Random physiological fluctuations may create apparent menopause response types
Menopause response types may reflect random threshold crossings rather than distinct classes. A fixed model must predict event timing and treatment effects; stable personal classes, lasting priming or biological-phase-linked reversals unexplained by the model would reject it as the dominant explanation
Stage of verification
- Hypothesis published2026-10-03
- Not enough research data
- Direct testAwaited
Map of the hypothesis
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Where in the body
Ageing mechanism
Kind of knowledge gap
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Target map
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Scale or classification
Menopause syndrome classification
A classification that groups vasomotor, sleep, mood and metabolic problems into proposed menopause syndromes
Where this hypothesis actsAcross reproductive stages and assigned endocrine or nonendocrine perturbations
Hypotheses on this target 5
Telling states apart5
Direct measurement
Indicator replacement

What is proposed
Telling states apart
Distinguish continuous physiological states from stable response types
With whatInstrument or assay
HowCompare a frozen first-passage model with fixed syndrome labels using repeated recordings and responses to randomized endocrine, nonendocrine and mild thermal perturbations
Possible result
Expected prediction of event timing and treatment effects without added treatment-selection value from fixed labels
From the recordfixed syndrome labels add no clinically meaningful treatment-selection value.
All targets of the lab
Every target read from the published hypotheses, each kind around its pictogram. A larger mark means more hypotheses act on that target. Point at a mark and the actions proposed on it branch out of it.
Solid and named: the targets of this hypothesis
Explore in depth
The logic
The train of thought that ends in this hypothesis. Each stage is the reason the next exists. The master question narrows to a goal, the goal to an unknown nobody has closed, the unknown to the hypothesis proposed here. Every step below says what it rests on and what carries it.
Patterns of symptoms around menopause may reflect changing conditions within a person rather than permanent differences between kinds of people. The unexpected move is to explain apparent response types through the size of random physiological fluctuations and how quickly those fluctuations settle. This is a hypothesis generated by the pipeline, not a measured result: it predicts that changing the variability of a mild temperature input, while keeping its average unchanged, will change symptom frequency without permanently changing a person's response category.
- Reproductive stage and treatment are proposed to set the internal drive's baseline, fluctuation size and speed of return.
- Unresolved fast biological inputs randomly push the drive away from its baseline.
- The drive is pulled back toward the same baseline rather than settling into a separate lasting state.
- A threshold crossing changes the state from no objectively defined hot-flash event to an event.
- Different fluctuation sizes and return speeds produce different event frequencies even when average hormone measurements are similar.
- Changing event patterns make the same person appear to switch response categories without lasting changes in how cells operate.
Two bowls can have the same average water level, yet the one shaken more unevenly spills more often. Spilling does not turn it into a different kind of bowl.
Where the picture breaks: The proposed internal drive is inferred from recordings rather than directly visible like water. The picture does not establish a biological symptom threshold, explain treatment effects, or rule out lasting changes caused by treatment.
- Master questionstep 01 of 04
Discovering menopause syndromes, meaning recurring combinations of symptoms around the end of menstrual cycles, might yield knowledge useful for radically extending lifespan.
Rests on: The goal connects understanding menopause with discovering ways to extend life.
AssumptionThe goal assumes that understanding menopause symptom patterns can inform radical lifespan extension. The supplied material establishes no such connection.
- Goal pillarstep 02 of 04
Validated menopause syndromes would form part of a protocol intended to produce lasting lifespan benefits.
Rests on: The master question supplies the ambition to connect menopause discovery with lifespan extension.
LeapThe move from discovering symptom patterns to a durable lifespan intervention requires evidence connecting those patterns and their treatment to survival. Neither the preceding goal nor the supplied sources provides it.
- Gap questionstep 03 of 04
Menopause response patterns could be distinct biological types or positions along a continuous range that changes with reproductive stage and treatment. Competing classifications would be compared by predicting responses to randomly assigned hormone-related and other interventions before those responses are observed.
Rests on: The preceding goal requires validated syndrome discovery; this stage makes prediction of intervention responses the proposed basis for validation.
AssumptionThe stage assumes that the chosen interventions, measurements and classifications can distinguish stable causal types from changing continuous states. The supplied material does not establish that they can.
