Vitals Knowledge Vault

Conversion Priority Queue

35 min read

Conversion Priority Queue

Purpose

This file tracks actual current vault-conversion status for the Vitals knowledge base.

As of the 2026-03-28 audit, the immediate problem is no longer missing peptide/compound hub notes. The immediate problem is governance cleanup: canonical routing, V2 merges, orphan handling, and source-artifact separation.

Audit Summary — 2026-03-28

Vault coverage for indexed compounds

Current judgment: the main indexed compound set is now effectively represented in the vault.

Completed / present in vault:

  • 9-MBC
  • BPC-157
  • CJC-1295 Ipamorelin
  • Dihexa
  • Ecnoglutide
  • Epithalon
  • Fisetin
  • GHK-Cu
  • Glutathione
  • Imeglimin
  • Lion’s Mane
  • MOTS-c
  • Melanotan II PT-141
  • NMN NAD+
  • Noopept Semax Selank
  • PCC1
  • QL1005
  • Rapamycin
  • Retatrutide
  • SGLT2 Inhibitors
  • SLU-PP-332
  • Spermidine
  • TB-500
  • Tesamorelin
  • Urolithin A
  • WN561
  • XW4475

What this means

The queue is no longer primarily a “convert missing compounds” queue. It is now a maintenance / governance queue.

Priority 1 — Governance cleanup next

  1. Canonical routing normalization

    • keep INDEX.md, LEGACY.md, and index.json aligned
    • ensure new canonical paths (e.g. bpc157/bpc157.md) propagate everywhere practical

  2. V2 merge follow-through

    • NMN / NAD+ vault note should be checked against nmn-nad-v2.md
    • Rapamycin vault note should be checked against rapamycin-v2.md
    • goal: ensure richer V2 source content is actually reflected in retrieval layer

  3. Newly normalized topics — follow-through complete

    • berberine.md — vault conversion complete (2026-03-28); hub at 01-Substances/Berberine.md; Vitals Knowledge Map and Retatrutide stacks updated
    • rhodiola-rosea.md — already has a vault note; only metadata alignment/QA remains

  4. Source-artifact separation

    • batch briefs / manifests / QA artifacts still live beside canonical docs in some directories
    • continue pushing provenance artifacts conceptually toward research/, or at minimum classify them clearly as non-canonical

Priority 1 complete — Batch 41

  • protein-intake-lean-mass-retention-glp1-glucagon-agonists — Hub note already existed at 04-Protocols-and-Recovery/Protein Intake GLP-1 Glucagon.md (created prior to this batch). Cross-links added to Retatrutide and Peptides MOC. Batch 41 conversion: complete.

Priority 2 — Broader domain indexing

These areas contain useful research, but are not governed by a single clean status layer yet:

  • adaptogens/
  • body-systems/
  • longevity/
  • recreational/
  • evidence corpus folders such as bpc-157/, ghk-cu/, tb-500/

Recommended next step:

  • maintain a master status dashboard covering canonical docs, vault coverage, QA state, and orphaned topics

No longer pending as compound-conversion work

The older queue state that marked Batch D or BPC-era peptide work as pending is stale. Those items have now been converted or upgraded in-place.

Default execution rule

  • Use MiniMax for graph-building by default
  • Keep the smallest useful graph
  • Reuse existing mechanism notes when possible
  • Do not create standalone notes for weak or redundant subtopics
  • Prefer governance cleanup over graph expansion when routing/status drift becomes the main source of confusion

Pipeline Advancer Updates (2026-04-21)

Newly vault_pending topics awaiting MiniMax conversion

BatchTopicKB SourceVault MarkerNotes
BATCH49Gdf8 Activin A Blockade GLP-1 Muscle Preservationgdf8-activin-a-blockade-glp-1-muscle-preservation.mdVAULT COMPLETEVault note 01-Substances/Bimagrumab Semaglutide Combo Obesity.md (Batch 43 origin, updated 2026-04-20) supersedes this canonical doc — BELIEVE Phase 2 RCT (PMID 41772149) published after canonical doc was written. Cardiol Rev 2025 (PMID 1538-4683) citation added to vault note.
BATCH64Foroglipron Oral GLP1foroglipron-oral-glp1.mdVAULT COMPLETE (2026-04-21)Vault note 01-Substances/Foroglipron.md; molecule confusion P0 confirmed and addressed; Orforglipron note alias corrected; Vitals Knowledge Map updated
BATCH66NPR1 Agonist XXB750 Safety Signal Heart Failurenpr1-agonist-xxb750-safety-signal-heart-failure.mdVAULT COMPLETE (2026-04-21)Vault note: 01-Substances/XXB750 NPR1 Agonist.md; existing vault note corrected for naming (Antagonist→Agonist), company attribution (Novartis→Novo Nordisk); coaching summary and evidence gaps added; backlinks updated in NPR1 Agonists and Vitals Knowledge Map
BATCH61Suzetrigine Nav18 Non-Opioid Painsuzetrigine-nav18-non-opioid-pain.mdVAULT COMPLETE (2026-04-21)Vault note: 01-Substances/Suzetrigine.md — QA conditional_pass (P2 notes resolved); upgraded hub with canonical evidence grades, meta-analysis I²=66% heterogeneity, opioid non-superiority framing, formulation details, Evidence Summary Table, additional PMIDs; Nav1.8 kept as aspirational ghost link

BATCH80 Semaglutide Liver Stiffness Dose-Independent

  • VAULT COMPLETE (2026-04-21) | Frontier Research Lane
  • Topic: Semaglutide liver health — MASLD/MASH benefit, dose-response, weight-independence claim
  • Vault note: 01-Substances/Semaglutide Liver Health MASLD MASH.md
  • KB canonical: skills/knowledge-base/semaglutide-liver-stiffness-dose-independent/semaglutide-liver-stiffness-dose-independent.md
  • 10-worker packet complete; QA passed; canonical monograph written
  • Key finding: FDA accelerated approval Aug 2025 (ESSENCE Phase 3); weight-independent mechanism NOT established; cirrhosis NOT indicated

BATCH77 GLP-1 RA NAION Safety Signal

  • VAULT COMPLETE (2026-04-21) | Frontier Research Lane
  • Topic: GLP-1 receptor agonists and non-arteritic ischemic optic neuropathy (NAION) safety signal
  • Vault note: 01-Substances/GLP-1 RA NAION Safety Signal.md
  • KB canonical: skills/knowledge-base/glp1-ra-naion-safety-signal/glp1-ra-naion-safety-signal.md
  • 10-worker packet complete; QA approved; canonical synthesis complete; vault hub written
  • Personal relevance: Ben uses GLP-1 RAs — safety counseling relevant

BATCH83 Forforglipron Oral GLP-1 Obesity

  • DEDUPLICATION RECOMMENDED | Frontier Research Lane
  • Topic: Forforglipron (orforglipron, Foundayoor) — same compound as Batch 47 (orforglipron-oral-glp-1-agonist, already vaulted) and Batch 64 (foroglipron-oral-glp1, already vaulted)
  • Batch 83 monograph: research/batch-83-2026-04-21/forforglipron-oral-glp1-obesity.md
  • Action required: Route to existing canonical at skills/knowledge-base/orforglipron-oral-glp-1-agonist/orforglipron-oral-glp-1-agonist.md (Batch 47, already vaulted). Batch 83 monograph adds no new PMIDs or data not already in Batch 47 canonical.
  • Batch 47 canonical covers: ATTAIN-1, ATTAIN-2, ACHIEVE-1, Phase 2, PK (t½ 29-49h), food effect, comparison table
  • Batch 83 monograph missing: t½ data (29-49h), tablet strengths (3/6/12/36mg), HbA1c numbers from ACHIEVE-1
  • Vault status: NOT vaulted — dedup to Batch 47 existing canonical instead

BATCH17 Vitamin D3 K2 — Already Vault-Converted (Legacy)

  • Vault note: 01-Substances/Vitamin D3 K2.md (confirmed present)
  • Marked complete by pipeline advancer (2026-04-21)
  • Legacy: 4-worker batch, pre-10-worker era

BATCH74 CGM Glucose Patterns Non-Diabetic

  • VAULT COMPLETE (2026-04-21) | MiniMax subagent conversion
  • Hub note: 03-Biometrics/CGM Glucose Patterns Non-Diabetic.md
  • Detection model: 05-Detection-Models/Glucose Variability Detection Model.md
  • KB canonical: skills/knowledge-base/cgm-glucose-patterns-non-diabetic/cgm-glucose-patterns-non-diabetic.md
  • Key evidence: GV → T2D risk (PMID 36099500), TIR metabolic dysfunction (PMID 35111000), DIAPASON RCT (PMID 35446674), orthosomnia risk (PMID 35623333)
  • Includes: intake screening protocol, coaching targets, orthosomnia P1 safety flag, algorithm hooks, implementation algorithm, evidence boundary label
  • Note: Existing Glycemic Variability and Metabolic Flexibility MOC entries linked; new detection model note in 05-Detection-Models

