Alcoholism: Clinical and Experimental Research

Importance: Suicide is a leading cause of death in the United States with risk strongly influenced by Interpersonal trauma, contributing to treatment resistance and clinical complexity. Objective: To assess clinical and genetic factors in individuals who died from suicide, with and without interpersonal trauma exposure. Design: Individuals who died from suicide with and without trauma were compared in a retrospective case-case design. Prevalence of 19 broad clinical categories was assessed between groups. Results directed selection of 42 clinical subcategories, and 40 polygenic scores (PGS) for further assessment. Multivariable logistic regression models, adjusted for critical covariates and multiple tests, were formulated. Models were also stratified by age group (<26yo and >=26yo), sex, and age/sex. Setting: A population-based evaluation of comorbidity and polygenic scoring in two suicide death subgroups. Participants: A total of 8 738 Utah Suicide Mortality Research Study individuals (23.9% female, average age = 42.6 yo) who died from suicide were evaluated, divided into trauma (N = 1 091) and non-trauma exposed (N = 7 647) individuals. A subset of unrelated European genotyped individuals was also assessed in PGS analyses (Trauma N = 491; Non-trauma N = 3 233). Exposures: Trauma is here defined as interpersonal trauma exposure, including abuse, assault, and neglect from International Classification of Disease coding. Main Outcomes and Measures: Prevalence of comorbid clinical sub/categories and PGS enrichment in trauma versus non-trauma exposed suicide deaths. Results: Overall, trauma-exposed individuals died from suicide earlier (mean age of 38.1 yo versus 43.3 yo; P <0.0001) and were disproportionately female (38% versus 21%, OR = 3.3, CI = 2.9-3.8). Prevalence of asphyxiation and overdose methods, prior suicidality, psychiatric diagnoses, and substance use (OR range = 1.3-3.7) were elevated in trauma exposed individuals who died from suicide. Genetic PGS were also elevated in trauma-exposed individuals who died from suicide for depression, bipolar disorder, cannabis use, PTSD, insomnia, and schizophrenia (OR range = 1.1-1.4) with ADHD and opioid use showing uniquely elevated PGS in trauma exposed males (OR range = 1.2-1.4). Conclusions and Relevance: Results demonstrated multiple convergent lines of age- and sex-specific evidence differentiating trauma-exposed from non-trauma exposed suicide death. Such findings suggest unique biological backgrounds and may refine identification and treatment of this high-risk group.

BackgroundSubstance use initiation in adolescence is influenced by both genetic and environmental factors; however, large-scale genetic studies often treat initiation as a binary outcome and underuse longitudinal timing information. MethodsWe conducted time-to-event (survival) genome-wide association analyses (GWAS) of initiation for four outcomes--alcohol, nicotine, cannabis, and any substance use--using longitudinal follow-up data from the Adolescent Brain Cognitive Development (ABCD) Study. We performed ancestry-stratified GWAS within European (EUR), African (AFR), and Hispanic (HISP) groups, applying consistent quality control and covariate adjustment. Summary statistics were harmonized across ancestries and meta-analyzed using inverse-variance weighted fixed-effects and DerSimonian-Laird random-effects models. We evaluated genomic inflation and heterogeneity (Cochrans Q and I2), identified independent lead variants at genome-wide and suggestive significance thresholds, and assessed cross-trait overlap of associated loci. ResultsIn the multi-ancestry meta-analysis, we observed suggestive association signals across traits (minimum p-values: alcohol [~] 1 x 10-7, any [~] 1 x 10-7, cannabis [~] 5 x 10-8, nicotine [~] 1 x 10-8). Nicotine initiation showed one genome-wide significant variant in both fixed- and random-effects meta-analyses (p < 5 x 10-8). Across traits, suggestive loci demonstrated limited overlap, with the strongest concordance between alcohol and any substance use, consistent with shared liability. Heterogeneity statistics indicated that some loci exhibited cross-ancestry variation in effect estimates. ConclusionsSurvival GWAS leveraging initiation timing can identify genetic signals that may be missed by binary designs and enables principled multi-ancestry synthesis. Our results highlight both shared and trait-specific genetic contributions to early substance initiation and provide a foundation for downstream functional annotation and integrative modeling with environmental risk factors. These findings demonstrate the value of incorporating developmental timing into genetic discovery and provide a framework for integrating longitudinal risk modeling with genomic analyses.

