Iter-4360dd15-0078-transcript
第 78 轮执行轨迹
→ call search_memory({"limit":10,"query":"4360dd15 PMID 候选 摘要 年龄判据 主要终点 保留 排除"}) → call list_recent({"n":8})
→ call list_by_tag({"limit":20,"tag":"4360dd15"})
【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0060-transcript", "tags": "iteration transcript", "modified": "20260424200117000", "preview": "!! 第 60 轮执行轨迹
→"}, {"title": "Iter-4360dd15-0059-transcript", "tags": "iteration transcript", "modified": "20260424195947000", "preview": "!! 第 59 轮执行轨迹 → call search_memory({\"limit\":8,\"query\":\"4360dd15 NEXT_FOCUS PMID 候选 摘要 年龄判据 主要终点\"}) → call list_recent({\"n\":6}) → call list_by_tag({\"limit\":10,\"tag\":\"4360dd15\"}) 【tool:search_memory】 {\"ok\": true, \"result【tool:list_recent】
{"ok": true, "items": [{"title": "Iter-4360dd15-0077-reflection", "modified": "20260424203148000", "tags": "iteration reflection"}, {"title": "NEXT_FOCUS", "modified": "20260424203148000", "tags": "pinned focus"}, {"title": "先最小化候选，再三字段补全", "modified": "20260424203148000", "tags": "lesson abstract-extraction trial-registry endpoint age"}, {"title": "Iter-4360dd15-0077-transcript", "modified": "20260424203143000", "tags": "iteration transcript"}, {"title": "Iter-4360dd15-0077-unified-longevity-classification-four-pmids", "modified": "20260424203137000", "tags": "4360dd15 knowledge fact method"}, {"title": "Iter-4360dd15-0076-reflection", "modified": "20260424203004000", "tags": "iteration reflection"}, {"title": "先用注册库补关键字段", "modified": "20260424203004000", "tags": "lesson abstract-extraction trial-registry endpoint age"}, {"title": "Iter-4360dd15-0076-transcript", "modified": "20260424202956000", "tags": "iteration transcript"}]}
【tool:list_by_tag】
{"ok": true, "items": [{"title": "Iter-4360dd15-0077-unified-longevity-classification-four-pmids", "modified": "20260424203137000"}, {"title": "Iter-4360dd15-0075-abstract-field-extraction-two-pmids", "modified": "20260424202951000"}, {"title": "Iter-4360dd15-0072-review-exclusion-first-rule", "modified": "20260424202103000"}, {"title": "Iter-4360dd15-0071-minimal-audit-rules", "modified": "20260424201843000"}, {"title": "Iter-4360dd15-0069-standardized-audit-table-two-trials", "modified": "20260424201621000"}, {"title": "Iter-4360dd15-0068-abstract-endpoint-extraction", "modified": "20260424201407000"}, {"title": "Iter-4360dd15-0067-abstract-endpoints-aging-criteria", "modified": "20260424201141000"}, {"title": "Iter-4360dd15-0066-TierA-abstracts-and-endpoints-for-aging-criteria", "modified": "20260424200925000"}, {"title": "Iter-4360dd15-0065-minimal-relevance-decision-rules-for-retained-mtor-trials", "modified": "20260424200748000"}, {"title": "Iter-4360dd15-0064-relevance-tiering-10-pmids", "modified": "20260424200602000"}, {"title": "Iter-4360dd15-0063-10-pmid-audit-table", "modified": "20260424200432000"}, {"title": "Iter-4360dd15-0062-pubmed-title-verification-10-pmids", "modified": "20260424200328000"}, {"title": "Iter-4360dd15-0061-candidate-audit-10-remaining-pmids", "modified": "20260424200221000"}, {"title": "PMID 38310895 is a review, not a primary trial", "modified": "20260424200109000"}, {"title": "PMID 35040506 longitudinal analysis is embedded in primary tria
→ call search_memory({"limit":10,"query":"35040506 38310895 4360dd15 research type age endpoint"})
【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0047-transcript", "tags": "iteration transcript", "modified": "20260424193836000", "preview": "!! 第 47 轮执行轨迹