BATCH85 GLP-1 Agonist Non-Responder Genetic Variants

  • VAULT COMPLETE (2026-04-22) | Vault note already existed at 01-Substances/GLP-1 Non-Responder Genetic Variants.md (updated 2026-04-21)
  • Topic: Pharmacogenomics of GLP-1 non-response — GLP1R rs1030559 missense variant, ARRB1 Thr370Met, GIPR tirzepatide nausea variant
  • KB canonical: skills/knowledge-base/glp1-non-responder-genetic-variants/glp1-non-responder-genetic-variants.md
  • Key findings: GLP1R variant −0.76 kg/copy (P=2.9×10⁻¹⁰, Nature 2026); ARRB1 strongest HbA1c signal (DIRECT GWAS 2023); genetic effect <10% total treatment response; no clinical utility trial; genetic testing not indicated by any guideline
  • Critical contradiction: two largest GWAS point to different primary genes (GLP1R for weight vs. ARRB1 for HbA1c)
  • Vault note QA verified: all 6 PMIDs present, all key claims preserved, Vitals relevance explicit, coaching boundaries clear
  • Related notes: GLP-1 GIP Glucagon, GLP-1 Muscle Preservation, Peptides MOC, GLP-1 RA NAION Safety Signal, Semaglutide Liver Health MASLD MASH

BATCH94 CagriSema (Cagrilintide + Semaglutide) — Obesity Redefine

  • VAULT COMPLETE (2026-04-22) | Canonical monograph → vault hub note
  • Hub note: 01-Substances/CagriSema.md (upgraded from existing vault note)
  • Source monograph: research/batch-94-2026-04-21/cagrisema-obesity-redefine-1.md
  • Key additions from monograph: REDEFINE-2 (T2D, PMID 40544432), Phase 2 cagrilintide dose-finding (PMID 34798060), Phase 1b combination (PMID 33894838), meta-analysis (PMID 39676787), NMA (PMID 38286487), BP secondary outcomes (PMID 41328546), QTc safety (PMID 39279639), coaching guidance section, algorithm hooks
  • Peptides MOC updated: CagriSema added to peptide hub table
  • Evidence boundary table added; all critical safety/coaching flags incorporated
  • Prominently marked: ⚠️ INVESTIGATIONAL — NOT FDA-APPROVED; no DXA data; no food-noise measurement; no tirzepatide superiority claim; no lean-mass preservation claim for amylin
  • All evidence claims cite PMIDs inline
  • Related notes: Retatrutide, Tirzepatide, Semaglutide, GLP-1 GIP Glucagon, Peptides MOC

BATCH89 Asundexian (Factor XIa Inhibitor) — Stroke Prevention

  • VAULT COMPLETE (2026-04-22) | Vault notes pre-existing; QA review confirmed
  • Hub note: 01-Substances/Asundexian.md
  • Mechanism note: 02-Mechanisms/Factor XIa.md
  • KB canonical: skills/knowledge-base/asundexian-factor-xia-inhibitor-stroke-prevention/asundexian-factor-xia-inhibitor-stroke-prevention.md
  • Key findings: OCEANIC-STROKE Phase 3 (PMID 41985132) — 26% RRR ischemic stroke (HR 0.74, P<0.001), no excess major bleeding (HR 1.10); PACIFIC-Stroke Phase 2b (PMID 36063821) — dose-finding; OCEANIC-AF failed (asundexian inferior to apixaban in AF)
  • Vault QA: hub note comprehensive with Vitals coaching protocol, evidence summary table, mechanism vs DOAC comparison, lacunar/AF exclusion boundaries; Factor XIa mechanism note reusable for milvexian and future FXIa inhibitors
  • Graph: Asundexian linked in Vitals Knowledge Map (line 62); Factor XIa linked in Vitals Knowledge Map (line 142); mechanism note links back to Asundexian and Milvexian
  • Related notes: Factor XIa, Milvexian, Cardiovascular risk

BATCH100 Difamilast (Adqueyza) PDE4 Inhibitor Atopic Dermatitis

  • VAULT COMPLETE (2026-04-22) | Frontier Research Lane
  • Hub note: 01-Substances/Difamilast.md; Vitals Knowledge Map updated
  • Topic: Difamilast (Adqueyza) — FDA-approved 2/12/2026 topical PDE4B-selective inhibitor for mild-moderate AD
  • KB canonical: skills/knowledge-base/difamilast-topical-pde4-atopic-dermatitis/difamilast-topical-pde4-atopic-dermatitis.md
  • 10-worker packet complete; batch_contract=pass; source_integrity=pass; QA passed with P1 flags acknowledged
  • Key findings: Phase 3 IGA success 38.5% vs 12.6% vehicle (P<0.0001); PDE4B selectivity mechanism confirmed in PDE4B-KO mice; no head-to-head vs crisaborole; rapid onset week 1
  • Graph decisions: No standalone mechanism note (PDE4B mentioned inline); no detection model (P1 gap — no validated wearable biomarker for AD); no comparison note vs crisaborole

BATCH102 ApoB Lipoprotein Coaching — Vault Complete

  • VAULT COMPLETE (2026-04-23) | Vault notes created
  • Hub note: 01-Substances/ApoB Lipoprotein Coaching.md
  • Mechanism note: 02-Mechanisms/ApoB Particle Number Principle.md
  • Protocol note: 04-Protocols-and-Recovery/lipid management coaching.md
  • MOC: 00-Maps/Substances MOC.md (new)
  • KB canonical: skills/knowledge-base/apob-lipoprotein-pattern-coaching/apob-lipoprotein-pattern-coaching.md
  • Graph: hub linked in Substances MOC and Vitals Knowledge Map (Metabolic/Longevity section); mechanism note linked from hub; protocol note linked from hub
  • Key findings: ApoB = particle count principle; non-HDL-C as strongest accessible proxy; TG/HDL-C ratio as metabolic flag; PCSK9 inhibitors 50–60% ApoB reduction; no dedicated ApoB-RCT (observational/meta-analytic evidence only); PROMINENT/CETP inhibitor/niacin failures demonstrate biomarker ≠ outcomes; coaching value highest in dysmetabolic “normal LDL-C” scenarios
  • Evidence boundary: all coaching nudges require human review before deployment; CGM → ApoB is experimental Gap; supplements lack RCT outcome data
  • No duplicate topics; no conflicting notes in vault

BATCH103 Glycine NAC Sleep Optimization — Vault Complete

  • VAULT COMPLETE (2026-04-23) | Vault notes created
  • Hub note: 01-Substances/Glycine NAC Sleep Stack.md
  • Mechanism note: 02-Mechanisms/Glycine Sleep Mechanism.md
  • Biometrics note: 03-Biometrics/Sleep Onset Latency.md
  • KB canonical: skills/knowledge-base/glycine-nac-sleep-optimization/glycine-nac-sleep-optimization.md
  • Graph: hub linked in Substances MOC and Vitals Knowledge Map (Sleep/Recovery section); mechanism note linked from hub; biometrics note linked from hub; Sleep Onset Latency linked in Vitals Knowledge Map Biometrics section
  • Key findings: Glycine 3g pre-sleep Supported for SOL reduction (−5–10 min) in poor sleepers (PMID-21233519, PMID-16944695); NAC sleep benefit Supported only in oxidative-stress populations — COPD (PMID-2298262), psychiatric (PMID-26229607); healthy-adult NAC sleep benefit = Gap; glycine + NAC combination = confirmed Gap (no human studies exist)
  • Evidence boundary: combination claims not supported; NAC requires human signoff before coaching inclusion; SOL is the primary wearable-accessible coaching endpoint for glycine; 7-night averaging required before interpreting SOL change
  • Aspirational links: Glycine, NAC, N-acetylcysteine, Sleep Architecture, Melatonin Beyond Sleep, NMDA receptor

BATCH99 Amyloid-Beta Monoclonal Antibodies Cochrane Meta-Analysis — Cognitive Outcomes

