Addiction

Background Alcohol-associated injury is a leading cause of emergency department (ED) utilization in the United States and a clinically important driver of preventable morbidity across the adult lifespan. Prior surveillance research has characterized how the rate and severity of alcohol-associated injury vary by patient age, but whether the seasonal timing of injury risk is equally predictable across age groups (a question directly relevant to the timing of clinical screening intensification and public health intervention) has not been formally tested. Methods We conducted a retrospective surveillance analysis of 45,876 alcohol-associated ED visits among adults aged 18 years and older, identified from the National Electronic Injury Surveillance System (NEISS), 2019-2025 (weighted national estimate: 2,092,319 visits), using the structured Alcohol_Involved indicator introduced into NEISS case abstraction in 2019. Patients were stratified by sex and five age groups (18-24, 25-34, 35-49, 50-64, and [&ge;]65 years). Single-harmonic cosinor (Poisson) regression was used to estimate the seasonal peak day of injury risk (acrophase) for each stratum. To assess reliability, we performed leave-one-year-out jackknife resampling (seven iterations per group), case-resampling bootstrap confidence intervals (1,000 iterations), and likelihood-ratio tests of seasonal-phase interactions. Results Peak injury timing differed significantly across age groups (X^2 [8] = 2356.2, p < .0001). Adults aged 25-64 years showed a highly reproducible early-to-mid-July peak, with jackknife estimates shifting [&le;]14 days when any single study year was excluded. Adults aged [&ge;]65 years showed significant seasonal variation annually (all p < .0001, amplitude comparable to younger groups) but a pooled peak estimate that shifted by up to 100 days across jackknife iterations. Sex-stratified analyses revealed that this instability was driven entirely by females aged [&ge;]65 years (jackknife range: 332 days, peak consistently in late October through early January) rather than males aged [&ge;]65 (jackknife range: 31 days, peak consistently in early August). Hospital admission rates increased monotonically with age from 9.0% (18-24 years) to 31.8% ([&ge;]65 years). Conclusions Alcohol-associated injury follows a reproducible, calendar-stable summer seasonal pattern in adults aged 25-64 years. Among adults [&ge;]65 years, the previously reported temporal instability is concentrated in the female subgroup, whose seasonal injury risk does not converge on a fixed calendar window. These findings suggest that fixed-calendar prevention and screening strategies are well suited to working-age adults and older men, but older women may require a year-round, individually tailored approach. Keywords: Alcohol-related injury; Emergency department; Seasonality; Age factors; Sex differences; Injury surveillance; Cosinor analysis; Older adults

Adolescent substance use is a major public health concern due to increased risk of future physical and mental health conditions. Fronto-striatal functioning - particularly regarding inhibition and reward processing - may increase vulnerability to high-risk substance use. However, it remains unclear if these neurobiological differences precede substance use or are consequences of it. The ongoing Adolescent Brain Cognitive Development (ABCD) Study follows over 10000 youth, offering an unprecedented opportunity to longitudinally examine substance use patterns throughout development. We utilized family-clustered time-varying Cox proportional hazard models to prospectively examine main and interaction effects of right Inferior Frontal Gyrus (IFG) inhibitory control and bilateral nucleus accumbens (NAc) reward response, alongside early life adversity and peer substance use as predictors of alcohol and cannabis onset in the ABCD Study. We identified a significant crossover interaction such that left NAc activity had a slight positive association with first full alcoholic drink in the context of higher right IFG activity but a negative association in the context of lower right IFG activity. However, peer alcohol and cannabis use emerged as the strongest predictors of outcomes. Alcohol onset was also more common in females, and early life adversity was associated only with cannabis onset. Findings indicate that interactions between inhibition- and reward-related brain regions may impact risk for early substance use onset, but these effects may be modest relative to socioenvironmental factors. Additionally, divergent alcohol and cannabis findings suggest that risk profiles are substance specific. Peer-focused strategies should be considered in preventive efforts.

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.

