailty, and neurodegeneration is expected to scale accordingly. Yet despite hundreds of preclinical studies and dozens of human trials, the clinical case for Resveratrol Biomarker Effects remains unresolved, with evidence split across heterogeneous outcomes, populations, and study designs. This introduction frames the stakes, the mechanistic rationale, the current trial landscape, and the unresolved tensions that motivate the present synthesis.", "type": "claim"}, {"id": "claim_6", "text": "The geroscience hypothesis posits that fundamental aging mechanisms — including cellular senescence, mitochondrial dysfunction, chronic low-grade inflammation, and impaired proteostasis — represent upstream drivers of multiple age-related pathologies. If this framework is correct, then interventions that modulate these core hallmarks could, in principle, delay or attenuate several diseases simultaneously, rather than addressing each condition in isolation. This logic has fueled interest in repurposing existing compounds with known safety profiles for geroprotective indications, a strategy that could compress the timeline from bench to bedside relative to de novo drug development. Resveratrol Biomarker Effects has been positioned within this repurposing paradigm as a naturally occurring polyphenol with proposed activity across several geroscience-relevant pathways, including sirtuin activation, AMPK signaling, and NF-κB–mediated inflammation modulation (Radeva 2025; Wang 2025). The appeal of Resveratrol as a candidate geroprotector appears to rest partly on its widespread availability as a dietary supplement, which circumvents many of the regulatory barriers that constrain novel pharmaceutical agents. However, the ease of consumer access also means that millions of individuals may be self-administering Resveratrol based on preliminary or preclinical evidence, without the clinical-trial infrastructure to confirm benefit or monitor harm. Whether the geroscience rationale for Resveratrol Biomarker Effects can be translated into measurable clinical outcomes in humans remains the central open question that this synthesis seeks to address.", "type": "claim"}, {"id": "claim_7", "text": "Resveratrol (trans-3,5,4′-trihydroxystilbene) is a stilbenoid polyphenol found in grape skins, peanuts, and certain berries, and it has been classified as a sirtuin-activating compound (STAC) since early reports of its interaction with SIRT1. Mechanistically, Resveratrol has been proposed to activate AMP-activated protein kinase (AMPK), inhibit mTOR signaling, scavenge reactive oxygen species, and modulate macrophage polarization — pathways that converge on inflammation, metabolic regulation, and cellular stress responses (Wang 2025; Radeva 2025). Regulatory status varies by jurisdiction, but Resveratrol is generally classified as a dietary supplement rather than a pharmaceutical, which means it has not undergone the rigorous Phase I–III approval pathway required for therapeutic claims. This regulatory ambiguity has created a landscape in which Resveratrol is simultaneously one of the most studied nutraceuticals in aging research and one of the least constrained by formal clinical evidence standards. The question of whether formulation innovations — including nanoparticle encapsulation, liposomal delivery, and combination with other bioenhancers — can bridge the bioavailability gap appears to be a prerequisite for any definitive clinical trial of Resveratrol.", "type": "claim"}, {"id": "claim_8", "text": "The human randomized controlled trial (RCT) landscape for Resveratrol Biomarker Effects spans multiple disease domains, yet the evidence base remains fragmented and, in several areas, underpowered or methodologically heterogeneous. In the frailty domain, Karim et al. reported that resveratrol reduced frailty scores, pain during walking, and WOMAC indices, and improved grip strength and Oxford Knee Scores, with all primary endpoints reaching statistical significance at P < 0.05 in a placebo-controlled trial of knee osteoarthritis patients (Karim 2025). A companion systematic review by the same group found that Resveratrol significantly improved balance, gait speed, knee range of motion, and handgrip strength (all P < 0.05), without affecting inflammatory markers (Karim 2026). However, a broader systematic review by Russo et al. identified no eligible trials that confirmed both adiposity and sarcopenia at baseline — a phenotype-defined inclusion criterion — highlighting a critical gap in the sarcopenic obesity literature (Russo 2026). This pattern — isolated signals of efficacy amid predominantly null or inconsistent findings — appears to characterize the Resveratrol trial literature across most outcome classes.", "type": "claim"}, {"id": "claim_9", "text": "Several unresolved questions appear to constrain the translational potential of Resveratrol as a geroprotective agent. First, the mechanism–function translation gap remains wide: in vitro evidence for SIRT1 activation, AMPK engagement, and anti-inflammatory macrophage polarization has not been consistently recapitulated in human trials at achievable plasma concentrations (Wang 2025; Radeva 2025). Second, population specificity is a recurring issue — the strongest positive signals for Resveratrol emerge from disease-enriched cohorts such as knee osteoarthritis patients (Karim 2025) or postmenopausal women with pain (Wu 2025), whereas trials in general adult or obesity populations tend toward null results (SHEN 2026). Third, dose–response relationships have not been adequately characterized: the range of doses tested across trials varies widely, and the bioavailability limitations documented by Radeva et al. suggest that much of the administered Resveratrol may never reach systemic circulation at pharmacologically relevant concentrations (Radeva 2025). Fourth, the interaction between Resveratrol and commonly prescribed medications in older adults — particularly antidiabetic and antihypertensive agents — has received insufficient systematic attention. Whether these unresolved issues reflect fundamental limitations