- Hypothesisstep 04 of 04
Apparent response types are proposed to arise when a continuously changing internal physiological drive crosses the level at which a symptom occurs. Reproductive stage and treatment would change both the size of random fluctuations and the speed of return toward baseline, allowing people with similar average hormone measurements to experience different numbers of events.
Rests on: The preceding question explicitly allows continuous states shaped by stage and treatment. The endpoint develops that possibility using a mathematical model of random fluctuations pulled toward one baseline.
AssumptionThe model assumes one baseline toward which the drive returns and a threshold whose crossing produces an event. It excludes hidden discrete syndrome states; that structural choice, rather than the proposal's untested status, is the assumption.
What is carried, and what is not. One screened source indirectly supports the fluctuation premise: the 2025 narrative review in Journal of Clinical Medicine reports an association between changing estrogen levels, meaning levels of a reproductive hormone, and sleep problems, but does not establish random threshold crossings or distinct versus continuous response types. None of the supplied sources establishes any of the six proposed mechanism links in its stated causal form, or the sequence end to end.
Where the reasoning is carried by something unstated · 4
- Master question. The goal assumes that understanding menopause symptom patterns can inform radical lifespan extension. The supplied material establishes no such connection.
- Goal pillar. The move from discovering symptom patterns to a durable lifespan intervention requires evidence connecting those patterns and their treatment to survival. Neither the preceding goal nor the supplied sources provides it. Establish the missing link before relying on this step.
- Gap question. The stage assumes that the chosen interventions, measurements and classifications can distinguish stable causal types from changing continuous states. The supplied material does not establish that they can.
- Hypothesis. The model assumes one baseline toward which the drive returns and a threshold whose crossing produces an event. It excludes hidden discrete syndrome states; that structural choice, rather than the proposal's untested status, is the assumption.
How a result here could mislead · 3
- More hot flashes under a more variable temperature input could be credited to random hormone fluctuations, although the temperature manipulation establishes sensitivity to external temperature variability rather than the hormonal origin of the internal fluctuations. What closes it: The temperature inputs must have equal averages and specified differences in variability. Hormone measurements and responses to randomly assigned treatments are separately required to connect the inferred fluctuations to menopause; the endpoint itself acknowledges this limit.
- A model adjusted after seeing the event recordings could appear to predict the same events from which its internal drive and threshold were inferred. What closes it: The event definition, fitting procedure and model must be fixed before evaluation on recordings excluded from fitting. The size of an improvement in treatment selection that would count as clinically meaningful must also be set beforehand; the supplied specification gives no numerical criterion.
- Temporary category switching could be attributed to random fluctuations even if it follows the body's daily timing cycle, while lingering effects of an earlier treatment could be mistaken for slow return toward baseline. What closes it: The comparison must track prior treatment exposure and measured internal daily phase, meaning position within the body's daily timing cycle, alongside event recordings. Follow-up after the temperature input ends must distinguish recovery from persistent reassignment; the supplied specification does not give its duration.
What would make this wrong. The endpoint would fail as the dominant explanation if repeated measurements revealed stable person-specific response classes, lasting treatment-induced changes in later responses, or reversals tied to internal daily phase that the fixed fluctuation model could not explain. Failure to predict previously unseen event waiting times, recovery times and treatment effects would undermine its proposed predictive basis. Conversely, successful symptom prediction would still leave the chain's connection to lifespan extension unestablished.
What it would change. If the hypothesis held, menopause classification would need to account for how symptoms fluctuate and recover over time, rather than treating average hormone measurements or fixed labels as sufficient for choosing treatment. A successful model would make changing physiological conditions a candidate basis for treatment selection. Even then, predicting hot-flash timing would not establish a unified explanation for sleep, mood and metabolic problems, or show that acting on these fluctuations extends lifespan.
Sources read · 8
Sleep Disturbance and Perimenopause: A Narrative Review. · Journal of clinical medicine · 2025
“Furthermore, some authors stated that the degree and the dynamics of estrogen fluctuation, rather the absolute hormone level, was strongly associated with sleep disorders [ ].”
Does not settle: The source does not establish stochastic threshold crossings, discrete versus continuous menopause response types, differences in event burden among participants with similar mean endocrine measurements, effects of stage or treatment on restoring rates or variance, or repeated switching of apparent categories without durable molecular reprogramming.