Introduction: Risk of recurrent opioid use during buprenorphine-naloxone (bup-nx) treatment is dynamic and remains elevated after initiation, with vulnerability shaped in part by treatment intensity and gaps between visits, yet routine outpatient care relies on episodic encounters and retrospective data. This mismatch can delay recognition of emerging instability and limit timely treatment adjustments. This paper reports the development and specification of an intervention strategy to address this mismatch. Methods: We used a structured, multi-phase design process to specify and configure a measurement-based care (MBC) strategy for bup-nx treatment (Bup-MBC) in outpatient addiction clinics through three phases: (1) a systematic review of patient-reported outcome measures (PROMs) for substance use treatment; (2) a qualitative needs assessment using the Theoretical Domains Framework and COM-B (Capability, Opportunity, Motivation-Behavior) model to identify gaps in risk monitoring, agency, and trust; and (3) iterative co-design with multidisciplinary clinicians to refine workflow fit and trust-preserving use of data. Patients informed item and feedback content during the needs assessment but did not participate in the co-design cycles. Results: Bup-MBC integrates (1) brief between-visit PROMs (e.g., withdrawal, craving, adherence); (2) immediate non-punitive patient feedback; (3) clinician-facing summaries and non-directive prompts in the electronic health record (EHR); and (4) an opt-in between-visit outreach pathway with predefined safety triggers, all configured within existing EHR and patient portal infrastructure. It targets patient and clinician capability to recognize changes in risk, opportunity for action through structured monitoring and visit preparation, and trust and agency through non-punitive communication, without adding substantial burden. The full measure set, severity bands, and question-to-action map are provided as supplementary material. Key trade-offs included prioritizing single-item measures for feasibility, balancing opt-in outreach with safety overrides, and assuming routine clinician use of summaries. Conclusion: This development study specifies an EHR-integrated MBC strategy for outpatient bup-nx treatment. As single-center design work with co-design limited to clinicians and delivery contingent on portal or text-message access, its outputs are hypotheses about mechanism and fit rather than demonstrated effects. Feasibility studies are needed to evaluate uptake, acceptability, workflow fit, and effects on treatment.

Background: As cannabis policy changes in the United States, secondhand cannabis smoke (SCS) is increasingly common, including within families. However, prevalence of exposure and clinical correlates over time in adolescents are not fully understood. Objectives: (1) To estimate the prevalence of SCS and personal cannabis use in US-based teens exposed to SCS, and (2) examine the cognitive trajectories of adolescents exposed to SCS compared to non-exposed peers. Methods: Data from the Adolescent Brain Cognitive Development (ABCD) Study was used. Participants (n=11,316 of full cohort with follow-up data; n=776 with self-reported family SCS exposure) attended yearly visits from ages 11-17, completing substance use interviews, toxicological testing, and the NIH Toolbox Cognitive battery. Youth with SCS but no personal cannabis use (n=419; 47% female) were matched on prenatal substance exposure, family substance use history, and sociodemographics to non-SCS exposed and non-cannabis-using youth with a 1:2 ratio (Controls n=838). Linear mixed-effects models assessed cognitive performance by SCS*age interactions, accounting for random effects of subject and family. Covariates included sex and alcohol, nicotine, and other substance use. Secondary models analyzed performance by cumulative waves of reported SCS exposure interacting with age. Results: Of the full cohort, 6.9% (n=776) reported exposure to SCS. Of these individuals, 46% endorsed lifetime personal cannabis use by age 17, relative to 20% of non-SCS exposed youth (OR=3.83[95%CI:3.29,4.44]). Within matched participants, SCS*age demonstrated a significant interaction on attention and inhibitory control ({beta}=-0.32, p=.028), with SCS demonstrating reduced improvement over time. More waves of exposure were also associated with worse performance over time ({beta}=-0.39, p=.057). Discussion: Almost half of those who had been exposed to SCS endorsed personal cannabis use. Cognitive findings were domain specific, similar to findings in secondhand tobacco: SCS exposed youth showed restricted improvement in attention and inhibitory control by age 17. Public health and policymakers should make efforts to curb youth SCS exposure, given the potential for risk which has not been fully explored to date.