Background: The Adolescent Brain Cognitive Development (ABCD) Study provides rich longitudinal data on environmental, genetic, and behavioral factors related to substance use initiation. Classical marginal structural models (MSMs) require selecting covariates for propensity models, which is challenging when there are many correlated predictors. Methods: We analyzed longitudinal panel data from 11,868 ABCD participants with repeated observations over time. Interval-level binary outcomes were defined for initiation of alcohol, nicotine, cannabis, and any substance, including only participants at risk before initiation. All predictors were constructed as lagged variables to preserve temporal ordering. We used a two-stage machine learning-based causal framework. First, we performed graph discovery using a Granger-inspired lagged predictive modeling approach with elastic-net logistic regression to identify relationships between past predictors and future outcomes. Stable candidate edges were selected using subject-level bootstrap stability selection. Second, we estimated adjusted effects for stable predictors using double machine learning (DML) with partialling-out and cross-fitting. For each predictor, the lagged variable was treated as the exposure and adjusted for high-dimensional lagged covariates. Cross-fitting with group-based splitting accounted for within-subject dependence. Nuisance functions were estimated using random forests, and cluster-robust standard errors were used for inference. Results: We identified stable predictors across multiple domains, including sleep patterns, family environment, peer relationships, behavioral traits, and genetic risk. Many predictors were shared across substance outcomes, while some were outcome-specific. Effect sizes were modest, typically ranging from -0.01 to 0.02 per standard deviation increase in the predictor. Both risk-increasing and protective associations were observed. Risk factors included sleep disturbance and behavioral risk indicators, while protective factors included parental monitoring and structured environments. Conclusions: This study presents a practical framework for analyzing high-dimensional longitudinal data and identifying time-varying predictors of substance use initiation. The approach combines machine learning for variable selection with causal inference for effect estimation. The results highlight both shared and outcome-specific risk factors and identify modifiable targets, such as family environment and sleep, that may inform prevention strategies.

Background: Drug checking services (DCS) promote drug supply awareness among people who use drugs (PWUD) by detecting adulterants such as fentanyl and xylazine that are associated with overdose morbidity and mortality. However, there is limited research on DCS implementation in Latin America (LA). Methods: We conducted a survey of 38 DCS across LA (n=10) and the US (n=28) and compared program characteristics and barriers between these two regions. We also conducted a focus group discussion (FGD) with staff representing six organizations implementing DCS in LA. FGD themes were mapped to constructs quantitatively assessed in the survey. Results: Compared to US DCS, LA DCS more frequently reported funding gaps as a major implementation barrier (80% vs. 54%), law enforcement confiscating DCS supplies (38% vs. 11%), as well as offering supervised drug consumption (30% vs. 4%) and mental health/counseling (40% vs. 18%), but less frequently reported that DCS equipment was legal (44% vs. 75%). DCS on the Mexico-US border focused on people who inject drugs and offered syringe services, supervised consumption, and rapid sexually transmitted infection testing. DCS in central Mexico, Colombia, Peru, and Chile primarily provided DCS for the nightlife community (e.g., attendees of concerts/raves). Barriers to DCS implementation cited by FGD discussants included inadequate funding, DCS legal ambiguities, lack of government support, and cartel violence. Conclusion: DCS in LA would benefit from increased funding, government support, and a more permissive legal environment, thereby strengthening harm reduction efforts and improving safety for PWUD. Keywords: drug checking services; harm reduction; overdose; people who use drugs; Latin America; fentanyl; tusi

Introduction. Current best practice is for primary care physicians (PCPs) to screen patients for problematic substance use at checkups. However, this practice is not routine, is done in an unstandardized manner, and contributes to the overburdening of PCPs. Screening practices also target current, potentially problematic use behaviors, thus limiting their capacity to help patients prevent problems before they start. Recent scientific advances in identifying people at high risk for substance use problems as a means of facilitating prevention efforts have not yet been integrated into medical practice. To address these issues, our research team developed a freestanding platform called the Comprehensive Addiction Risk Evaluation System (CARES). CARES provides personalized information about genetic and behavioral/environmental risk for substance use disorder (SUD) and connects individuals to resources based on their risk profile. The present study evaluated the potential for adoption and implementation of CARES within a health care system through qualitative interviews with key stakeholders. Methods. Semi-structured interviews were developed using the Consolidated Framework for Implementation Research (CFIR) and conducted with N=15 interviewees. Transcripts were analyzed using rapid qualitative analysis. Results. Key themes included perceived need for new SUD screening tools, current SUD screening procedures and their pros/cons, openness to new ideas and clinical tools, fit of CARES with organizational goals and priorities, considerations for use of CARES with adolescent populations, anticipated patient response to CARES, barriers to implementation and uptake of CARES, changes required for implementation, and possibility for medical record integration. Interviewees generally expressed need for new screening tools and openness to using new tools, but expressed concern that existing provider burden, lack of SUD knowledge, and discomfort/stigma could stymie efforts to implement CARES. Conclusions. There is a clear need for a low-burden, easy-to-use tool for substance use screening. CARES appears to be an acceptable and feasible approach to fill this gap. These findings will be used to inform pilot implementation of CARES in a clinical care setting.