Tamoxifen-induced hot flashes. · Clinical breast cancer · 2000
“Upon starting tamoxifen, women were asked to complete a hot flash diary daily for 3 months, and then daily for 1 week of each of the subsequent 9 months.”
Does not settle: The abstract does not analyze within-person stochastic fluctuations, symptom-expression thresholds, restoring rates, variance, endocrine measurements, switching between apparent response categories, or durable molecular reprogramming.
Sleep in women across the life cycle from adulthood through menopause. · Sleep medicine reviews · 2003
“Menopause is associated with insomnia due to several factors including hot flashes, mood disorders and increased sleep-disordered breathing.”
Does not settle: The abstract does not test whether menopause response types are transient threshold crossings, quantify restoring rates or stochastic variance, compare event burdens among participants with similar mean endocrine measurements, or show repeated category switching without durable molecular reprogramming.
Modeling women's health during the menopausal transition: a longitudinal analysis. · Menopause (New York, N.Y.) · 2007
“This was a 9-year prospective observational study of 438 Australian-born women, who at baseline were aged 45 to 55 years and had menstruated in the prior 3 months. Interviews were conducted and fasting blood and physical measurements were performed annually.”
Does not settle: The source does not test whether symptom-response types are transient threshold crossings, estimate restoring rates or stochastic variance, compare event burdens among women with similar mean endocrine measurements, or show individuals switching apparent categories without durable molecular reprogramming. Annual sampling also does not establish short-timescale physiological fluctuation dynamics.
Alternative medicine and the perimenopause an evidence-based review. · Obstetrics and gynecology clinics of North America · 2002
“In conditions like the perimenopause, where the symptoms may wax and wane unpredictably, quality research is needed to demonstrate the efficacy of interventions.”
Does not settle: The abstract does not establish whether symptom fluctuations arise from a continuous stochastic physiological drive crossing expression thresholds, whether stage or treatment changes restoring rates or variance, whether similar mean endocrine measurements can accompany different event burdens, or whether individuals switch apparent response categories without durable molecular reprogramming.
Early severe vasomotor menopausal symptoms are associated with diabetes. · Menopause (New York, N.Y.) · 2014
“Latent class analysis and generalized estimating equation models for binary repeated measures were performed. The VMS profiles were labeled as mild, moderate, early severe, and late severe.”
Does not settle: The source does not establish whether the profiles are discrete biological classes or transient threshold crossings of a continuous stochastic drive. It does not report endocrine means, restoring rates, fluctuation variance, symptom-expression thresholds, individual category switching, treatment effects, or durable molecular reprogramming.
Hormone Therapy in Menopause. · Advances in experimental medicine and biology · 2020
“Once thought to be relatively brief, they sometimes persist more than 10 years.”
Does not settle: The abstract does not examine physiological fluctuation statistics, symptom-expression thresholds, restoring rates, stochastic variance, discrete response classes, differences in event burden among participants with similar mean endocrine measurements, within-person category switching, or durable molecular reprogramming.
Regulation of specific target genes and biological responses by estrogen receptor subtype agonists. · Current opinion in pharmacology · 2010
“ERβ-selective agonists might be clinically useful for preventing breast cancer and treating hot flashes and inflammatory conditions associated with menopause.”
Does not settle: The source does not establish whether apparent menopause response types arise from stochastic physiological fluctuations, whether stage or treatment changes restoring rates or variance, whether similar mean endocrine measurements can coexist with different event burdens, or whether individuals switch categories without durable molecular reprogramming.
The gap this hypothesis explains
Two established results predict opposite outcomes, and both cannot be right.
Do menopause symptom groups predict different treatment effects, or reflect gradual changes with stage and treatment?
Original wording · exactly as the pipeline generated it
Do menopause syndromes represent distinct causal response types, or continuous states shaped by stage and treatment, when competing classifications prospectively predict responses to randomized endocrine and nonendocrine perturbations?
What this question is asking
The question asks whether patterns of symptoms around menopause identify genuinely different kinds of treatment response or describe changing positions along a continuum. It compares classifications that place people into separate groups with classifications that describe degrees of symptoms or states that can change over time. The proposed comparison asks whether these classifications predict responses to randomly assigned treatments that act through hormones and treatments that act through other routes. The pipeline assumes that evidence already supports competing representations, but the supplied sources establish only that researchers have identified statistical profiles. The requested standard is that definitions fixed beforehand work in independent populations and improve treatment selection over repeated follow-up.