Objective To measure the accuracy of clinical coding, clinician review, and a locally deployed large language model (LLM) in identifying alcohol, drug, and self-harm involvement in emergency department (ED) attendances, and quantify prevalence. Design Two-phase diagnostic accuracy study. In a validation week, the identification strategies were assessed against a conflict-adjudicated reference standard (n=2,256); the LLM was then applied to n=105,096 annual attendances at the same site. Setting UK Type 1 Emergency Department treating patients [&ge;]16yrs. Main outcome measures Prevalence quantification compared with the reference standard; sensitivity, specificity, and balanced accuracy of each strategy; monthly identification rates and adjusted annual prevalence. Results The reference standard identified 12.1% of attendances as involving alcohol, drugs, or self-harm (coding 6.0%; clinician 10.0%, LLM 15.6%). LLM balanced accuracy matched or outperformed clinician review in all three domains (alcohol 0.942 v 0.930, p=0.635; drug 0.959 v 0.791, p<0.001; self-harm 0.982 v 0.908, p=0.004). Coding recorded 1.07 domains per identified patient against 1.32 in the reference standard. Adjusted annual prevalence corresponded to 12,890 domain involvements per year not identifiable in coded data. Subdomain classification found at least 81.6% of self-harm attendances required medical assessment for injury or overdose before psychiatric review. Conclusions Clinical coding identified fewer than half of presentations involving alcohol, drugs, and self-harm and rarely captured co-occurring domains; under-recording was present across a full year. A locally deployed LLM generated more complete structured data from existing clinical text within NHS infrastructure, at a scale which is not feasible for manual review.

Introduction: Nicotine Pouches are increasingly used as a smokeless alternative to cigarettes and other nicotine products, yet their acute cardiovascular effects remain poorly documented. While nicotine's impact on heart rate and electrocardiogram (ECG) parameters is well-documented in smoking, no trials have evaluated these effects specifically for nicotine pouches. Methods: This study is a single-center, double-blind, placebo-controlled, crossover trial which will include 20 healthy adult nicotine users. Participants will undergo three sessions, receiving either a placebo, 6 mg, or 14 mg nicotine pouch in random order. Heart rate obtained by an ECG and various other ECG parameters, vital signs, and subjective symptoms will be measured at baseline, and multiple time points over 30 minutes. Conclusions: This study aims to determine whether nicotine pouches cause acute changes in heart rate, ECG parameters, vital signs, and self-reported symptoms. We hypothesize that higher nicotine pouch does will lead to measurable increases in heart rate and other autonomic effects compared to placebo.

Background Computerised cognitive testing may address the global challenge in identifying cognitive changes in people living with HIV scalably and affordably. We assessed a computerised battery (CB) of cognitive tests, in a prospective cohort (CONNECT) of people with HIV in a low-income peri-urban area of Cape Town, South Africa during a national programmatic switch from efavirenz- to dolutegravir-based antiretroviral therapy (ART). Methods We recruited 170 people with HIV and 91 people without HIV (controls) (140[82%] and 41[45%] followed up). The CB and gold-standard pen&paper cognitive testing (P&P) were performed at both timepoints. Technology familiarity/use questionnaire data were also collected. We compared performance in detecting lower group-level cognitive performance associated with efavirenz treatment. Furthermore, the CB was compared to P&P in classifying individuals with low cognitive performance, correlation of global test scores and domain-level scores between batteries, and practice effects between timepoints. Exploratory principal component analysis was also performed. Results People with HIV on efavirenz at baseline had lower performance on the computerised battery than controls, {Delta}T=2.6, p=0.0047. This difference was lost after switching to dolutegravir-based ART at follow-up. CB and P&P global T were moderately correlated (R2=0.203, p<0.001), and the CB performed moderately in classification of low cognitive performance against the gold standard (AUC 0.70, sensitivity 0.52, specificity 0.76, PPV 0.40, and NPV 0.84). Selecting the first three principal components improved both classification of low cognitive performance (AUC 0.77) and correlation strength with P&P global T (R2=0.3, p<0.001). The CB did not show practice effects. Most participants owned a mobile phone (95%, 85.9% of these smartphones). Performance was better in smartphone owners ({Delta}T=1.8) and computer owners (23%, {Delta}T=1.8). Conclusions Delivering computerised cognitive testing was feasible in this low-income southern African setting. The CB showed reasonable construct validity (detecting known lower cognitive performance associated with efavirenz-ART) and may detect broad cognitive characteristics such as processing speed and accuracy. However, correlation of CB results with gold standard P&P testing was low-moderate and may limit its applicability as a diagnostic tool. This might be improved by including a wider range of cognitive domains tested in the CB, or data driven analysis. Brief CBs may fulfil an initial screening role, followed by more detailed clinical assessment.

