npj Science of Learning

Working memory is capacity-limited, but interactions with episodic memory may offset this constraint. We tested moment-by-moment contributions of episodic representations to working memory by combining the N-back and Mnemonic Similarity tasks. Thirty-one participants, undergoing eye-tracking, first encoded items in a one-back task, classifying them as "same" or "similar" to their predecessor. In a subsequent two-back task, mnemonic discrimination showed a graded, item-specific benefit of prior experience: performance was best for previously compared items, whereas recognition of identical repeats was unaffected. Successful discrimination of previously compared items was accompanied by greater pupil dilation, gradually emerging gaze patterns resembling those elicited by their similar pair-mate, and higher gaze-similarity between one-back and two-back target viewing. Diverging gaze patterns between pair-mates during one-back further predicted two-back discrimination. These findings challenge working memory's characterization as an isolated system, demonstrating how it recruits episodic computations - encoding distinct traces, predicting upcoming content, and reinstating it at retrieval.

BACKGROUND: An individual's adaptation to threatening environments under uncertainty is reflected in stress responses. Predictability (the ability to anticipate events) and controllability (the ability to control outcomes) are central to how one adapts, yet their joint influence on aversive learning remains unclear. METHODS: Thirty healthy adults completed a probabilistic aversive learning task in which cue-outcome contingencies varied across levels of predictability and controllability, i.e. whether shock intensity depended on prediction accuracy. Prediction accuracy, reaction time, subjective stress ratings, and skin conductance responses were recorded throughout. Trial-wise learning dynamics were estimated using the Volatile Kalman Filter. RESULTS: Prediction accuracy reduced as environments became less predictable and negatively associated with higher learning rates across predictability levels, with the strongest relationship observed in highly predictable blocks. Skin conductance responses showed that moderately predictable environments elicited responses like those in highly predictable environments when accurate predictions reduced shock intensity, but resembled responses in unpredictable environments when shock intensity was uncontrollable. Model comparison revealed a double dissociation between subjective stress ratings and skin conductance responses. Subjective ratings were best explained by model-derived volatility when prediction accuracy determined shock intensity and by belief uncertainty when it was independent of prediction accuracy, whereas skin conductance responses showed the reverse pattern. Reaction times were best explained by belief uncertainty when predictions influenced shock intensity. Higher anxiety was associated with elevated learning rates in highly and moderately predictable blocks when predictions did not control shock intensity.

Background: Inequalities exist for many health outcomes, but there is limited evidence regarding menstrual symptoms despite their importance for health and wellbeing. We aimed to investigate inequalities in menstrual symptoms according to socioeconomic position and childhood adversity. Methods: In two generations (G0 mothers and G1 offspring) from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK prospective cohort study, we examined associations of multiple indicators of socioeconomic position (SEP) and adverse childhood experiences (ACEs) with menstrual symptoms (pain, abnormal uterine bleeding, and premenstrual syndrome (PMS) measured 3-8-years post-birth in G0 and 17-21-years-old in G1), using multivariable logistic regression. Samples ranged from 4,828 to 9,335 G0 participants and 1,288 to 2,757 G1 participants depending on the exposure-outcome association. Missing data were addressed using multiple imputation and inverse probability weighting. Results: Financial difficulties were associated with greater odds of menstrual pain (G1 OR 1.41; 95% CI 1.07, 1.86: G0 OR 1.55; 95% CI 1.36, 1.76) and irregular cycles (G1 OR 1.60; 95% CI 1.12, 2.29: G0 OR 1.48; 95% CI 1.27, 1.72) in both generations, as well as with short/long cycle lengths in G0 only. Lower education and manual social class were also associated with these three menstrual symptoms in at least one generation. Conversely, higher SEP was associated with PMS in both generations. Higher cumulative ACEs were consistently associated with menstrual pain (4+ compared to none: G1 OR 2.15; 95% CI 1.48, 3.11: G0 OR 1.52; 95% CI 1.29, 1.80) and irregular cycles (G1 OR 1.92; 95% CI 1.20, 3.09: G0 OR 1.54; 95% CI 1.26, 1.87) but not cycle length. Lower parental education, financial difficulties, and cumulative ACEs were associated with heavy bleeding in G1 offspring only, whereas financial difficulties, own manual social class, and cumulative ACEs were associated with prolonged bleeding in G0 mothers only. Higher cumulative ACEs were also associated with PMS in G1 offspring only. Conclusions: We found evidence of inequalities according to socioeconomic disadvantage and childhood adversity for multiple menstrual symptoms, although some associations were only observed in one generation. Findings suggest that menstrual symptoms are disproportionately experienced by socially and socioeconomically disadvantaged women.