- Menopause and menopausal stage
- Menopause is the end of menstrual periods associated with the end of ovarian reproductive function. Menopausal stage describes a person's position in the transition around that event; the question asks whether this position helps explain changing symptoms and treatment responses.
- Menopause syndrome or symptom profile
- A pattern of symptoms considered together. Calling a pattern a syndrome or profile does not itself establish a separate biological condition or a distinct response to treatment.
- Categorical classification
- A system that assigns observations or people to separate groups. Here, the issue is whether the boundaries between symptom groups predict meaningful differences in treatment effects.
- Dimensional or continuous representation
- A description using degrees along one or more scales instead of only separate group labels. The question asks whether such gradual differences explain treatment responses better than group membership.
- Hidden state
- An underlying condition inferred from measured observations rather than observed directly. A model can allow that state to change over time, but the supplied excerpts do not establish evidence for such transitions.
- Latent class analysis
- A statistical method that infers groups from patterns in measured data. A group identified by this method is a statistical result, not by itself proof of a separate cause or treatment-response type.
- Causal treatment-response type
- A group defined by how an intervention changes an outcome, rather than only by symptoms observed without that intervention. The question asks whether menopause symptom groups identify differences of this kind.
- Randomized endocrine and nonendocrine perturbations
- Interventions assigned by chance, with some acting through the hormone system and others through other routes. A perturbation means an imposed change used to observe a response; random assignment helps separate treatment effects from pre-existing differences between groups.
- Prospective prediction and longitudinal follow-up
- Prospective prediction specifies an expected outcome before it is observed. Longitudinal follow-up repeatedly observes the same people over time, allowing predictions to be assessed as symptoms and circumstances change.
- Locked phenotype definitions
- Rules for identifying observable characteristics or symptom patterns that are fixed before their predictive performance is assessed. Fixing the rules prevents the classification from being redefined to fit the outcomes being used to assess it.
- Externally reproducible eligibility
- The ability of the same classification rules to produce consistent qualification decisions when applied in independent populations. Here, eligibility concerns who would be included in a treatment or study group.
- Clinically meaningful incremental prediction
- An improvement in prediction beyond information already available that is large enough to matter for treatment decisions. The supplied material does not define the required improvement.
- Follicle-stimulating hormone and luteinizing hormone
- Hormones involved in regulating ovarian reproductive activity. S6 uses their measured levels, together with menstrual patterns, to help classify menopausal status.
- Depressive-symptom score
- A numerical summary of measured depression-related symptoms. S8 groups the ways these scores change over time; those trajectories do not themselves measure treatment effects.
Categorical and hidden-state approaches coexist with dimensional evidence, but none establishes distinct causal treatment-response classes; competing representations may imply different eligibility decisions.
The premise concerns ways of organizing menopause-related measurements: separate symptom groups, underlying states inferred from observations, and positions along continuous scales. It assumes that existing evidence supports these alternatives while leaving unresolved whether they identify different treatment effects. If that assumption holds, comparing their predictions could distinguish useful treatment-selection information from differences in how symptoms are described.
S5, S7 and S8 support the narrower claim that statistical methods have been used to identify symptom profiles. S6 also uses a statistical grouping method, but to determine menopausal status from hormone measurements and menstrual patterns. The supplied excerpts do not establish evidence for continuous alternatives or models of transitions between hidden states, show conflicting eligibility decisions, or support a literature-wide claim that no causal treatment-response classes have been established. Only four abstracts are represented, so the broader premise remains insufficiently assessed.S5S6S7S8
The same question asked without the part nothing read establishes:
- Do classifications using separate menopause symptom groups or continuous symptom measures better predict responses to randomly assigned hormone-based and other treatments?
- Do menopause symptom profiles predict treatment effects beyond information about menopausal stage and treatment history?
- Separate groups predict different treatment effects If fixed group definitions reproducibly distinguish the effects of randomly assigned treatments, group membership would provide information about which treatment produces which response. Group-based eligibility could then be informative, provided the distinctions improve prediction enough to matter for treatment decisions.