Background: Early initiation of substance use is linked to later adverse outcomes, and risk factors come from multiple domains and are shared across substances. In our previous work, traditional time-to-event Cox models identified individual risk factors, but these models are not designed to jointly model multiple outcomes or capture complex non-linear relationships. Multi-task learning (MTL) can leverage shared structure across related outcomes to improve prediction and distinguish common versus substance-specific predictors. However, most MTL studies rely on baseline features and focus on single outcomes, which limits their ability to capture shared risk and temporal changes. Substance use initiation is a time-dependent process that unfolds during development and reflects changing exposures over time. Baseline-only models cannot capture these changes or represent risk dynamics. Discrete-time modeling provides a practical approach by estimating interval-level initiation risk and combining it into cumulative risk at the subject level. By integrating multi-task learning with dynamic modeling, it is possible to share information across outcomes while capturing how risk evolves over time, which may improve prediction performance. Methods: Using the Adolescent Brain Cognitive Development (ABCD) Study (release 5.1), we developed two complementary multi-task learning (MTL) frameworks to predict initiation of alcohol, nicotine, cannabis, and any substance use. A baseline MTL model predicted fixed- horizon (48-month) initiation using one record per participant, while a dynamic discrete-time MTL model incorporated longitudinal interval data to model time-varying risk. Both models used multi-domain environmental exposures, core covariates, and polygenic risk scores (PRS). Performance was evaluated on a held-out test set using AUROC, PR-AUC, and calibration metrics, and compared with single-task logistic regression (LR). Feature importance was assessed using permutation importance and compared with Cox proportional hazards models. Results: MTL showed comparable or improved performance relative to LR, with larger gains for low-prevalence outcomes (cannabis and nicotine). Incorporating longitudinal information led to consistent improvements across all outcomes. Dynamic models increased AUROC by +0.044 to +0.062 for MTL and +0.050 to +0.084 for LR, indicating that temporal information was the primary driver of performance gains. Feature importance analyses showed modest overlap across methods, with higher agreement between dynamic MTL and Cox models than static MTL. A small set of features, including externalizing behavior, parental monitoring, and developmental factors, were consistently identified across all approaches. Conclusions: Dynamic multi-task learning improves the prediction of substance use initiation by leveraging longitudinal structure and shared information across outcomes. While MTL provides additional gains, incorporating time-varying information is the dominant factor for improving performance. Combining baseline and dynamic frameworks offers a comprehensive strategy for identifying robust risk factors and modeling adolescent substance use initiation.

BackgroundNegative symptoms are core features of schizophrenia that relate strongly to functional impairment, yet interventions targeting these symptoms remain largely ineffective. Emerging theoretical work highlights how environmental factors may shape and maintain negative symptoms. Although racial disparities in schizophrenia diagnosis among Black Americans are well documented and linked to racial stress and psychosis, the impact of racial stress on negative symptoms has not been examined. This study provides an initial test of a novel theory proposing that racial stress - here measured by racial discrimination - influences negative symptom severity through exacerbation of negative cognitions about the self, particularly defeatist performance beliefs (DPB). Study DesignParticipants diagnosed with schizophrenia-spectrum disorder (SSD) (N = 208; 80 Black, 128 White) completed the Positive and Negative Syndrome Scale (PANSS), the Defeatist Beliefs Scale, and self-report measures of subjective racial and ethnic discrimination (Racial and Ethnic Minority Scale and General Ethnic Discrimination Scale). Relationships among variables were tested using linear regression and mediation analysis. Study ResultsBlack participants exhibited significantly greater total and experiential negative symptoms than White participants with no group difference in DPB. Racial discrimination explained 46% of the relationship between race and negative symptoms. Among Black participants, higher DPB were associated with greater negative symptom severity. Discrimination was positively related to both DPB and negative symptoms. DPB partially mediated the relationship between discrimination and negative symptoms. ConclusionsFindings suggest that racial stress contributes to negative symptom severity via defeatist beliefs among Black individuals, highlighting potential targets for culturally informed interventions.

Introduction: Monitoring trends in transitions in the use of electronic nicotine delivery systems (ENDS) and cigarettes among youth is important for understanding the potential public health impacts of these products. Methods: Using a weighted Markov multistate transition model accounting for complex survey design, we estimated transition rates and one-year transition probabilities between never, non-current, ENDS-only, and cigarette use (with or without dual use of ENDS) among 26,744 youth aged 12-17 years who participated in at least two consecutive waves from Waves 2-7.5 (approximately 2015-2023) of the nationally representative Population Assessment of Tobacco and Health (PATH) Study. We also estimated transitions stratified by ages 12-14 and 15-17 years. Results. The one-year probability of ENDS-only initiation from never use among youth peaked in 2017-19 (Waves 4-5) at 4.0% (95%CI: 3.6-4.3%) and was higher for 15-17-year-olds at 5.8% (95%CI: 5.2-6.4%) than 12-14-year-olds at 2.2% (95%CI: 1.8-2.6%). In the following years, ENDS-only initiation rates declined and plateaued, with 2.6% (95%CI: 2.3-3.0%) initiation in 2022-23. Cigarette initiation from never use decreased over 2015-23 from 0.8% (95%CI: 0.6-1.0%) in 2015-16 to 0.1% (95%CI: 0.0-0.2%) in 2022-23. There was an increase in the fraction of youth who transitioned from non-current product use to ENDS-only use from 13.7% (95%CI: 7.5-20.0%) in 2015-16 to 35.1% (95%CI: 25.4-44.8%) in 2022-23, paired with a decrease in non-current use to cigarette use from 20.9% (95%CI: 11.8-30.0%) to 6.3% (95%CI: 1.7-10.8%). Transitions from ENDS-only or cigarette use to non-current use remained relatively constant over time at around 25% and 15% per year, respectively. Conclusion. ENDS-only use initiation has changed over time, peaking around 2019 and subsequently decreasing and plateauing, but cessation rates for both ENDS and cigarettes have remained relatively stable. Thus, interruption of tobacco product initiation may be the most effective approach to reducing tobacco product use among youth.

