{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Trained Immunity", "entry_form": "phenomenon", "gradeable_restatement": "Innate immune cells and their hematopoietic progenitors acquire intrinsic, long-lasting, autonomously maintained epigenetic and metabolic memory that enhances responses to later heterologous challenges.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Stimulus, cell compartment, dose, timing, donor condition, recipient conditioning and challenge specified before outcome", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Trained Immunity", "central_claim": "Innate immune cells and their hematopoietic progenitors acquire intrinsic, long-lasting, autonomously maintained epigenetic and metabolic memory that enhances responses to later heterologous challenges.", "proposed_mechanism": "Innate immune cells and their hematopoietic progenitors acquire intrinsic, long-lasting, autonomously maintained epigenetic and metabolic memory that enhances responses to later heterologous challenges.", "claimed_scope": "Defined post-exposure mature-cell and purified progenitor-transfer settings; persistence is finite and context dependent. Original inducer-independent maintenance is distinct from elimination of normal intracellular/homeostatic support. Universal antigen-free or wholly signal-free persistence and clinical protection are unestablished.", "claimed_level": [ "persistence", "heterologous responsiveness" ], "is_conjunctive": true, "conjunctive_note": "Use the index SC3 autonomy gate, with mandatory alternative aggregation. Clinical heterologous protection is scored separately and cannot establish signal-independent memory. Recheck the index assertion about maintenance evidence rather than adopting its implied result." }, "rubric_routing": { "primary_rubric": "05-immunology-inflammation.md", "secondary_rubrics": [ "03-epigenetics-gene-regulation.md" ], "index_notes_applied": [ "Use the index SC3 autonomy gate, with mandatory alternative aggregation. Clinical heterologous protection is scored separately and cannot establish signal-independent memory. Recheck the index assertion about maintenance evidence rather than adopting its implied result." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "A primary stimulus changes innate responses to heterologous secondary challenge.", "subclaim_type": "existence", "scope": "defined dose, timing and cell populations", "claimed_scope": "defined dose, timing and cell populations", "governing_rubric": "05-immunology-inflammation.md", "key_evidence_anchor": "Washout and heterologous challenge controls", "hsef_level": "Ζ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Multiple distinct causal manipulations establish altered heterologous innate responses, including lymphocyte-deficient protection, primary human vaccination/challenge and transferred cells. Responses may be protective, harmful or tolerant; enhanced cytokines are not universal benefit. Independent assay/context classes support Ζ for the phenomenon within defined settings." }, { "id": "SC2", "statement": "Histone and metabolic rewiring encode the altered state.", "subclaim_type": "mechanism", "scope": "specified chromatin/metabolic nodes", "claimed_scope": "specified chromatin/metabolic nodes", "governing_rubric": "03-epigenetics-gene-regulation.md", "key_evidence_anchor": "Selective induction and maintenance-stage perturbations", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Induction-stage metabolic nodes causally contribute in defined systems, but histone co-occurrence, broad p300/LDH inhibition and TF deletion do not isolate a specific inheritable chromatin carrier. The conjunctive histone-encoding claim remains Γ under rubric 03; metabolic contribution alone is stronger. A purified autoimmune HSC transfer yields enhanced function despite reduced metabolism, excluding universal increased glycolysis as the carrier." }, { "id": "SC3", "statement": "Memory persists cell-intrinsically without retained antigen or continued upstream signaling.", "subclaim_type": "necessity", "scope": "post-washout mature cells and progenitor compartments", "claimed_scope": "post-washout mature cells and progenitor compartments", "governing_rubric": "05-immunology-inflammation.md", "key_evidence_anchor": "Delayed withdrawal/blockade and transfer with ligand exclusion", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Purified LT-HSC transfer after resolved periodontitis and independent stringent autoimmune LT-HSC transfer into recipients without spontaneous autoimmune activity support donor-cell intrinsic persistence away from the original tissue input for months. This crosses the context-specific Ε boundary. It does not establish universal absence of retained molecular ligands, complete independence from recipient niches or normal intracellular maintenance, or permanent mark copying. Continued homeostatic TF activity alone does not refute original-inducer independence. Stronger signal/antigen exclusion remains an unmet scope expansion." }, { "id": "SC4", "statement": "Progenitor memory transmits through division to circulating progeny.", "subclaim_type": "mechanism", "scope": "lineage-defined HSPCs and descendants", "claimed_scope": "lineage-defined HSPCs and descendants", "governing_rubric": "05-immunology-inflammation.md", "key_evidence_anchor": "Purified transfer, lineage tracing and challenge", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Purified donor HSCs yield altered descendants and challenge responses after 12–18 weeks, with chimerism and lineage controls. The autoimmune experiment preserves overall lineage proportions, showing that differentiation bias is not the sole explanation. Irradiated niches, clonal selection and no direct mark copying limit the broader mechanistic inference to Ε. Human HSPC/monocyte concordance does not constitute human lineage tracing." }, { "id": "SC5", "statement": "Training produces clinically meaningful heterologous protection in humans.", "subclaim_type": "generalization", "scope": "prespecified BCG/vaccine contexts and incidence endpoints", "claimed_scope": "prespecified BCG/vaccine contexts and incidence endpoints", "governing_rubric": "05-immunology-inflammation.md", "key_evidence_anchor": "Randomized incidence and mechanistic mediation", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Clinical heterologous benefit occurs in defined vaccination contexts, but the examined trials do not selectively establish trained innate memory as the mediator. Combined BCG–OPV neonatal benefit, interim elderly infection benefit and attenuated yellow-fever viremia contrasts cannot be merged with adult COVID nulls into universal protection. Clinical efficacy in its tested setting can be Ε; trained-memory-specific clinical mediation is Γ." } ], "aggregation_rule": "primary-subclaim", "aggregation_preregistered": true, "aggregation_rationale": "Use the index SC3 autonomy gate, with mandatory alternative aggregation. Clinical heterologous protection is scored separately and cannot establish signal-independent memory. Recheck the index assertion about maintenance evidence rather than adopting its implied result.", "primary_subclaim_id": "SC3", "aggregation_derivation": "Preregistered primary-subclaim aggregation uses SC3 and returns Ε, context-dependent causality, with Moderate confidence. Purified post-resolution and long-term donor-cell transfer support conditional intrinsic persistence without continued original tissue exposure. Complete ligand exclusion and independence from all ongoing signaling are not demonstrated; normal homeostatic maintenance is compatible with cell-intrinsic memory. The strict universal signal/antigen-free extension remains Γ. Weakest-link sensitivity is Γ because histone-carrier specificity and human clinical mediation remain unresolved; scope-matched primary sensitivity is Ε. The final letter does not certify the full conjunctive mechanism or universal clinical protection.", "aggregation_alternatives": { "weakest_link_would_return": "Γ", "primary_subclaim_would_return": "Ε", "scope_matched_would_return": "Ε", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M3", "is_nominal": false, "name": "Dose- and context-dependent innate set-point", "core_claim": "Stimulus, tissue and lineage determine a persistent responsive state that can protect, tolerate or cause harm.", "explains_what_nominal_does_not": "Stimulus, tissue and lineage determine a persistent responsive state that can protect, tolerate or cause harm.", "strongest_supporting_evidence": [ "Distinct stimulus programs, AM transfer harm despite whole-animal benefit, and opposite microglial/clinical effects fit conditional memory." ], "strongest_contradictory_evidence": [ "A set-point description alone does not identify its molecular carrier." ], "hsef_level_for_this_model": "Ε", "rationale": "Distinct stimulus programs, AM transfer harm despite whole-animal benefit, and opposite microglial/clinical effects fit conditional memory. A set-point description alone does not identify its molecular carrier." }, { "rank_in_tournament": 2, "model_id": "M1", "is_nominal": true, "name": "Cell-intrinsic memory with unresolved carrier", "core_claim": "Cells/progenitors preserve altered responsiveness after removal from the original exposure context.", "explains_what_nominal_does_not": "Cells/progenitors preserve altered responsiveness after removal from the original exposure context.", "strongest_supporting_evidence": [ "Purified LT-HSC transfer after resolution and autoimmune LT-HSC transfer without recipient autoimmune activity sustain altered descendants." ], "strongest_contradictory_evidence": [ "Ligand quantification, normal niche dependence and selective histone inheritance remain unresolved." ], "hsef_level_for_this_model": "Ε", "rationale": "Purified LT-HSC transfer after resolution and autoimmune LT-HSC transfer without recipient autoimmune activity sustain altered descendants. Ligand quantification, normal niche dependence and selective histone inheritance remain unresolved." }, { "rank_in_tournament": 3, "model_id": "M5", "is_nominal": false, "name": "Progenitor selection and differentiation bias", "core_claim": "Some durable outputs arise from altered HSC composition, lineage propensity or selected clones.", "explains_what_nominal_does_not": "Some durable outputs arise from altered HSC composition, lineage propensity or selected clones.", "strongest_supporting_evidence": [ "β-glucan and periodontitis transfers produce myeloid bias, with matched chimerism." ], "strongest_contradictory_evidence": [ "Stringent autoimmune LT-HSC transfer yields functional memory without overall lineage skew; bias cannot explain every case." ], "hsef_level_for_this_model": "Ε", "rationale": "β-glucan and periodontitis transfers produce myeloid bias, with matched chimerism. Stringent autoimmune LT-HSC transfer yields functional memory without overall lineage skew; bias cannot explain every case." }, { "rank_in_tournament": 4, "model_id": "M4", "is_nominal": false, "name": "Maladaptive inflammatory amplification", "core_claim": "Past disease exposure can transmit a susceptibility state that amplifies later pathology.", "explains_what_nominal_does_not": "Past disease exposure can transmit a susceptibility state that amplifies later pathology.", "strongest_supporting_evidence": [ "Autoimmune, periodontal, diabetic, stroke and heart-failure transfer models alter subsequent disease or inflammatory response." ], "strongest_contradictory_evidence": [ "Not a universal explanation for protective or resolving macrophage states." ], "hsef_level_for_this_model": "Ε", "rationale": "Autoimmune, periodontal, diabetic, stroke and heart-failure transfer models alter subsequent disease or inflammatory response. Not a universal explanation for protective or resolving macrophage states." }, { "rank_in_tournament": 5, "model_id": "M2", "is_nominal": false, "name": "Persistent antigen, metabolites or external signaling", "core_claim": "Some long-lived effects reflect continuing inducer, microbiome or niche inputs.", "explains_what_nominal_does_not": "Some long-lived effects reflect continuing inducer, microbiome or niche inputs.", "strongest_supporting_evidence": [ "Live BCG dissemination, Western-diet backgrounds and constitutive mevalonate excess keep this alternative live." ], "strongest_contradictory_evidence": [ "Purified cells transferred after resolution and prolonged recipients reduce its sufficiency as a blanket explanation; not directly excluded in every model." ], "hsef_level_for_this_model": "Γ", "rationale": "Live BCG dissemination, Western-diet backgrounds and constitutive mevalonate excess keep this alternative live. Purified cells transferred after resolution and prolonged recipients reduce its sufficiency as a blanket explanation; not directly excluded in every model." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Apply delayed original-receptor/niche subtraction after measured ligand clearance in barcoded purified donor cells; require preserved baseline competence and separate clone/lineage effects from functional memory.", "study_separating_rank1_from_rank2": "Apply delayed original-receptor/niche subtraction after measured ligand clearance in barcoded purified donor cells; require preserved baseline competence and separate clone/lineage effects from functional memory.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "22988082", "title": "Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes.", "citation": "Kleinnijenhuis J, Quintin J, Preijers F et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proceedings of the National Academy of Sciences of the United States of America. 2012.", "doi": "10.1073/pnas.1202870109", "pmcid": "PMC3491454", "url": "https://pubmed.ncbi.nlm.nih.gov/22988082/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22988082/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID22988082", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "BCG-vaccinated volunteers show heterologous monocyte cytokine responses for three months; NOD2-dependent experiments and SCID Candida survival support innate contribution.", "what_it_does_not_show": "Human cytokines do not demonstrate clinical protection or elimination of all retained BCG/signaling; histone inhibitor specificity and adaptive cytokine contributions remain limits.", "confounders_present": [ "Human cytokines do not demonstrate clinical protection or elimination of all retained BCG/signaling; histone inhibitor specificity and adaptive cytokine contributions remain limits." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 2, "pmid": "22901542", "title": "Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes.", "citation": "Quintin J, Saeed S, Martens JHA et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell host & microbe. 2012.", "doi": "10.1016/j.chom.2012.06.006", "pmcid": "PMC3864037", "url": "https://pubmed.ncbi.nlm.nih.gov/22901542/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22901542/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID22901542", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Candida/β-glucan pretreatment protects lymphocyte-deficient mice in a monocyte-dependent manner and dectin-1/Raf-1 signaling contributes.", "what_it_does_not_show": "Induction necessity and stable marks do not isolate antigen-free maintenance or direct mark copying.", "confounders_present": [ "Induction necessity and stable marks do not isolate antigen-free maintenance or direct mark copying." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 3, "pmid": "25258083", "title": "mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity.", "citation": "Cheng SC, Quintin J, Cramer RA et al. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science (New York, N.Y.). 2014.", "doi": "10.1126/science.1250684", "pmcid": "PMC4226238", "url": "https://pubmed.ncbi.nlm.nih.gov/25258083/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25258083/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID25258083", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Akt/mTOR/HIF-1α perturbations block training; myeloid HIF-1α loss abolishes trained sepsis protection.", "what_it_does_not_show": "Predominantly induction-stage metabolic necessity is not mark-specific maintenance; broad metabolic/viability effects require control; linked author correction noted.", "confounders_present": [ "Predominantly induction-stage metabolic necessity is not mark-specific maintenance; broad metabolic/viability effects require control; linked author correction noted." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 4, "pmid": "25258085", "title": "Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity.", "citation": "Saeed S, Quintin J, Kerstens HH et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science (New York, N.Y.). 2014.", "doi": "10.1126/science.1251086", "pmcid": "PMC4242194", "url": "https://pubmed.ncbi.nlm.nih.gov/25258085/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25258085/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID25258085", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Primary monocyte-derived trained and tolerant macrophages acquire different transcriptomic/enhancer programs.", "what_it_does_not_show": "Differentiation and histone co-occurrence do not show the specific marks cause or autonomously store memory.", "confounders_present": [ "Differentiation and histone co-occurrence do not show the specific marks cause or autonomously store memory." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 5, "pmid": "27926861", "title": "Immunometabolic Pathways in BCG-Induced Trained Immunity.", "citation": "Arts RJW, Carvalho A, La Rocca C et al. Immunometabolic Pathways in BCG-Induced Trained Immunity. Cell reports. 2016.", "doi": "10.1016/j.celrep.2016.11.011", "pmcid": "PMC5177620", "url": "https://pubmed.ncbi.nlm.nih.gov/27926861/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27926861/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID27926861", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "BCG training requires glycolytic rewiring in pharmacological/genetic experiments, with associated histone changes.", "what_it_does_not_show": "Most tests target induction or broad metabolic enzymes, not delayed locus-specific histone maintenance.", "confounders_present": [ "Most tests target induction or broad metabolic enzymes, not delayed locus-specific histone maintenance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 6, "pmid": "27866838", "title": "Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity.", "citation": "Arts RJ, Novakovic B, Ter Horst R et al. Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity. Cell metabolism. 2016.", "doi": "10.1016/j.cmet.2016.10.008", "pmcid": "PMC5742541", "url": "https://pubmed.ncbi.nlm.nih.gov/27866838/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27866838/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID27866838", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Glutaminolysis/fumarate and mevalonate-related metabolism contribute to β-glucan induction; fumarate inhibits KDM5 and induces similar marks.", "what_it_does_not_show": "Metabolite sufficiency and broad inhibitors do not demonstrate exclusive mark-based inheritance or autonomous maintenance.", "confounders_present": [ "Metabolite sufficiency and broad inhibitors do not demonstrate exclusive mark-based inheritance or autonomous maintenance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 7, "pmid": "29328908", "title": "Metabolic Induction of Trained Immunity through the Mevalonate Pathway.", "citation": "Bekkering S, Arts RJW, Novakovic B et al. Metabolic Induction of Trained Immunity through the Mevalonate Pathway. Cell. 2018.", "doi": "10.1016/j.cell.2017.11.025", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29328908/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29328908/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID29328908", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Mevalonate/IGF1R/mTOR perturbations regulate training; mevalonate-kinase-deficient patients have constitutive trained phenotypes.", "what_it_does_not_show": "Constitutive metabolite excess is ongoing upstream stimulation, not antigen-independent memory; pleiotropy limits a selective epigenetic instrument.", "confounders_present": [ "Constitutive metabolite excess is ongoing upstream stimulation, not antigen-independent memory; pleiotropy limits a selective epigenetic instrument." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 8, "pmid": "29328910", "title": "Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity.", "citation": "Mitroulis I, Ruppova K, Wang B et al. Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity. Cell. 2018.", "doi": "10.1016/j.cell.2017.11.034", "pmcid": "PMC5766828", "url": "https://pubmed.ncbi.nlm.nih.gov/29328910/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29328910/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID29328910", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph24, 1:Results:paragraph28, 1:Results:paragraph38, 1:Results:paragraph103, 1:Results:paragraph108, 1:Results:paragraph109, 1:Results:paragraph113. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Sorted LT-HSCs taken 28 days after β-glucan transmit myeloid bias after 12 weeks in recipients with matched chimerism; heterologous LPS and chemotherapy responses improve.", "what_it_does_not_show": "Transfer lineage bias is not direct mark copying; IL-1/glycolysis/statin/GM-CSF interventions occur on days 0–1 and test induction, not delayed maintenance.", "confounders_present": [ "Transfer lineage bias is not direct mark copying; IL-1/glycolysis/statin/GM-CSF interventions occur on days 0–1 and test induction, not delayed maintenance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 9, "pmid": "29328912", "title": "BCG Educates Hematopoietic Stem Cells to Generate Protective Innate Immunity against Tuberculosis.", "citation": "Kaufmann E, Sanz J, Dunn JL et al. BCG Educates Hematopoietic Stem Cells to Generate Protective Innate Immunity against Tuberculosis. Cell. 2018.", "doi": "10.1016/j.cell.2017.12.031", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29328912/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29328912/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID29328912", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "BCG-educated HSCs generate protective macrophages; chimeric/parabiotic and transfer designs support sustainable lineage training.", "what_it_does_not_show": "BCG bone-marrow access and potential persistence constrain full ligand independence; exact original transfer/clearance details inaccessible here; Mtb challenge is mycobacterial, not a distant heterologous pathogen.", "confounders_present": [ "BCG bone-marrow access and potential persistence constrain full ligand independence; exact original transfer/clearance details inaccessible here; Mtb challenge is mycobacterial, not a distant heterologous pathogen." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 10, "pmid": "32169166", "title": "C/EBPβ-Dependent Epigenetic Memory Induces Trained Immunity in Hematopoietic Stem Cells.", "citation": "de Laval B, Maurizio J, Kandalla PK et al. C/EBPβ-Dependent Epigenetic Memory Induces Trained Immunity in Hematopoietic Stem Cells. Cell stem cell. 2020.", "doi": "10.1016/j.stem.2020.01.017", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/32169166/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32169166/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID32386557", "ErratumIn: PMID36608675" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID32169166", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Acute LPS produces persistent HSC enhancer accessibility and improved Pseudomonas defense; C/EBPβ deletion erases long-term marks/expression.", "what_it_does_not_show": "Exact deletion timing and viability/transfer controls are not examined; deletion of a transcription factor is not selective proof of mark copying; two corrections linked.", "confounders_present": [ "Exact deletion timing and viability/transfer controls are not examined; deletion of a transcription factor is not selective proof of mark copying; two corrections linked." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 11, "pmid": "35483374", "title": "Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities.", "citation": "Li X, Wang H, Yu X et al. Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities. Cell. 2022.", "doi": "10.1016/j.cell.2022.03.043", "pmcid": "PMC9106933", "url": "https://pubmed.ncbi.nlm.nih.gov/35483374/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35483374/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID35483374", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph4, 1:RESULTS:paragraph13, 1:RESULTS:paragraph14, 1:RESULTS:paragraph17, 1:RESULTS:paragraph18, 1:RESULTS:paragraph21, 3:LIMITATIONS OF THE STUDY:paragraph0. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "After 21-day periodontitis and 14-day resolution, purified LT-HSCs transmit myeloid bias and increased arthritis/LPS responses after 12–16 weeks; both CD41 strata transfer effects.", "what_it_does_not_show": "IL-1R deletion precedes training; no delayed maintenance-stage IL-1 subtraction, ligand quantification or exclusive epigenetic mechanism; irradiated niche and finite duration limit scope.", "confounders_present": [ "IL-1R deletion precedes training; no delayed maintenance-stage IL-1 subtraction, ligand quantification or exclusive epigenetic mechanism; irradiated niche and finite duration limit scope." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 12, "pmid": "29328911", "title": "Western Diet Triggers NLRP3-Dependent Innate Immune Reprogramming.", "citation": "Christ A, Günther P, Lauterbach MAR et al. Western Diet Triggers NLRP3-Dependent Innate Immune Reprogramming. Cell. 2018.", "doi": "10.1016/j.cell.2017.12.013", "pmcid": "PMC6324559", "url": "https://pubmed.ncbi.nlm.nih.gov/29328911/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29328911/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID29328911", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Western-diet withdrawal normalizes serum inflammation but retains myeloid responses; NLRP3 loss prevents diet-induced reprogramming.", "what_it_does_not_show": "Ldlr deficiency and remaining lipid/niche signals may persist; constitutive knockout tests induction and associated inflammation rather than late maintenance.", "confounders_present": [ "Ldlr deficiency and remaining lipid/niche signals may persist; constitutive knockout tests induction and associated inflammation rather than late maintenance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 13, "pmid": "34255973", "title": "Hyperglycemia Induces Trained Immunity in Macrophages and Their Precursors and Promotes Atherosclerosis.", "citation": "Edgar L, Akbar N, Braithwaite AT et al. Hyperglycemia Induces Trained Immunity in Macrophages and Their Precursors and Promotes Atherosclerosis. Circulation. 2021.", "doi": "10.1161/CIRCULATIONAHA.120.046464", "pmcid": "PMC8448412", "url": "https://pubmed.ncbi.nlm.nih.gov/34255973/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34255973/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID34255973", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Diabetic donor marrow produces macrophage changes in physiological glucose and increases atherosclerosis in normoglycemic Ldlr-null recipients.", "what_it_does_not_show": "Whole marrow and recipient Western diet allow selection/niche feedback; RUNX1 inhibition is broad; human signatures are associative.", "confounders_present": [ "Whole marrow and recipient Western diet allow selection/niche feedback; RUNX1 inhibition is broad; human signatures are associative." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 14, "pmid": "32544459", "title": "BCG Vaccination in Humans Elicits Trained Immunity via the Hematopoietic Progenitor Compartment.", "citation": "Cirovic B, de Bree LCJ, Groh L et al. BCG Vaccination in Humans Elicits Trained Immunity via the Hematopoietic Progenitor Compartment. Cell host & microbe. 2020.", "doi": "10.1016/j.chom.2020.05.014", "pmcid": "PMC7295478", "url": "https://pubmed.ncbi.nlm.nih.gov/32544459/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32544459/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "human-BCG-marrow-platform-overlap-not-resolved", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph10, 1:Results:paragraph16, 1:Results:paragraph40, 1:Results:paragraph43. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "15 BCG recipients versus five placebo controls show day-90 HSPC/monocyte remodeling and increased heterologous IL1β; marrow M. bovis testing is reported negative.", "what_it_does_not_show": "Assay data/sensitivity not shown, a skin lesion remains, and no human lineage tracing or causal HNF1 deletion; no significant adult cell-frequency shift despite transcriptional bias.", "confounders_present": [ "Assay data/sensitivity not shown, a skin lesion remains, and no human lineage tracing or causal HNF1 deletion; no significant adult cell-frequency shift despite transcriptional bias." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Possible overlap with later human BCG marrow report; treated conservatively, not independent causal replication." ] }, { "n": 15, "pmid": "39153479", "title": "BCG vaccination alters the epigenetic landscape of progenitor cells in human bone marrow to influence innate immune responses.", "citation": "Sun SJ, Aguirre-Gamboa R, de Bree LCJ et al. BCG vaccination alters the epigenetic landscape of progenitor cells in human bone marrow to influence innate immune responses. Immunity. 2024.", "doi": "10.1016/j.immuni.2024.07.021", "pmcid": "PMC11604037", "url": "https://pubmed.ncbi.nlm.nih.gov/39153479/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39153479/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID38077046" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "human-BCG-marrow-platform-overlap-not-resolved", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Single-cell human marrow before/90 days after BCG/placebo shows HSPC expression/accessibility changes correlated with paired PBMC IL1β.", "what_it_does_not_show": "Correlation across compartments does not demonstrate literal mark inheritance or no persistent ligand; indexed preprint is the same study, not replication.", "confounders_present": [ "Correlation across compartments does not demonstrate literal mark inheritance or no persistent ligand; indexed preprint is the same study, not replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Possible overlap with 2020 human BCG marrow cohort; exact participant identity not resolved." ] }, { "n": 16, "pmid": "33207187", "title": "BCG Vaccination Induces Long-Term Functional Reprogramming of Human Neutrophils.", "citation": "Moorlag SJCFM, Rodriguez-Rosales YA, Gillard J et al. BCG Vaccination Induces Long-Term Functional Reprogramming of Human Neutrophils. Cell reports. 2020.", "doi": "10.1016/j.celrep.2020.108387", "pmcid": "PMC7672522", "url": "https://pubmed.ncbi.nlm.nih.gov/33207187/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33207187/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33207187", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "BCG alters neutrophil antimicrobial function and H3K4me3 profiles for at least three months.", "what_it_does_not_show": "Repeated circulating cells cannot prove persistence in the same mature cell or autonomous progenitor mechanism; no clinical incidence endpoint.", "confounders_present": [ "Repeated circulating cells cannot prove persistence in the same mature cell or autonomous progenitor mechanism; no clinical incidence endpoint." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 17, "pmid": "30433869", "title": "Induction of Autonomous Memory Alveolar Macrophages Requires T Cell Help and Is Critical to Trained Immunity.", "citation": "Yao Y, Jeyanathan M, Haddadi S et al. Induction of Autonomous Memory Alveolar Macrophages Requires T Cell Help and Is Critical to Trained Immunity. Cell. 2018.", "doi": "10.1016/j.cell.2018.09.042", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/30433869/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30433869/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID30433869", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Respiratory-virus-experienced alveolar macrophages retain antibacterial memory; T-cell help is reported required for priming rather than maintenance.", "what_it_does_not_show": "Original detailed depletion/antigen controls unavailable; innate maintenance after adaptive induction differs from completely innate induction; normal niche requirements remain.", "confounders_present": [ "Original detailed depletion/antigen controls unavailable; innate maintenance after adaptive induction differs from completely innate induction; normal niche requirements remain." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 18, "pmid": "35856089", "title": "Trained immunity of alveolar macrophages requires metabolic rewiring and type 1 interferon signaling.", "citation": "Zahalka S, Starkl P, Watzenboeck ML et al. Trained immunity of alveolar macrophages requires metabolic rewiring and type 1 interferon signaling. Mucosal immunology. 2022.", "doi": "10.1038/s41385-022-00528-5", "pmcid": "PMC9385480", "url": "https://pubmed.ncbi.nlm.nih.gov/35856089/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35856089/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID35856089", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph5, 1:Results:paragraph7, 1:Results:paragraph8, 1:Results:paragraph13, 1:Results:paragraph14, 1:Results:paragraph21, 1:Results:paragraph22. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "LPS/IFN-β train cultured alveolar macrophages after rest; macrophage IFNAR loss blocks induction, while transferred trained AMs worsen pneumococcal infection despite whole-animal LPS protection.", "what_it_does_not_show": "Methylation/acetylation inhibitors during induction do not alter IL6 training here; six-day context and transfer niche differ from clinical vaccination; pooling technical replicates limits sample interpretation.", "confounders_present": [ "Methylation/acetylation inhibitors during induction do not alter IL6 training here; six-day context and transfer niche differ from clinical vaccination; pooling technical replicates limits sample interpretation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 19, "pmid": "33125891", "title": "M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity.", "citation": "Khan N, Downey J, Sanz J et al. M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity. Cell. 2020.", "doi": "10.1016/j.cell.2020.09.062", "pmcid": "PMC7599081", "url": "https://pubmed.ncbi.nlm.nih.gov/33125891/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33125891/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33125891", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Mtb IFN-I/iron signaling impairs myelopoiesis and trained defense, contrasting BCG/β-glucan IFN-II/IL1 programs.", "what_it_does_not_show": "Chronic pathogenic infection and progenitor death are distinct from autonomous beneficial memory; ongoing infection is a confounder for maintenance.", "confounders_present": [ "Chronic pathogenic infection and progenitor death are distinct from autonomous beneficial memory; ongoing infection is a confounder for maintenance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 20, "pmid": "27863248", "title": "β-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance.", "citation": "Novakovic B, Habibi E, Wang SY et al. β-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance. Cell. 2016.", "doi": "10.1016/j.cell.2016.09.034", "pmcid": "PMC5927328", "url": "https://pubmed.ncbi.nlm.nih.gov/27863248/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27863248/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID27863248", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "β-glucan partly reverses LPS tolerance in vitro and restores cytokines in monocytes from experimental endotoxemia.", "what_it_does_not_show": "Chromatin recovery accompanies reactivation; it does not prove the marks exclusively encode memory or clinical sepsis rescue.", "confounders_present": [ "Chromatin recovery accompanies reactivation; it does not prove the marks exclusively encode memory or clinical sepsis rescue." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 21, "pmid": "30293776", "title": "The Itaconate Pathway Is a Central Regulatory Node Linking Innate Immune Tolerance and Trained Immunity.", "citation": "Domínguez-Andrés J, Novakovic B, Li Y et al. The Itaconate Pathway Is a Central Regulatory Node Linking Innate Immune Tolerance and Trained Immunity. Cell metabolism. 2019.", "doi": "10.1016/j.cmet.2018.09.003", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/30293776/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30293776/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID30293776", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "IRG1/itaconate/SDH processes distinguish tolerance from β-glucan training, including human genetic variants.", "what_it_does_not_show": "Induction-stage metabolic control does not establish autonomous maintenance or a universal glycolytic phenotype.", "confounders_present": [ "Induction-stage metabolic control does not establish autonomous maintenance or a universal glycolytic phenotype." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 22, "pmid": "36999024", "title": "Transmission of stimulus-induced epigenetic changes through cell division is coupled to continuous transcription factor activity.", "citation": "Sun S, Aguirre-Gamboa R, Barreiro LB et al. Transmission of stimulus-induced epigenetic changes through cell division is coupled to continuous transcription factor activity. Frontiers in immunology. 2023.", "doi": "10.3389/fimmu.2023.1129577", "pmcid": "PMC10043173", "url": "https://pubmed.ncbi.nlm.nih.gov/36999024/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36999024/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID36999024", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph2, 2:Results:paragraph4, 2:Results:paragraph12, 2:Results:paragraph16, 2:Results:paragraph19, 2:Results:paragraph20, 2:Results:paragraph24. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "in vitro", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Immortalized macrophages retain changing molecular/function states after washout and 14 divisions; late Salmonella control parallels newly induced interferon programs.", "what_it_does_not_show": "TF necessity is inferred from expression/motif coupling, not directly tested by delayed TF loss; initial responder sorting and immortalization limit generalization; mark persistence does not prove mark copying.", "confounders_present": [ "TF necessity is inferred from expression/motif coupling, not directly tested by delayed TF loss; initial responder sorting and immortalization limit generalization; mark persistence does not prove mark copying." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Responder sorting and retroviral immortalization; not an independent primary-cell platform." ] }, { "n": 23, "pmid": "40318634", "title": "Long-term histone lactylation connects metabolic and epigenetic rewiring in innate immune memory.", "citation": "Ziogas A, Novakovic B, Ventriglia L et al. Long-term histone lactylation connects metabolic and epigenetic rewiring in innate immune memory. Cell. 2025.", "doi": "10.1016/j.cell.2025.03.048", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40318634/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40318634/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID40318634", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "H3K18 lactylation persists after washout and at 90 days after BCG; LDH/p300 inhibition attenuates training.", "what_it_does_not_show": "Exact inhibitor timing and viability controls unexamined; metabolic and p300 effects are broad, and correlation with H3K18la does not isolate that mark as the memory carrier.", "confounders_present": [ "Exact inhibitor timing and viability controls unexamined; metabolic and p300 effects are broad, and correlation with H3K18la does not isolate that mark as the memory carrier." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 24, "pmid": "42320478", "title": "Human macrophages encode stimulus-specific information of prior exposures through trained immunity.", "citation": "O'Farrell A, Niu Z, Li J et al. Human macrophages encode stimulus-specific information of prior exposures through trained immunity. Cell systems. 2026.", "doi": "10.1016/j.cels.2026.101647", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/42320478/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42320478/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID42320478", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Primary human macrophages retain stimulus-specific responses at six days, with stronger recall to similar challenges; some memories are lost by day 11.", "what_it_does_not_show": "Finite and stimulus-dependent persistence contradicts a uniform durable state; TF licensing/chromatin are associated rather than direct maintenance subtraction; same authors/design as 2025 preprint counted once.", "confounders_present": [ "Finite and stimulus-dependent persistence contradicts a uniform durable state; TF licensing/chromatin are associated rather than direct maintenance subtraction; same authors/design as 2025 preprint counted once." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Same authors and design as SciSpace 2025 preprint; one published primary report counted." ] }, { "n": 25, "pmid": "35133977", "title": "Single-cell RNA sequencing reveals induction of distinct trained-immunity programs in human monocytes.", "citation": "Zhang B, Moorlag SJ, Dominguez-Andres J et al. Single-cell RNA sequencing reveals induction of distinct trained-immunity programs in human monocytes. The Journal of clinical investigation. 2022.", "doi": "10.1172/JCI147719", "pmcid": "PMC8970681", "url": "https://pubmed.ncbi.nlm.nih.gov/35133977/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35133977/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID35133977", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Four inducers yield distinct monocyte programs/subpopulations, replicated with in vivo signatures.", "what_it_does_not_show": "Single-cell heterogeneity and patient signatures do not isolate self-maintenance or clinical protection.", "confounders_present": [ "Single-cell heterogeneity and patient signatures do not isolate self-maintenance or clinical protection." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 26, "pmid": "34320411", "title": "Establishment, maintenance, and recall of inflammatory memory.", "citation": "Larsen SB, Cowley CJ, Sajjath SM et al. Establishment, maintenance, and recall of inflammatory memory. Cell stem cell. 2021.", "doi": "10.1016/j.stem.2021.07.001", "pmcid": "PMC8500942", "url": "https://pubmed.ncbi.nlm.nih.gov/34320411/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34320411/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID34320411", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph19, 1:RESULTS:paragraph22, 1:RESULTS:paragraph26, 1:RESULTS:paragraph28. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "In epidermal stem cells, delayed STAT3 loss after resolution preserves recall; post-induction AFOS leaves memory domains accessible with homeostatic TF support.", "what_it_does_not_show": "Nonimmune tissue is a mechanistic comparator, not proof in myeloid cells; homeostatic maintenance factors are incompletely dissected.", "confounders_present": [ "Nonimmune tissue is a mechanistic comparator, not proof in myeloid cells; homeostatic maintenance factors are incompletely dissected." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 27, "pmid": "29643512", "title": "Innate immune memory in the brain shapes neurological disease hallmarks.", "citation": "Wendeln AC, Degenhardt K, Kaurani L et al. Innate immune memory in the brain shapes neurological disease hallmarks. Nature. 2018.", "doi": "10.1038/s41586-018-0023-4", "pmcid": "PMC6038912", "url": "https://pubmed.ncbi.nlm.nih.gov/29643512/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29643512/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID29643512", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Peripheral inflammatory schedules induce six-month microglial training or tolerance with opposite AD/stroke pathology effects.", "what_it_does_not_show": "Schedules and tissue context determine response; disease-transgene and persistent niche changes constrain intrinsic antigen-free maintenance.", "confounders_present": [ "Schedules and tissue context determine response; disease-transgene and persistent niche changes constrain intrinsic antigen-free maintenance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 28, "pmid": "34974067", "title": "Macrophages acquire a TNF-dependent inflammatory memory in allergic asthma.", "citation": "Lechner A, Henkel FDR, Hartung F et al. Macrophages acquire a TNF-dependent inflammatory memory in allergic asthma. The Journal of allergy and clinical immunology. 2022.", "doi": "10.1016/j.jaci.2021.11.026", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34974067/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34974067/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID34974067", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "HDM inflammation produces TNF/2-HG/PGE2-related macrophage memory; TNF blockade or myeloid Tnf loss prevents imprinting.", "what_it_does_not_show": "Allergen and disease milieu can continue; prevention does not establish delayed signal-independent maintenance.", "confounders_present": [ "Allergen and disease milieu can continue; prevention does not establish delayed signal-independent maintenance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 29, "pmid": "39413777", "title": "A distinct metabolic and epigenetic state drives trained immunity in HSC-derived macrophages from autoimmune mice.", "citation": "Mills TS, Kain B, Burchill MA et al. A distinct metabolic and epigenetic state drives trained immunity in HSC-derived macrophages from autoimmune mice. Cell stem cell. 2024.", "doi": "10.1016/j.stem.2024.09.010", "pmcid": "PMC11560650", "url": "https://pubmed.ncbi.nlm.nih.gov/39413777/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39413777/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID39413777", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph9, 1:RESULTS:paragraph11, 1:RESULTS:paragraph12, 1:RESULTS:paragraph13, 1:RESULTS:paragraph14, 1:RESULTS:paragraph17. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Stringently purified autoimmune-exposed LT-HSCs yield trained macrophages 18 weeks after transfer without spontaneous recipient autoimmune activity or lineage skewing.", "what_it_does_not_show": "Transferred progeny have reduced metabolism/accessibility despite increased killing/cytokines; irradiation and selection remain; not direct mark-copying or universal metabolic necessity.", "confounders_present": [ "Transferred progeny have reduced metabolism/accessibility despite increased killing/cytokines; irradiation and selection remain; not direct mark-copying or universal metabolic necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 30, "pmid": "37597510", "title": "Epigenetic memory of coronavirus infection in innate immune cells and their progenitors.", "citation": "Cheong JG, Ravishankar A, Sharma S et al. Epigenetic memory of coronavirus infection in innate immune cells and their progenitors. Cell. 2023.", "doi": "10.1016/j.cell.2023.07.019", "pmcid": "PMC10638861", "url": "https://pubmed.ncbi.nlm.nih.gov/37597510/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37597510/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID37597510", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Severe-COVID HSPC/myeloid epigenetic changes persist months to one year; early IL6 contributes in a mouse model.", "what_it_does_not_show": "Human infection/severity and residual inflammation are not randomized; cross-compartment signatures are not clonal inheritance or complete ligand exclusion.", "confounders_present": [ "Human infection/severity and residual inflammation are not randomized; cross-compartment signatures are not clonal inheritance or complete ligand exclusion." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 31, "pmid": "38787963", "title": "Heart failure promotes multimorbidity through innate immune memory.", "citation": "Nakayama Y, Fujiu K, Oshima T et al. Heart failure promotes multimorbidity through innate immune memory. Science immunology. 