- Responses vary continuously with stage and treatment If treatment effects change gradually with symptom measurements and menopausal stage, discrete labels would divide a continuous pattern. Treatment selection based on rigid boundaries could lose information about response differences within each group and similarities across its boundaries.
- Neither representation improves treatment prediction If neither classification adds useful information about treatment effects, describing symptom patterns would not establish a basis for choosing between treatments. Eligibility decisions derived from those classifications would lack the predictive justification sought by the question.
A symptom classification can influence who qualifies for a treatment and which treatment is selected. That use requires a connection between the classification and differences in treatment effects, beyond simply describing symptoms. If symptom groups identify different treatment effects, their boundaries could carry information relevant to treatment selection. If responses instead vary gradually or change with stage and treatment, fixed group boundaries could separate people whose responses are similar or combine people whose responses differ. The supplied evidence does not establish which chain applies.
RL-1 categorical and hidden-state approaches coexist with RL-2 dimensional evidence; none establishes distinct causal treatment-response classes.
Locked phenotype definitions yield externally reproducible eligibility and clinically meaningful incremental prediction across longitudinal follow-up.
Competing representations may imply different eligibility decisions, but no prospective perturbation comparison determines which distinctions improve intervention selection.
The mechanism it proposes
The engine's own statement of the hypothesis, in full.
Apparent menopause response types are transient excursions of a continuously varying physiological drive across symptom-expression thresholds. Stage and treatment alter the drive's restoring rate and stochastic variance; they do not create discrete biological classes. Consequently, two participants with similar mean endocrine measurements can have different event burdens because their fluctuation statistics differ. Repeatedly sampled individuals switch apparent categories without durable molecular reprogramming.
Where the idea comes from
The hypothesis borrows a result from another field. This is what it borrows, and from where.
Stochastic processes: an Ornstein-Uhlenbeck first-passage model, dx_t = -k(s,u)[x_t - m(s,u)]dt + sqrt(2D(s,u))dW_t. Here t is elapsed time; x_t is a latent physiological event-generating drive inferred from objective recordings; s is reproductive stage; u is the assigned endocrine or nonendocrine perturbation; k is the restoring rate toward the baseline drive; m is that stage- and treatment-specific baseline; D is biological fluctuation intensity; and W_t is a standard Wiener process representing unresolved fast biological inputs. An event occurs at the first crossing of threshold b, the drive level associated with an objectively defined vasomotor event. The testable outputs are distributions of crossing and recovery times. A single restoring basin is used; no bistable attractor or hidden discrete syndrome is assumed.
Testing and possible results
The prediction that would tell it apart
A hypothesis that predicts what its rivals predict is not worth running an experiment over. This is the observation on which this one differs.
A frozen first-passage model predicts held-out event waiting times, return times and treatment effects using estimated fluctuation variance and relaxation rate, while fixed syndrome labels add no clinically meaningful treatment-selection value. Under a bounded randomized mild thermal input with equal mean but different temporal variance, event rates change as predicted by the model without persistent reassignment after the input ends. Stable person-specific classes, enduring priming effects, or phase-locked reversals unexplained by the stochastic model would reject it as the dominant explanation.
Would tell it apart from at least one rival. The prediction specifies observable outcomes, a comparison under controlled input conditions, and explicit rejection conditions. No rival prediction is supplied. A paper already fetched for this hypothesis bears on it.
What testing it would take
The engine's own read on whether this is testable with methods that already exist.
Dense recording can test event distributions before any treatment-selection trial. The mild thermal manipulation identifies fluctuation sensitivity, not endocrine-noise causation by itself. Endocrine measurements and randomized treatment effects are needed to connect the inferred dynamics to menopause.
Other explanations
Every other hypothesis the engine wrote for the same gap, and the observation that would separate the two.
A frozen first-passage model predicts held-out event waiting times, return times and treatment effects using estimated fluctuation variance and relaxation rate, while fixed syndrome labels add no clinically meaningful treatment-selection value. Under a bounded randomized mild thermal input with equal mean but different temporal variance, event rates change as predicted by the model without persistent reassignment after the input ends. Stable person-specific classes, enduring priming effects, or phase-locked reversals unexplained by the stochastic model would reject it as the dominant explanation.