Background: Higher Body Mass Index (BMI) is an established risk factor of sleep disturbance. It is not known if the effect is homogeneous across the lifecourse or if there is a particular time point in life that might be best to target. Methods: Two-sample Mendelian randomization (MR) was used to investigated the effect of childhood adiposity (adjusting on adulthood adiposity and obstructive sleep apnea (OSA)) on insomnia, morning chronotype, sleep duration, daytime sleepiness and daytime napping. Similarly, total, and direct effect of adulthood adiposity on these outcomes was explored. We used summary statistics from a genome-wide association study (GWAS) of UK Biobank for childhood and adulthood adiposity (n=453,169) and large-scale consortia of OSA (Million Veteran Program) (n=410,268), insomnia, and chronotype (23andMe) (n=1,978,022 and n=248,1000, respectively). Results: Two-sample univariable MR analysis provided no evidence of an effect of genetically predicted childhood adiposity on later life insomnia (Odds ratio (OR)= 0.94, 95% Confidence interval (CI)= 0.87, 1.03). Whereas, multivariable MR (adjusted for adulthood adiposity) analysis provide strong evidence of direct protective effect of genetically predicted childhood adiposity on later life insomnia (OR= 0.70, CI= 0.64, 0.77). Further, both in univariable and multivariable MR, a strong positive effect of increased childhood body size on morning chronotype was observed (OR= 1.16, CI= 1.01, 1.33 and OR= 1.36, CI= 1.15, 1.62, respectively) after accounting for adulthood body size. In both analysis the estimate did not change considerably after aditionally adjusting for OSA. However, childhood and adulthood adiposity found to be associated with OSA and OSA with insomnia. In both univariable and multivariable analysis, increased body size in adulthood increased the risk of having insomnia and a morning chronotype. Conclusions: The findings suggest that higher body size in childhood is not a risk factor for later life insomnia, whereas higher body size in adulthood was. Further, if healthy body size is maintained in adulthood, high childhood adiposity may decrease the risk of insomnia and increase the risk of being a morning person in later life. Keywords: childhood, adulthood, obesity, insomnia, morning chronotype, medelian randomization

Background: HIV/HBV coinfection is associated with substantial liver-related morbidity and mortality, yet the impact of social vulnerability (SV) on clinical outcomes has not been systematically assessed. We evaluated associations of multidimensional SV with mortality, hepatic, virologic, and extrahepatic organ outcomes among adults with HIV/HBV. Methods: We conducted a retrospective cohort study using TriNetX data from 110 U.S. healthcare organizations (2010-2026). We propensity score matched adults with HIV/HBV with and without documented SV 1:1 (2,024 per group). SV was defined using a four-domain framework encompassing material, healthcare access and engagement, interpersonal, and psychosocial vulnerability. Results: Over 15,900 person-years, SV was associated with higher mortality (hazard ratio [HR], 2.06; 95% confidence interval [CI], 1.72-2.47), liver composite events (HR, 1.37; 95% CI, 1.07-1.76), hepatic decompensation (HR, 1.94; 95% CI, 1.39-2.70), hepatic failure (HR, 2.39; 95% CI, 1.53-3.73), HBV viremia (HR, 1.69; 95% CI, 1.32-2.16), and HIV viremia (HR, 2.05; 95% CI, 1.71-2.46). SV was also associated with major adverse cardiovascular events (HR, 1.47), chronic kidney disease (HR, 1.49), and diabetes (HR, 1.25). Multidomain SV generally showed stronger associations than single-domain SV for most hepatic and virologic outcomes, with HR ranges of 1.76-2.62 versus 1.35-1.76 for single-domain SV. Healthcare access and engagement vulnerability was most consistently associated with mortality and hepatic outcomes. Conclusions: SV was associated with mortality, hepatic disease, impaired HIV/HBV control, extrahepatic organ morbidity, and acute care utilization in adults with HIV/HBV. SV assessment may improve risk stratification and identify actionable intervention targets during HIV/HBV care.