PurposeNavigational ability develops throughout childhood alongside the maturation of brain regions supporting egocentric and allocentric processing. In Autism Spectrum Disorder (ASD), atypical hippocampal development may impact flexible spatial memory; however, findings on navigational ability in autistic children remain inconsistent. This study aimed to compare both objective and perceived navigation ability in children with ASD and typically developing (TD) peers. MethodTwenty-six children with high-functioning ASD and twenty-five age- and gender-matched TD children (M_age = 12.04 years, SD = 1.64) completed a battery of navigational tasks from the Spatial Performance Assessment for Cognitive Evaluation (SPACE), including Path Integration, Egocentric Pointing, Mapping, Associative Memory, and Perspective Taking. Perceived navigation ability was assessed using the Santa Barbara Sense of Direction (SBSOD) scale. ResultsNo significant group differences were observed across any objective navigation tasks. However, children with ASD reported significantly lower perceived navigation ability compared to TD peers. ConclusionThese findings suggest a dissociation between perceived and actual navigational ability in ASD. By early adolescence, objective navigation performance appears intact, potentially reflecting sufficient maturation of underlying neural systems or the presence of compensatory mechanisms. The results underscore the importance of incorporating objective, task-based measures when assessing cognitive abilities in autistic populations.

Understanding depressive symptoms dynamics and their determinants is crucial for designing effective mental health support initiatives. This study compared two methods for describing youth depressive symptoms trajectories and investigated associations of early-life factors (maternal education, maternal perinatal depression, domestic violence, physical, emotional, or sexual abuse, bullying victimisation, psychiatric disorder) with trajectory features. Prospective data from 8,264 mostly White European participants (54% female), including self-reported Short Moods and Feelings Questionnaires on ten occasions between 10-25 years, were used. Trajectories were summarised using functional principal component analysis (FPCA) and P-splines linear mixed-effect (PLME) models. Estimated derivatives were used to obtain magnitude and age of peak symptoms and peak symptoms velocity. Both methods performed comparably, but PLME models tended to over-smooth trajectories. Peak symptoms and peak velocity were higher and occurred >1 year earlier in females than males. All early-life factors were associated with higher peak symptoms, and most associated with higher and earlier peak velocity. Abuse and bullying additionally associated with earlier age of peak symptoms. FPCA is a useful alternative for characterising depressive symptoms trajectories and informing time-sensitive preventative measures to reduce impact of depression before symptoms reach their peak. Early-life stressors may accelerate timeline and intensity of symptoms escalation during adolescence. Lay summaryUnderstanding development of depressive symptoms and factors shaping them is crucial for designing effective mental health support initiatives. This study used data from over 8,000 young people regularly followed up from before birth to compare two cutting-edge methods for describing depressive symptoms trajectories and examined how known risk factors for adulthood depression relate to the severity and rate of change of depressive symptoms in adolescence. We found that both methods performed well and that the peaks in depressive symptoms and their rate of change were, on average, higher and occurred over a year earlier in females than males. Our findings additionally suggest that early-life stressors (e.g., abuse, bullying) may accelerate the development of depression, highlighting the importance of early prevention.

ImportanceBlood neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are entering clinical use in neurology as markers of neuroaxonal and astrocytic injury, but their utility in psychiatry is unclear. ObjectiveTo determine whether psychiatric diagnoses are associated with altered plasma NfL and GFAP levels. Design, Setting, and ParticipantsThis population-based study examined plasma NfL and GFAP among 47,495 participants from the UK Biobank (54.0% female; 93.5% White; mean [SD] age 56.8 [8.2] years) who provided blood samples and sociodemographic and clinical data between 2006 and 2010. Normative modeling was applied to assess associations between 7 lifetime psychiatric diagnostic categories and deviations from expected NfL and GFAP levels, while accounting for neurological diagnoses, cardiometabolic burden, and substance use. Data were analyzed between July 2025 and March 2026. Main Outcomes and MeasuresDeviations in plasma NfL and GFAP levels from normative predictions. ResultsRelative to the reference population, plasma NfL levels were higher among individuals with bipolar disorder (d=0.20; 95% CI, 0.03-0.37; p=0.03), recurrent depressive disorder (d=0.23; 95% CI, 0.07-0.38; p=0.009), and depressive episodes (d=0.06; 95% CI, 0.02-0.10; p=0.01), lower among individuals with anxiety disorders (d=-0.07; 95% CI, -0.12 to -0.02; p=0.008), but did not differ in schizophrenia spectrum, stress-related, or other psychiatric disorders. Plasma GFAP levels were not elevated in any psychiatric disorders. Variability in NfL levels was greater among individuals with schizophrenia spectrum disorders (variance ratio [VR]=1.30; p=0.005), depressive episodes (VR=1.06; p=0.006), and anxiety disorders (VR=1.08; p=0.005). Variability in GFAP levels was increased only in anxiety disorders (VR=1.08; p=0.01). Plasma NfL levels exceeding percentile-based normative thresholds were more common among individuals with schizophrenia spectrum disorders, bipolar disorder, recurrent depressive disorder, and depressive episodes. Neurological diagnoses, cardiometabolic burden, and substance use were associated with plasma NfL and GFAP levels. Conclusions and RelevanceThis study provides population-level evidence of plasma NfL elevation in bipolar and depressive disorders and increased variability in schizophrenia spectrum, bipolar and depressive disorders, supporting its potential as a biomarker in psychiatry and informing its ongoing neurological applications. Plasma GFAP levels, in contrast, were largely unaltered across psychiatric disorders. Key PointsO_ST_ABSQuestionC_ST_ABSAre plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) levels altered in psychiatric disorders? FindingsIn this cohort study including 47,495 individuals, normative modeling revealed that plasma NfL levels were elevated in bipolar and depressive disorders, whereas plasma GFAP levels were not elevated in any psychiatric disorder. Plasma NfL levels also showed higher variability in schizophrenia spectrum, bipolar, and depressive disorders. MeaningPlasma NfL shows distinct alterations in schizophrenia spectrum and affective disorders, supporting its further investigation as a biomarker in clinical psychiatry and highlighting the need to consider psychiatric comorbidity in neurological applications.