→ call search_memory({\\\"limit\\\":8,\\\"query\\\":\\\"4360dd15 PMID 38310895 mmc1.pdf supplementary tabl"}, {"title": "Iter-4360dd15-0037-transcript", "tags": "iteration transcript", "modified": "20260424191347000", "preview": "!! 第 37 轮执行轨迹 → call search_memory({\"limit\":8,\"query\":\"4360dd15 rapamycin review 2024 trial endpoint remaining 11\"}) → call list_recent({\"n\":8}) → call list_by_tag({\"limit\":20,\"tag\":\"4360dd15\"}) 【tool:search_memory】 { → call read_note({"title":"Iter-4360dd15-0077-unified-longevity-classification-four-pmids"})
→ call read_note({"title":"Iter-4360dd15-0075-abstract-field-extraction-two-pmids"})
→ call read_note({"title":"PMID 35040506 longitudinal analysis is embedded in primary trial"})
→ call read_note({"title":"PMID 38310895 is a review, not a primary trial"})
【tool:read_note】
{"ok": true, "title": "Iter-4360dd15-0077-unified-longevity-classification-four-pmids", "tags": "4360dd15 knowledge fact method", "text": "!! 第 77 轮：剩余候选 PMID 的统一 longevity 相关性分类\n\n本轮把已补齐字段的候选按统一阈值做了最终定位，避免继续在题名层面漂移。\n\n!! 分类规则（简化版）\n- 主要终点包含 //survival / mortality / death / lifespan / healthspan / disease-free / disability-free//，可视为更接近直接 longevity 证据。\n- 主要终点包含 //feasibility / safety//，归为 //feasibility_safety_pilot//。\n- 主要终点是 //infection / respiratory illness / RTI//，归为 //aging_proxy_infection_burden//。\n- 主要终点是疾病量表、//PFS//、功能量表或认知/体能指标，归为 //disease_specific_non_longevity//，除非它直接测寿命或失能自由生存。\n\n!! 当前四个候选的判定\n| PMID | 研究类型 | 年龄判据 | 主要终点 | 分类 |\n|---|---|---|---|---|\n| 35040506 | randomized double-blind placebo-controlled futility trial | 30–80 岁 | 48-week change in UMSARS total score | disease_specific_non_longevity |\n| 29992557 | single-arm phase IIIB trial | postmenopausal women | progression-free survival (PFS) | disease_specific_non_longevity（虽含 survival-like 词，但实际上是肿瘤 PFS，不是 longevity 终点） |\n| 33977284 | phase 2b + phase 3 randomized trials | at least 65 years | laboratory-confirmed RTIs / clinically symptomatic respiratory illness | aging_proxy_infection_burden |\n| 29408453 | randomized control trial feasibility pilot | 70–95 years | feasibility and safety; immune, cognitive, physical performance measures | feasibility_safety_pilot |\n\n!! 关键反事实提醒\n- 不能因为 endpoint 里出现 //survival// 就自动判为 longevity evidence；若语境是肿瘤学中的 //progression-free survival//，仍然是疾病控制指标。\n- 也不能因为对
【tool:read_note】
{"ok": true, "title": "Iter-4360dd15-0075-abstract-field-extraction-two-pmids", "tags": "4360dd15 knowledge fact classification", "text": "!! 第 76 轮：两个剩余候选 PMID 的摘要级字段抽取\n\n本轮只做一件事：把两个已锁定候选 PMID 的摘要/公开片段中的三个字段补齐：研究类型、年龄判据、主要终点。\n\n!! PMID 35040506\n- 题名：mTOR Inhibition with Sirolimus in Multiple System Atrophy: A Randomized, Double-Blind, Placebo-Controlled Futility Trial and 1-Year Biomarker Longitudinal Analysis\n- 研究类型：随机、双盲、安慰剂对照、phase II futility trial；并带 1-year biomarker longitudinal analysis\n- 年龄判据：公开临床试验页显示入组年龄 30–80 岁\n- 主要终点：48 周时 UMSARS total score 的变化（change from baseline to week 48）\n- 结论：属于原始临床研究，但疾病指向为 MSA，不是直接的 longevity 研究\n- 证据来源：PubMed 题名；ClinicalTrials.gov/NINDS 摘要片段；Europe PMC/snippet 显示 primary outcome 为 UMSARS total score\n\n!! PMID 29992557\n- 题名：Efficacy and safety of everolimus plus exemestane in postmenopausal women with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer: Results of the single-arm, phase IIIB 4EVER trial\n- 研究类型：单臂 phase IIIB 试验\n- 年龄判据：postmenopausal women（绝经后女性）\n- 主要终点：progression-free survival (PFS)\n- 结论：属于原始临床研究，但为肿瘤治疗研究，不是直接的 longevity 研究\n- 证据来源：PubMed 题名；公开摘要 snippet 明确写出 PFS 为 primary endpoint\n\n!! 可复现抽取规则\n1. 优先从题名识别 study design（randomized / placebo-controlled / single-arm / phase / futility）。\n2. 年龄判据优先读取公开 trial page 或摘要中的明确人群限定词（如 30–80 岁、postmenopausal women）。\n3. 主要终点优先抓 abstract/公开 snippet 中的 primary endpoint / primary outcome 语句。\n4. 如果研究对象是具体疾病或肿瘤且终点是疾病量表 / PFS，而非寿命、死亡或衰老生物标志物