Anxiety-related traits (ARTs) have been linked to altered fear learning, but previous studies have typically examined different experimental phases and response systems, limiting the comparability of findings and the accumulation of consistent evidence. Here, we comprehensively examined associations between ARTs and fear conditioning across acquisition, extinction and renewal and across subjective, physiological and neural response systems in a well-powered sample (N = 267) using a two-day differential conditioning paradigm. ARTs were operationalized as a composite of trait anxiety, neuroticism, and intolerance of uncertainty and conditioned responding was assessed using skin conductance responses, fear-potentiated startle, US expectancy ratings, fear ratings, and functional magnetic resonance imaging. Higher ARTs were consistently associated with elevated subjective fear and US expectancy to both threat and safety cues during extinction and renewal, without corresponding elevations in physiological responding. At the same time, ARTs were not associated with threat-safety discrimination in subjective or physiological measures across phases, while neural associations were limited to reduced dorsal anterior cingulate cortex discrimination during early renewal. These findings suggest that ARTs are characterized by a CS unspecific cognitive bias toward heightened threat expectancy and evaluation rather than altered associative fear learning, highlighting the importance of distinguishing conditioned discrimination from general levels of responding across response systems.

Background: A 2025 systematic review concluded there was "strong evidence of a likely relationship" between prenatal acetaminophen exposure and neurodevelopmental disorders, informing a federal health advisory, based on qualitative synthesis without quantitative pooling or bias correction. We reanalysed the same studies to test whether this association withstands standard meta-analytic and bias-correction methods. Methods: We used 24 of 46 studies from a 2025 Navigation Guide systematic review (PubMed search through 25 February 2025) that reported a ratio measure (hazard ratio, odds ratio, relative risk, or incidence rate ratio). Estimates were collapsed to one per study, outcome group, and design, yielding 30 study-level estimates (sample sizes, 307-2,480,797) for attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and other neurodevelopmental disorders. We applied random-effects meta-analysis, eight publication-bias-correction methods, a credibility-ceiling sensitivity analysis, and five quality-filtered subsets, then repeated all analyses after harmonising odds and hazard ratios onto a common risk-ratio scale. Results: The ASD association attenuated from 1.14 (95% CI, 1.01-1.28) to 1.08 (95% CI, 0.97-1.19; P=.17) once each study was weighted once rather than by its number of sub-analyses, before any bias correction. The ADHD association remained positive under most bias-correction methods (range, 1.02-1.31), but its 95% CI crossed 1.00 under a 15% credibility ceiling. The other-NDD association reversed direction under one method (ratio, 0.98; 95% CI, 0.65-1.19) and showed no right-skew on p-curve testing (P=.71). Conclusions: The claim of "strong evidence" for an acetaminophen-neurodevelopmental-disorder association was not supported by this reanalysis. A modest ADHD association persisted, while ASD and other-NDD estimates moved toward the null.

Generalization is a key cognitive process that allows humans to flexibly apply prior knowledge to guide new behaviors. Difficulties with generalization and flexibility are observed across neurodevelopmental disorders, especially autism, limiting adaptive function and quality of life. Cognitive-behavioral treatment benefits some but not all autistic individuals. As treatment requires application of learned skills to everyday life, variability in generalization ability may limit intervention success in autism. While cognitive substrates of learning and generalization are well established, their potential for explaining clinical outcomes is not known. Here, we combined a category learning task with computational modelling to distinguish two learning strategies underlying generalization -- prototype abstraction vs. exemplar memorization -- and tested whether individual differences in these learning strategies predicted real-world intervention outcomes in autistic youth. Fifty-four participants completed the category learning task at two pre-intervention timepoints, and then completed Unstuck and On Target:14-22 intervention targeting flexible problem solving, goal setting, and planning. We found that participants who consistently relied on prototype abstraction (N=26) were subsequently more likely to benefit from the intervention, showing improvement in parent- and self-reported flexibility. These findings identify prototype abstraction as a clinically relevant cognitive capacity that may help explain individual differences in intervention response and support the tailoring of interventions. More broadly, they demonstrate the value of linking basic cognitive mechanisms to clinical outcomes and may inform strategies to enhance the effectiveness of cognitive-behavioral interventions for youth with developmental disabilities.