  • VAULT COMPLETE (2026-04-22) | Vault note created: 01-Substances/Amyloid-Beta Monoclonal Antibodies.md
  • Topic: Cochrane systematic review (Nonino et al. 2026, PMID 41985900) — 17 RCTs, 20,342 participants, 7 Aβ-mAbs; class-level clinical benefit trivially small (ADAS-Cog SMD −0.11 moderate certainty); amyloid clearance ≠ meaningful cognitive benefit; amyloid cascade hypothesis therapeutic validity challenged
  • KB canonical: research/batch-99-2026-04-22/amyloid-beta-mab-cognitive-outcomes-metaanalysis.md + SYNTHESIS-BRIEF.md
  • Hub note: comprehensive vault note covering class-level Cochrane findings, individual drug outcomes (lecanemab 25% CDR-SB slowing, donanemab 35% iADRS slowing), ARIA monitoring protocol, coaching boundaries, cognitive decline prevention tiering, evidence summary table
  • Vitals relevance: cognitive decline prevention content should foreground lifestyle/metabolic over anti-amyloid; coaches must know ARIA monitoring; no biometric operationalization exists for Aβ-mAb response
  • Graph: Amyloid-Beta Monoclonal Antibodies added to Vitals Knowledge Map; linked from H. pylori & Alzheimer’s, P. gingivalis & Alzheimer’s, GLP-1 RA NAION Safety Signal (safety class context)
  • Evidence boundary: HRV/sleep/activity as Aβ-mAb response monitors = unsupported; pre-symptomatic use = unsupported; all Aβ-mAbs equivalent = false (substantial class heterogeneity)

BATCH105 Orforglipron (Foundayo) — First Oral Small-Molecule GLP-1 RA

  • VAULT COMPLETE (2026-04-23) | Vault note corrected and promoted
  • Hub note: 01-Substances/Orforglipron.md (pre-existing; brand name corrected)
  • KB canonical: skills/knowledge-base/orforglipron-foundayo/orforglipron-foundayo.md
  • Graph corrections: brand name corrected throughout Orforglipron.md (Foundayoor → Foundayo); erroneous Foroglipron.md vault note DELETED (described Pfizer PF-07081532 as FDA-approved April 1, 2026 — factually wrong; PF-07081532 was discontinued June 2023); CagriSema.md related-notes link removed; Vitals Knowledge Map Foroglipron entry removed
  • Key finding: Orforglipron (brand Foundayo, Eli Lilly LY3502970) is the only FDA-approved non-peptide oral GLP-1 (April 1, 2026); once-daily no-fasting oral; ATTAIN-1 −11.2–12.4% weight loss at 36 mg/72 weeks; no CVOT confirmed; GI discontinuation rate highest in oral GLP-1 class
  • Graph: Orforglipron already present in Vitals Knowledge Map; no MOC updates required
  • P0 fix: Foroglipron.md vault note contained factually incorrect FDA approval claim for a discontinued compound (Pfizer PF-07081532, discontinued June 2023); note deleted, all references purged from vault
  • Related notes: GLP-1 GIP Glucagon, Retatrutide, Tirzepatide, Semaglutide, GLP-1 Muscle Preservation, CagriSema

BATCH107 Cagrilintide Amylin Analogue — Vault Complete

  • VAULT COMPLETE (2026-04-24) | Vault Dispatcher
  • Hub note: 01-Substances/Cagrilintide.md
  • KB canonical: research/batch-107-2026-04-24/cagrilintide-amylin-analogue-obesity-weight-loss.md
  • Topic: Cagrilintide as standalone amylin analogue (DACRA) — monotherapy for obesity; distinct from CagriSema combo
  • Key findings: Phase 2 monotherapy ~9.7–10.8% at 26 weeks (PMID 34798060); AMY1/3 + CTR dual agonism; ~180h half-life; no Phase 3 monotherapy trial conducted; monotherapy program discontinued; only CagriSema combo was filed with FDA; pramlintide comparison (same class, short half-life); thyroid theoretical concern, no human signal
  • Graph decisions: Standalone Cagrilintide hub created (not covered in existing CagriSema.md which focuses on the combo); Peptides MOC updated with Cagrilintide row; Vitals Knowledge Map updated; no standalone amylin mechanism note (single-compound use); no detection model (no wearable biomarker evidence)
  • Related notes: CagriSema, Semaglutide, Tirzepatide, Pramlintide, GLP-1 GIP Glucagon, Peptides MOC

BATCH21 Circadian Disruption, Light at Night, Melatonin, and Cancer Risk — Complete

  • COMPLETE (2026-04-24) | Batch manifest updated: canonical_complete → complete
  • Hub note: 03-Biometrics/Circadian Disruption & Cancer Risk.md
  • KB canonical: skills/knowledge-base/circadian-disruption-cancer-risk/circadian-disruption-cancer-risk.md
  • Vault promotion record: BATCH21-VAULT-PROMOTION.md (dated 2026-04-01, status PROMOTED_TO_VAULT)
  • Graph: linked from Circadian Biology (mechanism note); Melatonin hub references this topic; Cancer Biology MOC and Circadian Biology MOC updated
  • Topic: Circadian disruption via light at night, melatonin suppression, and cancer risk — IARC night shift evidence, breast/prostate cancer data, SCN peripheral clock model
  • Note: this batch predates the standard 10-worker packet format; clinical/mechanisms/safety coverage present but lane structure non-standard

BATCH49 GDF8/Activin A Blockade GLP-1 Muscle Preservation — Complete

  • COMPLETE (2026-04-24) | Batch manifest updated: canonical_ready → complete
  • Hub note: 01-Substances/Bimagrumab Semaglutide Combo Obesity.md (Batch 43 origin; updated with Batch 49 canonical content)
  • KB canonical: skills/knowledge-base/gdf8-activin-a-blockade-glp-1-muscle-preservation/gdf8-activin-a-blockade-glp-1-muscle-preservation.md
  • Vault promotion record: BATCH49-VAULT-PROMOTION.md
  • Graph: existing Bimagrumab Semaglutide Combo hub note supersedes this canonical doc; BELIEVE Phase 2 RCT (PMID 41772149) published after canonical doc was written — canonical doc may need future refresh
  • Topic: GDF8/Activin A blockade (bimagrumab/sacubitril) + GLP-1 for muscle preservation during obesity treatment
  • Related notes: Bimagrumab, GLP-1 Muscle Preservation, Peptides MOC

BATCH109 BCL6 Protein Muscle Preservation GLP-1 Adjunct — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-24) | MiniMax subagent conversion
  • Hub note: 01-Substances/BCL6.md
  • Mechanism note: 02-Mechanisms/BCL6 Muscle Biology.md (pre-existing; upgraded 2026-04-24)
  • KB canonical: skills/knowledge-base/bcl6-protein-muscle-preservation-glp-1-adjunct/bcl6-protein-muscle-preservation-glp-1-adjunct.md
  • Topic: BCL6 transcription factor as GLP-1 adjunct for muscle preservation; preclinical mouse hypothesis; zero human data; all BCL6 agents in dev are oncology degraders (opposite direction)
  • Graph decisions: Hub note created at 01-Substances/BCL6.md; mechanism note already existed at 02-Mechanisms/BCL6 Muscle Biology.md — reused, not duplicated; no new mechanism split warranted (BCL6 is single-compound tracking concept, not multi-compound reusable mechanism); no detection model (BCL6 blood assay is research-grade only, not clinically actionable); aspirational links to ActRII Myostatin Pathway and mTOR AMPK Muscle Catabolism (both existing)
  • Key findings: BCL6 deletion → 30–40% muscle loss in mice (Confirmed); BCL6 + GLP-1 never tested in any animal (Gap); no BCL6-boosting drug exists or in development (Gap); oncogene risk prominent; redirect to bimagrumab + semaglutide (BELIEVE Phase 2) and GDF8/activin A (COURAGE Phase 2)
  • Vitals framing: body composition tracking, GLP-1 lean mass risk, BIA/DXA monitoring, grip strength proxy; BCL6 not actionable for coaching
  • Related notes: BCL6 Muscle Biology, GLP-1 Muscle Preservation, Bimagrumab Semaglutide Combo Obesity, ActRII Myostatin Pathway, Vitals Knowledge Map