- Rival 01 of 04What would separate them
An initial hormone challenge may create menopause response types through lasting gene priming predicts: Randomize an initial endocrine exposure or matched control, allow verified exposure clearance and recovery of prespecified clinical baselines, then independently randomize endocrine versus nonendocrine treatment. The initial exposure changes the later treatment contrast for objective physiological outcomes, with a persistent transcriptional recall signature preceding that change. A reproducible initial-exposure-by-later-treatment interaction supports this hypothesis; its absence within a prespecified clinically meaningful equivalence margin favors the other rivals. In matched cell models, erasing the candidate priming mark must abolish altered recall without changing genotype or current receptor exposure.
- Rival 02 of 04What would separate them
Reporting and selection may create apparent menopause syndromes from partly independent disorders predicts: In an externally recruited cohort with objective endpoints and randomized endocrine and nonendocrine assignments, each component's baseline severity and established clinical modifiers predict its response, but a frozen syndrome label supplies no additional treatment interaction within a prespecified equivalence margin. Residual objective responses across components show no reproducible shared response factor. Changing questionnaire framing alters category assignment without changing objective treatment effects. Reproducible shared stochastic dynamics, genotype-defined response classes, molecular priming or phase-dependent cross-domain treatment rankings would defeat this explanation.
- Rival 03 of 04What would separate them
Inherited regulatory combinations may create distinct menopause treatment-response types predicts: A prespecified regulatory-genotype classifier predicts a reproducible endocrine-versus-nonendocrine treatment interaction across stage transitions and independent cohorts, beyond flexible continuous baseline models. In matched isogenic cells, editing the implicated variant combination reverses the relevant endocrine transcriptional response at equal exposure; sham editing does not. If genotype effects are only smooth, weak modifiers without reproducible treatment-ranking partitions, this discrete-type hypothesis fails.
- What would separate them
Internal biological phase may determine menopause treatment response predicts: For interventions with sufficiently rapid pharmacodynamics, randomized administration at different measured biological phases produces a repeatable crossover in endocrine-versus-nonendocrine benefit. A controlled phase shift moves the response curve with internal phase rather than civil clock time. A frozen circular phase-response model then predicts held-out treatment response better than syndrome labels. No meaningful phase interaction, or an interaction confined to reporting rather than objective physiology, rejects this hypothesis.
What stands behind it
Which of the figures above have a study behind them, which are the engine's own, and what it would take to refute the hypothesis. This audit never judges the idea.
This hypothesis states no figure and cites no study, so there is nothing here to trace.
What it would take to refute it. 6 paper(s) already retrieved for this hypothesis carry its prediction’s terms. Reading them comes before running anything. Already retrieved: A Thematic Narrative Review of Osteoarthritis Risk Factors Across the Female Life Course.; Sex Differences in the Cardiovascular Significance of Albuminuria in Type 2 Diabetes: A Narrative Review.; Bacterial Vaginosis vs. Aerobic Vaginitis: An Unresolved Conundrum?.
6 papers retrieved around this hypothesis
- Acute wood smoke exposure is associated with cell-specific hippocampal transcriptomic responses in an accelerated ovarian failure mouse model.PMID 42214760 · full_text · 71,685 characters stored
- The Urogenital Microbiome-Metabolic Interface in Postmenopausal Recurrent Urinary Tract Infection: Estrogen Deficiency, Diabetes, Obesity, and Microbial Reservoirs.PMID 42589999 · full_text · 91,490 characters stored
- A Thematic Narrative Review of Osteoarthritis Risk Factors Across the Female Life Course.PMID 42794512 · full_text · 136,907 characters stored
- Sex Differences in the Cardiovascular Significance of Albuminuria in Type 2 Diabetes: A Narrative Review.PMID 42739916 · full_text · 73,957 characters stored
- Bacterial Vaginosis vs. Aerobic Vaginitis: An Unresolved Conundrum?PMID 42651697 · full_text · 94,855 characters stored
- A Multicenter Trial of an Enhanced Serum Comprised of 13 Plant-Based Adaptogens Targeting Skin Quality in Females Impacted by Hormonal Decline.PMID 42117281 · full_text · 31,070 characters stored
0 citation handles extracted; 1 Europe PMC search run; 8 records examined; 6 sources stored for enrichment, 6 with full text. A citation that did not resolve is a bibliographic failure, not proof that no such paper exists, and no hypothesis is blocked by this audit.