Museum visits typically follow curator-defined routes that constrain how visitors shape their own experience, yet choice is widely held to heighten engagement, autonomy, and enjoyment. Virtual reality (VR) offers a setting in which to study these processes because it combines ecological immersion with precise, continuous behavioral measurement. We investigated (i) whether VR- derived behavioral signals are associated with self-reported enjoyment during a virtual museum tour, and (ii) whether the level of agency afforded to visitors influences enjoyment. Forty-eight adults completed a room-scale, life-size VR tour (8 * 4 m) of seven paintings from the Tel Aviv Museum of Art, each accompanied by a synchronized audio guide. Synchronized gaze and head- position streams were logged continuously (50 Hz) and segmented into painting-level viewing episodes using a trial-and-tile pipeline that intersects each painting's trial interval with an empirically defined spatial window in front of the canvas. Participants were randomly assigned to one of three agency conditions, Active (choice before every artwork), Semi-Active (choice for the first three), or Passive (fixed route),while the artwork sequence was held identical. Self- reported enjoyment at the tour and painting levels did not differ reliably across agency conditions. Among VR-derived measures, gaze engagement during the audio guide showed the clearest (though modest) association with painting-level liking, whereas locomotion and pacing measures were weak and inconsistent predictors. Agency nonetheless reliably modulated several gaze- and time-based viewing measures. The findings reveal a dissociation between subjective enjoyment and the micro-structure of viewing, and establish a reusable framework for full-tour, painting-level behavioral analysis in immersive settings.

Wearable (accelerometer) data and machine-learning allow objective assessment of the amount of daily physical activity. However, wearable-derived human activity is subject to measurement error. No studies have corrected the dose-response association between physical activity and survival time to chronic diseases, including cardiovascular disease (CVD). The objective is to estimate the measurement error-corrected association between CVD events and multiple measures of daily duration of light and total physical activity, derived from machine-learning and conventional accelerometer-processing methods. Our method combined an accelerated failure time model, spline, and simulation-extrapolation (SIMEX). The method recovered the true dose-response non-linear association in simulated data, while the naive model failed to capture it due to substantial attenuation. Application to the UK Biobank accelerometer cohort also showed an increased protective association of total physical activity after SIMEX correction (Time Ratio [TR] = 1.56, 95% CI: 1.28-1.82 vs. TR = 1.38, 95% CI: 1.24-1.54 for SIMEX-corrected vs. uncorrected dose-response association between the 95th and 5th percentiles of total activity), with a similar increase for light physical activity. Sensitivity analysis indicates that the female population experiences a substantially larger protective association after SIMEX correction than males. Dose-response survival analysis is a widely used analytical method in physical activity epidemiology and benefits from measurement error correction.

A body of research suggests that autistic individuals are less likely to drink alcohol than neurotypicals. However, emerging studies support a link between autism and alcohol use. This complex relationship is also reflected in studies that have examined the genetic overlap between the two traits. However, it is unclear whether there is a direct causal relationship between them. To explore this, we applied a combination of polygenic score and Mendelian randomisation analyses using publicly available genome-wide summary statistics and phenotypic measures of autism and alcohol consumption from UK Biobank. LD score regression analyses did not provide evidence of a genetic correlation between genetic liability for autism and drinks consumed per week (rg=-0.08; CI95%=-0.19, 0.03). Further, findings from polygenic score analyses did not support an association between genetic liability for autism and overall monthly alcohol intake. Univariable Mendelian randomisation analyses showed little evidence for a total effect of autism, attention deficit hyperactivity disorder (ADHD) or depression on overall monthly alcohol consumption. Multivariable Mendelian randomisation analyses also showed little evidence of a direct effect of autism on drinks per week when controlling for ADHD and depression. It is plausible that genetic liability for autism does not directly increase the amount of alcohol consumed but instead operates via commonly co-occurring difficulties in the autistic community. However, our findings may be due to methodological shortcomings, including weak instruments biasing effects towards to the null. Consequently, results should be interpreted with caution and further research conducted to address these issues.