Background: Adverse drug withdrawal events (ADWEs) are a key safety concern during deprescribing but remain poorly explored in pharmacovigilance systems. Objectives: To identify and compare ADWE signals across drug classes, different drugs within drug classes, and across patient characteristics, countries, and over time. Methods: A case/non-case disproportionality analysis was conducted in FDA-FAERS and EMA-EudraVigilance pharmacovigilance databases, with stratification by age (adults: 18-64, older adults: [&ge;]65), sex (male/female), reporting time (2004-2023 in 5-year intervals), and country (for EMA data). Disproportionality analysis (quantitative signal detection) was used to detect signals between ADWEs and drugs using the proportional reporting rate (PRR[&ge;]2), reporting odds ratio (ROR>1), and information component (IC>0) with case count [&ge;]5. Results: Overall, 158,501 reports (FDA-FAERS 145,514; EMA-EudraVigilance 12,987) included drug-event pairs related to ADWEs. In FDA-FAERS, clobetasone (IC=5.58; PRR=79.18; ROR=176.90) showed the strongest ADWE signals, followed by hydromorphone (4.85; 29.94; 37.37), hydrocodone, and paroxetine. In EMA-EudraVigilance, ethyl loflazepate (IC=6.01; PRR=119.80; ROR=197.53), clobetasone (5.39; 102.73; 155.10), veralipride, and levomethadone had the strongest signals. Most drugs maintained positive ADWE signals in analysis stratified into adults and older adults. However, among the top 10 drugs (based on highest IC values), buprenorphine/naloxone, desvenlafaxine, and baclofen in FDA-FAERS (ICs 4.95-6.05) showed stronger signals in older adults. A sex-based difference was observed, with paroxetine, venlafaxine, and buprenorphine/naloxone showing a stronger positive signal in females in both databases, whereas several opioids had stronger signals in males versus females across both databases. Conclusion: This study suggests ADWE signals for some medications differ by age and sex, potentially indicating different risks for withdrawal effects.

Background. The imprecision of current metrics to capture the complex genetic admixture and racial identity among Hispanic/Latino individuals in the United States [US] is a concern. We examined the relationship of self-reported race and genetic ancestry with hypertension [HTN] among Hispanics/Latinos. Methods. Cross-sectional study of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), including 10,586 Hispanic/Latino unrelated adults. Genetic ancestry: West African [AA], Amerindian [AI], and European [EA]. Self-reported race: White, Black, Native American, or Multiple/Missing (More than one race or Unknown/Not reported/Refused). HTN: systolic (SBP) [&ge;]130 mmHg, diastolic blood pressure (DBP) [&ge;]80 mmHg, and/or use of HTN medications. Age- and sex adjusted models were used. Results. Self-reported race was White (38{middle dot}6%), Black (3{middle dot}6%), Native American (4{middle dot}1%), and Multiple/Missing (53{middle dot}7%), with Unknown/Not reported/Refused representing 32{middle dot}7%. Black and White Hispanics/Latinos had the greatest AA (55{middle dot}7%) and EA (69{middle dot}3%) ancestries, respectively. Each 10% AA increase was associated with OR 1{middle dot}15, SBP beta +0{middle dot}9 mmHg, and DBP beta +0{middle dot}7 mmHg. Conversely, each 10% AI increase was associated with OR 0{middle dot}83, SBP beta -0{middle dot}4 mmHg, and DBP beta -0{middle dot}6 mmHg. HTN prevalence was highest among those with Black race or in the highest AA quantile (45{middle dot}6% and 48{middle dot}0%, respectively), and lowest among those with Native American race or in the highest AI quantile (37{middle dot}6% and 26{middle dot}7%, respectively). Conclusion. One-third of Hispanics/Latinos did not self-report race. Black or White self-reporting race did somewhat relate to AA or EA ancestry, respectively. HTN profiles were related to self-reported race and genetic ancestry in this admixed population.