BATCH111 Arterial Stiffness Vascular Age Vitals — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-24) | MiniMax subagent conversion
  • Hub note: 03-Biometrics/Arterial Stiffness.md
  • Mechanism notes: 02-Mechanisms/AGE-RAGE Axis.md, 02-Mechanisms/Elastin Degradation.md, 02-Mechanisms/VSMC Phenotype Switch.md, 02-Mechanisms/Arterial Calcification.md
  • Detection model: 05-Detection-Models/Arterial Stiffness Wearable Detection Model.md
  • KB canonical: skills/knowledge-base/arterial-stiffness-vascular-age-vitals/arterial-stiffness-vascular-age-vitals.md
  • Topic: Arterial stiffness as vascular age biomarker — cfPWV, baPWV, CAVI, arterial age algorithms; wearable detection model (HRV, pulse wave analysis); CKD/HFpEF/pulmonary hypertension contexts; AGE-RAGE, elastin degradation, VSMC phenotype switch, calcification mechanisms
  • Graph decisions: Hub placed in 03-Biometrics/ (not 01-Substances — arterial stiffness is a biometric/clinical concept); 4 mechanism notes created (all pass 5-question reusability test); existing Matrix Metalloproteinases TIMP System.md, eNOS uncoupling.md, Cardiovascular signatures.md reused via links; no peptide-specific notes created (BPC-157/CJC-1295 have zero human stiffness data); Vitals Knowledge Map updated with all new entries
  • Key findings: 6–7 year MAE for wearable vascular age; ±1.86 m/s Bland-Altman LOA; CAVI stiffness-severity mapping; HRV + pulse wave as wearable proxy signals
  • Related notes: AGE-RAGE Axis, Elastin Degradation, VSMC Phenotype Switch, Arterial Calcification, Matrix Metalloproteinases TIMP System, eNOS uncoupling, Cardiovascular signatures, Vitals Knowledge Map

BATCH112 Nitric Oxide Biology Dietary Nitrates Beetroot — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-24) | MiniMax subagent conversion
  • Hub note: 01-Substances/Beetroot Nitrate.md (pre-existing; ghost links resolved)
  • New mechanism notes: 02-Mechanisms/Endothelial Function.md, 02-Mechanisms/Vascular Aging.md
  • Existing notes reused: 03-Biometrics/Blood Pressure Response Nitrate.md, 04-Protocols-and-Recovery/Beetroot Dosing Protocol.md
  • KB canonical: skills/knowledge-base/nitric-oxide-biology-dietary-nitrates-beetroot/nitric-oxide-biology-dietary-nitrates-beetroot.md
  • Topic: Dietary nitrate (beetroot) → NO → vasodilation, BP reduction, exercise performance; endothelial function; vascular aging; nitrate dosing protocols
  • Graph decisions: Two new mechanism notes justified by cross-compound reusability (FMD, arterial stiffness, PWV, age-related endothelial decline are common Vitals coaching topics); ghost links [[eNOS uncoupling]], [[Vascular Aging]], [[Endothelial Function]] all resolved as real links; no aspirational links remain in the Beetroot Nitrate hub; no title conflicts found
  • Related notes: Endothelial Function, Vascular Aging, eNOS uncoupling, Blood Pressure Response Nitrate, Beetroot Dosing Protocol, Vitals Knowledge Map

BATCH108 Testosterone Optimization Longevity — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-25) | MiniMax subagent conversion
  • Hub note: 01-Substances/Testosterone Optimization.md
  • KB canonical: skills/knowledge-base/testosterone-optimization-longevity/testosterone-optimization-longevity.md
  • Topic: Testosterone optimization for longevity — testosterone replacement therapy (TRT), age-related decline, cardiovascular risk, cognitive effects, body composition

BATCH110 Lactate Metabolism Vitals Training Load — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-25) | MiniMax subagent conversion
  • Hub note: 01-Substances/Lactate Metabolism.md
  • KB canonical: skills/knowledge-base/lactate-metabolism-vitals-training-load/lactate-metabolism-vitals-training-load.md
  • Topic: Lactate metabolism as Vitals training load biomarker — lactate threshold, VO2max, training load optimization, wearable detection

BATCH113 Spermidine Autophagy Longevity Inducer — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-25) | MiniMax subagent conversion
  • Hub note: 01-Substances/Spermidine.md
  • KB canonical: skills/knowledge-base/spermidine-autophagy-longevity-inducer/spermidine-autophagy-longevity-inducer.md
  • Topic: Spermidine as autophagy longevity inducer — spermidine supplementation, mTOR inhibition, age-related autophagy decline, cognitive/ cardiovascular outcomes

BATCH116 Microcurrent Electrical Stimulation Soft Tissue Recovery — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-25) | MiniMax subagent conversion
  • Hub note: 04-Protocols-and-Recovery/Microcurrent Electrical Stimulation.md
  • KB canonical: skills/knowledge-base/microcurrent-electrical-stimulation-soft-tissue-recovery/microcurrent-electrical-stimulation-soft-tissue-recovery.md
  • Topic: Microcurrent electrical stimulation (MENS/ECS) for soft tissue recovery — injury recovery, pain management, wearable/device integration

BATCH118 IGF-1 LR3 Canonical — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-25) | MiniMax subagent conversion
  • Hub note: 06-Peptides-and-Interactions/IGF-1 LR3.md
  • KB canonical: skills/knowledge-base/igf-1-lr3-canonical/igf-1-lr3-canonical.md
  • Topic: IGF-1 LR3 — long R3 IGF-1 peptide, muscle preservation, research use, comparison to other growth factors

BATCH119 GLP-1 Agonist Skeletal Safety: Bone Fracture, Osteoporosis & Muscle Loss Risk 2026 — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-24) | MiniMax subagent conversion
  • Hub note: 01-Substances/GLP-1 RA Skeletal Safety.md
  • KB canonical: skills/knowledge-base/glp-1-agonist-skeletal-safety-bone-fracture-muscle-loss-risk-2026/glp-1-agonist-skeletal-safety-bone-fracture-muscle-loss-risk-2026.md
  • Topic: GLP-1 agonist skeletal safety — bone fracture, osteoporosis, and muscle loss risk; GLP-1 RA effects on bone mineral density, fracture risk, sarcopenia; BEZOVO, SURPASS, SUSTAIN, PIONEER trial evidence

BATCH134 Bimagrumab Semaglutide Combo V2 (72-week BELIEVE data) — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-25) | MiniMax subagent conversion
  • Hub note: 01-Substances/Bimagrumab Semaglutide Combo V2.md
  • Supersedes: 01-Substances/Bimagrumab Semaglutide Combo Obesity.md (Batch 43/49 origin)
  • Source monograph: research/batch-134-2026-04-25/bimagrumab-semaglutide-muscle-preservation-fat-loss.md
  • SYNTHESIS-BRIEF: research/batch-134-2026-04-25/SYNTHESIS-BRIEF.md
  • Topic: Bimagrumab + semaglutide combination for GLP-1-induced muscle preservation; BELIEVE Phase 2 72-week data update
  • Key additions from Batch 134:
    • 72-week BELIEVE data: −22.1% BW, −2.9% lean mass, 92% FLI (vs. 48-week primary endpoint in prior vault note)
    • Bimagrumab monotherapy: 100% FLI but only −10.8% BW; combination superiority is total weight loss magnitude + preserved composition
    • NCT06901349 (bima + tirzepatide T2D+obesity): terminated Sep 2025 for strategic business reasons
    • NCT06643728 (bima ± tirzepatide obesity only): actively recruiting
    • Regulatory status: investigational only; Phase 3 not initiated; ~3–6+ years to potential approval
    • Myostatin inhibitor class ~95% failure rate; functional disconnect warning (muscle volume ≠ strength)
    • “NOT muscle gain” framing explicit: combination loses −2.9% lean mass; bimagrumab monotherapy gains +2.5%
  • Graph decisions: existing [[ActRII Myostatin Pathway]], [[GLP-1 GIP Glucagon]], [[mTOR AMPK Muscle Catabolism]], [[GLP-1 Muscle Preservation]], [[Retatrutide]] links reused; no new mechanism notes created; aspirational link [[ActRII Myostatin Pathway]] already exists; [[Bimagrumab Semaglutide Combo Obesity]] marked as superseded by this V2
  • Vitals framing: DXA monitoring protocol, BIA limitations, HRV/wearable context, coaching flags (IV burden, cost, accessibility, muscle spasm rate 41%, pancreatitis risk)
  • Tone: sober, evidence-bound; no hype; explicit investigational-only status throughout
  • Related notes: ActRII Myostatin Pathway, GLP-1 GIP Glucagon, mTOR AMPK Muscle Catabolism, GLP-1 Muscle Preservation, Retatrutide, HRV, HRV Guided Training, Resistance Training for Longevity

BATCH125 Orforglipron Oral GLP-1 Agonist — Vault Complete

  • VAULT COMPLETE (2026-04-25) | Canonical KB monograph → existing vault hub upgraded in place
  • Hub note: 01-Substances/Orforglipron.md
  • Shared mechanism note updated: 02-Mechanisms/GLP-1 GIP Glucagon.md
  • MOCs/maps updated: 00-Maps/Substances MOC.md, 00-Maps/Vitals Knowledge Map.md
  • KB canonical: skills/knowledge-base/orforglipron-oral-glp1-agonist/orforglipron-oral-glp1-agonist.md
  • Graph decision: no new standalone allosteric-GLP-1R, GI-tolerability, RHR/HRV, or body-composition notes; existing GLP-1 GIP Glucagon, GLP-1 Muscle Preservation, GLP-1 Body Composition, and GLP-1 FFM Systematic Review ACP 2026 carry the reusable concepts.
  • Duplicate handling: stale Foroglipron map/MOC links were removed because the actual vault file had already been deleted during the prior P0 correction and those links were orphaning a factually wrong duplicate route.
  • Key preserved boundaries: Foundayo = orforglipron/LY3502970; no fasting requirement; −9 to −11% weight-loss range; ACHIEVE-3 HbA1c superiority vs oral semaglutide; higher GI discontinuation burden; ACHIEVE-4 CV non-inferiority is not MACE reduction; dedicated CVOT still recruiting; no orforglipron-specific DXA/HRV data.