【tool:read_note】
{"ok": true, "title": "PMID 35040506 longitudinal analysis is embedded in primary trial", "tags": "4360dd15 knowledge fact critique clinical-trials classification", "text": "!! PMID 35040506 的“longitudinal analysis”不是自动排除信号\n\nPMID 35040506（[[mTOR Inhibition with Sirolimus in Multiple System Atrophy: A Randomized, Double-Blind, Placebo-Controlled Futility Trial and 1-Year Biomarker Longitudinal Analysis.]]）是一个[[原始临床试验]]，而不是应被当作 extension / follow-up / secondary analysis 自动剔除的后续论文。\n\n!! 证据\n- PubMed 记录给出的题名同时包含 ''Randomized, Double-Blind, Placebo-Controlled Futility Trial'' 与 ''1-Year Biomarker Longitudinal Analysis''。\n- PMC 全文摘要/首页明确写道：''Objective: To investigate the efficacy and safety of sirolimus in patients with MSA using a futility design. We also analyzed 1-year biomarker trajectories in the trial participants.''\n\n!! 严厉审稿人式判定规则\n- 若题名是“主试验 + 生物标志物纵向分析”这类并列结构，且摘要显示纵向分析是对同一试验参与者的附加分析，则默认仍属原始试验。\n- 只有当题名或摘要明确出现 ''extension of''、''follow-up of''、''postextension''、''secondary analysis''、''ancillary study'' 等后续/派生信号时，才应排除。\n- 因此，''longitudinal analysis'' 只能算//警报词//，不能单独作为排除词。\n\n!! 可复现检查路径\n1. PubMed PMID：35040506\n2. PMC：https://pmc.ncbi.nlm.nih.gov/articles/PMC9018525/\n3. 检查题名是否把主试验与纵向分析并列，而非把纵向分析标成独立后续研究。\n"}
【tool:read_note】
{"ok": true, "title": "PMID 38310895 is a review, not a primary trial", "tags": "4360dd15 fact method clinical-trials classification", "text": "!! PMID 38310895 的审计结论\n- PMID 38310895 = [[Targeting ageing with rapamycin and its derivatives in humans: a systematic review.]]（Lancet Healthy Longev, 2024 Feb）\n- 证据来源：PubMed 检索结果与 Europe PMC 页面。\n- 该文是 //systematic review//，不是原始临床试验；在当前候选审计里应判为 ''secondary analysis / review'' 并排除。\n\n!! 为什么重要\n- 它明确报告“19 included studies”，说明它更像是证据汇总与参考链入口，而不是待纳入的独立试验。\n- 对剩余候选的判定要继续优先剔除 extension / follow-up / secondary analysis / review。\n\n!! 可复用规则\n- 若题名或摘要明确含有 systematic review / review / meta-analysis / secondary analysis，默认排除。\n- 但要保留它作为“参考链入口”：从文中提取被综述的原始人类试验，再逐条审计原始试验本身。\n\n!! 可引用来源\n- PubMed: https://pubmed.ncbi.nlm.nih.gov/38310895/\n- Europe PMC: https://europepmc.org/article/MED/38310895\n- 综述线索：检索摘要显示该文“resulting in 19 included studies”。"}
→ call search_memory({"limit":10,"query":"4360dd15 remaining two PMID candidates 35040506 29992557 33977284 29408453"})
【tool:search_memory】
{"ok": true, "results": [{"title": "Iter-4360dd15-0060-transcript", "tags": "iteration transcript", "modified": "20260424200117000", "preview": "!! 第 60 轮执行轨迹
→"}, {"title": "Iter-4360dd15-0059-transcript", "tags": "iteration transcript", "modified": "20260424195947000", "preview": "!! 第 59 轮执行轨迹 → call search_memory({\"limit\":10,\"query\":\"4360dd15 PMID 候选 摘要 年龄判据 主要终点 分类\"}) → call list_recent({\"n\":8}) 【tool:search_memory】 {\"ok\": true, \"results\": [{\"title\": \"Iter-4360dd15-0060-transcript\", \"tags\": \"i → call web_search({"limit":5,"query":"PMID 35040506 PubMed sirolimus multiple system atrophy age 30 80 primary outcome"})
→ call web_search({"limit":5,"query":"PMID 29992557 PubMed 4EVER trial progression-free survival postmenopausal women"})
→ call web_search({"limit":5,"query":"PMC 35040506 sirolimus multiple system atrophy trial objective primary outcome"})
→ call web_search({"limit":5,"query":"PMC 29992557 everolimus exemestane 4EVER trial primary endpoint PFS"})
【tool:web_search】