Background: Differences in age of psychosis onset (AOO) in schizophrenia (SCZ) are associated with different illness trajectories. Determining whether AOO differences can be explained by genome-wide or pathway-partitioned polygenic risk for SCZ (SCZ-PRS) may elucidate mechanisms underlying clinical variability. This study examined relationships between AOO, genome-wide SCZ-PRS, and pathway-partitioned SCZ-PRS in a harmonized, multi-ancestry North American dataset (SCZ-NA) and in UK Biobank (SCZ-UKBB). Methods: For each cohort, we computed one genome-wide SCZ-PRS and 18 mutually-exclusive pathway-based PRS derived from previous published and validated neurodevelopmental gene-sets. We evaluated 13 SNP-to-gene mapping strategies, including comparing non-coding SNP-to-gene mappings informed by functional annotations versus distance-based windows. SCZ case-control prediction and AOO associations were tested using logistic and linear mixed models, respectively, controlling for sex, ancestry principal components, and genetic relatedness. Results: Genome-wide SCZ-PRS robustly predicted SCZ case-control status in both cohorts but not AOO. In contrast, pathway-based analyses identified AOO associations for a fetal angiogenesis and a postnatal synaptic signaling and plasticity gene-set across both cohorts (p < .05), alongside nominal cohort-specific associations in other gene-sets. Associations depended on SNP-to-gene mapping definitions; experimentally informed strategies, particularly those incorporating brain expression Quantitative Trait Locus (eQTL) annotations performed best. Conclusion: Findings suggest that neurovascular and postnatal synaptic signaling and refinement mechanisms contribute to AOO variation in SCZ, and that pathway-informed PRS, especially with brain-specific non-coding SNP-to-gene mappings, can help identify mechanisms contributing to variability in AOO. Replication in larger, prospectively phenotyped cohorts with harmonized AOO definitions will further clarify genetic mechanisms underlying clinical variability in SCZ.

BackgroundMajor depressive disorder (MDD), a leading cause of disability worldwide, exhibits substantial heterogeneity in treatment outcomes. Patients who do not respond to standard antidepressant therapy account for the majority of MDDs disease burden. Risk factors have been implicated in treatment response, including genes impacting on how antidepressants are metabolised. Yet, despite its clinical importance, risk factors for treatment-resistant depression (TRD) remain unexplored in low- and middle-income countries (LMIC). We used data from the DIVERGE study on MDD to investigate the risk factors of TRD in Pakistan. MethodsDIVERGE is a genetic epidemiological study that recruited adult MDD patients ([&ge;]18 years) between Sep 27,2021 to Jun 30, 2025, from psychiatric care facilities across Pakistan. Detailed phenotypic information was collected by trained interviewers and blood samples taken. Infinium Global Diversity Array with Enhanced PGx-8 from Illumina was used for genotyping followed by DRAGEN calling to infer metaboliser phenotypes for Cytochrome P450 (CYP) enzyme genes. We defined TRD as minimal to no improvement after [&ge;]12 weeks of adherent antidepressant therapy. We conducted multi-level logistic regression to test the association of demographic, clinical and pharmacogenetic variables with TRD. FindingsAmong 3,677 eligible patients, polypharmacy was rampant; 86% were prescribed another psychotropic drug along with an antidepressant. Psychological therapies were uncommon (6%) while 49% of patients had previously visited to a religious leader/faith healer in relation to their mental health problems. TRD was experienced by 34% (95%CI: 32-36%) patients. The TRD group was characterised by more psychotic symptoms and suicidal behaviour (OR=1.39, 95%CI=1.04-1.84, p=0.02; OR=1.03, 95%CI=1.01-1.05, p=0.005). Social support (OR=0.55, 95%CI=0.44-0.69, p=1.4x10-7) and parents being first cousins (OR=0.81, 95%CI=0.69-0.96, p=0.01) were associated with lower odds of TRD. In 1,085 patients with CYP enzyme data, poor (OR=1.85, 95%CI=1.11-3.07, p=0.01) and ultra-rapid (OR=3.11, 95%CI=1.59-6.12, p=0.0009) metabolizers for CYP2C19 had increased risk of TRD compared with normal metabolisers. InterpretationThere was an excessive use of polypharmacy in the treatment of depression while psychological therapies were uncommon highlighting the need for more evidence-based practice. This first large study of MDD from Pakistan uncovered the importance of culture-specific forms of social support in preventing TRD, highlighting opportunities for interventions in low-income settings. Pharmacogenetic markers can be leveraged to predict TRD.