Kinaesthetic motor imagery (kMI) is widely used in sport to enhance motor performance by engaging cortical sensorimotor networks. Neurofeedback may further support kMI, but the optimal neural target to reinforce remains unclear. Maximal sensorimotor event-related desynchronisation (SMR-ERD) represents a relevant target as it may index sensorimotor cortex engagement, yet sport expertise has been associated with reduced SMR-ERD, potentially reflecting neural efficiency. The optimal neurofeedback target may therefore depend on sport expertise, movement expertise, and individual kMI ability. This study examined how these factors influence sensorimotor activity during kMI. We compared 17 basketball players (Experts) and 16 individuals without formal basketball training (Novices). kMI ability and frequency of use were assessed using questionnaires, while SMR-ERD was quantified using electroencephalography (EEG) during kMI. Participants imagined either a basketball-specific movement (Free throw), for which only Experts had extensive experience, or a generic movement (Box lifting), familiar to both groups. Experts reported greater kMI ability and more frequent kMI use than Novices. Only Experts exhibited significant and sustained SMR-ERD during kMI. Moreover, SMR-ERD was stronger in Experts than Novices specifically during Free throw kMI, corresponding to their movement of expertise. Nonetheless, within the Expert group, higher kMI ability was associated with reduced SMR-ERD. These findings suggest that sport expertise initially enhances voluntary recruitment of sensorimotor networks during kMI, whereas greater kMI ability may subsequently promote neural efficiency, resulting in reduced overall sensorimotor cortical activation. These results highlight the need to tailor kMI-based neurofeedback training to users' sport expertise and kMI ability levels.

Laboratory stress tasks are widely used to assess individual differences in acute stress reactivity, yet it remains unclear how these responses correspond to stress experienced in everyday life. Here, we combined the Montreal imaging stress task (MIST) with ecological momentary assessment (EMA) over three months to assess acute and everyday stress in 67 healthy women. Greater within-person variability in everyday stress, but not average stress levels, were associated with stronger overall stress-related brain responses (b = 0.73, p = .039), with a whole-brain association particularly evident in the bilateral caudate (rROI = .32, pcluster.FWE < .001). Greater everyday stress variability was also associated with stronger stress-related functional connectivity between the ventromedial prefrontal cortex (vmPFC) and parietal and posterior medial regions (pcluster.FWE < .001). We conclude that acute neural stress responses relate more closely to fluctuations in perceived stress than to how stressed an individual feels on average. This suggests that laboratory stress tasks capture acute stress responsivity that is distinct from average stress exposure, highlighting the importance of considering what these tasks measure when interpreting individual differences in acute stress responses.

Background Childhood respiratory mortality in China has fallen by over 90% in three decades alongside sustained national warming, yet national long-run evidence on temperature and child respiratory mortality is lacking. Methods We linked Global Burden of Disease (GBD) 2021 mortality estimates for China - lower respiratory infections (LRI), ages 0-19, and asthma, ages 0-24, 1990-2021 - with C-LSAT 0.5 deg gridded temperature data (1990-2019), aggregated nationally and to five climate zones. Four annual indicators (mean temperature, diurnal temperature range, seasonal amplitude, interannual variability) entered regressions of log mortality rates with Newey-West standard errors. A bootstrapped (500 resamples) quadratic model probed the minimum mortality temperature (MMT), with PM2.5-adjusted analyses and future-exposure, permutation, and detrended falsification tests. Results LRI deaths fell by 96.3% (330,194 in 1990 to 12,098 in 2021; 95% uncertainty interval 9,669-14,891) and asthma deaths by 94.9% (3,287 to 167), while mean temperature rose 0.364 deg C per decade and diurnal temperature range narrowed 0.092 deg C per decade. Baseline coefficients were large (mean temperature -1.696, SE 0.174; diurnal temperature range +2.408, SE 0.336; seasonal amplitude -0.162, SE 0.082; interannual variability +2.924, SE 1.514, per 1 deg C in log rate), but the future-exposure test failed and detrending nullified every coefficient: the associations are trend-level, and short-cycle causal effects are not identifiable. Nor was the national MMT identifiable - observed temperature support spans only 6.66-8.13 deg C, and the nominal turning point of 35.84 deg C is an extrapolation artifact (quadratic term p = 0.963). Within the observed range, warming and declining mortality moved in the same direction. Conclusions The 96% decline in childhood respiratory mortality cannot be attributed to warming. China sits on the low-temperature side of the optimum, and the marginal direction of future warming requires stronger designs to establish. The falsification framework offers a discipline for climate-health inference in China.