{"ok": true, "query": "PMID 35040506 PubMed sirolimus multiple system atrophy age 30 80 primary outcome", "results": [{"title": "mTOR Inhibition with Sirolimus in Multiple System Atrophy: A ... - PubMed", "url": "https://pubmed.ncbi.nlm.nih.gov/35040506/?dopt=Abstract", "snippet": "Background: Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by the aggregation of α-synuclein in glia and neurons. Sirolimus (rapamycin) is an mTOR inhibitor that promotes α-synuclein autophagy and reduces its associated neurotoxicity in preclinical models."}, {"title": "mTOR Inhibition with Sirolimus in Multiple System Atrophy: A Randomized ...", "url": "https://europepmc.org/article/MED/35040506", "snippet": "Abstract Background: Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by the aggregation of α-synuclein in glia and neurons. Sirolimus (rapamycin) is an mTOR inhibitor that promotes α-synuclein autophagy and reduces its associated neurotoxicity in preclinical models."}, {"title": "mTOR inhibition with sirolimus in multiple system atrophy: a randomized ...", "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9018525/", "snippet": "Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by the aggregation of α-synuclein in glia and neurons. Sirolimus (rapamycin) is an mTOR inhibitor that promotes α-synuclein autophagy and reduces its associated neurotoxicity in preclinical models."}, {"title": "PRIME PubM
【tool:web_search】
{"ok": true, "query": "PMID 29992557 PubMed 4EVER trial progression-free survival postmenopausal women", "results": [{"title": "Efficacy and safety of everolimus plus exemestane in ... - PubMed", "url": "https://pubmed.ncbi.nlm.nih.gov/29992557/", "snippet": "Here, we report on the open-label, single-arm, phase IIIB 4EVER trial (NCT01626222). This trial evaluated the clinical effectiveness of everolimus plus exemestane in postmenopausal women with HR+, HER2- aBC who had progressed on or after an NSAI, but with no restrictions on the time of progression after NSAI, prior chemotherapy for advanced ..."}, {"title": "Efficacy and safety of everolimus plus exemestane in postmenopausal ...", "url": "https://www.semanticscholar.org/paper/Efficacy-and-safety-of-everolimus-plus-exemestane-Tesch-Stoetzer/5ddc51835d665716e433f6e561c7f88ee3fc68c9", "snippet": "The 4EVER trial evaluated the clinical effectiveness of everolimus plus exemestane in postmenopausal women with HR+, HER2− aBC who had progressed on or after an NSAI, but with no restrictions on the time of progression after NSAI. In BOLERO‐2, adding everolimus to exemestane resulted in a twofold increase in median progression‐free survival (PFS) vs exemestane in postmenopausal women ..."}, {"title": "Study Details | NCT01626222 | 4EVER - Efficacy, Safety, Health ...", "url": "https://clinicaltrials.gov/study/NCT01626222", "snippet": "Efficacy and safety of everolimus plus exemestane in postmenopausal women with hormone receptor-po
【tool:web_search】
{"ok": true, "query": "PMC 35040506 sirolimus multiple system atrophy trial objective primary outcome", "results": [{"title": "mTOR inhibition with sirolimus in multiple system atrophy: a randomized ...", "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9018525/", "snippet": "Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by the aggregation of α-synuclein in glia and neurons. Sirolimus (rapamycin) is an mTOR inhibitor that promotes α-synuclein autophagy and reduces its associated ..."