2024.", "doi": "10.1126/sciimmunol.ade3814", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38787963/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38787963/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID38787963", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Heart-failure donor marrow transmits cardiac dysfunction and altered susceptibility, with HSC TGFβ changes.", "what_it_does_not_show": "Whole marrow/niche and disease carryover can coexist; TGFβ perturbation is not locus-specific epigenetic inheritance.", "confounders_present": [ "Whole marrow/niche and disease carryover can coexist; TGFβ perturbation is not locus-specific epigenetic inheritance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 32, "pmid": "39043180", "title": "Innate immune memory after brain injury drives inflammatory cardiac dysfunction.", "citation": "Simats A, Zhang S, Messerer D et al. Innate immune memory after brain injury drives inflammatory cardiac dysfunction. Cell. 2024.", "doi": "10.1016/j.cell.2024.06.028", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39043180/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39043180/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID39043180", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Post-stroke myeloid changes transmit cardiac dysfunction; IL1β neutralization/CCR2/5 blockade prevent remote cardiac injury.", "what_it_does_not_show": "Intervention timing and whole-cell milieu do not isolate late autonomous memory; patient concordance is observational.", "confounders_present": [ "Intervention timing and whole-cell milieu do not isolate late autonomous memory; patient concordance is observational." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 33, "pmid": "40053582", "title": "Trained immunity causes myeloid cell hypercoagulability.", "citation": "Rehill AM, McCluskey S, Ledwith AE et al. Trained immunity causes myeloid cell hypercoagulability. Science advances. 2025.", "doi": "10.1126/sciadv.ads0105", "pmcid": "PMC11887800", "url": "https://pubmed.ncbi.nlm.nih.gov/40053582/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40053582/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID40053582", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "β-glucan/heme training increases myeloid procoagulant responses and four-week splenic activity via sphingomyelinase/tissue-factor decryption.", "what_it_does_not_show": "Enhanced responsiveness can be harmful; systemic thrombotic clinical outcomes and autonomous maintenance are not demonstrated.", "confounders_present": [ "Enhanced responsiveness can be harmful; systemic thrombotic clinical outcomes and autonomous maintenance are not demonstrated." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 34, "pmid": "39515317", "title": "Interleukin-1β induces trained innate immunity in human hematopoietic progenitor cells in vitro.", "citation": "Flores-Gomez D, Hobo W, van Ens D et al. Interleukin-1β induces trained innate immunity in human hematopoietic progenitor cells in vitro. Stem cell reports. 2024.", "doi": "10.1016/j.stemcr.2024.09.004", "pmcid": "PMC11751800", "url": "https://pubmed.ncbi.nlm.nih.gov/39515317/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39515317/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID39515317", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Four-hour IL1β exposure of human marrow progenitors produces monocyte offspring with enhanced heterologous cytokines and metabolism.", "what_it_does_not_show": "Culture expansion/differentiation and normal growth signaling remain; no in vivo transplant or delayed maintenance blockade.", "confounders_present": [ "Culture expansion/differentiation and normal growth signaling remain; no in vivo transplant or delayed maintenance blockade." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 35, "pmid": "39178113", "title": "Trained immunity is regulated by T cell-induced CD40-TRAF6 signaling.", "citation": "Jacobs MME, Maas RJF, Jonkman I et al. Trained immunity is regulated by T cell-induced CD40-TRAF6 signaling. Cell reports. 2024.", "doi": "10.1016/j.celrep.2024.114664", "pmcid": "PMC11536040", "url": "https://pubmed.ncbi.nlm.nih.gov/39178113/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39178113/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID39178113", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "T-cell CD40-TRAF6 regulates myeloid functional/metabolic/chromatin training; combined blockade promotes graft acceptance.", "what_it_does_not_show": "Adaptive crosstalk and combined CTLA4-Ig effects prevent attributing outcome solely to cell-autonomous innate memory.", "confounders_present": [ "Adaptive crosstalk and combined CTLA4-Ig effects prevent attributing outcome solely to cell-autonomous innate memory." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 36, "pmid": "35642634", "title": "Lymphocyte crosstalk is required for monocyte-intrinsic trained immunity to Plasmodium falciparum.", "citation": "Crabtree JN, Caffrey DR, de Souza Silva L et al. Lymphocyte crosstalk is required for monocyte-intrinsic trained immunity to Plasmodium falciparum. The Journal of clinical investigation. 2022.", "doi": "10.1172/JCI139298", "pmcid": "PMC9151696", "url": "https://pubmed.ncbi.nlm.nih.gov/35642634/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35642634/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID35642634", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "in vitro", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Malaria-trained purified monocytes fail without lymphocytes; transwell CD4/IFNγ restores heterologous cytokine responses.", "what_it_does_not_show": "This tests induction crosstalk, not proof that every established memory requires ongoing lymphocyte signals.", "confounders_present": [ "This tests induction crosstalk, not proof that every established memory requires ongoing lymphocyte signals." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 37, "pmid": "36456739", "title": "Parenteral BCG vaccine induces lung-resident memory macrophages and trained immunity via the gut-lung axis.", "citation": "Jeyanathan M, Vaseghi-Shanjani M, Afkhami S et al. Parenteral BCG vaccine induces lung-resident memory macrophages and trained immunity via the gut-lung axis. Nature immunology. 2022.", "doi": "10.1038/s41590-022-01354-4", "pmcid": "PMC9747617", "url": "https://pubmed.ncbi.nlm.nih.gov/36456739/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36456739/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID37161093" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID36456739", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Subcutaneous BCG induces AM memory via gut microbiome/metabolite changes and mycobacterial dissemination, independently of circulating monocytes.", "what_it_does_not_show": "Distal persistent upstream changes provide an alternative to direct cell-intrinsic induction; linked correction unexamined.", "confounders_present": [ "Distal persistent upstream changes provide an alternative to direct cell-intrinsic induction; linked correction unexamined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 38, "pmid": "35235831", "title": "BCG vaccination provides protection against IAV but not SARS-CoV-2.", "citation": "Kaufmann E, Khan N, Tran KA et al. BCG vaccination provides protection against IAV but not SARS-CoV-2. Cell reports. 2022.", "doi": "10.1016/j.celrep.2022.110502", "pmcid": "PMC8858710", "url": "https://pubmed.ncbi.nlm.nih.gov/35235831/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35235831/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID35235831", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "BCG protects against influenza but not SARS-CoV-2, with different tissue tropism and cytokine responses.", "what_it_does_not_show": "Pathogen-specific animal benefit cannot establish universal human heterologous protection or purely innate mediation.", "confounders_present": [ "Pathogen-specific animal benefit cannot establish universal human heterologous protection or purely innate mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 39, "pmid": "39383035", "title": "LPS-induced lung tissue-resident trained innate immunity provides differential protection against pneumococci and SARS-CoV-2.", "citation": "Kang A, Ye G, Afkhami S et al. LPS-induced lung tissue-resident trained innate immunity provides differential protection against pneumococci and SARS-CoV-2. Cell reports. 2024.", "doi": "10.1016/j.celrep.2024.114849", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39383035/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39383035/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID39383035", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Acute LPS generates persistent resident-AM phenotypes and pneumococcal protection with minimal SARS-CoV-2 protection.", "what_it_does_not_show": "Whole-lung response and stable population size do not isolate same-cell autonomous memory or universal protection.", "confounders_present": [ "Whole-lung response and stable population size do not isolate same-cell autonomous memory or universal protection." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 40, "pmid": "36807642", "title": "Influenza-trained mucosal-resident alveolar macrophages confer long-term antitumor immunity in the lungs.", "citation": "Wang T, Zhang J, Wang Y et al. Influenza-trained mucosal-resident alveolar macrophages confer long-term antitumor immunity in the lungs. Nature immunology. 2023.", "doi": "10.1038/s41590-023-01428-x", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36807642/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36807642/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID36807642", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Influenza-experienced AMs exert long-lasting tissue-specific antitumor effects with IFNγ/NK induction dependence.", "what_it_does_not_show": "Human tumor association is observational; induction dependence is not continued maintenance dependence.", "confounders_present": [ "Human tumor association is observational; induction dependence is not continued maintenance dependence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 41, "pmid": "37615937", "title": "Trained immunity of alveolar macrophages enhances injury resolution via KLF4-MERTK-mediated efferocytosis.", "citation": "Chakraborty S, Singh A, Wang L et al. Trained immunity of alveolar macrophages enhances injury resolution via KLF4-MERTK-mediated efferocytosis. The Journal of experimental medicine. 2023.", "doi": "10.1084/jem.20221388", "pmcid": "PMC10450795", "url": "https://pubmed.ncbi.nlm.nih.gov/37615937/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37615937/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID37615937", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Lineage tracing and AM transfer identify a KLF4/MERTK efferocytic trained subset that limits lung injury.", "what_it_does_not_show": "Subset expansion/differentiation and tissue niche contribute; anti-inflammatory resolution differs from simply higher cytokine secretion.", "confounders_present": [ "Subset expansion/differentiation and tissue niche contribute; anti-inflammatory resolution differs from simply higher cytokine secretion." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 42, "pmid": "32433977", "title": "β-Glucan Induces Protective Trained Immunity against Mycobacterium tuberculosis Infection: A Key Role for IL-1.", "citation": "Moorlag SJCFM, Khan N, Novakovic B et al. β-Glucan Induces Protective Trained Immunity against Mycobacterium tuberculosis Infection: A Key Role for IL-1. Cell reports. 2020.", "doi": "10.1016/j.celrep.2020.107634", "pmcid": "PMC7242907", "url": "https://pubmed.ncbi.nlm.nih.gov/32433977/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32433977/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID32433977", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "β-glucan protects against Mtb and expands myeloid progenitors; IL1R deficiency abolishes protection.", "what_it_does_not_show": "Constitutive receptor deficiency and early stimulus do not distinguish induction/maintenance; human ex vivo response is not clinical efficacy.", "confounders_present": [ "Constitutive receptor deficiency and early stimulus do not distinguish induction/maintenance; human ex vivo response is not clinical efficacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 43, "pmid": "25880788", "title": "Defective trained immunity in patients with STAT-1-dependent chronic mucocutaneaous candidiasis.", "citation": "Ifrim DC, Quintin J, Meerstein-Kessel L et al. Defective trained immunity in patients with STAT-1-dependent chronic mucocutaneaous candidiasis. Clinical and experimental immunology. 2015.", "doi": "10.1111/cei.12642", "pmcid": "PMC4557379", "url": "https://pubmed.ncbi.nlm.nih.gov/25880788/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25880788/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID25880788", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "STAT1 CMC patient cells have Candida-specific training defects while STAT3 HIES cells train normally.", "what_it_does_not_show": "Genetic pleiotropy and pathogen specificity prevent a universal innate-memory instrument or proof of antigen-free maintenance.", "confounders_present": [ "Genetic pleiotropy and pathogen specificity prevent a universal innate-memory instrument or proof of antigen-free maintenance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 44, "pmid": "32716363", "title": "β-Glucan-induced reprogramming of human macrophages inhibits NLRP3 inflammasome activation in cryopyrinopathies.", "citation": "Camilli G, Bohm M, Piffer AC et al. β-Glucan-induced reprogramming of human macrophages inhibits NLRP3 inflammasome activation in cryopyrinopathies. The Journal of clinical investigation. 2020.", "doi": "10.1172/JCI134778", "pmcid": "PMC7456248", "url": "https://pubmed.ncbi.nlm.nih.gov/32716363/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32716363/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID32716363", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "β-glucan-experienced human macrophages reduce NLRP3/caspase1/IL1β responses, including CAPS patient cells.", "what_it_does_not_show": "Cytokine attenuation can coexist with memory; ex vivo anti-inflammatory effects do not establish clinical disease trajectory.", "confounders_present": [ "Cytokine attenuation can coexist with memory; ex vivo anti-inflammatory effects do not establish clinical disease trajectory." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 45, "pmid": "33826894", "title": "The anti-inflammatory cytokine interleukin-37 is an inhibitor of trained immunity.", "citation": "Cavalli G, Tengesdal IW, Gresnigt M et al. The anti-inflammatory cytokine interleukin-37 is an inhibitor of trained immunity. Cell reports. 2021.", "doi": "10.1016/j.celrep.2021.108955", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33826894/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33826894/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33826894", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "IL37 reverses training-associated metabolic/mark changes and reduces Candida protection in models.", "what_it_does_not_show": "Broad anti-inflammatory effects and treatment timing do not isolate a specific self-maintaining histone carrier.", "confounders_present": [ "Broad anti-inflammatory effects and treatment timing do not isolate a specific self-maintaining histone carrier." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 46, "pmid": "34740960", "title": "β-Glucan Induces Distinct and Protective Innate Immune Memory in Differentiated Macrophages.", "citation": "Stothers CL, Burelbach KR, Owen AM et al. β-Glucan Induces Distinct and Protective Innate Immune Memory in Differentiated Macrophages. Journal of immunology (Baltimore, Md. : 1950). 2021.", "doi": "10.4049/jimmunol.2100107", "pmcid": "PMC8612974", "url": "https://pubmed.ncbi.nlm.nih.gov/34740960/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34740960/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID34740960", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "β-glucan-trained differentiated macrophage transfer protects Pseudomonas; sustained metabolic/chemokine state is independent of Dectin1/TLR2 here.", "what_it_does_not_show": "Constitutive chemokine secretion differs from a fully resting state; ligand clearance and feedback remain unresolved; receptor dependence differs by model.", "confounders_present": [ "Constitutive chemokine secretion differs from a fully resting state; ligand clearance and feedback remain unresolved; receptor dependence differs by model." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 47, "pmid": "40552375", "title": "BCG-Derived Outer Membrane Vesicles Induce TLR2-Dependent Trained Immunity to Protect Against Polymicrobial Sepsis.", "citation": "Gong Y, Hao W, Xu L et al. BCG-Derived Outer Membrane Vesicles Induce TLR2-Dependent Trained Immunity to Protect Against Polymicrobial Sepsis. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2025.", "doi": "10.1002/advs.202504101", "pmcid": "PMC12499445", "url": "https://pubmed.ncbi.nlm.nih.gov/40552375/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40552375/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID40552375", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "BCG outer-membrane vesicles induce TLR2-dependent progenitor expansion/metabolism and sepsis protection.", "what_it_does_not_show": "Vesicle cargo/duration and experimental sepsis do not establish long-term autonomous maintenance or human safety/benefit.", "confounders_present": [ "Vesicle cargo/duration and experimental sepsis do not establish long-term autonomous maintenance or human safety/benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 48, "pmid": "34603295", "title": "Trained Immunity Confers Prolonged Protection From Listeriosis.", "citation": "Théroude C, Reverte M, Heinonen T et al. Trained Immunity Confers Prolonged Protection From Listeriosis. Frontiers in immunology. 2021.", "doi": "10.3389/fimmu.2021.723393", "pmcid": "PMC8484647", "url": "https://pubmed.ncbi.nlm.nih.gov/34603295/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34603295/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID34603295", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "β-glucan nine weeks before Listeria increases antimicrobial myeloid responses and survival.", "what_it_does_not_show": "Elapsed time alone does not exclude retained particulate ligand or ongoing niche stimulation; multiple population/metabolic changes coexist.", "confounders_present": [ "Elapsed time alone does not exclude retained particulate ligand or ongoing niche stimulation; multiple population/metabolic changes coexist." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 49, "pmid": "37697097", "title": "Control of nutrient uptake by IRF4 orchestrates innate immune memory.", "citation": "Santosa EK, Kim H, Rückert T et al. Control of nutrient uptake by IRF4 orchestrates innate immune memory. Nature immunology. 2023.", "doi": "10.1038/s41590-023-01620-z", "pmcid": "PMC11098052", "url": "https://pubmed.ncbi.nlm.nih.gov/37697097/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37697097/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID37697097", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "IRF4 controls metabolic uptake and memory expansion of virus-specific NK cells.", "what_it_does_not_show": "Antigen-specific NK memory is a comparator, not demonstration of nonspecific trained myeloid memory; generic survival effects constrain mechanism.", "confounders_present": [ "Antigen-specific NK memory is a comparator, not demonstration of nonspecific trained myeloid memory; generic survival effects constrain mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 50, "pmid": "30787276", "title": "Outcomes of controlled human malaria infection after BCG vaccination.", "citation": "Walk J, de Bree LCJ, Graumans W et al. Outcomes of controlled human malaria infection after BCG vaccination. Nature communications. 2019.", "doi": "10.1038/s41467-019-08659-3", "pmcid": "PMC6382772", "url": "https://pubmed.ncbi.nlm.nih.gov/30787276/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30787276/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID30787276", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Randomized human BCG/malaria challenge alters activation and yields earlier/more severe symptoms; parasitemia inversely correlates with activation.", "what_it_does_not_show": "20 volunteers and correlational mediation do not establish clinical protection; enhanced activation can accompany adverse effects.", "confounders_present": [ "20 volunteers and correlational mediation do not establish clinical protection; enhanced activation can accompany adverse effects." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 51, "pmid": "29324233", "title": "BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity.", "citation": "Arts RJW, Moorlag SJCFM, Novakovic B et al. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell host & microbe. 2018.", "doi": "10.1016/j.chom.2017.12.010", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29324233/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29324233/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID29324233", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Randomized BCG attenuated-yellow-fever challenge reduces viremia with IL1β-associated monocyte changes.", "what_it_does_not_show": "Vaccine-strain viremia is not ordinary clinical disease; correlated cytokines do not prove innate mediation or autonomous persistence.", "confounders_present": [ "Vaccine-strain viremia is not ordinary clinical disease; correlated cytokines do not prove innate mediation or autonomous persistence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 52, "pmid": "32941801", "title": "Activate: Randomized Clinical Trial of BCG Vaccination against Infection in the Elderly.", "citation": "Giamarellos-Bourboulis EJ, Tsilika M, Moorlag S et al. Activate: Randomized Clinical Trial of BCG Vaccination against Infection in the Elderly. Cell. 2020.", "doi": "10.1016/j.cell.2020.08.051", "pmcid": "PMC7462457", "url": "https://pubmed.ncbi.nlm.nih.gov/32941801/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32941801/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID32941801", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "ACTIVATE interim report of 198 elderly patients finds longer time to first infection and fewer infections with BCG.", "what_it_does_not_show": "Small interim analysis/probable viral diagnoses and clinical heterogeneity limit generalization; no selective trained-memory mediation test.", "confounders_present": [ "Small interim analysis/probable viral diagnoses and clinical heterogeneity limit generalization; no selective trained-memory mediation test." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 53, "pmid": "40983468", "title": "Effect of BCG Danish and oral polio vaccine on neonatal mortality in newborn babies weighing less than 2000 g in India: multicentre open label randomised controlled trial (BLOW2).", "citation": "Adhisivam B, Kamalarathnam C, Bhat BV et al. Effect of BCG Danish and oral polio vaccine on neonatal mortality in newborn babies weighing less than 2000 g in India: multicentre open label randomised controlled trial (BLOW2). BMJ (Clinical research ed.). 2025.", "doi": "10.1136/bmj-2025-084745", "pmcid": "PMC12452093", "url": "https://pubmed.ncbi.nlm.nih.gov/40983468/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40983468/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID40983468", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "BLOW2 randomizes 5420 NICU newborns under 2000 g to early BCG plus OPV and reduces neonatal all-cause mortality.", "what_it_does_not_show": "Combined vaccines cannot isolate BCG or trained innate mechanism; infection-death secondary outcome added during trial; setting/timing-specific clinical benefit.", "confounders_present": [ "Combined vaccines cannot isolate BCG or trained innate mechanism; infection-death secondary outcome added during trial; setting/timing-specific clinical benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 54, "pmid": "25210141", "title": "Heterologous immunological effects of early BCG vaccination in low-birth-weight infants in Guinea-Bissau: a randomized-controlled trial.", "citation": "Jensen KJ, Larsen N, Biering-Sørensen S et al. Heterologous immunological effects of early BCG vaccination in low-birth-weight infants in Guinea-Bissau: a randomized-controlled trial. The Journal of infectious diseases. 2015.", "doi": "10.1093/infdis/jiu508", "pmcid": "PMC4340366", "url": "https://pubmed.ncbi.nlm.nih.gov/25210141/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25210141/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "Guinea-Bissau-LBW-BCG-trial-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Randomized low-birthweight infant BCG substudy shows increased heterologous cytokines four weeks later.", "what_it_does_not_show": "Same Guinea-Bissau trial platform and immune substudy do not establish cytokine mediation of mortality or independent clinical replication.", "confounders_present": [ "Same Guinea-Bissau trial platform and immune substudy do not establish cytokine mediation of mortality or independent clinical replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Guinea-Bissau immune substudy shares the early-BCG clinical trial platform." ] }, { "n": 55, "pmid": "27429204", "title": "Nonspecific effect of BCG vaccination at birth on early childhood infections: a randomized, clinical multicenter trial.", "citation": "Kjærgaard J, Birk NM, Nissen TN et al. Nonspecific effect of BCG vaccination at birth on early childhood infections: a randomized, clinical multicenter trial. Pediatric research. 