Communities exposed to flooding can experience markedly different mental health outcomes, yet conventional resilience indicators capture only part of the social and contextual conditions that may explain this variation. This study develops a multilevel and predictive framework for examining community resilience and depressive symptoms following flood exposure in Indonesia. Data were drawn from 20,303 respondents aged 15 years and older nested within 312 communities in the Indonesia Family Life Survey (IFLS-5). Depressive symptoms were assessed using the 10-item Centre for Epidemiologic Studies Depression Scale (CES-D-10), with Rasch Partial Credit Model calibration used to examine measurement properties. Bayesian multilevel models quantified between-community heterogeneity and assessed how far observable structural resources accounted for this variation. Community resilience was represented through two complementary constructs: structural resilience, based on observable socioeconomic and social-capital resources, and Latent Community Protective Capacity (LCPC), a model-derived proxy for residual contextual variation in depressive-symptom risk. Approximately 6 percent of variation was attributable to between-community differences, while observable structural resources explained only part of this heterogeneity. Structural resilience and LCPC were weakly correlated (r = 0.155). Moderation analyses provided no clear evidence that structural resilience altered the flood-depression association, while LCPC showed a directionally consistent but uncertain buffering pattern. Predictive models incorporating community-level information improved discrimination, with the best-performing model reaching an ROC-AUC of approximately 0.71. The findings suggest that observable resource-based indices provide an incomplete account of community-level mental health vulnerability and that residual contextual measures may provide complementary information, while requiring cautious interpretation and independent validation.

Background: Evidence suggests chronic distress influences ovarian cancer (OC) etiology and metabolomic profiles. Here, we evaluated the association of a metabolite-based distress score (MDS) and OC risk. Methods: We included two matched case-control studies nested within the Nurses' Health Studies (N=584) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N=348). Metabolites were measured 3-27 years before diagnosis using liquid-chromatography tandem mass spectrometry. We examined the association of quintiles of MDS and 19 constituent metabolites with OC risk using unconditional logistic regression and stratified by tumor histotype, menopausal status, and age at diagnosis. Results: We observed women in the highest versus lowest quintile of MDS had an increased OC risk (OR=1.62,95%CI=1.03-2.54,ptrend=0.07), and type 2 tumors (OR=1.71,95%CI=1.03-2.83,ptrend=0.11). Associations were suggestively stronger for premenopausal and <69-year-old women, and driven by pseudouridine, and N2,N2-dimethylguanosine. Conclusion: Our findings suggest chronic distress-associated metabolic dysregulation may represent a novel OC risk factor, especially among younger women.

Introduction: Decision making for selecting an object or a course of action from possible alternatives largely depends on our perceptual ability modulated by attention. When multiple stimuli appear close together in time, processing one stimulus can temporarily impair the processing of another due to temporal limitations of attention. Observers frequently fail to detect the second target (T2) presented within a few hundred milliseconds after the first target (T1) in a stream of stimuli, which is commonly known as attentional blink (AB). Existing theories attribute this perceptual lapse to T1 processing, distractor interference, or transient attentional gating; however, the computations underlying suppressive mechanism remains unresolved. We investigated whether pupil-size could reveal the underlying mechanisms of AB and predict conscious perception on a trial-by-trial basis. Methods: Pupil diameter and gaze locations were recorded using an infrared eye tracker. Machine learning techniques were used to classify trials when T2 was detected versus when it was not, after correct identification of T1, during an AB task from the pupil dynamics, which also yielded attentional episode (AE) associated with each element in the stream of visual stimuli when deconvolved. Results: Cross-validating classifiers achieved near-perfect accuracy not only in distinguishing but also predicting perceptual outcomes on a single-trial basis. AEs exhibited greater power when T2 was detected than when it was missed; the differential power in AEs on a logarithmic scale was highly synced with the differential pupil size. Conclusions: Collectively, these findings establish a framework for predicting attention-driven perceptual outcomes from pupil-dynamics at finer time-scale.