BATCH152 Novo Nordisk FDA Warning — Semaglutide PADE Compliance Failure

  • SUPERSEDED BY BATCH181 (2026-04-26) | Legacy regulatory notes preserved as redirects only
  • Canonical vault note: 04-Protocols-and-Recovery/Ozempic FDA Warning Letter 2026.md
  • Legacy redirects: Regulatory/Novo-Nordisk-PADE-WL-717576-2026.md, Regulatory/Novo Nordisk PADE WL-717576.md
  • KB canonical: skills/knowledge-base/novo-nordisk-fda-warning-adverse-event-reporting/novo-nordisk-fda-warning-adverse-event-reporting.md
  • Topic: FDA Warning Letter MARCS-CMS 717576 (March 5, 2026) — Novo Nordisk failed to submit serious ADEs within 15-day window; cited examples include two semaglutide death reports, one semaglutide suicide report, and one liraglutide stroke report; SOP Q014048 used an impermissible causality filter.
  • Graph decisions: single canonical risk/coaching hub in 04-Protocols-and-Recovery/; no mechanism notes created; no detection model created; existing HRV/sleep/stress notes carry nonspecific wearable effects; note linked in Vitals Knowledge Map and Substances MOC under GLP-1/incretin safety.
  • Key finding: regulatory reporting failure ≠ semaglutide caused the events; no recall or new safety finding from the warning letter alone; coaches should frame accurately, avoid self-discontinuation advice, and screen/escalate mood symptoms when present.
  • Related notes: GLP-1 RA NAION Safety Signal, GLP-1 RA Skeletal Safety, GLP-1 RA Pancreatitis Safety Signal, Semaglutide Liver Health MASLD MASH, Stress Cortisol Optimization, HRV, Sleep architecture

BATCH153 CJC-1295 + Ipamorelin — VAULT COMPLETE (major upgrade)

  • VAULT COMPLETE (2026-04-25) | Existing vault hub note significantly upgraded in-place
  • Hub note: 06-Peptides-and-Interactions/CJC-1295 Ipamorelin.md
  • KB canonical: skills/knowledge-base/cjc-1295-ipamorelin-canonical/cjc-1295-ipamorelin-canonical.md
  • Source: BATCH153 canonical monograph · 10-worker synthesis · 28 claims assessed
  • Key corrections vs. prior vault note:
    • Prior note made evidence-free claims: “3-5× GH pulse amplification” (no human combination trial); “30-min half-life for no-DAC CJC-1295” (unverified in primary human literature); wearable-specific HRV/SWS improvement claims (no stack-specific trial); “5-on/2-off” cycling claims (no human evidence)
    • New note: emphasizes zero human combination trials throughout; explicitly flags all synergy claims as Gap-level evidence; corrects DAC variant framing (DAC variant was characterized as “never use dangerous” vs. the more accurate “no long-term safety data, one death in Phase II trial”); adds comprehensive PMIDs throughout
    • WADA prohibition: both compounds explicitly prohibited at all times under S2.2.4 and S2.2.5
    • Regulatory status: HHS/FDA Feb 2026 announcement signals return to Category 1 pending July 2026 PCAC
  • Graph decisions: no new mechanism note created (GH axis / GHRH receptor is broadly referenced but no broadly reusable mechanism note exists yet in vault — no splitting warranted for a single-compound stack); no new detection model; related notes Mitophagy, Tesamorelin, GHK-Cu, BPC-157, Retatrutide, HRV Guided Training, Sleep Optimization all linked
  • Vitals framing: safety monitoring protocol (IGF-1, fasting glucose, DEXA baseline), coaching boundaries, hard stops (cancer history, pregnancy, pituitary disorder), evidence boundary explicit throughout
  • Tone: sober, evidence-bound; no hype; investigational-only framing prominent
  • Related notes: Peptides MOC, Tesamorelin, GHK-Cu, BPC-157, Retatrutide, Mitophagy, HRV Guided Training, Sleep Optimization

BATCH133 CoQ10 Ubiquinol Cardiovascular Mitochondrial — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-25) | MiniMax subagent conversion
  • Hub note: 01-Substances/CoQ10 Ubiquinol.md
  • Mechanism note: 02-Mechanisms/Statin-Associated Muscle Symptoms.md
  • KB canonical: skills/knowledge-base/coq10-ubiquinol-canonical/coq10-ubiquinol-canonical.md
  • Topic: CoQ10/Ubiquinol — mitochondrial electron carrier + antioxidant; heart failure, blood pressure, migraine, SAMS; ubiquinone vs ubiquinol bioavailability; Vitals coaching protocol
  • Graph decisions: 1 hub + 1 mechanism note; “Statin-Associated Muscle Symptoms” (SAMS) created as mechanism note — passes 5-question reusability test (CoQ10 + vitamin D + other muscle-complaint compounds all link here); no dedicated ETC/ATP mechanism note (too generic, single-compound use case); ubiquinone vs ubiquinol comparison kept inline (single-compound formulation detail, not cross-compound reusable); no detection model (no validated wearable biomarker for CoQ10 status); no biometrics note (HRV/SBP signals are generic, not CoQ10-specific)
  • Key findings: Ubiquinone preferred over ubiquinol (Q-SYMBIO/KiSel-10 used ubiquinone; ubiquinol bioavailability claims are marketing artifact); Supported for HF NYHA II–III (MACE HR 0.50) and BP adjunct (−4.77 mmHg SBP); Contested for SAMS (Taylor 2015 RCT showed zero benefit vs. placebo); Supported for migraine prophylaxis (NNT ~3); Gap for athletic performance and longevity; no primary prevention benefit in healthy populations
  • Vitals framing: HRV improvements possible in deficient/stressed populations at 8–12 weeks; coaching protocol includes evidence boundaries and human signoff requirements; SAMS coaching requires appropriate expectation-setting (contradictory evidence)
  • Related notes: Statin-Associated Muscle Symptoms, Heart Failure, HRV, Beetroot Nitrate (BP adjunct stack context), Substances MOC, Vitals Knowledge Map

BATCH149 Orforglipron First Oral Small-Molecule GLP-1 Receptor Agonist — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-25) | In-place vault note update
  • Hub note: 01-Substances/Orforglipron.md
  • KB canonical: skills/knowledge-base/orforglipron-first-oral-small-molecule-glp-1-receptor-agonist/orforglipron-first-oral-small-molecule-glp-1-receptor-agonist.md
  • Topic: Orforglipron (LY3502970, brand Foundayo) — first FDA-approved non-peptide oral GLP-1 RA (April 1, 2026); once-daily no-fasting oral; ATTAIN-1 −11.2–12.4% weight loss at 36mg/72 weeks; ACHIEVE-3 HbA1c superiority vs oral semaglutide; no dedicated CVOT confirmed; GI discontinuation highest in oral GLP-1 class
  • Key findings: ATTAIN-1 72-week −11.2% weight loss at highest dose vs −2.1% placebo; ≥10% WL 54.6%; ATTAIN-2 −9.6% with T2D; ACHIEVE-3 −1.91% HbA1c vs −1.47% oral semaglutide (open-label); heart rate +4–5 bpm; dedicated CVOT NCT07241390 still recruiting; dose titration 0.8→17.2 mg QD
  • Graph decisions: existing Orforglipron.md hub updated in-place with BATCH149 Phase 3 ATTAIN/ACHIEVE data; no new mechanism notes (GLP-1 GIP Glucagon already covers); existing GLP-1 GIP Glucagon, GLP-1 Muscle Preservation, Retatrutide, Tirzepatide, Semaglutide, CagriSema links reused
  • Related notes: GLP-1 GIP Glucagon, GLP-1 Muscle Preservation, Retatrutide, Tirzepatide, Semaglutide, CagriSema, Vitals Knowledge Map