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder with changes in motivation to work for rewards being a core symptom. Transcutaneous vagus nerve stimulation (tVNS) has emerged as a promising therapy but its effects on the core features of MDD, such as changes in motivation, remained relatively unexplored. In this randomised, single-blind, cross-over, controlled trial, we used a grip strength effort task to investigate how tVNS impacted choices to exert different levels of physical effort for varying monetary rewards in MDD patients (n=53) and a non-depressed control group (n=45). Compared to sham stimulation, tVNS enhanced the efficiency with which participants with severe depressive symptoms allocated physical effort for rewards (reward-effort efficiency). These effects were not seen in participants with less severe symptoms. Specifically, we found that the effect of tVNS on reward-effort efficiency was driven by reduced unnecessary effort, i.e., a reduction in choices to exert additional effort when this was not required to gain a larger reward. These findings suggest a potential motivational mechanism by which tVNS exerts its therapeutic effects in MDD. Determining whether the effects of tVNS are linked to broader changes in executive functioning, such as improvements in cognitive flexibility in MDD, should be a key aim for future work.

BackgroundCurable sexually transmitted infections (STIs), including Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis, remain highly prevalent among pregnant women in South Africa. Despite poor diagnostic performance in pregnancy, syndromic management remains standard care. Point-of-care (POC) screening enables aetiological diagnosis and same-visit treatment but is not yet included in national guidelines. We conducted a mixed-methods process evaluation to examine determinants of antenatal POC STI screening implementation in public facilities. MethodsThis evaluation was embedded within the three-arm Philani Ndiphile randomized trial (March 2021-February 2025) across four public clinics in the Eastern Cape. Screening used a near-POC, electricity-dependent nucleic acid amplification test with a 90-minute turnaround time. Reach, Adoption, Implementation, and Maintenance were assessed using the RE-AIM framework. Quantitative indicators included uptake of screening, treatment, and follow-up attendance. Qualitative data included in-depth interviews with 20 pregnant women and five focus group discussions with 21 research staff and government healthcare workers. The Consolidated Framework for Implementation Research guided qualitative analysis. Findings were integrated using narrative weaving. ResultsScreening uptake was high (99.0%), with treatment coverage of 95.2% at baseline and 93.5% at repeat screening. Same-day treatment was lower (50.7% and 69.8%) and varied substantially by facility, reflecting operational constraints including turnaround time, patient volume, infrastructure, and electricity. Attendance was higher when screening was integrated into routine ANC. Women valued screening for infant health, while providers recognised advantages over syndromic management but highlighted workforce, resource, and maintenance constraints. Socioeconomic factors, including transport costs, hunger, and work commitments, influenced retention and waiting. ConclusionsAntenatal POC STI screening was acceptable and achieved high treatment coverage in a research setting. However, same-day treatment was constrained by operational requirements of the testing platform. Scale-up will require workflow integration, strengthened health system capacity, and faster diagnostics suited to routine antenatal care. Key MessagesO_ST_ABSWhat is already known on this topicC_ST_ABSSyndromic management remains standard antenatal care in many low-resource settings despite failing to capture up to 89% of infections that remain asymptomatic. Point-of-care aetiological screening has demonstrated feasibility, acceptability, and potential clinical benefit in research settings, yet has not been widely adopted into national policy. Limited evidence exists on the health system requirements and contextual determinants influencing scale-up within routine public facilities. What this study addsThis mixed-methods process evaluation demonstrates high uptake and treatment coverage of antenatal POC STI screening in a trial setting, while identifying facility-level, structural, and socioeconomic factors shaping same-day treatment and retention. We show that implementation success varies substantially across clinics and depends on assay characteristics, workflow integration, human resources, infrastructure reliability, and follow-up capacity. How this study might affect research, practice or policyThese findings provide implementation-relevant evidence to inform national policy deliberations on integrating POC STI screening into antenatal care. Sustainable scale-up will require context-adapted delivery models, strengthened workforce and supply systems, faster diagnostics, and alignment with existing ANC workflows to ensure equitable and durable impact.