Establishing causality in nutrition research is challenging. While randomised controlled trials (RCTs) provide robust evidence, long-term dietary intervention studies with disease endpoints are often impractical. Short-term RCTs can instead identify intermediate traits that may lie on the causal pathway between diet and disease. Mendelian randomisation (MR) is an epidemiological approach that uses genetic variants as proxies for modifiable exposures to estimate the effects of lifelong differences in exposure on disease risk. However, the utility of MR is limited for complex dietary patterns because genetic variants typically reflect biological mechanisms rather than specific diets. We propose a two-step framework integrating dietary RCTs with MR to infer potential lifetime effects of dietary interventions. First, RCT data identify molecular traits altered by an intervention. Second, MR evaluates whether these traits are associated with long-term disease risk. We demonstrate this framework using the Diabetes Remission Clinical Trial (DiRECT), which measured circulating proteins and diabetes remission. Using protein data alone, 216 of 4,601 proteins changed following the intervention (step 1), and 10 were associated with diabetes risk using MR (step 2). We then compared these MR estimates with observed protein-remission associations from DiRECT. The broad agreement between the two (r{approx}-0.645, R2=0.416) supports this framework as a useful approach for estimating long-term effects of dietary interventions.

Background: Despite several trials on the hematological outcomes of intravenous (IV) iron in pregnancy, only few have examined its effect on birth outcomes. We estimated the causal effect of IV-iron on moderate or severe anaemia and birth outcomes. Methods: Women presenting to routine antenatal care in Pakistan with haemoglobin <10 g/dL were eligible for treatment. We used target trial emulation (TTE) methodology to estimate the effect of IV-iron treatment within 14 days of anaemia identification, compared to no treatment, on anaemia status at follow-up. A modified TTE analysis examined birth outcomes at delivery for singleton pregnancies, including birthweight, size-for-gestational-age, and mortality. We conducted a separate TTE for each of five gestational-age periods and pooled the results of each TTE. Results: We screened 3115 pregnancies of which 1715 were eligible for IV-iron; 1043 participants were treated during pregnancy. Those who received IV-iron had half the risk of moderate or severe anaemia in pregnancy compared with no treatment (pooled relative risk (RR) 0.40; 95% confidence interval (CI): 0.27, 0.59). The pooled effect of IV-iron on stillbirth suggested an 83% risk reduction (95% CI 55-94%), and trends were similar for perinatal and neonatal mortality. Conclusion: IV-iron treatment improved haematological status in pregnant women and was associated with a large reduction in stillbirth. Given limited data from randomised trials regarding fetal death and treatment earlier in pregnancy, this study contributes important information to the potential benefit of IV-iron in contexts where anaemia and its sequelae are a major public health problem.

Introduction: Polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome (PCOS), is a common endocrine disorder affecting women of reproductive age. Besides reproductive and metabolic disturbances, PMOS negatively impacts psychological well-being and quality of life. Despite available treatment options, there remains a need for safe and effective therapies that improve both clinical symptoms and fertility outcomes. Aim: To compare the efficacy of VAMHA and MYRHA tablet combination therapy with standard non-hormonal therapy in restoring regular menstruation. Secondary objectives included assessment of ovulation, menstrual symptoms, polycystic ovarian morphology, hormonal and metabolic parameters, anthropometric measures, and skin manifestations. Study Design: Open-label, randomized, multicentre, prospective comparative clinical study. Methods: Seventy-one women with PMOS were randomized to Group A (n=37) or Group B (n=34). Group A received VAMHA and MYRHA tablets (2 tablets each), while Group B received Metformin 500 mg plus Myoinositol 600 mg (1 tablet), twice daily for 180 days. Data were recorded in Case Report Forms. Statistical Analysis: Continuous variables were summarized using mean and standard deviation, while categorical variables were expressed as frequencies and percentages. Appropriate statistical tests, including Chi-square, were used. A p-value [&le;]0.05 was considered significant. Results: Significantly more participants in Group A achieved regular menstrual cycles than Group B (31 vs. 22; p<0.05). Ovulation occurred in 16 participants in Group A compared with 6 in Group B (p<0.05). Both groups showed significant improvement in menstrual irregularity and related symptoms. Significant reductions in Anti-Mullerian Hormone (AMH), fasting insulin, and body mass index (BMI) were observed in both groups (p<0.05). Resolution of polycystic ovarian morphology occurred in 13 participants (38.23%) in Group A and 10 (33.33%) in Group B. Both treatments were well tolerated with no major safety concerns. Conclusions: VAMHA and MYRHA combination therapy was superior to standard non-hormonal therapy in improving menstrual regularity and ovulation. It also produced favourable metabolic, hormonal, and ultrasonographic outcomes, suggesting its potential as a safe and effective option for comprehensive PMOS management and fertility enhancement.