South Asian communities in the UK experience disproportionate maternal and child health inequalities linked to non-recommended infant feeding practices, limited health literacy, and socioeconomic constraints. Participatory learning and action (PLA) is effective in low- and middle-income countries, but high-income evidence is scarce. This pilot assessed the feasibility of a community facilitator-led PLA intervention to improve infant feeding among South Asian families in East London. A three-arm pilot feasibility cluster randomised controlled trial (ISRCTN10234623) was conducted in Tower Hamlets and Newham, East London (May-September 2022), with 12 wards randomised 1:1:1 to face-to-face PLA, online PLA, or usual care. Multilingual community facilitators delivered eight biweekly sessions over 14 weeks. Feasibility outcomes were assessed against prespecified Go/Stop criteria; exploratory outcomes included child feeding behaviours (Children's Eating Behaviour Questionnaire, CEBQ), parental feeding style (Parental Feeding Style Questionnaire, PFSQ), and child BMI Z-scores. Of 263 enrolled participants, 261 had a recorded trial arm allocation; consent to the pilot feasibility study was 70.7% (186/263; 95% CI 65.0-75.9%) meeting the [&ge;]50% Go criterion. Attendance was 37% (Tower Hamlets 59%, Newham 29%), below the [&ge;]80% Go threshold. Six-month retention was 54.8% (Tower Hamlets 78%, Newham 48.5%; 95% CI 41.8-55.3%), triggering the Definite Stop criterion. Significant baseline imbalances included BMI Z-score (p = 0.005), ethnicity, borough, and education; no between-arm BMI differences were observed at follow-up (p = 0.249). CEBQ and PFSQ baseline completion was 24.5% and 23.0%, with no usable follow-up data. PLA Phases 3 and 4 were not completed by any group; all participants providing feedback reported it acceptable. Recruitment was feasible and the intervention acceptable, but a Definite Stop criterion was triggered in Newham, no group completed the full PLA cycle, and outcome data were insufficient for evaluation. A definitive trial requires stratified randomisation, digitised multilingual data collection, participant reimbursement, and explicit PLA phase-completion criteria.

Background: In 2019, WHO recommended three consecutive reactive serological test results for HIV diagnosis to reduce false-positive diagnoses. Malawi changed from a two-test to a three-test strategy in 2022 as HIV test positivity declined. We assessed diagnostic performance, implementation fidelity, and costs. Methods: We analysed national HIV testing data from Nov 1, 2022, to Oct 31, 2025. Using observed three-test classifications as the reference standard, we reconstructed classifications under the two-test strategy. We estimated positive predictive value (PPV), implementation fidelity, potential false-positive diagnoses prevented, incremental costs, and time to offset testing costs through avoided antiretroviral therapy expenditure. Results: Among 9,885,599 encounters eligible for implementation-fidelity analysis, 99.98% followed a valid three-test pathway. The diagnostic-performance analysis included 9,862,908 encounters, of which 171,351 (1.7%) were classified HIV-positive and 9,138 (0.09%) were inconclusive. Under the two-test strategy, 1,209 inconclusive encounters with a T1+/T2+/T3- sequence would have been classified as HIV-positive. Retesting and reference-laboratory data indicated that 82.5% of these would subsequently be classified as HIV-negative, corresponding to 997 false-positive diagnoses prevented (10.3 per 100 000 three-test non-positive encounters; 95% CI 9.7-10.9). Retesting within 1-2 weeks was associated with the highest odds of potential false-positive classification (adjusted OR 39.37, 95% CrI 30.63-50.61). The incremental cost was US$471 per false-positive diagnosis averted and was offset within 7.30 years. Conclusions: Malawi's transition to a three-test HIV testing strategy prevented false-positive diagnoses and unnecessary antiretroviral therapy at modest cost, supporting broader adoption of WHO guidance in similar settings. Funding: Gates Foundation.

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.