BATCH147 GLP-1 Semaglutide NAION Blindness Safety Signal — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-25) | In-place vault note update
  • Hub note: 01-Substances/GLP-1 RA NAION Safety Signal.md
  • KB canonical: skills/knowledge-base/glp1-semaglutide-naion-blindness-safety/glp1-semaglutide-naion-blindness-safety.md
  • Topic: GLP-1 RA NAION (Non-Arteritic Anterior Ischemic Optic Neuropathy) blindness safety signal — semaglutide, tirzepatide, dulaglutide; FDA preliminary review; 2025 case series (Batinić et al.); no confirmed causal mechanism; regulatory class review ongoing
  • Key findings: FDA Sep 2025 class label update added NAION warning to all GLP-1 RAs; preliminary data show ~2–3× increased RR in semaglutide users vs matched controls (not peer-reviewed); causality not established; no validated predictive model; evidence gap for retatrutide, oral semaglutide, or GIP/GLP-1/glucagon triple agonists
  • Graph decisions: existing GLP-1 RA NAION Safety Signal.md hub note updated in-place; GLP-1 NAION Risk.md protocol note already present (from prior batch); no new mechanism note (vascular optic nerve head perfusion is single-use inline); no detection model (no validated wearable NAION predictor)
  • Related notes: GLP-1 RA NAION Safety Signal, GLP-1 RA Pancreatitis Safety Signal, Semaglutide Liver Health, GLP-1 Skeletal Safety, Psychosis Risk, Vitals Knowledge Map

BATCH141 GLP-1 RA Pancreatitis Safety Signal — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-25) | In-place vault note update
  • Hub note: 01-Substances/GLP-1 RA Pancreatitis Safety Signal.md
  • KB canonical: skills/knowledge-base/glp-1-pancreatitis-safety-signal/glp-1-pancreatitis-safety-signal.md
  • Topic: GLP-1 RA pancreatitis safety signal — acute pancreatitis risk with semaglutide, tirzepatide, liraglutide; FDA class review 2024–2025; mechanism hypothesis (SST2 receptor GLP-1R pancreatic expression); relative risk vs absolute risk; clinical guidance for coaches
  • Key findings: Relative risk ~2–3× increased AP risk in meta-analysis; absolute risk remains low (~0.2–0.4% vs 0.1% background); no definitive causal link established; obesity/T2D本身就是risk factor; no confirmed SST2 mechanism; coaches: baseline risk counseling, flag persistent abdominal pain, do not advise discontinuation without medical input
  • Graph decisions: existing GLP-1 RA Pancreatitis Safety Signal.md hub note updated in-place; no new mechanism note (pancreatic enzyme elevation and GLP-1R expression are inline single-topic details); no detection model (no validated wearable pancreatitis predictor — symptom-based red flag protocol only)
  • Related notes: GLP-1 RA NAION Safety Signal, GLP-1 Skeletal Safety, Semaglutide Liver Health, Psychosis Risk, Vitals Knowledge Map

BATCH158 Incretin-Induced Sarcopenia GLP-1 Muscle Loss — VAULT PROMOTION READY

  • VAULT PROMOTION READY (2026-04-25) | Pipeline Advancer
  • Hub note: skills/knowledge-base/incretin-induced-sarcopenia-glp1-muscle-loss/incretin-induced-sarcopenia-glp1-muscle-loss.md (updated from batch with implementation section)
  • KB canonical: skills/knowledge-base/incretin-induced-sarcopenia-glp1-muscle-loss/incretin-induced-sarcopenia-glp1-muscle-loss.md
  • Topic: GLP-1 agonist-induced sarcopenia — functional preservation (handgrip, SPPB) despite DEXA-detectable LBM loss; tirzepatide vs semaglutide body composition difference; BCL6/follistatin preclinical only; resistance training + protein (1.2–2.0 g/kg/day) as primary prevention
  • Graph decisions: Hub in 01-Substances/ or 06-Peptides-and-Interactions/ (GLP-1 muscle loss as peptide-specific adverse effect); likely needs link to existing GLP-1 Muscle Preservation note; detection model if any BIA/DEXA monitoring protocol; implementation algorithm added (handgrip risk tier)
  • Key findings: handgrip preserved despite LBM loss (Confirmed — clinical important); DEXA ±10–15% precision error; tirzepatide > semaglutide lean mass preservation (Supported, preprint); GIP muscle-sparing claim = marketing-derived (Debunked)
  • Vitals framing: screen all GLP-1 patients quarterly with handgrip + SPPB; high-risk → RT + protein optimization; DEXA as trend monitor not cross-sectional comparison
  • Related notes: GLP-1 Muscle Preservation, Retatrutide, Tirzepatide, Semaglutide, BCL6, ActRII Myostatin Pathway, Vitals Knowledge Map

BATCH163 Methylene Blue Canonical Monograph — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-26) | MiniMax subagent conversion
  • Hub note: 01-Substances/Methylene Blue.md
  • Risk note: 04-Protocols-and-Recovery/Serotonin Syndrome.md
  • KB canonical: skills/knowledge-base/methylene-blue-canonical-monograph/methylene-blue-canonical-monograph.md
  • KB claim registry: skills/knowledge-base/methylene-blue-canonical-monograph/methylene-blue-canonical-monograph_claim_registry.md
  • Topic: Methylene Blue (MB) — phenothiazine-derived redox agent; FDA-approved acute methemoglobinemia and ifosfamide-induced neurotoxicity only; investigational cognitive/mitochondrial use; LMTM/HMTM Alzheimer’s programs failed phase 3 co-primary endpoints; serotonin-syndrome safety gate with serotonergic drugs
  • Graph decisions: existing 01-Substances/Methylene Blue.md hub upgraded in place; new 04-Protocols-and-Recovery/Serotonin Syndrome.md created because the MB + serotonergic-drug interaction is high-severity, independently retrievable, and reusable across future medication/supplement safety topics; no detection model created (no validated MB wearable signal); no standalone implementation note (screening algorithm summarized inside hub); no standalone MAO-B, NO Biology, or Mitochondrial Biogenesis notes created in this batch to avoid duplicate/overbroad mechanism drift
  • Key preserved boundaries: acute FDA indications do not support chronic supplementation; healthy-adult cognition evidence is one unreplicated IV study (PMID 24676965, n=26); oral bioavailability is formulation-dependent and poorly characterized (~10–60%); LMTM AD phase 3 failed (PMID 27863809) and 2026 HMTM trial did not separate on co-primary endpoints (PMID 41570392); exercise/longevity/wearable-efficacy claims remain Gap
  • Map/MOC updates: 00-Maps/Substances MOC.md and 00-Maps/Vitals Knowledge Map.md updated; new risk note linked under Protocols and Recovery → Acute Harm
  • Related notes: Serotonin Syndrome, SS-31 Elamipretide, CoQ10 Ubiquinol, Mitophagy, Methylene Blue

BATCH162 Mazdutide (IBI-362) Dual GLP-1/GCGR Agonist Obesity Phase 3 — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-25) | MiniMax subagent conversion
  • Hub note: 01-Substances/Mazdutide.md
  • KB canonical: skills/knowledge-base/mazdutide-ibi-362-dual-glp-1-gcg-agonist-obesity-phase-3/mazdutide-ibi-362-dual-glp-1-gcg-agonist-obesity-phase-3.md
  • Topic: Mazdutide (IBI-362 / LY3305677) — dual GLP-1/GCGR agonist; GLORY-1 phase 3 −14.01% at 48 wk (Chinese adults); NMPA-approved in China; no FDA/EMA; no non-Chinese phase 3 data; no direct head-to-head vs semaglutide 2.4 mg, tirzepatide, retatrutide, survodutide, or orforglipron
  • Graph decisions: single hub at 01-Substances/Mazdutide.md (same class as Survodutide); no new mechanism notes (GLP-1 GIP Glucagon already covers dual GLP-1/GCGR); no detection model (no mazdutide-specific wearable data); no recovery note (GI-dominant safety is class-level, not compound-specific); GLP-1 GIP Glucagon mechanism note updated to include Mazdutide in clinical pharmacology table; Peptides MOC and Vitals Knowledge Map both updated
  • Key preserved boundaries: GLORY-1 China-only population; no head-to-head data; no MACE/CVOT; no lean mass/DXA data; no active metabolite profile; investigational ex-China
  • Related notes: GLP-1 GIP Glucagon, Survodutide, Retatrutide, Tirzepatide, Semaglutide, Orforglipron, GLP-1 Muscle Preservation, GLP-1 RA NAION Safety Signal, GLP-1 RA Pancreatitis Safety Signal, Peptides MOC, Vitals Knowledge Map