Background & Aims: Fatigue is a central symptom of chronic liver disease (CLD), substantially impacting health-related quality of life (HRQoL). This study aimed to further understand CLD symptomatology, including fatigue, and its impact on HRQoL from a patient perspective. Methods: Abbott Global Assessment of Patients unmet needs (aGAP) was a multinational, cross-sectional survey in adults with compensated CLD in China, India and Mexico, conducted between July and November 2024. Adult participants who self-reported that they had physician-diagnosed CLD and were experiencing fatigue completed a quantitative survey to assess symptom burden and included three HRQoL patient-reported outcome (PRO) questionnaires (Patient-Reported Outcomes Measurement Information System [PROMIS]-29+2, Work Productivity and Activity Impairment - Specific Health Problem version 2.0 [WPAI: SHP], Multidimensional Fatigue Inventory [MFI]). Results: Overall, 505 participants (China: 200; Mexico: 105; India: 200) completed the study. Participants reported that their CLD-related fatigue sometimes, often or always affected their self-esteem/confidence (45.1%) and ability to maintain or acquire new employment (38.6%). Most participants reported moderate (51.3%) or serious (26.9%) fatigue, with 33.5% experiencing fatigue every day or almost every day. Many participants felt their social life was negatively impacted by their fatigue (47.3%) and that there were related financial difficulties (53.9%). Use of validated PRO tools demonstrated severe fatigue (MFI: overall mean [SD] 13.9 [3.4] general fatigue and 13.4 [3.6] physical fatigue) as well as substantial levels of work and activity impairment (WPAI: SHP overall mean [SD] 53.0 [26.4]) and high levels of anxiety, pain interference, depression and sleep interference (PROMIS T-scores [&ge;]54). Conclusions: Fatigue has a substantial impact on HRQoL among adults with CLD across several countries, highlighting a global unmet need for targeted interventions to effectively identify and manage the condition.

Importance: Evidence on GLP-1/GIP therapies is largely derived from trials enrolling selected populations or medical records that miss utilization outside healthcare channels. No nationally representative cohort has characterized real-world uptake, indications, and access. Objective: To characterize GLP-1/GIP prevalence, indication, clinical profile, and access. Design: Prospective cohort study with three GLP-1/GIP surveillance waves (March 2024, December 2024, October 2025). Setting: The Understanding America Study, an address-based, nationally representative panel of approximately 15,000 US adults aged 18+ years initiated in 2014. Participants: UAS participants responding to at least one surveillance wave (n=9150). Exposures: GLP-1/GIP use status (never vs any use, comprising current and former use), self-reported primary indication (diabetes, weight loss, or other), and access pathway (traditional vs non-traditional). Main Outcomes and Measures: Survey-weighted prevalence of GLP-1/GIP use, overall and by indication and access pathway; sociodemographic, cardiometabolic, treatment, and access characteristics; and smartwatch-derived resting heart rate, heart rate variability, maximum activity heart rate, step count, and sleep duration and variability. Results: Among n=9150 adults (1274 with any use; 60.9% female; median age 53 years), weighted prevalence increased 46%, from 8.2% (March 2024) to 12.0% (October 2025) representing 32 million. Weight-loss indications grew, reaching nearly half of use (4.1% to 5.6%); diabetes-indicated use was stable (5.3% to 5.4%). Users carried high cardiometabolic burden (obesity, 68.2%; diabetes, 53.6%) but diverged by indication: diabetes-indicated users were older (median, 59 vs 49 years), whereas weight-loss-indicated users were more often female (69.9% vs 51.3%) and healthier. One in three users (~9 million) had non-traditional access, especially in weight-loss-indicated users, of whom 33% had no conventional prescription; 41% used compounding, online, or foreign pharmacies; and, 43% lacked coverage. Non-traditional users were five times as likely to report an unlisted, likely compounded formulation (19.8% vs 4.1%). All p<0.05. Conclusions and Relevance: Real-world GLP-1/GIP use has grown rapidly and diversified substantially in indication, access, and population profile. One in 3 users obtained treatment through nontraditional channels largely invisible to claims data, raising long-term safety, efficacy, and coverage questions. GLIMMER provides a public, nationally representative longitudinal evidence base for future payer and provider decisions.