}, {"title": "mTOR Inhibition with Sirolimus in Multiple System Atrophy ... - Europe PMC", "url": "https://europepmc.org/article/MED/35040506", "snippet": "Background Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by the aggregation of α-synuclein in glia and neurons. Sirolimus (rapamycin) is an mTOR inhibitor that promotes α-synuclein autophagy and reduces its associated neurotoxicity in preclinical models. Objective To investigate the efficacy and safety of sirolimus in patients with MSA using a futility ..."}, {"title": "mTOR Inhibition with Sirolimus in Multiple System Atrophy: A Randomized ...", "url": "https://read.qxmd.com/read/35040506/mtor-inhibition-with-sirolimus-in-multiple-system-atrophy-a-randomized-double-blind-placebo-controlled-futility-trial-and-1-year-biomarker-longitudinal-analysis", "snippet": "Sirolimus (rapamycin) is an mTOR inhibitor that promotes α-synuclein autophagy and reduces its associated neuroto
【tool:web_search】
{"ok": true, "query": "PMC 29992557 everolimus exemestane 4EVER trial primary endpoint PFS", "results": [{"title": "Efficacy and safety of everolimus plus exemestane in ... - PubMed", "url": "https://pubmed.ncbi.nlm.nih.gov/29992557/", "snippet": "The ORR in 4EVER was lower than in BOLERO-2, likely due to inclusion of patients with more advanced disease and extensive pretreatment. These data confirm the clinical benefits and known safety profile of everolimus plus exemestane in postmenopausal women with HR+, HER2- aBC."}, {"title": "Efficacy and safety of everolimus plus exemestane in postmenopausal ...", "url": "https://www.semanticscholar.org/paper/Efficacy-and-safety-of-everolimus-plus-exemestane-Tesch-Stoetzer/5ddc51835d665716e433f6e561c7f88ee3fc68c9", "snippet": "The 4EVER trial evaluated the clinical effectiveness of everolimus plus exemestane in postmenopausal women with HR+, HER2− aBC who had progressed on or after an NSAI, but with no restrictions on the time of progression after NSAI. In BOLERO‐2, adding everolimus to exemestane resulted in a twofold increase in median progression‐free survival ( PFS ) vs exemestane in postmenopausal women ..."}, {"title": "Efficacy and safety of everolimus plus exemestane in postmenopausal ...", "url": "https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.31738", "snippet": "The ORR in 4EVER was lower than in BOLERO-2, likely due to inclusion of patients with more advanced disease and extensive pretreatment. These data confirm the
→ call write_note({"tags":["4360dd15","knowledge","fact","classification"],"text":"!! 第 78 轮：剩余两个 PMID 的证据核验与最终判定\n\n本轮只做一件事：用可公开访问的 web snippet 再核对剩余两个候选 PMID 的研究类型、年龄判据和主要终点，并把保留/排除判定钉死。\n\n!! PMID 35040506\n- 题名：mTOR Inhibition with Sirolimus in Multiple System Atrophy: A Randomized, Double-Blind, Placebo-Controlled Futility Trial and 1-Year Biomarker Longitudinal Analysis\n- 研究类型：randomized, double-blind, place)
【tool:write_note】
{"ok": true, "path": "C:\\Users\\yh599\\Documents\\GitHub\\LLM-yh\\Sisyphus\\wiki\\tiddlers\\Iter-4360dd15-0078-two-pmid-evidence-verification.tid", "title": "Iter-4360dd15-0078-two-pmid-evidence-verification"}
【assistant】
本轮已完成：对剩余两个 PMID 做了公开证据核验，并把三字段和最终判定钉死。
- PMID 35040506：randomized, double-blind, placebo-controlled futility trial；30–80 岁；主要终点为 48-week UMSARS total score change；**排除**
- PMID 29992557：open-label, single-arm, phase IIIB 4EVER trial；postmenopausal women；主要终点为疾病控制语境下的 PFS/ORR；**排除**
已写入记忆：
- `Iter-4360dd15-0078-two-pmid-evidence-verification`
下一轮最窄、最值得做的事：把 PMID 38310895 综述里提到的 **19 项原始研究** 拉成可审计清单，逐个确认哪些才是真正的人体原始试验，而不是综述、二次分析或派生分析。
<NEXT_FOCUS>从 PMID 38310895 的 19 个 included studies 中抽出最小原始试验清单，并逐项核验是否存在可保留的直接 longevity 证据。</NEXT_FOCUS>