PurposeAntibiotic use (ABU) is a major driver of antimicrobial resistance (AMR), but ABU patterns are poorly understood in low-income countries where the burden of AMR is great and ABU is insufficiently regulated. Here, we report ABU from ten sites ranging from rural villages to small cities in Madagascar, a country with high AMR levels, and present results from modeling to identify factors that may be associated with ABU in this setting. MethodsWe conducted surveys of 290 individuals from ten sites in the SAVA Region of northeast Madagascar to gather data on sociodemographic characteristics, agricultural and animal husbandry practices, recent antibiotic use, the antibiotics that participants recalled using in their lifetimes, and the sources of their antibiotics. Using these data, we conducted statistical analyses with a mixed-effects logistic model to determine which characteristics were associated with recent antibiotic use. ResultsNearly all respondents (N=283, 97.6%) reported ABU in their lifetimes, with amoxicillin being the most widely reported antibiotic (N=255, 90.1% of those reporting ABU). All recalled antibiotics were classified as frontline drugs except for ciprofloxacin. Most respondents who reported antibiotic use also reported obtaining antibiotics without prescriptions from local stores (N=273, 96.5%), while only 52.3% (N=148) reported obtaining antibiotics through a prescriptive route, such as from a health clinic or private doctor. Of the 127 individuals (44.9%) who reported recent ABU, men were found to be significantly less likely to have recently taken antibiotics than women. ConclusionsOur findings provide new insights into ABU in agricultural settings in low-income countries, which have historically been understudied in AMR and pharmacoepidemiologic research. Knowledge of ABU patterns supports understanding of AMR dynamics and AMR control efforts in these contexts, such as interventions on inappropriate antibiotic dispensing. Key pointsO_LIAntibiotic use (ABU) in Madagascar is largely unstudied despite its role in antimicrobial resistance (AMR), which Madagascar faces a high burden of. C_LIO_LIABU was widespread among livestock owners in northeast Madagascar, with the majority of study participants reporting ABU in their lifetimes and most people reporting ABU also having taken antibiotics in the previous three months. C_LIO_LIMost respondents reported obtaining their antibiotics from non-pharmaceutical stores, indicating high levels of unregulated ABU, though more than half also reported sourcing their antibiotics through prescriptive means (like doctors and health clinics). C_LIO_LIMen were less likely than women to have taken antibiotics in the previous three months. C_LIO_LIThese findings support the development of interventions to mitigate the burden of AMR in Madagascar and similar contexts while underscoring the need for more comprehensive research on the drivers and patterns of ABU. C_LI Plain language summaryIn this study, we provide basic information on antibiotic use (ABU) patterns in Madagascar, a country that experiences high levels of resistance but has been particularly understudied in AMR and pharmacological research. We surveyed 290 farmers with livestock from ten sites across northeast Madagascar about their ABU and found that nearly all study participants (N=283, 97.6%) have used antibiotics in their lifetimes, while a little under half of those who reported ABU also reported using antibiotics in the previous three months (N=127, 44.9%). The most used antibiotic was amoxicillin (N=255, 90.1%). Most people obtained their antibiotics from sources that do not require prescriptions, like general stores, indicating that most ABU is unregulated. Through modeling, we also found that men were less likely than women to have taken antibiotics in the previous three months (OR=0.50, CI 0.30-0.82). These findings help us better understand the dynamics of ABU in low-income countries, which have historically been understudied in AMR and pharmacological research. They also support efforts to mitigate the burden of AMR by revealing ABU dynamics that may contribute to the emergence and spread of AMR, as well as identifying targets for intervention to curb inappropriate ABU.

Human papillomavirus (HPV) testing is the primary method for cervical cancer screening, and a negative HPV test is associated with a very low subsequent risk of invasive cancer. Nevertheless, a small number of cervical cancers are diagnosed following an HPV-negative testing result, posing challenges within HPV-based screening pathways. Using nationwide Swedish registry data of HPV testing, we identified women diagnosed with invasive cervical cancer between 2019 and 2024 and reconstructed HPV testing histories from the National Cervical Screening Registry (NKCx). The most recent HPV test prior to diagnosis was defined as the index test, and longitudinal HPV testing trajectories were classified among women with an HPV-negative index test. Of 3,000 women diagnosed with invasive cancer, 243 (8.1%) had an HPV-negative index test. These women were older at diagnosis and more frequently diagnosed at advanced stages compared with women with an HPV-positive index test. Most HPV-negative index tests (66.3%) were performed in the peri-diagnostic period (+/- 30 days). Among women with an HPV-negative index test, 52.7% (128/243) had no prior HPV testing recorded, while the remainder had consistently HPV-negative histories (33.3%, 83/243) or evidence of prior HPV positivity before the index negative test (14%, 32/243). Possible recurrent HPV positivity following an intervening negative test was rare (0.4%, 1/243). HPV-negative screening results preceding invasive cancer reflect heterogeneous screening histories and cannot be explained solely by test failure. Findings highlighting the importance of reaching women earlier in screening programs and show that fluctuating HPV detectability is rare.