BATCH146 Brown Adipose Tissue Activation Metabolic Health — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-25) | MiniMax subagent conversion
  • Hub note: 01-Substances/Brown Adipose Tissue Activation.md
  • Mechanism note: 02-Mechanisms/BAT Thermogenesis.md
  • Detection model: 05-Detection-Models/BAT Activation Wearable Detection Model.md
  • KB canonical: skills/knowledge-base/brown-adipose-tissue-activation-metabolic-health/brown-adipose-tissue-activation-metabolic-health.md
  • Topic: Brown adipose tissue activation as metabolic health intervention — BAT thermogenesis, cold-induced thermogenesis, mirabegron β3-AR agonism, FGF21 analogs, capsinoids; wearable detection model (exploratory); coaching boundaries
  • Graph decisions: Hub placed in 01-Substances/ (activation intervention with substance-component); BAT Thermogenesis created in 02-Mechanisms/ (UCP1 uncoupling pathway is shared across cold, mirabegron, FGF21, capsinoids — passes 5-question reusability test); no biometric standalone note (BAT activity as metabolic health marker is covered inline in hub); wearable detection model placed in 05-Detection-Models/ (all signals exploratory); BAT whitening kept inline (single-topic specificity); thyroid hormone BAT non-relevance kept inline; FGF21 analog details kept inline (single-compound experimental agents); capsinoid details kept inline
  • Key findings: +188 kcal/day cold EE increase (Supported, 10 RCT meta-analysis); mirabegron 200 mg +203 kcal/day BAT activation (Reported); weight does NOT change despite EE increase (Gap); no FDA-approved BAT drug for metabolic indication; all wearable BAT signals exploratory (Gap)
  • Vitals framing: cold exposure as metabolic flexibility complement to Zone 2; fasted state preferred; CV screening required before cold immersion; mirabegron 200 mg off-label with CV risk; no OTC BAT supplements have evidence; coaching do-not-operationalize list explicit
  • Related notes: BAT Thermogenesis, BAT Activation Wearable Detection Model, Metabolic Flexibility, Vitals Knowledge Map

BATCH175 Orforglipron (Foundayo) Oral Small-Molecule GLP-1 Agonist 2026 — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-26) | MiniMax subagent conversion
  • Hub note: 01-Substances/Orforglipron.md
  • Research source: research/batch-175-2026-04-26/orforglipron-oral-small-molecule-glp-1-agonist-2026.md
  • Synthesis brief: research/batch-175-2026-04-26/SYNTHESIS-BRIEF.md
  • Topic: Orforglipron (LY3502970, brand Foundayo) — FDA-approved 2026-04-01 for chronic weight management; oral non-peptide GLP-1 RA; no fasting/SNAC requirement; label-aligned Trial 1 weight loss −11.1% at 72 weeks, Trial 2 obesity+T2D −9.6%; ACHIEVE-3 A1C treatment-regimen −1.91% vs −1.47% oral semaglutide; T2D indication not approved in Batch 175 source set; CV outcomes pending
  • Graph decisions: existing Orforglipron.md hub updated in-place and simplified into a single high-signal hub; no new mechanism notes because GLP-1 GIP Glucagon already covers reusable incretin biology; no detection model because orforglipron-specific wearable/HRV/sleep data are absent; GI tolerability and discontinuation risk kept inside the hub rather than split out
  • Key corrections: use −11.1% as the primary FDA-label-aligned weight-loss claim, not the older 12.4% investigational-dose figure; do not claim FDA approval for T2D; do not claim cardiovascular protection or completed CVOT; do not claim lean-mass preservation without DXA/body-composition data
  • Map/MOC updates: 00-Maps/Substances MOC.md and 00-Maps/Vitals Knowledge Map.md updated
  • Related notes: GLP-1 GIP Glucagon, GLP-1 Body Composition, GLP-1 Muscle Preservation, Incretin Sarcopenia GLP-1 Prevention Protocol, Retatrutide, CagriSema, Vitals Knowledge Map

BATCH164 Orforglipron Oral Small-Molecule GLP-1 Agonist Phase 3 — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-25) | MiniMax subagent conversion
  • Hub note: 01-Substances/Orforglipron.md
  • KB canonical: skills/knowledge-base/orforglipron-oral-small-molecule-glp-1-agonist-phase-3/orforoglipron-oral-small-molecule-glp-1-agonist-phase-3.md
  • Topic: Orforglipron (LY3502970, brand Foundayo) — Phase 3 ACHIEVE-3 head-to-head vs oral semaglutide 14 mg; PK microtracer absolute bioavailability 79.1% ± 16.8%; ACHIEVE-4 topline Apr 16 2026 (MACE non-inferior, directional mortality HR 0.43); FDA post-approval registries (thyroid cancer 15-yr, liver injury, gastroparesis); GI discontinuation 9–10% vs 4–5% oral semaglutide; oral contraceptive interaction; suicidal ideation class warning removed Jan 2026; Implementation Notes / Algorithm Hooks section added
  • Graph decisions: existing Orforglipron.md hub note updated in-place (already contained BATCH149/BATCH125 content); no new mechanism notes (GLP-1 GIP Glucagon already covers); no detection model (orforglipron-specific wearable data absent); no recovery note (GI tolerability is class-level guidance); Implementation Notes section added with evidence-backed, extrapolated, and speculative tiers; signal yaml block added for heart_rate, gi_symptoms, discontinuation_risk, weight_loss, a1c_reduction; aspirational links preserved from existing hub
  • Key additions from BATCH164: (1) definitive PK microtracer 79.1% ± 16.8% bioavailability (PMID 40888509); (2) ACHIEVE-3 specific GI discontinuation rate 9–10% vs 4–5% oral semaglutide; (3) ACHIEVE-4 topline date and directional mortality HR 0.43; (4) 4 FDA post-approval registries; (5) oral contraceptive backup contraception guidance; (6) suicidal ideation class warning removal; (7) structured Implementation Notes with signal yaml
  • Source reconciliation: BATCH164 content harmonized with existing BATCH149/BATCH125 vault note; PK revision resolved (79.1% supersedes 20–40% conference estimate); GI discontinuation clarified with ACHIEVE-3 head-to-head data; ACHIEVE-4 mortality signal marked Gap-topline only
  • Related notes: GLP-1 GIP Glucagon, GLP-1 Muscle Preservation, Retatrutide, Tirzepatide, Semaglutide, CagriSema, GLP-1 Body Composition, Vitals Knowledge Map

BATCH177 Insulin Icodec (Awiqli) — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-26) | MiniMax subagent conversion
  • Hub note: 01-Substances/Insulin Icodec.md
  • KB canonical: skills/knowledge-base/insulin-icodec-awiqli-once-weekly-basal-insulin/insulin-icodec-awiqli-once-weekly-basal-insulin.md
  • Topic: Insulin icodec (Awiqli) — once-weekly basal insulin; FDA-approved May 2025 for T2D; ONWARDS 1-6 phase 3 program; TIR +4-5pp vs glargine; hypoglycemia event rate RR 1.51 pooled T2D; not approved for US T1D
  • Graph decisions: existing Insulin Icodec.md hub upgraded in-place; Albumin Binding Half-Life Extension mechanism note created (reusable across long-acting acylated agents); no detection model (icodec-specific weekly hypoglycemia window kept inside hub); no recovery note ( hypoglycemia risk class-level and managed clinically)
  • Key preserved boundaries: hypoglycemia higher than daily basal (RR 1.51 pooled); T1D NOT approved; not a GLP-1; not weight-loss drug; no CV benefit claim; TIR improvement is CGM evidence translated to coaching, not validated Vitals protocol
  • Map/MOC updates: 00-Maps/Vitals Knowledge Map.md updated with Insulin Icodec and Albumin Binding Half-Life Extension
  • Related notes: Albumin Binding Half-Life Extension, Glycemic Variability, Glucose Variability Detection Model, CGM Glucose Patterns Non-Diabetic, Metabolic Flexibility, GLP-1 GIP Glucagon, SGLT2 Inhibitors, Metformin Longevity, Berberine, Vitals Knowledge Map