of the molecule or gaps in trial design remains an open empirical question.", "type": "claim"}, {"id": "claim_10", "text": "The present synthesis addresses these gaps by applying a structured evidence-weighting framework to 12 curated reference papers spanning mechanistic reviews, systematic reviews, meta-analyses, and randomized controlled trials of Resveratrol Biomarker Effects. A key methodological contribution is the explicit separation of clinical evidence (outcomes in human populations) from mechanistic evidence (pathway-level biology), recognizing that Resveratrol may demonstrate plausible biological activity without corresponding clinical efficacy — a pattern documented across multiple outcome classes in this literature (Radeva 2025; Wu 2025b; Milosavljevic 2026). The synthesis surfaces cross-study disagreements across outcome classes, most notably the discordance between the null finding of Russo et al. in phenotype-defined sarcopenic obesity and the positive signals reported by Karim et al. in knee osteoarthritis-related frailty (Russo 2026; Karim 2025; Karim 2026). Cross-domain analysis reveals that Resveratrol shows a context-dependent efficacy profile: isolated positive signals in pain, balance, and specific cardiometabolic surrogates coexist with predominantly null findings in obesity-related endpoints, immune markers, and composite frailty measures assessed outside disease-enriched populations. The anti-aging case for Resveratrol as currently constituted appears to be incomplete — mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions for clinical benefit remain to be established. By mapping these tensions systematically, this synthesis aims to provide a transparent foundation for prioritizing future trials, refining target populations, and distinguishing genuine biological signal from publication and confirmation bias in the Resveratrol Biomarker Effects literature.", "type": "claim"}, {"id": "claim_11", "text": "The background evidence for resveratrol biomarker effects is heterogeneous rather than uniformly confirmatory. Direct clinical sources such as Karim 2025 are interpreted separately from mechanistic studies such as the retained evidence base, because these evidence roles answer different questions about aging biology and clinical translation.", "type": "claim"}, {"id": "claim_12", "text": "The direct evidence establishes what has been observed in human or adjacent clinical settings. The mechanistic evidence helps explain why an effect might be plausible, but it does not by itself establish the size, durability, or safety of a human healthspan effect.", "type": "claim"}, {"id": "claim_13", "text": "Across the retained sources, positive signals cluster around no dominant outcome class; null signals around the contextual adjacent evidence, cardiometabolic and frailty outcome classes; and negative or adverse signals around the dosing and pharmacokinetics outcome class. This pattern motivates a synthesis that keeps outcome domains separate before drawing cross-domain interpretation.", "type": "claim"}, {"id": "claim_14", "text": "The study-level structure also prevents selective emphasis. Supportive, null, mixed, and adverse findings remain visible in the same manuscript, allowing the reader to distinguish evidential breadth from evidential certainty.", "type": "claim"}, {"id": "claim_15", "text": "The resulting paper is therefore a calibrated synthesis: it can identify plausible mechanisms, direct interventional hard-endpoint signals, unresolved tensions, and trial-design priorities without converting them into claims stronger than the retained corpus can support.", "type": "claim"}, {"id": "claim_16", "text": "This distinction matters for publication because it makes the paper falsifiable. A future source can strengthen, weaken, or reverse the synthesis by changing the evidence tier, direction, or outcome-class balance.", "type": "claim"}, {"id": "claim_17", "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_18", "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_19", "text": "Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, frailty, immune, immune and inflammation); 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_20", "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_21", "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_22", "text": "| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |", "type": "claim"}, {"id": "claim_23", "text": "| Contextual Adjacent Evidence | n=5; claims=158 | no extracted directional signal in 5/5 sources | 2 indirect; 3 review | limited corpus depth in this outcome class |", "type": "claim"}, {"id": "claim_24", "text": "Contextual Adjacent Evidence: n=5; claims=158; no extracted directional signal in 5/5 sources | directness: 2 indirect; 3 review; main limitation: no direct clinical anchor.", "type": "claim"}, {"id": "claim_25", "text": "The retained resveratrol biomarker effects corpus is reported by outcome class before any cross-domain interpretation. This structure prevents favorable, null, mixed, and adverse evidence from being blended across biologically different endpoints.", "type": "claim"}, {"id": "claim_26", "text": "The contextual adjacent evidence packet includes 5 source-level summaries and 158 high-confidence observations. Directional coding within this packet is null=5, and directness coding is indirect=2, review=3. These counts describe the frozen evidence state for this outcome, not a pooled treatment estimate.", "type": "claim"}, {"id": "claim_27", "text": "The frailty evidence packet includes 3 source-level summaries and 3 high-confidence observations. Directional coding within this packet is null=1, unclear=2, and directness coding is direct=1, review=2.", "type": "claim"}, {"id": "claim_28", "text": "Directional coding within this packet is null=1, and directness coding is review=1.", "type": "claim"}, {"id": "claim_29", "text": "Across outcome classes, the manuscript treats disagreement as part of the evidence rather than as noise to smooth away. A null or adverse signal in one section does not cancel a favorable signal