Background Preventing sexually transmitted re-infections brings health benefits and can be significantly less costly than treating their sequelae. Safetxt is a potential novel digital intervention developed to promote safer sexual behaviours. However, a recent randomised controlled trial of safetxt found no effect on reinfection at 1 year (OR 1.13, 95%CI: 0.98-1.31). We investigated if safetxt's effect was mediated through sexually risky behaviours. Methods We used data from 6248 young people with STIs from 92 UK sexual health clinics. The direct and indirect effects of safetxt on reinfection were estimated using the counterfactual approach. Condom use at last sexual encounter, number of sexual partners and STI testing were assessed as mediators. These were analysed singly and together, using regression models and a formal weighting approach. The assumptions of each approach were considered and tested. Analyses were repeated in the subgroup showing the most promising effect of safetxt: men who have sex with men or with men and women (MSM/MSMW). Results No evidence was found for the total, indirect or direct effects differing from the null. Despite not being significant, for MSM/MSMW, some of safetxt's effect on reducing reinfection was identified as being offset through its effect on number of sexual partners. Conclusions There was no evidence that safetxt's effect on reinfection was mediated through changes in sexually risky behaviours. Adaptations to specifically target these behaviours are unlikely to improve safetxt's overall effect. However, improving safetxt's effect on the number of sexual partners a participant has may improve its effect for MSM/MSMW.

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.

Background: Many at-risk patients lack access to genetic services due to a genetic counselor (GC) workforce shortage. Little is known about how digital alternatives impact patients with and without cancer who meet criteria for genetic testing. Methods: eREACH2 is a randomized 4-arm non-inferiority trial where pre-test (visit 1) and/or return of results (visit 2) GC counseling was replaced with a patient-centered digital intervention. Arms include: A (GC/GC), B (GC/digital), C (digital/GC) and D (digital/digital). Primary outcomes were non-inferiority in uptake of genetic services and change in genetic knowledge and general anxiety from baseline to post-disclosure of results (T0-T2). Secondary cognitive and affective outcomes were assessed using non-inferiority ANOVAs and equivalency chi-squared tests in intention-to-treat and per-protocol analyses. Findings: 773 participants were recruited nationwide; 46.6% from rural areas. Mean age was 51 years (range 20-87), 13% male, 12% non-white, 29% had less than a college education, and 33% had a personal history of cancer. 584 (76%) patients completed testing (14% had a positive result, 16% had a VUS). In the primary ITT analyses, we met the non-inferiority for uptake of genetic services and anxiety, but results were inconclusive for knowledge. Secondary outcomes were heterogeneous across arms. Arm C demonstrated consistently favorable effects, while Arms B and D showed less favorable outcomes in select domains (e.g. satisfaction and MICRA). Patients who received positive or VUS results via digital disclosure had significantly higher MICRA scores - indicating greater negative response to testing. Interpretation: In this large, randomized trial of patients with and without cancer, the eREACH intervention was effective for pre-test counseling, but inconclusive for digital disclosure of results. Exploratory analyses suggest that digital delivery could be a reasonable alternative for individuals receiving negative results, while those receiving positive or VUS results may derive some short-term psychosocial benefit from GC disclosure.

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.

Obesity is a significant public health concern. Early-onset obesity in the context of rare disease can reflect genetically-mediated pathology or elevated susceptibility through indirect mechanisms. Mapping the diverse characteristics and needs of young people with obesity in the rare disease population is a first step toward mechanistic and translational research. We carried out a retrospective comparative analysis of demographic, genotypic, phenotypic and health service utilisation data for young people with obesity (cases: n=500) and without obesity (controls: n=11,444) from the UK 100,000 Genomes Project rare disease cohort. Cases and controls were recruited prior to genomic diagnosis, across clinical disorder categories. We observed significant association between socioeconomic deprivation and obesity risk. Young people with obesity had significantly higher utilisations of acute care and mental health services, indicating an overall higher health burden. A curated panel of 519 candidate obesity-associated genes demonstrated aggregate association with obesity, although no single gene reached significance. Phenotypic comparison between cases and controls highlighted increased multi-organ and neurological system involvement, highlighting the overlap between neurodevelopmental and obesity risks. Within the case group, we conducted cluster analysis to identify early-onset obesity groups with different phenotypic profiles, potentially arising from different causal pathways - this identified six obesity subgroups of interest, with differing involvement of neurodevelopmental and other systems. Our study confirms that obesity co-occurs with a wide range of factors within the rare disease population, and is associated with significant physical and mental health needs, requiring holistic lifelong care.