2016.", "doi": "10.1038/pr.2016.142", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/27429204/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27429204/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID27429204", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "Danish neonatal randomized trial finds no overall benefit in parent-reported infections through 13 months.", "what_it_does_not_show": "Maternal-BCG early subgroup is not the overall endpoint; low-mortality context may differ from NICU/LBW settings.", "confounders_present": [ "Maternal-BCG early subgroup is not the overall endpoint; low-mortality context may differ from NICU/LBW settings." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 56, "pmid": "37774494", "title": "Using BCG Vaccine to Enhance Nonspecific Protection of Health Care Workers During the COVID-19 Pandemic: A Randomized Controlled Trial.", "citation": "Madsen AMR, Schaltz-Buchholzer F, Nielsen S et al. Using BCG Vaccine to Enhance Nonspecific Protection of Health Care Workers During the COVID-19 Pandemic: A Randomized Controlled Trial. The Journal of infectious diseases. 2024.", "doi": "10.1093/infdis/jiad422", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/37774494/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37774494/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID37774494", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "1221 Danish healthcare workers show no overall BCG benefit for absenteeism, COVID or hospitalization.", "what_it_does_not_show": "Secondary revaccination analyses diverge and have wide intervals; clinical null does not disprove all cellular memory.", "confounders_present": [ "Secondary revaccination analyses diverge and have wide intervals; clinical null does not disprove all cellular memory." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 57, "pmid": "37099341", "title": "Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers.", "citation": "Pittet LF, Messina NL, Orsini F et al. Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers. The New England journal of medicine. 2023.", "doi": "10.1056/NEJMoa2212616", "pmcid": "PMC10497190", "url": "https://pubmed.ncbi.nlm.nih.gov/37099341/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37099341/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "BRACE-stage2-and-combined-stage-platform", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Methods, 1:Results. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "BRACE stage-2 randomized 3988 healthcare workers shows no lower six-month symptomatic/severe COVID risk.", "what_it_does_not_show": "Early recruitment stop and vaccine-related censoring limit precision; severe chiefly means incapacitated three days, not hospital disease; no verified selective innate engagement in this report.", "confounders_present": [ "Early recruitment stop and vaccine-related censoring limit precision; severe chiefly means incapacitated three days, not hospital disease; no verified selective innate engagement in this report." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 58, "pmid": "39127450", "title": "BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial.", "citation": "Messina NL, Pittet LF, McDonald E et al. BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial. The Journal of infection. 2024.", "doi": "10.1016/j.jinf.2024.106245", "pmcid": "PMC11409612", "url": "https://pubmed.ncbi.nlm.nih.gov/39127450/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39127450/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "BRACE-stage2-and-combined-stage-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "BRACE 12-month follow-up shows increased symptomatic COVID and no severe/breakthrough benefit.", "what_it_does_not_show": "Same trial as six-month report, not independent replication; severity definition and evolving vaccination/exposure limit universal conclusions.", "confounders_present": [ "Same trial as six-month report, not independent replication; severity definition and evolving vaccination/exposure limit universal conclusions." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 59, "pmid": "36976004", "title": "BCG Vaccination of Health Care Workers Does Not Reduce SARS-CoV-2 Infections nor Infection Severity or Duration: a Randomized Placebo-Controlled Trial.", "citation": "Claus J, Ten Doesschate T, Gumbs C et al. BCG Vaccination of Health Care Workers Does Not Reduce SARS-CoV-2 Infections nor Infection Severity or Duration: a Randomized Placebo-Controlled Trial. mBio. 2023.", "doi": "10.1128/mbio.00356-23", "pmcid": "PMC10128007", "url": "https://pubmed.ncbi.nlm.nih.gov/36976004/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36976004/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID36976004", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "Dutch healthcare-worker randomization with serologic detection shows no infection/duration/severity benefit despite early antibody effects.", "what_it_does_not_show": "Small hospitalized counts and clinical context constrain severe-disease estimates; antibody enhancement is not clinical or innate-memory mediation.", "confounders_present": [ "Small hospitalized counts and clinical context constrain severe-disease estimates; antibody enhancement is not clinical or innate-memory mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 60, "pmid": "36736662", "title": "Bacillus Calmette-Guérin vaccine for prevention of COVID-19 and other respiratory tract infections in older adults with comorbidities: a randomized controlled trial.", "citation": "Koekenbier EL, Fohse K, van de Maat JS et al. Bacillus Calmette-Guérin vaccine for prevention of COVID-19 and other respiratory tract infections in older adults with comorbidities: a randomized controlled trial. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2023.", "doi": "10.1016/j.cmi.2023.01.019", "pmcid": "PMC9892323", "url": "https://pubmed.ncbi.nlm.nih.gov/36736662/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36736662/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID36736662", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "BCG-PRIME randomizes 6112 older comorbid adults and finds no COVID or clinically relevant respiratory benefit.", "what_it_does_not_show": "Six-month regimen-specific null does not eliminate every clinical context or demonstrate selective mechanistic engagement.", "confounders_present": [ "Six-month regimen-specific null does not eliminate every clinical context or demonstrate selective mechanistic engagement." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 61, "pmid": "38774675", "title": "Bacille Calmette-Guérin vaccination to prevent febrile and respiratory illness in adults (BRACE): secondary outcomes of a randomised controlled phase 3 trial.", "citation": "Pittet LF, Messina NL, McDonald E et al. Bacille Calmette-Guérin vaccination to prevent febrile and respiratory illness in adults (BRACE): secondary outcomes of a randomised controlled phase 3 trial. EClinicalMedicine. 2024.", "doi": "10.1016/j.eclinm.2024.102616", "pmcid": "PMC11106519", "url": "https://pubmed.ncbi.nlm.nih.gov/38774675/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38774675/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "BRACE-stage2-and-combined-stage-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "BRACE combined-stage secondary analysis reports modestly more febrile/respiratory illness without severe-disease benefit.", "what_it_does_not_show": "6828 combined stages differs from 3988 stage-2 primary denominator; same trial, not independent cohort.", "confounders_present": [ "6828 combined stages differs from 3988 stage-2 primary denominator; same trial, not independent cohort." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 62, "pmid": "29579158", "title": "Early BCG-Denmark and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial.", "citation": "Biering-Sørensen S, Aaby P, Lund N et al. Early BCG-Denmark and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2017.", "doi": "10.1093/cid/cix525", "pmcid": "PMC5849087", "url": "https://pubmed.ncbi.nlm.nih.gov/29579158/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29579158/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID29579158", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Third Guinea-Bissau early-BCG trial has lower infection-related neonatal mortality and favorable pooled neonatal estimate.", "what_it_does_not_show": "Its standalone primary neonatal all-cause contrast is nonsignificant; polio-campaign censoring and pooled trials must be separated; mechanism unisolated.", "confounders_present": [ "Its standalone primary neonatal all-cause contrast is nonsignificant; polio-campaign censoring and pooled trials must be separated; mechanism unisolated." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 63, "pmid": "21673035", "title": "Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period?", "citation": "Aaby P, Roth A, Ravn H et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? The Journal of infectious diseases. 2011.", "doi": "10.1093/infdis/jir240", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/21673035/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21673035/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "Guinea-Bissau-LBW-BCG-trial-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Early BCG in 2320 low-birthweight infants has a favorable four-week secondary mortality contrast.", "what_it_does_not_show": "Primary infant mortality is nonsignificant; neonatal secondary effect and subgroup weights do not turn the primary endpoint positive or establish autonomous training.", "confounders_present": [ "Primary infant mortality is nonsignificant; neonatal secondary effect and subgroup weights do not turn the primary endpoint positive or establish autonomous training." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 69, "verified": 69, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC2", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Histone mark co-occurrence alone", "specific_trigger": "Induction-stage metabolic nodes causally contribute in defined systems, but histone co-occurrence, broad p300/LDH inhibition and TF deletion do not isolate a specific inheritable chromatin carrier. The conjunctive histone-encoding claim remains Γ under rubric 03; metabolic contribution alone is stronger. A purified autoimmune HSC transfer yields enhanced function despite reduced metabolism, excluding universal increased glycolysis as the carrier.", "resulting_ceiling": "Γ" }, { "subclaim_id": "SC5", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Correlational human data plus in vitro mechanism", "specific_trigger": "Clinical heterologous benefit occurs in defined vaccination contexts, but the examined trials do not selectively establish trained innate memory as the mediator. Combined BCG–OPV neonatal benefit, interim elderly infection benefit and attenuated yellow-fever viremia contrasts cannot be merged with adult COVID nulls into universal protection. Clinical efficacy in its tested setting can be Ε; trained-memory-specific clinical mediation is Γ.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Innate immune cells and their hematopoietic progenitors acquire intrinsic, long-lasting, autonomously maintained epigenetic and metabolic memory that enhances responses to later heterologous challenges.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "Rubric 05 governs the immune phenomenon, conditional persistence and clinical scope. Rubric 03 separately governs the conjunctive SC2 histone-encoding mechanism and its literal co-occurrence cap. Cell-transfer evidence is not re-capped merely because another leg is associative. Conversely, transfer of function does not by itself identify a histone carrier. The primary aggregation was registered before retrieval; Γ weakest-link sensitivity is retained beside Ε rather than hidden.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Cell-type-specific conditional knockout or depletion\n- Pathway-specific blockade (not broad immunosuppression) changing disease course\n- Human targeted therapy with mechanistic alignment showing disease-modifying effect", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID22988082, PMID22901542, PMID25258083, PMID29328910, PMID29328912, PMID35483374, PMID29328911, PMID34255973, PMID32544459, PMID33207187, PMID30433869, PMID35856089, PMID33125891, PMID27863248, PMID30293776, PMID36999024, PMID42320478, PMID35133977, PMID29643512, PMID34974067, PMID39413777, PMID38787963, PMID39043180, PMID40053582, PMID39515317, PMID39178113, PMID35642634, PMID36456739, PMID35235831, PMID39383035, PMID36807642, PMID37615937, PMID32433977, PMID25880788, PMID32716363, PMID33826894, PMID34740960, PMID40552375, PMID34603295, PMID37697097, PMID30787276, PMID29324233, PMID25210141", "gamma_hard_rules_triggered": [ "Histone marks and chromatin accessibility alone do not establish a memory carrier.", "Induction-stage blockade is not delayed maintenance necessity.", "Whole-body clinical benefit does not identify the trained-innate mediator.", "Purified transfer with functional challenge crosses a different, context-specific boundary than isolated ex vivo cytokines." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Multiple distinct causal manipulations establish altered heterologous innate responses, including lymphocyte-deficient protection, primary human vaccination/challenge and transferred cells. Responses may be protective, harmful or tolerant; enhanced cytokines are not universal benefit. Independent assay/context classes support Ζ for the phenomenon within defined settings.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Endogenous degron of a condensate component with matched rescue, AND evidence that the specific condensate state (not generic protein loss) drives the phenotype\n- Locus-specific disruption of looping with locus-specific effect\n- Combinatorial histone-mark perturbation showing direct output dependence\n- Critically: specificity against cell-cycle collapse, global transcriptional collapse, and replication stress must be demonstrated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID22988082, PMID22901542, PMID25258083, PMID27926861, PMID27866838, PMID29328908, PMID29328910, PMID32169166, PMID29328911, PMID34255973, PMID32544459, PMID39153479, PMID33207187, PMID35856089, PMID33125891, PMID27863248, PMID30293776, PMID36999024, PMID40318634, PMID42320478, PMID35133977, PMID34320411, PMID29643512, PMID34974067, PMID39413777, PMID40053582, PMID39178113, PMID32433977, PMID25880788, PMID32716363, PMID33826894, PMID34740960, PMID40552375, PMID37697097, PMID29324233", "gamma_hard_rules_triggered": [ "Histone mark co-occurrence alone; broad enzyme/TF interventions fail carrier specificity." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Induction-stage metabolic nodes causally contribute in defined systems, but histone co-occurrence, broad p300/LDH inhibition and TF deletion do not isolate a specific inheritable chromatin carrier. The conjunctive histone-encoding claim remains Γ under rubric 03; metabolic contribution alone is stronger. A purified autoimmune HSC transfer yields enhanced function despite reduced metabolism, excluding universal increased glycolysis as the carrier.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Cell-type-specific conditional knockout or depletion\n- Pathway-specific blockade (not broad immunosuppression) changing disease course\n- Human targeted therapy with mechanistic alignment showing disease-modifying effect", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID22988082, PMID29328908, PMID29328910, PMID29328912, PMID32169166, PMID35483374, PMID29328911, PMID34255973, PMID32544459, PMID39153479, PMID30433869, PMID35856089, PMID36999024, PMID40318634, PMID42320478, PMID34320411, PMID29643512, PMID34974067, PMID39413777, PMID38787963, PMID39043180, PMID39515317, PMID39178113, PMID35642634, PMID36456739, PMID39383035, PMID36807642, PMID37615937, PMID34740960, PMID34603295", "gamma_hard_rules_triggered": [ "None for conditional purified-cell persistence; antigen-free universal scope remains unestablished." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Purified LT-HSC transfer after resolved periodontitis and independent stringent autoimmune LT-HSC transfer into recipients without spontaneous autoimmune activity support donor-cell intrinsic persistence away from the original tissue input for months. This crosses the context-specific Ε boundary. It does not establish universal absence of retained molecular ligands, complete independence from recipient niches or normal intracellular maintenance, or permanent mark copying. Continued homeostatic TF activity alone does not refute original-inducer independence. Stronger signal/antigen exclusion remains an unmet scope expansion.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC4", "field_valid_perturbation_quote": "\n- Cell-type-specific conditional knockout or depletion\n- Pathway-specific blockade (not broad immunosuppression) changing disease course\n- Human targeted therapy with mechanistic alignment showing disease-modifying effect", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID29328910, PMID29328912, PMID32169166, PMID35483374, PMID29328911, PMID34255973, PMID32544459, PMID39153479, PMID33207187, PMID33125891, PMID36999024, PMID39413777, PMID38787963, PMID39043180, PMID39515317, PMID32433977, PMID40552375, PMID34603295", "gamma_hard_rules_triggered": [ "Histone marks and chromatin accessibility alone do not establish a memory carrier.", "Induction-stage blockade is not delayed maintenance necessity.", "Whole-body clinical benefit does not identify the trained-innate mediator.", "Purified transfer with functional challenge crosses a different, context-specific boundary than isolated ex vivo cytokines." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Purified donor HSCs yield altered descendants and challenge responses after 12–18 weeks, with chimerism and lineage controls. The autoimmune experiment preserves overall lineage proportions, showing that differentiation bias is not the sole explanation. Irradiated niches, clonal selection and no direct mark copying limit the broader mechanistic inference to Ε. Human HSPC/monocyte concordance does not constitute human lineage tracing.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC5", "field_valid_perturbation_quote": "\n- Cell-type-specific conditional knockout or depletion\n- Pathway-specific blockade (not broad immunosuppression) changing disease course\n- Human targeted therapy with mechanistic alignment showing disease-modifying effect", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID22988082, PMID35856089, PMID35235831, PMID39383035, PMID30787276, PMID29324233, PMID32941801, PMID40983468, PMID25210141, PMID27429204, PMID37774494, PMID37099341, PMID39127450, PMID36976004, PMID36736662, PMID38774675, PMID29579158, PMID21673035", "gamma_hard_rules_triggered": [ "Randomized efficacy is available; innate-memory mediation remains correlational or laboratory-supported." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Clinical heterologous benefit occurs in defined vaccination contexts, but the examined trials do not selectively establish trained innate memory as the mediator. Combined BCG–OPV neonatal benefit, interim elderly infection benefit and attenuated yellow-fever viremia contrasts cannot be merged with adult COVID nulls into universal protection. Clinical efficacy in its tested setting can be Ε; trained-memory-specific clinical mediation is Γ.", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.", "satisfied": "yes", "supporting_evidence": [ "[1] BCG-vaccinated volunteers show heterologous monocyte cytokine responses for three months; NOD2-dependent experiments and SCID Candida survival support innate contribution.", "[2] Candida/β-glucan pretreatment protects lymphocyte-deficient mice in a monocyte-dependent manner and dectin-1/Raf-1 signaling contributes.", "[3] Akt/mTOR/HIF-1α perturbations block training; myeloid HIF-1α loss abolishes trained sepsis protection.", "[8] Sorted LT-HSCs taken 28 days after β-glucan transmit myeloid bias after 12 weeks in recipients with matched chimerism; heterologous LPS and chemotherapy responses improve.", "[9] BCG-educated HSCs generate protective macrophages; chimeric/parabiotic and transfer designs support sustainable lineage training.", "[11] After 21-day periodontitis and 14-day resolution, purified LT-HSCs transmit myeloid bias and increased arthritis/LPS responses after 12–16 weeks; both CD41 strata transfer effects.", "[12] Western-diet withdrawal normalizes serum inflammation but retains myeloid responses; NLRP3 loss prevents diet-induced reprogramming.", "[13] Diabetic donor marrow produces macrophage changes in physiological glucose and increases atherosclerosis in normoglycemic Ldlr-null recipients.", "[14] 15 BCG recipients versus five placebo controls show day-90 HSPC/monocyte remodeling and increased heterologous IL1β; marrow M. bovis testing is reported negative.", "[16] BCG alters neutrophil antimicrobial function and H3K4me3 profiles for at least three months.", "[17] Respiratory-virus-experienced alveolar macrophages retain antibacterial memory; T-cell help is reported required for priming rather than maintenance.", "[18] LPS/IFN-β train cultured alveolar macrophages after rest; macrophage IFNAR loss blocks induction, while transferred trained AMs worsen pneumococcal infection despite whole-animal LPS protection.", "[19] Mtb IFN-I/iron signaling impairs myelopoiesis and trained defense, contrasting BCG/β-glucan IFN-II/IL1 programs.", "[20] β-glucan partly reverses LPS tolerance in vitro and restores cytokines in monocytes from experimental endotoxemia.", "[21] IRG1/itaconate/SDH processes distinguish tolerance from β-glucan training, including human genetic variants.", "[22] Immortalized macrophages retain changing molecular/function states after washout and 14 divisions; late Salmonella control parallels newly induced interferon programs.", "[24] Primary human macrophages retain stimulus-specific responses at six days, with stronger recall to similar challenges; some memories are lost by day 11.", "[25] Four inducers yield distinct monocyte programs/subpopulations, replicated with in vivo signatures.", "[27] Peripheral inflammatory schedules induce six-month microglial training or tolerance with opposite AD/stroke pathology effects.", "[28] HDM inflammation produces TNF/2-HG/PGE2-related macrophage memory; TNF blockade or myeloid Tnf loss prevents imprinting.", "[29] Stringently purified autoimmune-exposed LT-HSCs yield trained macrophages 18 weeks after transfer without spontaneous recipient autoimmune activity or lineage skewing.", "[31] Heart-failure donor marrow transmits cardiac dysfunction and altered susceptibility, with HSC TGFβ changes.", "[32] Post-stroke myeloid changes transmit cardiac dysfunction; IL1β neutralization/CCR2/5 blockade prevent remote cardiac injury.", "[33] β-glucan/heme training increases myeloid procoagulant responses and four-week splenic activity via sphingomyelinase/tissue-factor decryption.", "[34] Four-hour IL1β exposure of human marrow progenitors produces monocyte offspring with enhanced heterologous cytokines and metabolism.", "[35] T-cell CD40-TRAF6 regulates myeloid functional/metabolic/chromatin training; combined blockade promotes graft acceptance.", "[36] Malaria-trained purified monocytes fail without lymphocytes; transwell CD4/IFNγ restores heterologous cytokine responses.", "[37] Subcutaneous BCG induces AM memory via gut microbiome/metabolite changes and mycobacterial dissemination, independently of circulating monocytes.", "[38] BCG protects against influenza but not SARS-CoV-2, with different tissue tropism and cytokine responses.", "[39] Acute LPS generates persistent resident-AM phenotypes and pneumococcal protection with minimal SARS-CoV-2 protection.", "[40] Influenza-experienced AMs exert long-lasting tissue-specific antitumor effects with IFNγ/NK induction dependence.", "[41] Lineage tracing and AM transfer identify a KLF4/MERTK efferocytic trained subset that limits lung injury.", "[42] β-glucan protects against Mtb and expands myeloid progenitors; IL1R deficiency abolishes protection.", "[43] STAT1 CMC patient cells have Candida-specific training defects while STAT3 HIES cells train normally.", "[44] β-glucan-experienced human macrophages reduce NLRP3/caspase1/IL1β responses, including CAPS patient cells.", "[45] IL37 reverses training-associated metabolic/mark changes and reduces Candida protection in models.", "[46] β-glucan-trained differentiated macrophage transfer protects Pseudomonas; sustained metabolic/chemokine state is independent of Dectin1/TLR2 here.", "[47] BCG outer-membrane vesicles induce TLR2-dependent progenitor expansion/metabolism and sepsis protection.", "[48] β-glucan nine weeks before Listeria increases antimicrobial myeloid responses and survival.", "[49] IRF4 controls metabolic uptake and memory expansion of virus-specific NK cells.", "[50] Randomized human BCG/malaria challenge alters activation and yields earlier/more severe symptoms; parasitemia inversely correlates with activation.", "[51] Randomized BCG attenuated-yellow-fever challenge reduces viremia with IL1β-associated monocyte changes.", "[54] Randomized low-birthweight infant BCG substudy shows increased heterologous cytokines four weeks later." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Ε", "requirement_quoted": "Requires context-specific causality with explicit scope restriction.", "satisfied": "yes", "supporting_evidence": [ "[1] BCG-vaccinated volunteers show heterologous monocyte cytokine responses for three months; NOD2-dependent experiments and SCID Candida survival support innate contribution.", "[2] Candida/β-glucan pretreatment protects lymphocyte-deficient mice in a monocyte-dependent manner and dectin-1/Raf-1 signaling contributes.", "[3] Akt/mTOR/HIF-1α perturbations block training; myeloid HIF-1α loss abolishes trained sepsis protection.", "[8] Sorted LT-HSCs taken 28 days after β-glucan transmit myeloid bias after 12 weeks in recipients with matched chimerism; heterologous LPS and chemotherapy responses improve.", "[9] BCG-educated HSCs generate protective macrophages; chimeric/parabiotic and transfer designs support sustainable lineage training.", "[11] After 21-day periodontitis and 14-day resolution, purified LT-HSCs transmit myeloid bias and increased arthritis/LPS responses after 12–16 weeks; both CD41 strata transfer effects.", "[12] Western-diet withdrawal normalizes serum inflammation but retains myeloid responses; NLRP3 loss prevents diet-induced reprogramming.", "[13] Diabetic donor marrow produces macrophage changes in physiological glucose and increases atherosclerosis in normoglycemic Ldlr-null recipients.", "[14] 15 BCG recipients versus five placebo controls show day-90 HSPC/monocyte remodeling and increased heterologous IL1β; marrow M. bovis testing is reported negative.", "[16] BCG alters neutrophil antimicrobial function and H3K4me3 profiles for at least three months.", "[17] Respiratory-virus-experienced alveolar macrophages retain antibacterial memory; T-cell help is reported required for priming rather than maintenance.", "[18] LPS/IFN-β train cultured alveolar macrophages after rest; macrophage IFNAR loss blocks induction, while transferred trained AMs worsen pneumococcal infection despite whole-animal LPS protection.", "[19] Mtb IFN-I/iron signaling impairs myelopoiesis and trained defense, contrasting BCG/β-glucan IFN-II/IL1 programs.", "[20] β-glucan partly reverses LPS tolerance in vitro and restores cytokines in monocytes from experimental endotoxemia.", "[21] IRG1/itaconate/SDH processes distinguish tolerance from β-glucan training, including human genetic variants.", "[22] Immortalized macrophages retain changing molecular/function states after washout and 14 divisions; late Salmonella control parallels newly induced interferon programs.", "[24] Primary human macrophages retain stimulus-specific responses at six days, with stronger recall to similar challenges; some memories are lost by day 11.", "[25] Four inducers yield distinct monocyte programs/subpopulations, replicated with in vivo signatures.", "[27] Peripheral inflammatory schedules induce six-month microglial training or tolerance with opposite AD/stroke pathology effects.", "[28] HDM inflammation produces TNF/2-HG/PGE2-related macrophage memory; TNF blockade or myeloid Tnf loss prevents imprinting.", "[29] Stringently purified autoimmune-exposed LT-HSCs yield trained macrophages 18 weeks after transfer without spontaneous recipient autoimmune activity or lineage skewing.", "[31] Heart-failure donor marrow transmits cardiac dysfunction and altered susceptibility, with HSC TGFβ changes.", "[32] Post-stroke myeloid changes transmit cardiac dysfunction; IL1β neutralization/CCR2/5 blockade prevent remote cardiac injury.", "[33] β-glucan/heme training increases myeloid procoagulant responses and four-week splenic activity via sphingomyelinase/tissue-factor decryption.", "[34] Four-hour IL1β exposure of human marrow progenitors produces monocyte offspring with enhanced heterologous cytokines and metabolism.", "[35] T-cell CD40-TRAF6 regulates myeloid functional/metabolic/chromatin training; combined blockade promotes graft acceptance.", "[36] Malaria-trained purified monocytes fail without lymphocytes; transwell CD4/IFNγ restores heterologous cytokine responses.", "[37] Subcutaneous BCG induces AM memory via gut microbiome/metabolite changes and mycobacterial dissemination, independently of circulating monocytes.", "[38] BCG protects against influenza but not SARS-CoV-2, with different tissue tropism and cytokine responses.", "[39] Acute LPS generates persistent resident-AM phenotypes and pneumococcal protection with minimal SARS-CoV-2 protection.", "[40] Influenza-experienced AMs exert long-lasting tissue-specific antitumor effects with IFNγ/NK induction dependence.", "[41] Lineage tracing and AM transfer identify a KLF4/MERTK efferocytic trained subset that limits lung injury.", "[42] β-glucan protects against Mtb and expands myeloid progenitors; IL1R deficiency abolishes protection.", "[43] STAT1 CMC patient cells have Candida-specific training defects while STAT3 HIES cells train normally.", "[44] β-glucan-experienced human macrophages reduce NLRP3/caspase1/IL1β responses, including CAPS patient cells.", "[45] IL37 reverses training-associated metabolic/mark changes and reduces Candida protection in models.", "[46] β-glucan-trained differentiated macrophage transfer protects Pseudomonas; sustained metabolic/chemokine state is independent of Dectin1/TLR2 here.", "[47] BCG outer-membrane vesicles induce TLR2-dependent progenitor expansion/metabolism and sepsis protection.", "[48] β-glucan nine weeks before Listeria increases antimicrobial myeloid responses and survival.", "[49] IRF4 controls metabolic uptake and memory expansion of virus-specific NK cells.", "[50] Randomized human BCG/malaria challenge alters activation and yields earlier/more severe symptoms; parasitemia inversely correlates with activation.", "[51] Randomized BCG attenuated-yellow-fever challenge reduces viremia with IL1β-associated monocyte changes.", "[54] Randomized low-birthweight infant BCG substudy shows increased heterologous cytokines four weeks later." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Ζ", "requirement_quoted": "Requires multiple convergent causal manipulations and reduced plausibility of downstream-only interpretations.", "satisfied": "yes", "supporting_evidence": [ "[1] BCG-vaccinated volunteers show heterologous monocyte cytokine responses for three months; NOD2-dependent experiments and SCID Candida survival support innate contribution.", "[2] Candida/β-glucan pretreatment protects lymphocyte-deficient mice in a monocyte-dependent manner and dectin-1/Raf-1 signaling contributes.", "[3] Akt/mTOR/HIF-1α perturbations block training; myeloid HIF-1α loss abolishes trained sepsis protection.", "[8] Sorted LT-HSCs taken 28 days after β-glucan transmit myeloid bias after 12 weeks in recipients with matched chimerism; heterologous LPS and chemotherapy responses improve.", "[9] BCG-educated HSCs generate protective macrophages; chimeric/parabiotic and transfer designs support sustainable lineage training.", "[11] After 21-day periodontitis and 14-day resolution, purified LT-HSCs transmit myeloid bias and increased arthritis/LPS responses after 12–16 weeks; both CD41 strata transfer effects.", "[12] Western-diet withdrawal normalizes serum inflammation but retains myeloid responses; NLRP3 loss prevents diet-induced reprogramming.", "[13] Diabetic donor marrow produces macrophage changes in physiological glucose and increases atherosclerosis in normoglycemic Ldlr-null recipients.", "[14] 15 BCG recipients versus five placebo controls show day-90 HSPC/monocyte remodeling and increased heterologous IL1β; marrow M. bovis testing is reported negative.", "[16] BCG alters neutrophil antimicrobial function and H3K4me3 profiles for at least three months.", "[17] Respiratory-virus-experienced alveolar macrophages retain antibacterial memory; T-cell help is reported required for priming rather than maintenance.", "[18] LPS/IFN-β train cultured alveolar macrophages after rest; macrophage IFNAR loss blocks induction, while transferred trained AMs worsen pneumococcal infection despite whole-animal LPS protection.", "[19] Mtb IFN-I/iron signaling impairs myelopoiesis and trained defense, contrasting BCG/β-glucan IFN-II/IL1 programs.", "[20] β-glucan partly reverses LPS tolerance in vitro and restores cytokines in monocytes from experimental endotoxemia.", "[21] IRG1/itaconate/SDH processes distinguish tolerance from β-glucan training, including human genetic variants.", "[22] Immortalized macrophages retain changing molecular/function states after washout and 14 divisions; late Salmonella control parallels newly induced interferon programs.", "[24] Primary human macrophages retain stimulus-specific responses at six days, with stronger recall to similar challenges; some memories are lost by day 11.", "[25] Four inducers yield distinct monocyte programs/subpopulations, replicated with in vivo signatures.", "[27] Peripheral inflammatory schedules induce six-month microglial training or tolerance with opposite AD/stroke pathology effects.", "[28] HDM inflammation produces TNF/2-HG/PGE2-related macrophage memory; TNF blockade or myeloid Tnf loss prevents imprinting.", "[29] Stringently purified autoimmune-exposed LT-HSCs yield trained macrophages 18 weeks after transfer without spontaneous recipient autoimmune activity or lineage skewing.", "[31] Heart-failure donor marrow transmits cardiac dysfunction and altered susceptibility, with HSC TGFβ changes.", "[32] Post-stroke myeloid changes transmit cardiac dysfunction; IL1β neutralization/CCR2/5 blockade prevent remote cardiac injury.", "[33] β-glucan/heme training increases myeloid procoagulant responses and four-week splenic activity via sphingomyelinase/tissue-factor decryption.", "[34] Four-hour IL1β exposure of human marrow progenitors produces monocyte offspring with enhanced heterologous cytokines and metabolism.", "[35] T-cell CD40-TRAF6 regulates myeloid functional/metabolic/chromatin training; combined blockade promotes graft acceptance.", "[36] Malaria-trained purified monocytes fail without lymphocytes; transwell CD4/IFNγ restores heterologous cytokine responses.", "[37] Subcutaneous BCG induces AM memory via gut microbiome/metabolite changes and mycobacterial dissemination, independently of circulating monocytes.", "[38] BCG protects against influenza but not SARS-CoV-2, with different tissue tropism and cytokine responses.", "[39] Acute LPS generates persistent resident-AM phenotypes and pneumococcal protection with minimal SARS-CoV-2 protection.", "[40] Influenza-experienced AMs exert long-lasting tissue-specific antitumor effects with IFNγ/NK induction dependence.", "[41] Lineage tracing and AM transfer identify a KLF4/MERTK efferocytic trained subset that limits lung injury.", "[42] β-glucan protects against Mtb and expands myeloid progenitors; IL1R deficiency abolishes protection.", "[43] STAT1 CMC patient cells have Candida-specific training defects while STAT3 HIES cells train normally.", "[44] β-glucan-experienced human macrophages reduce NLRP3/caspase1/IL1β responses, including CAPS patient cells.", "[45] IL37 reverses training-associated metabolic/mark changes and reduces Candida protection in models.", "[46] β-glucan-trained differentiated macrophage transfer protects Pseudomonas; sustained metabolic/chemokine state is independent of Dectin1/TLR2 here.", "[47] BCG outer-membrane vesicles induce TLR2-dependent progenitor expansion/metabolism and sepsis protection.", "[48] β-glucan nine weeks before Listeria increases antimicrobial myeloid responses and survival.", "[49] IRF4 controls metabolic uptake and memory expansion of virus-specific NK cells.", "[50] Randomized human BCG/malaria challenge alters activation and yields earlier/more severe symptoms; parasitemia inversely correlates with activation.", "[51] Randomized BCG attenuated-yellow-fever challenge reduces viremia with IL1β-associated monocyte changes.", "[54] Randomized low-birthweight infant BCG substudy shows increased heterologous cytokines four weeks later." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Η", "requirement_quoted": "Requires robust upstream causal evidence across systems and interventions.", "satisfied": "no", "supporting_evidence": [ "[1] BCG-vaccinated volunteers show heterologous monocyte cytokine responses for three months; NOD2-dependent experiments and SCID Candida survival support innate contribution.", "[2] Candida/β-glucan pretreatment protects lymphocyte-deficient mice in a monocyte-dependent manner and dectin-1/Raf-1 signaling contributes.", "[3] Akt/mTOR/HIF-1α perturbations block training; myeloid HIF-1α loss abolishes trained sepsis protection.", "[8] Sorted LT-HSCs taken 28 days after β-glucan transmit myeloid bias after 12 weeks in recipients with matched chimerism; heterologous LPS and chemotherapy responses improve.", "[9] BCG-educated HSCs generate protective macrophages; chimeric/parabiotic and transfer designs support sustainable lineage training.", "[11] After 21-day periodontitis and 14-day resolution, purified LT-HSCs transmit myeloid bias and increased arthritis/LPS responses after 12–16 weeks; both CD41 strata transfer effects.", "[12] Western-diet withdrawal normalizes serum inflammation but retains myeloid responses; NLRP3 loss prevents diet-induced reprogramming.", "[13] Diabetic donor marrow produces macrophage changes in physiological glucose and increases atherosclerosis in normoglycemic Ldlr-null recipients.", "[14] 15 BCG recipients versus five placebo controls show day-90 HSPC/monocyte remodeling and increased heterologous IL1β; marrow M. bovis testing is reported negative.", "[16] BCG alters neutrophil antimicrobial function and H3K4me3 profiles for at least three months.", "[17] Respiratory-virus-experienced alveolar macrophages retain antibacterial memory; T-cell help is reported required for priming rather than maintenance.", "[18] LPS/IFN-β train cultured alveolar macrophages after rest; macrophage IFNAR loss blocks induction, while transferred trained AMs worsen pneumococcal infection despite whole-animal LPS protection.", "[19] Mtb IFN-I/iron signaling impairs myelopoiesis and trained defense, contrasting BCG/β-glucan IFN-II/IL1 programs.", "[20] β-glucan partly reverses LPS tolerance in vitro and restores cytokines in monocytes from experimental endotoxemia.", "[21] IRG1/itaconate/SDH processes distinguish tolerance from β-glucan training, including human genetic variants.", "[22] Immortalized macrophages retain changing molecular/function states after washout and 14 divisions; late Salmonella control parallels newly induced interferon programs.", "[24] Primary human macrophages retain stimulus-specific responses at six days, with stronger recall to similar challenges; some memories are lost by day 11.", "[25] Four inducers yield distinct monocyte programs/subpopulations, replicated with in vivo signatures.", "[27] Peripheral inflammatory schedules induce six-month microglial training or tolerance with opposite AD/stroke pathology effects.", "[28] HDM inflammation produces TNF/2-HG/PGE2-related macrophage memory; TNF blockade or myeloid Tnf loss prevents imprinting.", "[29] Stringently purified autoimmune-exposed LT-HSCs yield trained macrophages 18 weeks after transfer without spontaneous recipient autoimmune activity or lineage skewing.", "[31] Heart-failure donor marrow transmits cardiac dysfunction and altered susceptibility, with HSC TGFβ changes.", "[32] Post-stroke myeloid changes transmit cardiac dysfunction; IL1β neutralization/CCR2/5 blockade prevent remote cardiac injury.", "[33] β-glucan/heme training increases myeloid procoagulant responses and four-week splenic activity via sphingomyelinase/tissue-factor decryption.", "[34] Four-hour IL1β exposure of human marrow progenitors produces monocyte offspring with enhanced heterologous cytokines and metabolism.", "[35] T-cell CD40-TRAF6 regulates myeloid functional/metabolic/chromatin training; combined blockade promotes graft acceptance.", "[36] Malaria-trained purified monocytes fail without lymphocytes; transwell CD4/IFNγ restores heterologous cytokine responses.", "[37] Subcutaneous BCG induces AM memory via gut microbiome/metabolite changes and mycobacterial dissemination, independently of circulating monocytes.", "[38] BCG protects against influenza but not SARS-CoV-2, with different tissue tropism and cytokine responses.", "[39] Acute LPS generates persistent resident-AM phenotypes and pneumococcal protection with minimal SARS-CoV-2 protection.", "[40] Influenza-experienced AMs exert long-lasting tissue-specific antitumor effects with IFNγ/NK induction dependence.", "[41] Lineage tracing and AM transfer identify a KLF4/MERTK efferocytic trained subset that limits lung injury.", "[42] β-glucan protects against Mtb and expands myeloid progenitors; IL1R deficiency abolishes protection.", "[43] STAT1 CMC patient cells have Candida-specific training defects while STAT3 HIES cells train normally.", "[44] β-glucan-experienced human macrophages reduce NLRP3/caspase1/IL1β responses, including CAPS patient cells.", "[45] IL37 reverses training-associated metabolic/mark changes and reduces Candida protection in models.", "[46] β-glucan-trained differentiated macrophage transfer protects Pseudomonas; sustained metabolic/chemokine state is independent of Dectin1/TLR2 here.", "[47] BCG outer-membrane vesicles induce TLR2-dependent progenitor expansion/metabolism and sepsis protection.", "[48] β-glucan nine weeks before Listeria increases antimicrobial myeloid responses and survival.", "[49] IRF4 controls metabolic uptake and memory expansion of virus-specific NK cells.", "[50] Randomized human BCG/malaria challenge alters activation and yields earlier/more severe symptoms; parasitemia inversely correlates with activation.", "[51] Randomized BCG attenuated-yellow-fever challenge reduces viremia with IL1β-associated monocyte changes.", "[54] Randomized low-birthweight infant BCG substudy shows increased heterologous cytokines four weeks later." ], "what_would_cross_it": "Independent staged interventions with clonal/lineage controls predicting functional response across the registered cell and stimulus classes, including tolerance and adverse-response boundaries." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires at least one endogenous perturbation showing the proposed feature contributes causally to the claimed output.", "satisfied": "no", "supporting_evidence": [ "[1] BCG-vaccinated volunteers show heterologous monocyte cytokine responses for three months; NOD2-dependent experiments and SCID Candida survival support innate contribution.", "[2] Candida/β-glucan pretreatment protects lymphocyte-deficient mice in a monocyte-dependent manner and dectin-1/Raf-1 signaling contributes.", "[3] Akt/mTOR/HIF-1α perturbations block training; myeloid HIF-1α loss abolishes trained sepsis protection.", "[5] BCG training requires glycolytic rewiring in pharmacological/genetic experiments, with associated histone changes.", "[6] Glutaminolysis/fumarate and mevalonate-related metabolism contribute to β-glucan induction; fumarate inhibits KDM5 and induces similar marks.", "[7] Mevalonate/IGF1R/mTOR perturbations regulate training; mevalonate-kinase-deficient patients have constitutive trained phenotypes.", "[8] Sorted LT-HSCs taken 28 days after β-glucan transmit myeloid bias after 12 weeks in recipients with matched chimerism; heterologous LPS and chemotherapy responses improve.", "[10] Acute LPS produces persistent HSC enhancer accessibility and improved Pseudomonas defense; C/EBPβ deletion erases long-term marks/expression.", "[12] Western-diet withdrawal normalizes serum inflammation but retains myeloid responses; NLRP3 loss prevents diet-induced reprogramming.", "[13] Diabetic donor marrow produces macrophage changes in physiological glucose and increases atherosclerosis in normoglycemic Ldlr-null recipients.", "[14] 15 BCG recipients versus five placebo controls show day-90 HSPC/monocyte remodeling and increased heterologous IL1β; marrow M. bovis testing is reported negative.", "[15] Single-cell human marrow before/90 days after BCG/placebo shows HSPC expression/accessibility changes correlated with paired PBMC IL1β.", "[16] BCG alters neutrophil antimicrobial function and H3K4me3 profiles for at least three months.", "[18] LPS/IFN-β train cultured alveolar macrophages after rest; macrophage IFNAR loss blocks induction, while transferred trained AMs worsen pneumococcal infection despite whole-animal LPS protection.", "[19] Mtb IFN-I/iron signaling impairs myelopoiesis and trained defense, contrasting BCG/β-glucan IFN-II/IL1 programs.", "[20] β-glucan partly reverses LPS tolerance in vitro and restores cytokines in monocytes from experimental endotoxemia.", "[21] IRG1/itaconate/SDH processes distinguish tolerance from β-glucan training, including human genetic variants.", "[22] Immortalized macrophages retain changing molecular/function states after washout and 14 divisions; late Salmonella control parallels newly induced interferon programs.", "[23] H3K18 lactylation persists after washout and at 90 days after BCG; LDH/p300 inhibition attenuates training.", "[24] Primary human macrophages retain stimulus-specific responses at six days, with stronger recall to similar challenges; some memories are lost by day 11.", "[25] Four inducers yield distinct monocyte programs/subpopulations, replicated with in vivo signatures.", "[26] In epidermal stem cells, delayed STAT3 loss after resolution preserves recall; post-induction AFOS leaves memory domains accessible with homeostatic TF support.", "[27] Peripheral inflammatory schedules induce six-month microglial training or tolerance with opposite AD/stroke pathology effects.", "[28] HDM inflammation produces TNF/2-HG/PGE2-related macrophage memory; TNF blockade or myeloid Tnf loss prevents imprinting.", "[29] Stringently purified autoimmune-exposed LT-HSCs yield trained macrophages 18 weeks after transfer without spontaneous recipient autoimmune activity or lineage skewing.", "[33] β-glucan/heme training increases myeloid procoagulant responses and four-week splenic activity via sphingomyelinase/tissue-factor decryption.", "[35] T-cell CD40-TRAF6 regulates myeloid functional/metabolic/chromatin training; combined blockade promotes graft acceptance.", "[42] β-glucan protects against Mtb and expands myeloid progenitors; IL1R deficiency abolishes protection.", "[43] STAT1 CMC patient cells have Candida-specific training defects while STAT3 HIES cells train normally.", "[44] β-glucan-experienced human macrophages reduce NLRP3/caspase1/IL1β responses, including CAPS patient cells.", "[45] IL37 reverses training-associated metabolic/mark changes and reduces Candida protection in models.", "[46] β-glucan-trained differentiated macrophage transfer protects Pseudomonas; sustained metabolic/chemokine state is independent of Dectin1/TLR2 here.", "[47] BCG outer-membrane vesicles induce TLR2-dependent progenitor expansion/metabolism and sepsis protection.", "[49] IRF4 controls metabolic uptake and memory expansion of virus-specific NK cells.", "[51] Randomized BCG attenuated-yellow-fever challenge reduces viremia with IL1β-associated monocyte changes." ], "what_would_cross_it": "Delayed endogenous, locus/mark-specific subtraction and matched rescue that remove recall while preserving viability, differentiation and baseline inducibility; separate mark storage from TF/metabolic maintenance." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.", "satisfied": "yes", "supporting_evidence": [ "[1] BCG-vaccinated volunteers show heterologous monocyte cytokine responses for three months; NOD2-dependent experiments and SCID Candida survival support innate contribution.", "[7] Mevalonate/IGF1R/mTOR perturbations regulate training; mevalonate-kinase-deficient patients have constitutive trained phenotypes.", "[8] Sorted LT-HSCs taken 28 days after β-glucan transmit myeloid bias after 12 weeks in recipients with matched chimerism; heterologous LPS and chemotherapy responses improve.", "[9] BCG-educated HSCs generate protective macrophages; chimeric/parabiotic and transfer designs support sustainable lineage training.", "[10] Acute LPS produces persistent HSC enhancer accessibility and improved Pseudomonas defense; C/EBPβ deletion erases long-term marks/expression.", "[11] After 21-day periodontitis and 14-day resolution, purified LT-HSCs transmit myeloid bias and increased arthritis/LPS responses after 12–16 weeks; both CD41 strata transfer effects.", "[12] Western-diet withdrawal normalizes serum inflammation but retains myeloid responses; NLRP3 loss prevents diet-induced reprogramming.", "[13] Diabetic donor marrow produces macrophage changes in physiological glucose and increases atherosclerosis in normoglycemic Ldlr-null recipients.", "[14] 15 BCG recipients versus five placebo controls show day-90 HSPC/monocyte remodeling and increased heterologous IL1β; marrow M. bovis testing is reported negative.", "[15] Single-cell human marrow before/90 days after BCG/placebo shows HSPC expression/accessibility changes correlated with paired PBMC IL1β.", "[17] Respiratory-virus-experienced alveolar macrophages retain antibacterial memory; T-cell help is reported required for priming rather than maintenance.", "[18] LPS/IFN-β train cultured alveolar macrophages after rest; macrophage IFNAR loss blocks induction, while transferred trained AMs worsen pneumococcal infection despite whole-animal LPS protection.", "[22] Immortalized macrophages retain changing molecular/function states after washout and 14 divisions; late Salmonella control parallels newly induced interferon programs.", "[23] H3K18 lactylation persists after washout and at 90 days after BCG; LDH/p300 inhibition attenuates training.", "[24] Primary human macrophages retain stimulus-specific responses at six days, with stronger recall to similar challenges; some memories are lost by day 11.", "[26] In epidermal stem cells, delayed STAT3 loss after resolution preserves recall; post-induction AFOS leaves memory domains accessible with homeostatic TF support.", "[27] Peripheral inflammatory schedules induce six-month microglial training or tolerance with opposite AD/stroke pathology effects.", "[28] HDM inflammation produces TNF/2-HG/PGE2-related macrophage memory; TNF blockade or myeloid Tnf loss prevents imprinting.", "[29] Stringently purified autoimmune-exposed LT-HSCs yield trained macrophages 18 weeks after transfer without spontaneous recipient autoimmune activity or lineage skewing.", "[31] Heart-failure donor marrow transmits cardiac dysfunction and altered susceptibility, with HSC TGFβ changes.", "[32] Post-stroke myeloid changes transmit cardiac dysfunction; IL1β neutralization/CCR2/5 blockade prevent remote cardiac injury.", "[34] Four-hour IL1β exposure of human marrow progenitors produces monocyte offspring with enhanced heterologous cytokines and metabolism.", "[35] T-cell CD40-TRAF6 regulates myeloid functional/metabolic/chromatin training; combined blockade promotes graft acceptance.", "[36] Malaria-trained purified monocytes fail without lymphocytes; transwell CD4/IFNγ restores heterologous cytokine responses.", "[37] Subcutaneous BCG induces AM memory via gut microbiome/metabolite changes and mycobacterial dissemination, independently of circulating monocytes.", "[39] Acute LPS generates persistent resident-AM phenotypes and pneumococcal protection with minimal SARS-CoV-2 protection.", "[40] Influenza-experienced AMs exert long-lasting tissue-specific antitumor effects with IFNγ/NK induction dependence.", "[41] Lineage tracing and AM transfer identify a KLF4/MERTK efferocytic trained subset that limits lung injury.", "[46] β-glucan-trained differentiated macrophage transfer protects Pseudomonas; sustained metabolic/chemokine state is independent of Dectin1/TLR2 here.", "[48] β-glucan nine weeks before Listeria increases antimicrobial myeloid responses and survival." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ε", "requirement_quoted": "Requires context-specific causality with explicit scope restriction.", "satisfied": "yes", "supporting_evidence": [ "[1] BCG-vaccinated volunteers show heterologous monocyte cytokine responses for three months; NOD2-dependent experiments and SCID Candida survival support innate contribution.", "[7] Mevalonate/IGF1R/mTOR perturbations regulate training; mevalonate-kinase-deficient patients have constitutive trained phenotypes.", "[8] Sorted LT-HSCs taken 28 days after β-glucan transmit myeloid bias after 12 weeks in recipients with matched chimerism; heterologous LPS and chemotherapy responses improve.", "[9] BCG-educated HSCs generate protective macrophages; chimeric/parabiotic and transfer designs support sustainable lineage training.", "[10] Acute LPS produces persistent HSC enhancer accessibility and improved Pseudomonas defense; C/EBPβ deletion erases long-term marks/expression.", "[11] After 21-day periodontitis and 14-day resolution, purified LT-HSCs transmit myeloid bias and increased arthritis/LPS responses after 12–16 weeks; both CD41 strata transfer effects.", "[12] Western-diet withdrawal normalizes serum inflammation but retains myeloid responses; NLRP3 loss prevents diet-induced reprogramming.", "[13] Diabetic donor marrow produces macrophage changes in physiological glucose and increases atherosclerosis in normoglycemic Ldlr-null recipients.", "[14] 15 BCG recipients versus five placebo controls show day-90 HSPC/monocyte remodeling and increased heterologous IL1β; marrow M. bovis testing is reported negative.", "[15] Single-cell human marrow before/90 days after BCG/placebo shows HSPC expression/accessibility changes correlated with paired PBMC IL1β.", "[17] Respiratory-virus-experienced alveolar macrophages retain antibacterial memory; T-cell help is reported required for priming rather than maintenance.", "[18] LPS/IFN-β train cultured alveolar macrophages after rest; macrophage IFNAR loss blocks induction, while transferred trained AMs worsen pneumococcal infection despite whole-animal LPS protection.", "[22] Immortalized macrophages retain changing molecular/function states after washout and 14 divisions; late Salmonella control parallels newly induced interferon programs.", "[23] H3K18 lactylation persists after washout and at 90 days after BCG; LDH/p300 inhibition attenuates training.", "[24] Primary human macrophages retain stimulus-specific responses at six days, with stronger recall to similar challenges; some memories are lost by day 11.", "[26] In epidermal stem cells, delayed STAT3 loss after resolution preserves recall; post-induction AFOS leaves memory domains accessible with homeostatic TF support.", "[27] Peripheral inflammatory schedules induce six-month microglial training or tolerance with opposite AD/stroke pathology effects.", "[28] HDM inflammation produces TNF/2-HG/PGE2-related macrophage memory; TNF blockade or myeloid Tnf loss prevents imprinting.", "[29] Stringently purified autoimmune-exposed LT-HSCs yield trained macrophages 18 weeks after transfer without spontaneous recipient autoimmune activity or lineage skewing.", "[31] Heart-failure donor marrow transmits cardiac dysfunction and altered susceptibility, with HSC TGFβ changes.", "[32] Post-stroke myeloid changes transmit cardiac dysfunction; IL1β neutralization/CCR2/5 blockade prevent remote cardiac injury.", "[34] Four-hour IL1β exposure of human marrow progenitors produces monocyte offspring with enhanced heterologous cytokines and metabolism.", "[35] T-cell CD40-TRAF6 regulates myeloid functional/metabolic/chromatin training; combined blockade promotes graft acceptance.", "[36] Malaria-trained purified monocytes fail without lymphocytes; transwell CD4/IFNγ restores heterologous cytokine responses.", "[37] Subcutaneous BCG induces AM memory via gut microbiome/metabolite changes and mycobacterial dissemination, independently of circulating monocytes.", "[39] Acute LPS generates persistent resident-AM phenotypes and pneumococcal protection with minimal SARS-CoV-2 protection.", "[40] Influenza-experienced AMs exert long-lasting tissue-specific antitumor effects with IFNγ/NK induction dependence.", "[41] Lineage tracing and AM transfer identify a KLF4/MERTK efferocytic trained subset that limits lung injury.", "[46] β-glucan-trained differentiated macrophage transfer protects Pseudomonas; sustained metabolic/chemokine state is independent of Dectin1/TLR2 here.", "[48] β-glucan nine weeks before Listeria increases antimicrobial myeloid responses and survival." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ζ", "requirement_quoted": "Requires multiple convergent causal manipulations and reduced plausibility of downstream-only interpretations.", "satisfied": "no", "supporting_evidence": [ "[1] BCG-vaccinated volunteers show heterologous monocyte cytokine responses for three months; NOD2-dependent experiments and SCID Candida survival support innate contribution.", "[7] Mevalonate/IGF1R/mTOR perturbations regulate training; mevalonate-kinase-deficient patients have constitutive trained phenotypes.", "[8] Sorted LT-HSCs taken 28 days after β-glucan transmit myeloid bias after 12 weeks in recipients with matched chimerism; heterologous LPS and chemotherapy responses improve.", "[9] BCG-educated HSCs generate protective macrophages; chimeric/parabiotic and transfer designs support sustainable lineage training.", "[10] Acute LPS produces persistent HSC enhancer accessibility and improved Pseudomonas defense; C/EBPβ deletion erases long-term marks/expression.", "[11] After 21-day periodontitis and 14-day resolution, purified LT-HSCs transmit myeloid bias and increased arthritis/LPS responses after 12–16 weeks; both CD41 strata transfer effects.", "[12] Western-diet withdrawal normalizes serum inflammation but retains myeloid responses; NLRP3 loss prevents diet-induced reprogramming.", "[13] Diabetic donor marrow produces macrophage changes in physiological glucose and increases atherosclerosis in normoglycemic Ldlr-null recipients.", "[14] 15 BCG recipients versus five placebo controls show day-90 HSPC/monocyte remodeling and increased heterologous IL1β; marrow M. bovis testing is reported negative.", "[15] Single-cell human marrow before/90 days after BCG/placebo shows HSPC expression/accessibility changes correlated with paired PBMC IL1β.", "[17] Respiratory-virus-experienced alveolar macrophages retain antibacterial memory; T-cell help is reported required for priming rather than maintenance.", "[18] LPS/IFN-β train cultured alveolar macrophages after rest; macrophage IFNAR loss blocks induction, while transferred trained AMs worsen pneumococcal infection despite whole-animal LPS protection.", "[22] Immortalized macrophages retain changing molecular/function states after washout and 14 divisions; late Salmonella control parallels newly induced interferon programs.", "[23] H3K18 lactylation persists after washout and at 90 days after BCG; LDH/p300 inhibition attenuates training.", "[24] Primary human macrophages retain stimulus-specific responses at six days, with stronger recall to similar challenges; some memories are lost by day 11.", "[26] In epidermal stem cells, delayed STAT3 loss after resolution preserves recall; post-induction AFOS leaves memory domains accessible with homeostatic TF support.", "[27] Peripheral inflammatory schedules induce six-month microglial training or tolerance with opposite AD/stroke pathology effects.", "[28] HDM inflammation produces TNF/2-HG/PGE2-related macrophage memory; TNF blockade or myeloid Tnf loss prevents imprinting.", "[29] Stringently purified autoimmune-exposed LT-HSCs yield trained macrophages 18 weeks after transfer without spontaneous recipient autoimmune activity or lineage skewing.", "[31] Heart-failure donor marrow transmits cardiac dysfunction and altered susceptibility, with HSC TGFβ changes.", "[32] Post-stroke myeloid changes transmit cardiac dysfunction; IL1β neutralization/CCR2/5 blockade prevent remote cardiac injury.", "[34] Four-hour IL1β exposure of human marrow progenitors produces monocyte offspring with enhanced heterologous cytokines and metabolism.", "[35] T-cell CD40-TRAF6 regulates myeloid functional/metabolic/chromatin training; combined blockade promotes graft acceptance.", "[36] Malaria-trained purified monocytes fail without lymphocytes; transwell CD4/IFNγ restores heterologous cytokine responses.", "[37] Subcutaneous BCG induces AM memory via gut microbiome/metabolite changes and mycobacterial dissemination, independently of circulating monocytes.", "[39] Acute LPS generates persistent resident-AM phenotypes and pneumococcal protection with minimal SARS-CoV-2 protection.", "[40] Influenza-experienced AMs exert long-lasting tissue-specific antitumor effects with IFNγ/NK induction dependence.", "[41] Lineage tracing and AM transfer identify a KLF4/MERTK efferocytic trained subset that limits lung injury.", "[46] β-glucan-trained differentiated macrophage transfer protects Pseudomonas; sustained metabolic/chemokine state is independent of Dectin1/TLR2 here.", "[48] β-glucan nine weeks before Listeria increases antimicrobial myeloid responses and survival." ], "what_would_cross_it": "Purified-cell transfer with sensitive original-ligand quantification, delayed removal of original upstream receptor/niche input, matched resting-state controls and preserved viability; reproduce across mature cells and progenitors." }, { "subclaim_id": "SC4", "threshold": "Δ", "requirement_quoted": "Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.", "satisfied": "yes", "supporting_evidence": [ "[8] Sorted LT-HSCs taken 28 days after β-glucan transmit myeloid bias after 12 weeks in recipients with matched chimerism; heterologous LPS and chemotherapy responses improve.", "[9] BCG-educated HSCs generate protective macrophages; chimeric/parabiotic and transfer designs support sustainable lineage training.", "[10] Acute LPS produces persistent HSC enhancer accessibility and improved Pseudomonas defense; C/EBPβ deletion erases long-term marks/expression.", "[11] After 21-day periodontitis and 14-day resolution, purified LT-HSCs transmit myeloid bias and increased arthritis/LPS responses after 12–16 weeks; both CD41 strata transfer effects.", "[12] Western-diet withdrawal normalizes serum inflammation but retains myeloid responses; NLRP3 loss prevents diet-induced reprogramming.", "[13] Diabetic donor marrow produces macrophage changes in physiological glucose and increases atherosclerosis in normoglycemic Ldlr-null recipients.", "[14] 15 BCG recipients versus five placebo controls show day-90 HSPC/monocyte remodeling and increased heterologous IL1β; marrow M. bovis testing is reported negative.", "[15] Single-cell human marrow before/90 days after BCG/placebo shows HSPC expression/accessibility changes correlated with paired PBMC IL1β.", "[16] BCG alters neutrophil antimicrobial function and H3K4me3 profiles for at least three months.", "[19] Mtb IFN-I/iron signaling impairs myelopoiesis and trained defense, contrasting BCG/β-glucan IFN-II/IL1 programs.", "[22] Immortalized macrophages retain changing molecular/function states after washout and 14 divisions; late Salmonella control parallels newly induced interferon programs.", "[29] Stringently purified autoimmune-exposed LT-HSCs yield trained macrophages 18 weeks after transfer without spontaneous recipient autoimmune activity or lineage skewing.", "[31] Heart-failure donor marrow transmits cardiac dysfunction and altered susceptibility, with HSC TGFβ changes.", "[32] Post-stroke myeloid changes transmit cardiac dysfunction; IL1β neutralization/CCR2/5 blockade prevent remote cardiac injury.", "[34] Four-hour IL1β exposure of human marrow progenitors produces monocyte offspring with enhanced heterologous cytokines and metabolism.", "[42] β-glucan protects against Mtb and expands myeloid progenitors; IL1R deficiency abolishes protection.", "[47] BCG outer-membrane vesicles induce TLR2-dependent progenitor expansion/metabolism and sepsis protection.", "[48] β-glucan nine weeks before Listeria increases antimicrobial myeloid responses and survival." ], "what_would_cross_it": "" }, { "subclaim_id": "SC4", "threshold": "Ε", "requirement_quoted": "Requires context-specific causality with explicit scope restriction.", "satisfied": "yes", "supporting_evidence": [ "[8] Sorted LT-HSCs taken 28 days after β-glucan transmit myeloid bias after 12 weeks in recipients with matched chimerism; heterologous LPS and chemotherapy responses improve.", "[9] BCG-educated HSCs generate protective macrophages; chimeric/parabiotic and transfer designs support sustainable lineage training.", "[10] Acute LPS produces persistent HSC enhancer accessibility and improved Pseudomonas defense; C/EBPβ deletion erases long-term marks/expression.", "[11] After 21-day periodontitis and 14-day resolution, purified LT-HSCs transmit myeloid bias and increased arthritis/LPS responses after 12–16 weeks; both CD41 strata transfer effects.", "[12] Western-diet withdrawal normalizes serum inflammation but retains myeloid responses; NLRP3 loss prevents diet-induced reprogramming.", "[13] Diabetic donor marrow produces macrophage changes in physiological glucose and increases atherosclerosis in normoglycemic Ldlr-null recipients.", "[14] 15 BCG recipients versus five placebo controls show day-90 HSPC/monocyte remodeling and increased heterologous IL1β; marrow M. bovis testing is reported negative.", "[15] Single-cell human marrow before/90 days after BCG/placebo shows HSPC expression/accessibility changes correlated with paired PBMC IL1β.", "[16] BCG alters neutrophil antimicrobial function and H3K4me3 profiles for at least three months.", "[19] Mtb IFN-I/iron signaling impairs myelopoiesis and trained defense, contrasting BCG/β-glucan IFN-II/IL1 programs.", "[22] Immortalized macrophages retain changing molecular/function states after washout and 14 divisions; late Salmonella control parallels newly induced interferon programs.", "[29] Stringently purified autoimmune-exposed LT-HSCs yield trained macrophages 18 weeks after transfer without spontaneous recipient autoimmune activity or lineage skewing.", "[31] Heart-failure donor marrow transmits cardiac dysfunction and altered susceptibility, with HSC TGFβ changes.", "[32] Post-stroke myeloid changes transmit cardiac dysfunction; IL1β neutralization/CCR2/5 blockade prevent remote cardiac injury.", "[34] Four-hour IL1β exposure of human marrow progenitors produces monocyte offspring with enhanced heterologous cytokines and metabolism.", "[42] β-glucan protects against Mtb and expands myeloid progenitors; IL1R deficiency abolishes protection.", "[47] BCG outer-membrane vesicles induce TLR2-dependent progenitor expansion/metabolism and sepsis protection.", "[48] β-glucan nine weeks before Listeria increases antimicrobial myeloid responses and survival." ], "what_would_cross_it": "" }, { "subclaim_id": "SC4", "threshold": "Ζ", "requirement_quoted": "Requires multiple convergent causal manipulations and reduced plausibility of downstream-only interpretations.", "satisfied": "no", "supporting_evidence": [ "[8] Sorted LT-HSCs taken 28 days after β-glucan transmit myeloid bias after 12 weeks in recipients with matched chimerism; heterologous LPS and chemotherapy responses improve.", "[9] BCG-educated HSCs generate protective macrophages; chimeric/parabiotic and transfer designs support sustainable lineage training.", "[10] Acute LPS produces persistent HSC enhancer accessibility and improved Pseudomonas defense; C/EBPβ deletion erases long-term marks/expression.", "[11] After 21-day periodontitis and 14-day resolution, purified LT-HSCs transmit myeloid bias and increased arthritis/LPS responses after 12–16 weeks; both CD41 strata transfer effects.", "[12] Western-diet withdrawal normalizes serum inflammation but retains myeloid responses; NLRP3 loss prevents diet-induced reprogramming.", "[13] Diabetic donor marrow produces macrophage changes in physiological glucose and increases atherosclerosis in normoglycemic Ldlr-null recipients.", "[14] 15 BCG recipients versus five placebo controls show day-90 HSPC/monocyte remodeling and increased heterologous IL1β; marrow M. bovis testing is reported negative.", "[15] Single-cell human marrow before/90 days after BCG/placebo shows HSPC expression/accessibility changes correlated with paired PBMC IL1β.", "[16] BCG alters neutrophil antimicrobial function and H3K4me3 profiles for at least three months.", "[19] Mtb IFN-I/iron signaling impairs myelopoiesis and trained defense, contrasting BCG/β-glucan IFN-II/IL1 programs.", "[22] Immortalized macrophages retain changing molecular/function states after washout and 14 divisions; late Salmonella control parallels newly induced interferon programs.", "[29] Stringently purified autoimmune-exposed LT-HSCs yield trained macrophages 18 weeks after transfer without spontaneous recipient autoimmune activity or lineage skewing.", "[31] Heart-failure donor marrow transmits cardiac dysfunction and altered susceptibility, with HSC TGFβ changes.", "[32] Post-stroke myeloid changes transmit cardiac dysfunction; IL1β neutralization/CCR2/5 blockade prevent remote cardiac injury.", "[34] Four-hour IL1β exposure of human marrow progenitors produces monocyte offspring with enhanced heterologous cytokines and metabolism.", "[42] β-glucan protects against Mtb and expands myeloid progenitors; IL1R deficiency abolishes protection.", "[47] BCG outer-membrane vesicles induce TLR2-dependent progenitor expansion/metabolism and sepsis protection.", "[48] β-glucan nine weeks before Listeria increases antimicrobial myeloid responses and survival." ], "what_would_cross_it": "Barcoded single-HSC serial transfer with matched engraftment and clone composition, recipient ligand surveillance and mark-specific functional rescue across generations." }, { "subclaim_id": "SC5", "threshold": "Δ", "requirement_quoted": "Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.", "satisfied": "no", "supporting_evidence": [ "[1] BCG-vaccinated volunteers show heterologous monocyte cytokine responses for three months; NOD2-dependent experiments and SCID Candida survival support innate contribution.", "[18] LPS/IFN-β train cultured alveolar macrophages after rest; macrophage IFNAR loss blocks induction, while transferred trained AMs worsen pneumococcal infection despite whole-animal LPS protection.", "[38] BCG protects against influenza but not SARS-CoV-2, with different tissue tropism and cytokine responses.", "[39] Acute LPS generates persistent resident-AM phenotypes and pneumococcal protection with minimal SARS-CoV-2 protection.", "[50] Randomized human BCG/malaria challenge alters activation and yields earlier/more severe symptoms; parasitemia inversely correlates with activation.", "[51] Randomized BCG attenuated-yellow-fever challenge reduces viremia with IL1β-associated monocyte changes.", "[52] ACTIVATE interim report of 198 elderly patients finds longer time to first infection and fewer infections with BCG.", "[53] BLOW2 randomizes 5420 NICU newborns under 2000 g to early BCG plus OPV and reduces neonatal all-cause mortality.", "[54] Randomized low-birthweight infant BCG substudy shows increased heterologous cytokines four weeks later.", "[55] Danish neonatal randomized trial finds no overall benefit in parent-reported infections through 13 months.", "[56] 1221 Danish healthcare workers show no overall BCG benefit for absenteeism, COVID or hospitalization.", "[57] BRACE stage-2 randomized 3988 healthcare workers shows no lower six-month symptomatic/severe COVID risk.", "[58] BRACE 12-month follow-up shows increased symptomatic COVID and no severe/breakthrough benefit.", "[59] Dutch healthcare-worker randomization with serologic detection shows no infection/duration/severity benefit despite early antibody effects.", "[60] BCG-PRIME randomizes 6112 older comorbid adults and finds no COVID or clinically relevant respiratory benefit.", "[61] BRACE combined-stage secondary analysis reports modestly more febrile/respiratory illness without severe-disease benefit.", "[62] Third Guinea-Bissau early-BCG trial has lower infection-related neonatal mortality and favorable pooled neonatal estimate.", "[63] Early BCG in 2320 low-birthweight infants has a favorable four-week secondary mortality contrast." ], "what_would_cross_it": "A prespecified human heterologous clinical endpoint with randomized intervention and a selective trained-memory mediator contrast, distinguishing adaptive immunity, combined vaccines and baseline exposure." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "BCG versus Mtb progenitor effects", "AM transfer harm versus whole-animal LPS protection", "No BCG COVID protection in BRACE/BCG-PRIME/Dutch and Danish healthcare-worker trials", "Preserved baseline/chimerism and lineage proportions in purified autoimmune transfer", "Reduced metabolism despite enhanced autoimmune-derived macrophage function", "Malaria monocyte training requires lymphocyte help during induction", "Some primary-macrophage memories fade by day 11" ], "note": "Cell type, induction schedule, ligand, age, baseline disease and challenge determine direction and duration. Human clinical nulls constrain protection but do not refute every cellular memory mechanism. Human signatures are not a substitute for clonal lineage or ligand exclusion." }, "falsification_patterns_met": [ { "pattern": "Universal heterologous protection fails", "evidence": "BRACE, BCG-PRIME and independent healthcare-worker trials are null for clinical COVID benefit; animal influenza/SARS-CoV-2 responses also differ.", "downgrade_applied": false }, { "pattern": "Universal enhanced metabolism fails", "evidence": "Purified autoimmune LT-HSC progeny retain enhanced killing/cytokines despite lower metabolic flux and ATP.", "downgrade_applied": false }, { "pattern": "Purely autonomous induction fails in some contexts", "evidence": "Malaria monocyte induction needs T-cell IFNγ and CD40-TRAF6 crosstalk can determine training. This does not test all later maintenance.", "downgrade_applied": false }, { "pattern": "Permanent uniform persistence is unsupported", "evidence": "Primary human macrophage responses are stimulus specific and some fade by day 11. Months of HSC transfer memory remain finite.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Induction treated as maintenance", "where": "Day 0–1 metabolic/IL1 interventions, pre-training IL1R deletion and constitutive IFNAR/Cebpb deletion do not automatically prove delayed necessity." }, { "pitfall": "TF association treated as demonstrated TF necessity", "where": "Sun expression/motif coupling is not a delayed TF-loss experiment; self-renewing immortalized responder-sorted cells differ from normal primary cells." }, { "pitfall": "Homeostatic maintenance confused with persistent original stimulus", "where": "A memory state can require normal endogenous regulation. Resetting every TF/metabolite to naive state would erase the state being tested." }, { "pitfall": "Clinical endpoint and mechanism conflated", "where": "BCG+OPV neonatal mortality benefit does not isolate BCG or trained innate mediation; viremia is not clinical disease." }, { "pitfall": "Provider gap statement treated as exhaustive absence", "where": "Consensus No Papers outputs and substituted papers cannot establish scientific absence." } ], "causal_tally_audit": { "tally_claimed_by_document": 61, "tally_after_audit": 61, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Null RCTs and harmful transfer results are counted as discriminating contrasts, not positive causal crossings.", "BRACE primary, follow-up and combined-stage secondary reports are one trial platform, with different denominators.", "Nonimmune epidermal memory and antigen-specific NK memory are explicit comparators, not myeloid or clinical proof." ] }, "steelman": { "case_one_rung_higher": "The strongest Ζ case combines resolved-periodontitis purified HSC transfer, independent autoimmune LT-HSC transfer without recipient inflammation, acute-LPS HSC memory and virus-experienced AM maintenance without continuing T-cell help. These causal lines make a blanket downstream-only or persistent-tissue explanation implausible for all settings.", "case_one_rung_lower": "The strongest Γ case demands strict direct proof that no original ligand survives, and that no continuing upstream niche feedback maintains the state; most interventions test induction, and transferred recipients are conditioned. Mark and metabolic associations do not identify a self-copying carrier.", "which_rejected": "Reject a blanket Γ for conditional persistence because purified donor-cell transfer after source-context removal and long-term functional challenge are genuine causal evidence. Reject broad Ζ for SC3 because sensitive ligand exclusion, delayed maintenance-selective intervention and unconditioned cross-compartment replication remain incomplete. Retain Ε with a Γ strict universal extension and Γ weakest-link sensitivity. These qualifications are not post hoc changes to the registered claim.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: After a defined nonreplicating inducer has cleared by sensitive labeled-ligand and molecular assays, isolate barcoded LT-HSCs and self-renewing primary macrophages. Randomize delayed cell-specific removal of original receptor/niche signaling, candidate chromatin-maintenance machinery and matched rescue. Transfer into ligand-free recipients with matched conditioning and engraftment; follow clones, baseline competence and heterologous challenge function over months." }, "final_score": { "hsef_level": "Ε", "hsef_descriptor": "Context-specific causality established", "confidence": "Moderate", "confidence_rationale": "Evidence density and reproducibility set the band, not correctness and not reviewer access depth: the heterologous-response phenomenon is replicated across many independent groups, models and assay classes, while the purified-transfer persistence result that sets the letter rests on few laboratories with heterogeneous conditioning and purification controls, and the clinical arm is split between replicated adult nulls and single-setting neonatal benefits.", "rests_on_non_peer_reviewed_work": false, "rationale": "Preregistered primary-subclaim aggregation uses SC3 and returns Ε, context-dependent causality, with Moderate confidence. Purified post-resolution and long-term donor-cell transfer support conditional intrinsic persistence without continued original tissue exposure. Complete ligand exclusion and independence from all ongoing signaling are not demonstrated; normal homeostatic maintenance is compatible with cell-intrinsic memory. The strict universal signal/antigen-free extension remains Γ. Weakest-link sensitivity is Γ because histone-carrier specificity and human clinical mediation remain unresolved; scope-matched primary sensitivity is Ε. The final letter does not certify the full conjunctive mechanism or universal clinical protection." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "Prior exposure establishes a later response state; that state modulates or amplifies subsequent immunity and disease in defined settings. It may protect, worsen injury or favor resolution. It is not established as a universal initiating cause of disease or universal clinical protection.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "The named 2025 H3K18-lactylation study and 2026 primary-macrophage stimulus-specific study refine candidate carriers and temporal boundaries; no presently recruiting decisive clinical mediation trial is asserted.", "justification": "The named 2025 H3K18-lactylation study and 2026 primary-macrophage stimulus-specific study refine candidate carriers and temporal boundaries; no presently recruiting decisive clinical mediation trial is asserted." }, "stability": { "value": "Stable", "trigger": "No verified pending decisive result is identified as likely to move SC3 imminently; current carrier and clinical-mediation limits remain open.", "justification": "No verified pending decisive result is identified as likely to move SC3 imminently; current carrier and clinical-mediation limits remain open." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Ε", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "Ranking categorical verdict visible; no prior letter used as a target", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": false, "new_level": "Ε", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "After a defined nonreplicating inducer has cleared by sensitive labeled-ligand and molecular assays, isolate barcoded LT-HSCs and self-renewing primary macrophages. Randomize delayed cell-specific removal of original receptor/niche signaling, candidate chromatin-maintenance machinery and matched rescue. Transfer into ligand-free recipients with matched conditioning and engraftment; follow clones, baseline competence and heterologous challenge function over months.", "readout": "Single-clone descendants, preserved viability/baseline inducibility, ligand burden, mark/TF/metabolic trajectories and challenge killing or disease phenotype", "critical_control": "Naive transferred cells; ligand-spiked assay sensitivity; induction-only versus delayed blockade; clone and lineage matching; inactive degron/rescue; nonconditioned or matched-niche comparison; adaptive-cell controls", "supporting_result": "Recall persists after verified original-input removal, disappears selectively after delayed candidate-carrier subtraction and returns with matched rescue without baseline impairment", "falsifying_result": "Recall tracks detectable original ligand/niche input, disappears with input removal rather than carrier-specific subtraction, or apparent loss is explained by clone selection or general cell dysfunction" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Sensitive original-ligand quantification and delayed source-input removal are missing across the main mature-cell and progenitor contexts; elapsed time or washout alone is insufficient.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Separate induction from maintenance with delayed, cell-specific intervention and preserved baseline competence; most examined metabolic/receptor knockouts intervene early.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Identify specific chromatin marks/readers as causal carriers with endogenous, locus-relevant subtraction and rescue, rather than broad p300/LDH effects or histone correlation.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Disentangle clone selection, lineage propensity and literal information transmission using barcoded single-HSC serial transfer and matched engraftment.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Test whether conditional memory persists in an unconditioned physiological niche; irradiation and support marrow can reset selection and feedback.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Explain enhanced function with reduced metabolism in autoimmune-derived progeny; a single glycolytic-memory signature cannot cover every state.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 7", "statement": "Map induction stimulus, cell class, dose and duration boundaries, including fading primary-macrophage memory, tolerance, resolution and harmful transfer phenotypes.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 8", "statement": "Identify selective innate-memory mediation of human clinical benefit separately from adaptive responses, combined vaccines, exposure and setting; preserve adult clinical nulls.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 9", "statement": "Resolve linked correction details for de Laval, HIF-1α and microbiome/BCG reports before publication-grade claims about exact assays or maintenance timing.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 10", "statement": "Resolve human marrow cohort overlap and obtain complete Methods, supplements and raw-data/image checks for the major purified-transfer and clinical claims.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-07", "reviewer": "Codex", "evidence_base_note": "63 primary reports; literature cutoff 2026-10-07; source examination UTC date 2026-10-08; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez; attempted Europe PMC XML and successful public NCBI PMC direct HTTPS access are separately logged. Signed-in Consensus browser discovery and targeted indexed full-text checks are reconciled with original sections; failed matches and source substitutions remain explicit. Zero Consensus API calls. SciSpace discovery was also used; matched primary leads were resolved to original records before counting. See scispace-leads.json.", "skill_version": "5.3", "validator_run": "exact archived v5.3 validator 2.3; see validator.txt", "validator_warnings_addressed": "Phenomenon entry was restated as the preregistered causal claim. No real phenomenon is labelled refuted; warning is explicitly justified.", "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Upper levels remain live. Human vaccination and clinical randomized outcomes, receptor/natural genetic defects, dose/context contrasts and orthogonal purified-cell transfers were considered. They support the response phenomenon and conditional persistence, but do not jointly identify an exclusive histone carrier, eliminate retained inputs across all compartments, or selectively mediate clinical benefit. Ethical impossibility of universal human receptor subtraction is not itself a ceiling; endogenous staged animal/cell and human natural experiments can advance the claim." }, { "kind": "natural_experiment", "available": true, "why_not_sufficient": "Upper levels remain live. Human vaccination and clinical randomized outcomes, receptor/natural genetic defects, dose/context contrasts and orthogonal purified-cell transfers were considered. They support the response phenomenon and conditional persistence, but do not jointly identify an exclusive histone carrier, eliminate retained inputs across all compartments, or selectively mediate clinical benefit. Ethical impossibility of universal human receptor subtraction is not itself a ceiling; endogenous staged animal/cell and human natural experiments can advance the claim." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Upper levels remain live. Human vaccination and clinical randomized outcomes, receptor/natural genetic defects, dose/context contrasts and orthogonal purified-cell transfers were considered. They support the response phenomenon and conditional persistence, but do not jointly identify an exclusive histone carrier, eliminate retained inputs across all compartments, or selectively mediate clinical benefit. Ethical impossibility of universal human receptor subtraction is not itself a ceiling; endogenous staged animal/cell and human natural experiments can advance the claim." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Upper levels remain live. Human vaccination and clinical randomized outcomes, receptor/natural genetic defects, dose/context contrasts and orthogonal purified-cell transfers were considered. They support the response phenomenon and conditional persistence, but do not jointly identify an exclusive histone carrier, eliminate retained inputs across all compartments, or selectively mediate clinical benefit. Ethical impossibility of universal human receptor subtraction is not itself a ceiling; endogenous staged animal/cell and human natural experiments can advance the claim." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "Upper levels remain live. Human vaccination and clinical randomized outcomes, receptor/natural genetic defects, dose/context contrasts and orthogonal purified-cell transfers were considered. They support the response phenomenon and conditional persistence, but do not jointly identify an exclusive histone carrier, eliminate retained inputs across all compartments, or selectively mediate clinical benefit. Ethical impossibility of universal human receptor subtraction is not itself a ceiling; endogenous staged animal/cell and human natural experiments can advance the claim." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 63, "claims_total": 69, "claims_verified": 69, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 63, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "BCG-vaccinated volunteers show heterologous monocyte cytokine responses for three months; NOD2-dependent experiments and SCID Candida survival support innate contribution. Human cytokines do not demonstrate clinical protection or elimination of all retained BCG/signaling; histone inhibitor specificity and adaptive cytokine contributions remain limits.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC5" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C2", "text": "Candida/β-glucan pretreatment protects lymphocyte-deficient mice in a monocyte-dependent manner and dectin-1/Raf-1 signaling contributes. Induction necessity and stable marks do not isolate antigen-free maintenance or direct mark copying.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C3", "text": "Akt/mTOR/HIF-1α perturbations block training; myeloid HIF-1α loss abolishes trained sepsis protection. Predominantly induction-stage metabolic necessity is not mark-specific maintenance; broad metabolic/viability effects require control; linked author correction noted.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C4", "text": "Primary monocyte-derived trained and tolerant macrophages acquire different transcriptomic/enhancer programs. Differentiation and histone co-occurrence do not show the specific marks cause or autonomously store memory.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C5", "text": "BCG training requires glycolytic rewiring in pharmacological/genetic experiments, with associated histone changes. Most tests target induction or broad metabolic enzymes, not delayed locus-specific histone maintenance.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C6", "text": "Glutaminolysis/fumarate and mevalonate-related metabolism contribute to β-glucan induction; fumarate inhibits KDM5 and induces similar marks. Metabolite sufficiency and broad inhibitors do not demonstrate exclusive mark-based inheritance or autonomous maintenance.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C7", "text": "Mevalonate/IGF1R/mTOR perturbations regulate training; mevalonate-kinase-deficient patients have constitutive trained phenotypes. Constitutive metabolite excess is ongoing upstream stimulation, not antigen-independent memory; pleiotropy limits a selective epigenetic instrument.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C8", "text": "Sorted LT-HSCs taken 28 days after β-glucan transmit myeloid bias after 12 weeks in recipients with matched chimerism; heterologous LPS and chemotherapy responses improve. Transfer lineage bias is not direct mark copying; IL-1/glycolysis/statin/GM-CSF interventions occur on days 0–1 and test induction, not delayed maintenance.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph24, 1:Results:paragraph28, 1:Results:paragraph38, 1:Results:paragraph103, 1:Results:paragraph108, 1:Results:paragraph109, 1:Results:paragraph113. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C9", "text": "BCG-educated HSCs generate protective macrophages; chimeric/parabiotic and transfer designs support sustainable lineage training. BCG bone-marrow access and potential persistence constrain full ligand independence; exact original transfer/clearance details inaccessible here; Mtb challenge is mycobacterial, not a distant heterologous pathogen.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C10", "text": "Acute LPS produces persistent HSC enhancer accessibility and improved Pseudomonas defense; C/EBPβ deletion erases long-term marks/expression. Exact deletion timing and viability/transfer controls are not examined; deletion of a transcription factor is not selective proof of mark copying; two corrections linked.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C11", "text": "After 21-day periodontitis and 14-day resolution, purified LT-HSCs transmit myeloid bias and increased arthritis/LPS responses after 12–16 weeks; both CD41 strata transfer effects. IL-1R deletion precedes training; no delayed maintenance-stage IL-1 subtraction, ligand quantification or exclusive epigenetic mechanism; irradiated niche and finite duration limit scope.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph4, 1:RESULTS:paragraph13, 1:RESULTS:paragraph14, 1:RESULTS:paragraph17, 1:RESULTS:paragraph18, 1:RESULTS:paragraph21, 3:LIMITATIONS OF THE STUDY:paragraph0. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C12", "text": "Western-diet withdrawal normalizes serum inflammation but retains myeloid responses; NLRP3 loss prevents diet-induced reprogramming. Ldlr deficiency and remaining lipid/niche signals may persist; constitutive knockout tests induction and associated inflammation rather than late maintenance.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C13", "text": "Diabetic donor marrow produces macrophage changes in physiological glucose and increases atherosclerosis in normoglycemic Ldlr-null recipients. Whole marrow and recipient Western diet allow selection/niche feedback; RUNX1 inhibition is broad; human signatures are associative.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C14", "text": "15 BCG recipients versus five placebo controls show day-90 HSPC/monocyte remodeling and increased heterologous IL1β; marrow M. bovis testing is reported negative. Assay data/sensitivity not shown, a skin lesion remains, and no human lineage tracing or causal HNF1 deletion; no significant adult cell-frequency shift despite transcriptional bias.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph10, 1:Results:paragraph16, 1:Results:paragraph40, 1:Results:paragraph43. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C15", "text": "Single-cell human marrow before/90 days after BCG/placebo shows HSPC expression/accessibility changes correlated with paired PBMC IL1β. Correlation across compartments does not demonstrate literal mark inheritance or no persistent ligand; indexed preprint is the same study, not replication.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C16", "text": "BCG alters neutrophil antimicrobial function and H3K4me3 profiles for at least three months. Repeated circulating cells cannot prove persistence in the same mature cell or autonomous progenitor mechanism; no clinical incidence endpoint.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C17", "text": "Respiratory-virus-experienced alveolar macrophages retain antibacterial memory; T-cell help is reported required for priming rather than maintenance. Original detailed depletion/antigen controls unavailable; innate maintenance after adaptive induction differs from completely innate induction; normal niche requirements remain.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C18", "text": "LPS/IFN-β train cultured alveolar macrophages after rest; macrophage IFNAR loss blocks induction, while transferred trained AMs worsen pneumococcal infection despite whole-animal LPS protection. Methylation/acetylation inhibitors during induction do not alter IL6 training here; six-day context and transfer niche differ from clinical vaccination; pooling technical replicates limits sample interpretation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC5" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph5, 1:Results:paragraph7, 1:Results:paragraph8, 1:Results:paragraph13, 1:Results:paragraph14, 1:Results:paragraph21, 1:Results:paragraph22. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C19", "text": "Mtb IFN-I/iron signaling impairs myelopoiesis and trained defense, contrasting BCG/β-glucan IFN-II/IL1 programs. Chronic pathogenic infection and progenitor death are distinct from autonomous beneficial memory; ongoing infection is a confounder for maintenance.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C20", "text": "β-glucan partly reverses LPS tolerance in vitro and restores cytokines in monocytes from experimental endotoxemia. Chromatin recovery accompanies reactivation; it does not prove the marks exclusively encode memory or clinical sepsis rescue.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C21", "text": "IRG1/itaconate/SDH processes distinguish tolerance from β-glucan training, including human genetic variants. Induction-stage metabolic control does not establish autonomous maintenance or a universal glycolytic phenotype.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C22", "text": "Immortalized macrophages retain changing molecular/function states after washout and 14 divisions; late Salmonella control parallels newly induced interferon programs. TF necessity is inferred from expression/motif coupling, not directly tested by delayed TF loss; initial responder sorting and immortalization limit generalization; mark persistence does not prove mark copying.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph2, 2:Results:paragraph4, 2:Results:paragraph12, 2:Results:paragraph16, 2:Results:paragraph19, 2:Results:paragraph20, 2:Results:paragraph24. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C23", "text": "H3K18 lactylation persists after washout and at 90 days after BCG; LDH/p300 inhibition attenuates training. Exact inhibitor timing and viability controls unexamined; metabolic and p300 effects are broad, and correlation with H3K18la does not isolate that mark as the memory carrier.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C24", "text": "Primary human macrophages retain stimulus-specific responses at six days, with stronger recall to similar challenges; some memories are lost by day 11. Finite and stimulus-dependent persistence contradicts a uniform durable state; TF licensing/chromatin are associated rather than direct maintenance subtraction; same authors/design as 2025 preprint counted once.