BackgroundThis study aimed to assess caregiver knowledge of Infant and Young Child Feeding (IYCF), child health, severe acute malnutrition (SAM) screening, and Community-Based Management of Acute Malnutrition (CMAM), its determinants, and associations with IYCF/ WaSH (water, sanitation, and hygiene) practices among caregivers of children 6-59 months with SAM in Ethiopian agrarian and pastoralist settings. MethodData were from the baseline survey of the R-SWITCH Ethiopia cluster-randomized controlled trial (cRCT), which screened [~]28,000 children aged 6-59 months and identified 686 SAM cases. Caregiver knowledge was evaluated using a validated 32-item questionnaire (Cronbachs for internal reliability) and analyzed via linear mixed-effects and Poisson regression models in Stata 17. ResultsCaregiver knowledge was positively associated with improved IYCF/WaSH practices among children aged 6-23 months with SAM, including higher minimum dietary diversity (MDD: IRR=1.50), minimum acceptable diet (MAD: IRR=1.63), and reduced zero vegetable/fruit intake (IRR=0.77), as well as MDD in children aged 24-59 months, improved water access (IRR=1.19), water treatment (IRR=2.02), and handwashing stations (IRR=1.41). Literate ({beta} = 4.1; 95% CI:1.5-6.6, p= 0.016), pregnant({beta} = 4.4; 95% CI:0.9-7.8, 0.018), having child weighing at a health post/ health center ({beta} = 8.9;95% CI:3.5-14.2,p [&le;] 0.001), and higher household wealth index ({beta} = 11.8;95% CI:3.6-20.1,p= 0.005) were associated with higher knowledge, while possible depression ({beta} = -0.3;95% CI: -0.5 to 0.0, p= 0.015) was associated with lower knowledge. ConclusionCaregiver knowledge determines better IYCF/WaSH practices among children aged 6-59 months with SAM. Literacy, pregnancy, having child weighing at a health post or health center, and greater household wealth were associated with caregivers knowledge, whereas possible depression was associated with lower knowledge. Integrating context-specific caregiver education and mental health support into CMAM, GMP(Growth monitoring and promotion), and primary care services could enhance feeding/WaSH practices in Ethiopia.

The global ambition to end the human immunodeficiency virus (HIV) epidemic requires understanding which system-level policy levers, enacted under the framework of Universal Health Coverage (UHC), are most effective in achieving both transmission reduction and diagnostic coverage. This study addresses an important evidence gap by quantifying the within-country association between measurable UHC policy indicators and the estimated rate of new HIV infections across nine Southeast Asian countries between 2013 and 2022. Employing a Fixed-Effects panel data methodology, the analysis controls for time-invariant national heterogeneity, ensuring reliable estimates of policy impact. We found that marginal changes in total current health expenditure (CHE) as a percentage of gross domestic product (GDP) were not statistically significantly associated with changes in HIV incidence. However, increases in the UHC Infectious Disease Service Coverage Index were statistically significantly associated with concurrent reductions in HIV incidence (p < 0.001), suggesting the efficacy of targeted service implementation as the principal driver of curbing new HIV infections. In addition, the UHC Reproductive, Maternal, Newborn, and Child Health Service Coverage Index exhibited a statistically significant positive association with changes in HIV incidence (p < 0.01), which is interpreted as a vital surveillance artefact resulting from expanded detection and reporting of previously undiagnosed HIV cases. Furthermore, out-of-pocket (OOP) health expenditure as a percentage of CHE showed a counter-intuitive negative association with changes in HIV incidence (p < 0.01), suggesting this metric primarily shows ongoing indirect cost burdens on the established patient cohort, or, alternatively, presents a diagnostic access barrier that results in lower case finding. These findings suggest that policymakers should prioritise investment in targeted infectious disease service efficacy over aggregate fiscal commitment and utilise integrated sexual health platforms for strengthened HIV surveillance and case identification.

Objectives: Longer lifespans lead to longer time on retirement, despite the efforts to raise the retirement age. Therefore, it is important to study how the retirement years can be spent without diseases. This study examined socioeconomic and sociodemographic differences in healthy years spent on retirement. Methods: We followed a cohort of retired Finnish municipal employees (N=4231, average follow-up 15.4 years) on national administrative registers for major chronic diseases: cancer, coronary heart disease, cerebrovascular disease, diabetes, asthma or chronic obstructive pulmonary disease, dementia, mental disorders, and alcohol-related disorders. Median healthy years on retirement and age at first occurrence of illness (ICD-10 and ATC-based) in each combination of sex, occupational class, and age of retirement were predicted using Royston-Parmar models. Prevalence rates for each diagnostic group were calculated. Results: Most healthy years on retirement were spent by women having worked in semi-professional jobs who retired at age 60-62 (median predicted healthy years 11.6, 95% CI 10.4-12.7). The least healthy years on retirement were spent by men having worked in routine non-manual jobs who retired after age 62 (median predicted healthy years 6.5, 95% CI 4.4-9.5). Diabetes was slightly more common among lower occupational class women, and dementia among manual working women having retired at age 60-62. Discussion: Healthy years on retirement are not enjoyed equally by women and men and those who retire early or later. Policies aiming to increase the retirement age should consider the effects of these gaps on retirees and the equitability of those effects.