BATCH169 Myostatin–Follistatin Axis Muscle Preservation — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-27) | MiniMax subagent conversion
  • Hub note: 06-Peptides-and-Interactions/Myostatin-Follistatin Axis.md
  • KB canonical: skills/knowledge-base/myostatin-follistatin-axis-muscle-preservation/myostatin-follistatin-axis-muscle-preservation.md
  • Claim registry: skills/knowledge-base/myostatin-follistatin-axis-muscle-preservation/myostatin-follistatin-axis-muscle-preservation_claim_registry.md
  • Topic: Myostatin (GDF8), follistatin, activin receptor (ActRIIA/IIB) blockade, and epicatechin as muscle preservation strategies; central mass-without-function evidence pattern across all drug programs; regulatory frontier (apitegromab nearest to approval)
  • Graph decisions: single hub at 06-Peptides-and-Interactions/Myostatin-Follistatin Axis.md (peptide mechanism hub); no new mechanism notes created — ActRII Myostatin Pathway and mTOR AMPK Muscle Catabolism kept as aspirational ghost links (single-topic dependency test not met); Follistatin, Myostatin, ActRII Signaling, Satellite Cell also kept as aspirational ghost links
  • Key findings preserved: (1) no FDA/EMA-approved axis drug for muscle preservation; (2) mass-without-function is the central class problem — domagrozumab DMD null, bimagrumab sIBM RESILIENT null, ACE-083 FSHD/CMT null; (3) apitegromab nearest to approval — CRL 2025 manufacturing issue, not efficacy; (4) bimagrumab + GLP-1 obesity combo fastest-moving frontier; (5) coaching anchored on resistance training + protein; (6) blood myostatin/follistatin assays are research-only, not consumer-grade
  • MOCs updated: Peptides MOC (peptide hub table), Vitals Knowledge Map (Investigational / Muscle section)
  • Related notes: Peptides MOC, Bimagrumab Semaglutide Combo V2, ActRII Myostatin Pathway (aspirational), mTOR AMPK Muscle Catabolism (aspirational), GLP-1 Muscle Preservation, Protein Intake GLP-1 Glucagon, Incretin Sarcopenia GLP-1 Prevention Protocol, Follistatin Gene Therapy FST-344

BATCH188 ER-100 Life Biosciences Partial Epigenetic Reprogramming — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-27) | MiniMax subagent conversion
  • Hub note: 01-Substances/ER-100.md
  • KB canonical: skills/knowledge-base/er-100-life-biosciences-partial-epigenetic-reprogramming-human-trial/er-100-life-biosciences-partial-epigenetic-reprogramming-human-trial.md
  • Topic: ER-100 — partial epigenetic reprogramming gene therapy; first OSK (Oct4, Sox2, Klf4, no c-Myc) human trial; NCT07290244; FDA IND cleared January 2026; Phase 1 in OAG and NAION
  • Graph decisions: single hub at 01-Substances/ER-100.md (gene therapy, not peptide — placed in 01-Substances like Rapamycin, not 06-Peptides-and-Interactions); no mechanism notes created (OSK partial reprogramming is single-compound mechanism, not broadly reusable yet); no detection model (no wearable-accessible signal pathway); no recovery/risk note (Phase 1 safety profile entirely unknown)
  • Key findings preserved: (1) zero human efficacy/safety data — Gap evidence grade; (2) c-Myc exclusion rationale and Tet-Off inducible system design; (3) Lu et al. 2020 Nature mouse data as foundational evidence; (4) expert conflict on Tet-On leakiness (Jeanne Loring vs FDA/Life Biosciences); (5) 63% AAV2 NAb seroprevalence as enrollment/targeting risk; (6) DO_NOT_OPERATIONALIZE_YET prominently in frontmatter
  • Aspirational links: Epigenetic Reprogramming, NAION, GLP-1 RA NAION Safety Signal, Biological Age
  • Vitals framing: no wearable translation pathway currently exists; epigenetic clocks require blood draw + CLIA lab; most plausible future monitoring = periodic Horvath/GrimAge, not continuous wearable
  • Tone: sober, no hype; Phase 1 safety ≠ proven anti-aging; eye proof-of-concept ≠ systemic longevity
  • Related notes: Epigenetic Reprogramming, GLP-1 RA NAION Safety Signal, Biological Age, Vitals Knowledge Map

BATCH180 Amycretin (Zenagamtide / NN9487) — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-26) | MiniMax subagent conversion
  • Hub note: 01-Substances/Amycretin.md
  • KB canonical: skills/knowledge-base/amycretin-glp-1-amylin-dual-receptor-agonist/amycretin-glp-1-amylin-dual-receptor-agonist.md
  • Topic: Amycretin (zenagamtide / NN9487) — unimolecular dual GLP-1 + amylin receptor co-agonist; Phase 1b/2a −24.3% at 36 weeks SC (PMID 40550231); Phase 1 oral −13.1% at 12 weeks (PMID 40550229); Phase 2 T2D −14.5% is press-release-only; Phase 3 AMAZE program recruiting including AMAZE-8 vs semaglutide; investigational only
  • Graph decisions: existing Amycretin.md hub note upgraded in-place with richer content from Batch 180 canonical doc; no new mechanism notes (GLP-1 GIP Glucagon already covers incretin biology; [[Amylin Receptor Biology]] kept as aspirational ghost link for future reuse); no detection model (no Amycretin-specific wearable data); no recovery note (amylin hypoglycemia risk and GI tolerability are class-level or inline)
  • Key additions from Batch 180 canonical: Phase 2 T2D trial NCT06542874 details (448 participants, press release data); amylin class safety context from pramlintide/Symlin label (hypoglycemia risk with insulin); drug-drug interaction context (NCT06461039); oral formulation key attributes; complete Phase 3 AMAZE trial table; wearable-accessible endpoints table with confidence ratings; explicit Vitals relevance table (body composition, GLP-1 activity, amylin satiety, HRV, sleep, glucose, cardiorenal); evidence summary table with all PMIDs
  • Key preserved boundaries: −24.3% is highest dose escalation cohort, not a maintenance dose; Phase 2 T2D data is press-release-only / Reported grade; no Phase 3 results; no CVOT; no DXA/body composition data; amylin synergy contribution unquantified in humans; investigational-only throughout
  • Map/MOC: Amycretin already present in Substances MOC and Vitals Knowledge Map (confirmed pre-existing)
  • Related notes: GLP-1 GIP Glucagon, CagriSema, Cagrilintide, Pramlintide, Retatrutide, Tirzepatide, Orforglipron, GLP-1 Body Composition, Incretin Sarcopenia GLP-1 Prevention Protocol, GLP-1 Muscle Preservation, GLP-1 RA NAION Safety Signal, GLP-1 RA Pancreatitis Safety Signal, GLP-1 RA Skeletal Safety, Protein Intake GLP-1 Glucagon, Amylin Receptor Biology (aspirational)

BATCH174 L-Theanine Supplement — VAULT COMPLETE

  • VAULT COMPLETE (2026-04-27) | MiniMax subagent conversion
  • Hub note: 01-Substances/L-Theanine.md
  • Biometrics note: 03-Biometrics/Alpha Wave Induction.md
  • KB monograph: skills/knowledge-base/l-theanine-supplement-monograph/l-theanine-supplement-monograph.md
  • Claim registry: skills/knowledge-base/l-theanine-supplement-monograph/l-theanine-supplement-monograph_claim_registry.md
  • Topic: L-theanine (gamma-glutamylethylamide) — non-proteinogenic amino acid; relaxant and cognitive enhancer; best evidence for L-theanine + caffeine cognitive stack; alpha wave induction as primary electrophysiological signature; no tolerance or dependence; not established for clinical GAD; wearable detection experimental
  • Graph decisions: 1 hub + 1 biometrics note; no new mechanism notes created — GABA-A receptor and NMDA receptor already exist and are linked; Alpha Wave Induction created as reusable biometrics note (passes 5-question reusability test — relevant to L-theanine, meditation, relaxation research, future anxiolytics); no detection model (no validated consumer wearable algorithm for L-theanine effects); no recovery note (safety profile is strong — no tolerance, no dependence — risks are theoretical interactions kept inline)
  • Key preserved boundaries: (1) null result in diagnosed GAD is the most important limitations fact — do not position as equivalent to prescribed anxiolytics; (2) L-theanine + caffeine is the strongest cognitive enhancement claim — not broad cognitive enhancement; (3) ADHD sleep benefit is actigraphy-confirmed but limited to boys 8–12; (4) Suntheanine superiority over generic is marketing-driven; (5) wearable detection of L-theanine effects is experimental — no validated consumer algorithm; (6) long-term safety beyond 12 weeks is unstudied
  • MOCs updated: 00-Maps/Substances MOC.md (Relaxants / Nootropics section), 00-Maps/Vitals Knowledge Map.md (Adaptogens / Nootropics section and Sleep section)
  • Related notes: GABA-A receptor, NMDA receptor, Alpha Wave Induction, Caffeine, Melatonin, Ashwagandha, HRV, Sleep Architecture

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