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C25", "text": "Four inducers yield distinct monocyte programs/subpopulations, replicated with in vivo signatures. Single-cell heterogeneity and patient signatures do not isolate self-maintenance or clinical protection.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C26", "text": "In epidermal stem cells, delayed STAT3 loss after resolution preserves recall; post-induction AFOS leaves memory domains accessible with homeostatic TF support. Nonimmune tissue is a mechanistic comparator, not proof in myeloid cells; homeostatic maintenance factors are incompletely dissected.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph19, 1:RESULTS:paragraph22, 1:RESULTS:paragraph26, 1:RESULTS:paragraph28. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C27", "text": "Peripheral inflammatory schedules induce six-month microglial training or tolerance with opposite AD/stroke pathology effects. Schedules and tissue context determine response; disease-transgene and persistent niche changes constrain intrinsic antigen-free maintenance.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C28", "text": "HDM inflammation produces TNF/2-HG/PGE2-related macrophage memory; TNF blockade or myeloid Tnf loss prevents imprinting. Allergen and disease milieu can continue; prevention does not establish delayed signal-independent maintenance.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C29", "text": "Stringently purified autoimmune-exposed LT-HSCs yield trained macrophages 18 weeks after transfer without spontaneous recipient autoimmune activity or lineage skewing. Transferred progeny have reduced metabolism/accessibility despite increased killing/cytokines; irradiation and selection remain; not direct mark-copying or universal metabolic necessity.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph9, 1:RESULTS:paragraph11, 1:RESULTS:paragraph12, 1:RESULTS:paragraph13, 1:RESULTS:paragraph14, 1:RESULTS:paragraph17. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C30", "text": "Severe-COVID HSPC/myeloid epigenetic changes persist months to one year; early IL6 contributes in a mouse model. Human infection/severity and residual inflammation are not randomized; cross-compartment signatures are not clonal inheritance or complete ligand exclusion.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C31", "text": "Heart-failure donor marrow transmits cardiac dysfunction and altered susceptibility, with HSC TGFβ changes. Whole marrow/niche and disease carryover can coexist; TGFβ perturbation is not locus-specific epigenetic inheritance.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C32", "text": "Post-stroke myeloid changes transmit cardiac dysfunction; IL1β neutralization/CCR2/5 blockade prevent remote cardiac injury. Intervention timing and whole-cell milieu do not isolate late autonomous memory; patient concordance is observational.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C33", "text": "β-glucan/heme training increases myeloid procoagulant responses and four-week splenic activity via sphingomyelinase/tissue-factor decryption. Enhanced responsiveness can be harmful; systemic thrombotic clinical outcomes and autonomous maintenance are not demonstrated.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C34", "text": "Four-hour IL1β exposure of human marrow progenitors produces monocyte offspring with enhanced heterologous cytokines and metabolism. Culture expansion/differentiation and normal growth signaling remain; no in vivo transplant or delayed maintenance blockade.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C35", "text": "T-cell CD40-TRAF6 regulates myeloid functional/metabolic/chromatin training; combined blockade promotes graft acceptance. Adaptive crosstalk and combined CTLA4-Ig effects prevent attributing outcome solely to cell-autonomous innate memory.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C36", "text": "Malaria-trained purified monocytes fail without lymphocytes; transwell CD4/IFNγ restores heterologous cytokine responses. This tests induction crosstalk, not proof that every established memory requires ongoing lymphocyte signals.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C37", "text": "Subcutaneous BCG induces AM memory via gut microbiome/metabolite changes and mycobacterial dissemination, independently of circulating monocytes. Distal persistent upstream changes provide an alternative to direct cell-intrinsic induction; linked correction unexamined.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C38", "text": "BCG protects against influenza but not SARS-CoV-2, with different tissue tropism and cytokine responses. Pathogen-specific animal benefit cannot establish universal human heterologous protection or purely innate mediation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C39", "text": "Acute LPS generates persistent resident-AM phenotypes and pneumococcal protection with minimal SARS-CoV-2 protection. Whole-lung response and stable population size do not isolate same-cell autonomous memory or universal protection.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "SC5" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C40", "text": "Influenza-experienced AMs exert long-lasting tissue-specific antitumor effects with IFNγ/NK induction dependence. Human tumor association is observational; induction dependence is not continued maintenance dependence.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C41", "text": "Lineage tracing and AM transfer identify a KLF4/MERTK efferocytic trained subset that limits lung injury. Subset expansion/differentiation and tissue niche contribute; anti-inflammatory resolution differs from simply higher cytokine secretion.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C42", "text": "β-glucan protects against Mtb and expands myeloid progenitors; IL1R deficiency abolishes protection. Constitutive receptor deficiency and early stimulus do not distinguish induction/maintenance; human ex vivo response is not clinical efficacy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C43", "text": "STAT1 CMC patient cells have Candida-specific training defects while STAT3 HIES cells train normally. Genetic pleiotropy and pathogen specificity prevent a universal innate-memory instrument or proof of antigen-free maintenance.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C44", "text": "β-glucan-experienced human macrophages reduce NLRP3/caspase1/IL1β responses, including CAPS patient cells. Cytokine attenuation can coexist with memory; ex vivo anti-inflammatory effects do not establish clinical disease trajectory.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C45", "text": "IL37 reverses training-associated metabolic/mark changes and reduces Candida protection in models. Broad anti-inflammatory effects and treatment timing do not isolate a specific self-maintaining histone carrier.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C46", "text": "β-glucan-trained differentiated macrophage transfer protects Pseudomonas; sustained metabolic/chemokine state is independent of Dectin1/TLR2 here. Constitutive chemokine secretion differs from a fully resting state; ligand clearance and feedback remain unresolved; receptor dependence differs by model.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C47", "text": "BCG outer-membrane vesicles induce TLR2-dependent progenitor expansion/metabolism and sepsis protection. Vesicle cargo/duration and experimental sepsis do not establish long-term autonomous maintenance or human safety/benefit.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C48", "text": "β-glucan nine weeks before Listeria increases antimicrobial myeloid responses and survival. Elapsed time alone does not exclude retained particulate ligand or ongoing niche stimulation; multiple population/metabolic changes coexist.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C49", "text": "IRF4 controls metabolic uptake and memory expansion of virus-specific NK cells. Antigen-specific NK memory is a comparator, not demonstration of nonspecific trained myeloid memory; generic survival effects constrain mechanism.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C50", "text": "Randomized human BCG/malaria challenge alters activation and yields earlier/more severe symptoms; parasitemia inversely correlates with activation. 20 volunteers and correlational mediation do not establish clinical protection; enhanced activation can accompany adverse effects.", "carries_number": false, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C51", "text": "Randomized BCG attenuated-yellow-fever challenge reduces viremia with IL1β-associated monocyte changes. Vaccine-strain viremia is not ordinary clinical disease; correlated cytokines do not prove innate mediation or autonomous persistence.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC5" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C52", "text": "ACTIVATE interim report of 198 elderly patients finds longer time to first infection and fewer infections with BCG. Small interim analysis/probable viral diagnoses and clinical heterogeneity limit generalization; no selective trained-memory mediation test.", "carries_number": true, "load_bearing_for": [ "SC5" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C53", "text": "BLOW2 randomizes 5420 NICU newborns under 2000 g to early BCG plus OPV and reduces neonatal all-cause mortality. Combined vaccines cannot isolate BCG or trained innate mechanism; infection-death secondary outcome added during trial; setting/timing-specific clinical benefit.", "carries_number": true, "load_bearing_for": [ "SC5" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C54", "text": "Randomized low-birthweight infant BCG substudy shows increased heterologous cytokines four weeks later. Same Guinea-Bissau trial platform and immune substudy do not establish cytokine mediation of mortality or independent clinical replication.", "carries_number": false, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C55", "text": "Danish neonatal randomized trial finds no overall benefit in parent-reported infections through 13 months. Maternal-BCG early subgroup is not the overall endpoint; low-mortality context may differ from NICU/LBW settings.", "carries_number": true, "load_bearing_for": [ "SC5" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C56", "text": "1221 Danish healthcare workers show no overall BCG benefit for absenteeism, COVID or hospitalization. Secondary revaccination analyses diverge and have wide intervals; clinical null does not disprove all cellular memory.", "carries_number": true, "load_bearing_for": [ "SC5" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C57", "text": "BRACE stage-2 randomized 3988 healthcare workers shows no lower six-month symptomatic/severe COVID risk. Early recruitment stop and vaccine-related censoring limit precision; severe chiefly means incapacitated three days, not hospital disease; no verified selective innate engagement in this report.", "carries_number": true, "load_bearing_for": [ "SC5" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Methods, 1:Results. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C58", "text": "BRACE 12-month follow-up shows increased symptomatic COVID and no severe/breakthrough benefit. Same trial as six-month report, not independent replication; severity definition and evolving vaccination/exposure limit universal conclusions.", "carries_number": true, "load_bearing_for": [ "SC5" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C59", "text": "Dutch healthcare-worker randomization with serologic detection shows no infection/duration/severity benefit despite early antibody effects. Small hospitalized counts and clinical context constrain severe-disease estimates; antibody enhancement is not clinical or innate-memory mediation.", "carries_number": false, "load_bearing_for": [ "SC5" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C60", "text": "BCG-PRIME randomizes 6112 older comorbid adults and finds no COVID or clinically relevant respiratory benefit. Six-month regimen-specific null does not eliminate every clinical context or demonstrate selective mechanistic engagement.", "carries_number": true, "load_bearing_for": [ "SC5" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C61", "text": "BRACE combined-stage secondary analysis reports modestly more febrile/respiratory illness without severe-disease benefit. 6828 combined stages differs from 3988 stage-2 primary denominator; same trial, not independent cohort.", "carries_number": false, "load_bearing_for": [ "SC5" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C62", "text": "Third Guinea-Bissau early-BCG trial has lower infection-related neonatal mortality and favorable pooled neonatal estimate. Its standalone primary neonatal all-cause contrast is nonsignificant; polio-campaign censoring and pooled trials must be separated; mechanism unisolated.", "carries_number": false, "load_bearing_for": [ "SC5" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C63", "text": "Early BCG in 2320 low-birthweight infants has a favorable four-week secondary mortality contrast. Primary infant mortality is nonsignificant; neonatal secondary effect and subgroup weights do not turn the primary endpoint positive or establish autonomous training.", "carries_number": true, "load_bearing_for": [ "SC5" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "CSC1", "text": "Multiple distinct causal manipulations establish altered heterologous innate responses, including lymphocyte-deficient protection, primary human vaccination/challenge and transferred cells. Responses may be protective, harmful or tolerant; enhanced cytokines are not universal benefit. Independent assay/context classes support Ζ for the phenomenon within defined settings.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 2, 3, 4, 8, 9, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 54 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-08", "note": "" }, { "id": "CSC2", "text": "Induction-stage metabolic nodes causally contribute in defined systems, but histone co-occurrence, broad p300/LDH inhibition and TF deletion do not isolate a specific inheritable chromatin carrier. The conjunctive histone-encoding claim remains Γ under rubric 03; metabolic contribution alone is stronger. A purified autoimmune HSC transfer yields enhanced function despite reduced metabolism, excluding universal increased glycolysis as the carrier.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 33, 35, 42, 43, 44, 45, 46, 47, 49, 51 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-08", "note": "" }, { "id": "CSC3", "text": "Purified LT-HSC transfer after resolved periodontitis and independent stringent autoimmune LT-HSC transfer into recipients without spontaneous autoimmune activity support donor-cell intrinsic persistence away from the original tissue input for months. This crosses the context-specific Ε boundary. It does not establish universal absence of retained molecular ligands, complete independence from recipient niches or normal intracellular maintenance, or permanent mark copying. Continued homeostatic TF activity alone does not refute original-inducer independence. Stronger signal/antigen exclusion remains an unmet scope expansion.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 22, 23, 24, 26, 27, 28, 29, 30, 31, 32, 34, 35, 36, 37, 39, 40, 41, 46, 48 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-08", "note": "" }, { "id": "CSC4", "text": "Purified donor HSCs yield altered descendants and challenge responses after 12–18 weeks, with chimerism and lineage controls. The autoimmune experiment preserves overall lineage proportions, showing that differentiation bias is not the sole explanation. Irradiated niches, clonal selection and no direct mark copying limit the broader mechanistic inference to Ε. Human HSPC/monocyte concordance does not constitute human lineage tracing.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 8, 9, 10, 11, 12, 13, 14, 15, 16, 19, 22, 29, 30, 31, 32, 34, 42, 47, 48 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-08", "note": "" }, { "id": "CSC5", "text": "Clinical heterologous benefit occurs in defined vaccination contexts, but the examined trials do not selectively establish trained innate memory as the mediator. Combined BCG–OPV neonatal benefit, interim elderly infection benefit and attenuated yellow-fever viremia contrasts cannot be merged with adult COVID nulls into universal protection. Clinical efficacy in its tested setting can be Ε; trained-memory-specific clinical mediation is Γ.", "carries_number": false, "load_bearing_for": [ "SC5" ], "source_ns": [ 1, 18, 38, 39, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-08", "note": "" }, { "id": "CH", "text": "Trained innate responsiveness is causally demonstrated, and conditional cell-intrinsic persistence is supported; a universal autonomous histone–metabolic memory mechanism and universal clinical protection remain unestablished.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 11, 29, 22, 57, 53 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-08", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Kleinnijenhuis J, Quintin J, Preijers F et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proceedings of the National Academy of Sciences of the United States of America. 2012.", "tier": "A", "kind": "primary", "pmid": "22988082", "doi": "10.1073/pnas.1202870109", "url": "https://pubmed.ncbi.nlm.nih.gov/22988082/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID22988082", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC1", "CSC2", "CSC3", "CSC5" ] }, { "n": 2, "citation": "Quintin J, Saeed S, Martens JHA et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell host & microbe. 2012.", "tier": "A", "kind": "primary", "pmid": "22901542", "doi": "10.1016/j.chom.2012.06.006", "url": "https://pubmed.ncbi.nlm.nih.gov/22901542/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID22901542", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC1", "CSC2" ] }, { "n": 3, "citation": "Cheng SC, Quintin J, Cramer RA et al. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science (New York, N.Y.). 2014.", "tier": "A", "kind": "primary", "pmid": "25258083", "doi": "10.1126/science.1250684", "url": "https://pubmed.ncbi.nlm.nih.gov/25258083/", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID25258083", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC1", "CSC2" ] }, { "n": 4, "citation": "Saeed S, Quintin J, Kerstens HH et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. 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The Journal of infectious diseases. 2011.", "tier": "A", "kind": "rct", "pmid": "21673035", "doi": "10.1093/infdis/jir240", "url": "https://pubmed.ncbi.nlm.nih.gov/21673035/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "Guinea-Bissau-LBW-BCG-trial-platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C63", "CSC5" ] } ], "independence_basis": { "required": true, "lines": [ { "label": "Heterologous response without adaptive lymphocytes", "sources": [ 2, 1 ], "excludes_error": "Lymphocyte-deficient survival and monocyte-pathway perturbations exclude adaptive memory as the sole explanation in those models; not every human clinical mediator." }, { "label": "Original-context removal and purified long-term progenitor transfer", "sources": [ 11, 29 ], "excludes_error": "Different donor disease models, purification schemes and stable chimerism reduce ongoing original-tissue input and bulk composition explanations. Shared recipient conditioning remains a failure mode." }, { "label": "Human intervention and functional challenge", "sources": [ 51, 50 ], "excludes_error": "Randomization and heterologous human challenge differ from mouse transplantation and isolated cytokine assays; benefit and harm bound scope rather than proving identical molecular mediation." } ], "shared_failure_mode_checked": true, "note": "SC1 Ζ rests on different assay/context classes, not publication count. Purified transfer, lymphocyte-deficient functional challenge and randomized human exposure exclude distinct alternatives. β-glucan/BCG laboratory platforms and human marrow cohorts may share methods/participants; irradiated transfer recipients share niche confounding. Repeated BRACE reports are one randomization. No single comparison establishes literal epigenetic inheritance." }, "consensus_validation": { "completed": true, "status": "documented_historical_discovery_and_reconciliation", "provider": "Consensus", "provider_mode": "Historical browser/connector use as recorded in the source artifacts", "local_audit_date": "2026-10-09", "primary_comparison_count": null, "reported_usage": [], "grade_changed": false, "score_before": { "hsef_level": "Ε", "hsef_descriptor": "Context-specific causality established", "confidence": "Moderate", "confidence_rationale": "Evidence density and reproducibility set the band, not correctness and not reviewer access depth: the heterologous-response phenomenon is replicated across many independent groups, models and assay classes, while the purified-transfer persistence result that sets the letter rests on few laboratories with heterogeneous conditioning and purification controls, and the clinical arm is split between replicated adult nulls and single-setting neonatal benefits.", "rests_on_non_peer_reviewed_work": false, "rationale": "Preregistered primary-subclaim aggregation uses SC3 and returns Ε, context-dependent causality, with Moderate confidence. Purified post-resolution and long-term donor-cell transfer support conditional intrinsic persistence without continued original tissue exposure. Complete ligand exclusion and independence from all ongoing signaling are not demonstrated; normal homeostatic maintenance is compatible with cell-intrinsic memory. The strict universal signal/antigen-free extension remains Γ. Weakest-link sensitivity is Γ because histone-carrier specificity and human clinical mediation remain unresolved; scope-matched primary sensitivity is Ε. The final letter does not certify the full conjunctive mechanism or universal clinical protection." }, "score_after": { "hsef_level": "Ε", "hsef_descriptor": "Context-specific causality established", "confidence": "Moderate", "confidence_rationale": "Evidence density and reproducibility set the band, not correctness and not reviewer access depth: the heterologous-response phenomenon is replicated across many independent groups, models and assay classes, while the purified-transfer persistence result that sets the letter rests on few laboratories with heterogeneous conditioning and purification controls, and the clinical arm is split between replicated adult nulls and single-setting neonatal benefits.", "rests_on_non_peer_reviewed_work": false, "rationale": "Preregistered primary-subclaim aggregation uses SC3 and returns Ε, context-dependent causality, with Moderate confidence. Purified post-resolution and long-term donor-cell transfer support conditional intrinsic persistence without continued original tissue exposure. Complete ligand exclusion and independence from all ongoing signaling are not demonstrated; normal homeostatic maintenance is compatible with cell-intrinsic memory. The strict universal signal/antigen-free extension remains Γ. Weakest-link sensitivity is Γ because histone-carrier specificity and human clinical mediation remain unresolved; scope-matched primary sensitivity is Ε. The final letter does not certify the full conjunctive mechanism or universal clinical protection." }, "independent_blinded_audit": false, "raw_receipts": [ { "path": "deliverables\\hsef_v53_popularity_ranks_26_30_2026-10-07\\trained-immunity\\consensus\\broad-browser-snapshot.txt", "sha256": "662f435c774e64a84c3f78a966a1487c91cab192c11706d9ab7e7b18fb946b46" }, { "path": "deliverables\\hsef_v53_popularity_ranks_26_30_2026-10-07\\trained-immunity\\consensus\\query-ledger.json", "sha256": "0714981246fe4a747d9e3cb25def5e17192ce43c2bffabf2fa1af5a9bff78a2b" }, { "path": "deliverables\\hsef_v53_popularity_ranks_26_30_2026-10-07\\trained-immunity\\consensus\\reconciliation.md", "sha256": "d1244d2bec42d3ea61e00b92d2284d321c43d72c2d0cbbd2ab04fd982d51efb4" }, { "path": "deliverables\\hsef_v53_popularity_ranks_26_30_2026-10-07\\trained-immunity\\consensus\\targeted-browser-snapshot.txt", "sha256": "5e0ffa2665ab4c0941e4b059b6e56001c6d83a2285c566ce0c964c3cca7cd974" } ], "limitations": "This verifies documented historical use and links the record to the final edition. It adds no primary-source, full-text, independence or verification credit. Original access remains limited to the source-specific record." } }