in another; it defines the boundary condition for interpretation.", "type": "claim"}, {"id": "claim_30", "text": "Descriptive findings remain separate from interpretation and endpoint-specific boundaries. Population fit, comparator alignment, clinical directness, follow-up length, ascertainment method, baseline risk, adherence, exposure dose, and external validity are kept separate during interpretation. The interpretation", "type": "claim"}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.3389/fphar.2025.1588284", "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": "Effects of resveratrol on postmenopausal women: a systematic review and meta-analysis", "type": "source", "url": "https://doi.org/10.3389/fphar.2025.1588284", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.21873/invivo.14235", "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": "Resveratrol Supplementation and its Potential Benefits in Obesity-related Non-communicable Diseases", "type": "source", "url": "https://doi.org/10.21873/invivo.14235", "year": 2026}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.3389/fragi.2025.1727244", "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": "Trans-resveratrol reduces visible signs of skin ageing in healthy adult females over 40: an 8-week randomized placebo-controlled trial", "type": "source", "url": "https://doi.org/10.3389/fragi.2025.1727244", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3390/ijms26115044", "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": "Resveratrol Attenuates CSF Markers of Neurodegeneration and Neuroinflammation in Individuals with Alzheimer’s Disease", "type": "source", "url": "https://doi.org/10.3390/ijms26115044", "year": 2025}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.3389/fimmu.2025.1617694", "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": "Efficacy and safety of dietary polyphenol supplements for COPD: a systematic review and meta-analysis", "type": "source", "url": "https://doi.org/10.3389/fimmu.2025.1617694", "year": 2025}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.3390/ijms27062817", "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": "Neurotrophin System Alterations Associated with Neurotoxicity Accompanied by Carotid Artery Diseases—A Systematic Review", "type": "source", "url": "https://doi.org/10.3390/ijms27062817", "year": 2026}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3390/pharmaceutics17010134", "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": "Resveratrol—A Promising Therapeutic Agent with Problematic Properties", "type": "source", "url": "https://doi.org/10.3390/pharmaceutics17010134", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3389/fphar.2024.1516609", "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": "Resveratrol-driven macrophage polarization: unveiling mechanisms and therapeutic potential", "type": "source", "url": "https://doi.org/10.3389/fphar.2024.1516609", "year": 2025}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1002/ptr.8431", "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": "Clinical Efficacy of Curcumin, Resveratrol, Silymarin, and Berberine on Cardio-Metabolic Risk Factors Among Patients With Type 2 Diabetes Mellitus: A Systemic Review and Bayesian Network Meta-Analysis.", "type": "source", "url": "https://doi.org/10.1002/ptr.8431", "year": 2025}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.3389/fnut.2026.1818450", "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": "Vitamin D and resveratrol in sarcopenic obesity: a systematic review highlighting the gap in phenotype-defined randomized controlled trials", "type": "source", "url": "https://doi.org/10.3389/fnut.2026.1818450", "year": 2026}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1016/j.explore.2026.103341", "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": "Improvement in postural imbalance with intake of resveratrol (polyphenolic phytoalexin) in patients of knee osteoarthritis.", "type": "source", "url": "https://doi.org/10.1016/j.explore.2026.103341", "year": 2026}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1080/09637486.2025.2563670", "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": "Resveratrol treatment increases sirtuin 1 levels and alleviates frailty phenotype in knee osteoarthritis patients: a randomised placebo-controlled clinical trial.", "type": "source", "url": "https://doi.org/10.1080/09637486.2025.2563670", "year": 2025}, {"comparator": "not extracted", "directness": "citation", "doi": null, "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": "**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_14", "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_15", "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_16", "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}, {"comparator": "not extracted", "directness": "citation", "doi": "10.1001/jama.2010.1923", "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": "Studenski 2011", "type": "source", "url": "https://doi.org/10.1001/jama.2010.1923", "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": "10.1093/ageing/26.1.15", "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": "Bohannon 1997", "type": "source", "url": "https://doi.org/10.1093/ageing/26.1.15", "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": "10.1371/journal.pmed.0020124", "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": "Ioannidis 2005", "type": "source", "url": "https://doi.org/10.1371/journal.pmed.0020124", "year": null}], "publication_id": "75290622-273a-4e57-9a84-36d920af19b1", "screening": {"excluded": 0, "exclusion_reasons": ["No PRISMA full-text exclusion-stage filter was applied."], "flow": ["identified", "screened", "excluded_with_reasons", "included"], "identified": 12, "included": 12, "included_or_retained": 12, "screened": 12, "wording": "12 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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  "sidecar_url": "https://api.researka.org/publications/75290622-273a-4e57-9a84-36d920af19b1/sidecars/claim_graph.json"
}