Alcohol, Clinical and Experimental Research

Background: Prior neuroimaging suggests brain differences between children with attention deficit hyperactivity disorder due to prenatal alcohol exposure (ADHD+PAE) and non-exposed children with ADHD due to other, e.g., familial, causes (ADHD-PAE). There has been interest in regional brain levels of ;gamma-aminobutyric acid (GABA) and glutamate (Glu) measured in vivo with magnetic resonance spectroscopy (MRS) as possible indicators of local inhibitory, respectively, excitatory activity in ADHD. For the first time, we report here a comparison of GABA and Glu in ADHD+PAE vs. ADHD-PAE. Methods: At 3 T, we used J-difference-edited single-voxel MRS to assay GABA and Glu in 28 children with ADHD+PAE, 20 with ADHD-PAE, and 28 typically developing (TD) controls, all aged 8-14 years. MRS was sampled from midline anterior middle cingulate cortex (aMCC), the cognitive cingulate considered functionally relevant to ADHD. Spectra were fit with custom software, including a unique technique for isolating the GABA signal from the confounding macromolecular baseline (MMBL). Results: aMCC GABA was higher in ADHD+PAE and ADHD-PAE than in TD. GABA increased with age in TD, but not in ADHD+PAE or ADHD-PAE. Similar effects were observed for the ratios GABA/Glu and GABA/Glx. For GABA+MMBL (GABA+) these effects were not seen, rather GABA+ and MMBL increased with age for the ADHD+PAE group only. No significant effects were found for Glu or Glx. Conclusions: GABA in the aMCC does not distinguish the two etiologies of ADHD, rather elevated GABA that follows an abnormal developmental appears to be common to both. High GABA may reflect increased inhibition of the aMCC impairing its cognitive functions. GABA+ results in ADHD may not tract reliably with underlying GABA values. Negative results for Glu and Glx should be reexamined at shorter echo-times.

In a single-blind randomized controlled trial, we investigated the effectiveness of real-time fMRI neurofeedback delivered in 7 runs over three sessions across two weeks in N = 65 patients with alcohol use disorder. The intervention targeted modulation of ventral striatal cue reactivity to alcohol-related cues as well as enhancement of prefrontal control mechanisms in the right inferior frontal gyrus. The study design incorporate three experimental groups that either were instructed to downregulate a ventral striatum signal, upregulate the right inferior frontal gyrus, or upregulate negative functional connectivity between these two structures. In two active control groups participants were instructed to either up- or downregulate the primary auditory cortex. We did not find an effect of ventral striatal downregulation or negative connectivity feedback, and a reduced striatal activation in the right inferior frontal gyrus upregulation group was accompanied by concurrent lower activation in the target structure, suggesting that our intended modulation approaches were not effective. Identified problems that might have contributed to this unexpected outcome might have been the use of continuous feedback presentation that potentially confuses regulation target and reward processing in the ventral striatum, counterintuitive regulation directions, a lack of explicit strategy guidance and transparency about the targeted process, and generally the difficulty to recruit a sufficient number of eligible voluntary participants for a well-powered study with a complex design. These insights emphasize the complex challenges of real-time fMRI neurofeedback interventions for the treatment of substance use disorders and could provide guidance for the development of more effective future approaches.

Aim: To determine whether the neural phenotype (whole-brain resting-state functional connectivity pattern) of attention deficit hyperactivity disorder associated with prenatal alcohol exposure (ADHD+PAE) differs from that in unexposed children with ADHD of probable familial origin (ADHD-PAE). Method: Resting-state functional MRI was acquired from 26 children with ADHD+PAE, 25 with ADHD-PAE, and 25 typically developing (TD) children, all aged 8-13 years. Mean connectivity matrices based on the Cole-Anticevic Brainwide Network Parcellation of the brain were compared between the groups. Results: Within the frontoparietal network (FPN), children with ADHD+PAE showed widespread lower group-mean connectivity than children with ADHD-PAE; effects were concentrated primarily in cerebellar-cerebral cortical and cerebral cortical-cerebral cortical connections. Children with ADHD-PAE showed widespread hyperconnectivity relative to TD children. Children with ADHD+PAE showed mixed hyper- and hypoconnectivity relative to TD. Interpretation: These results are consistent with other MRI findings indicating that ADHD+PAE is neurally distinct from ADHD-PAE; PAE may be associated with broadly reduced connectivity, especially across cerebellar-cerebral cortical systems.

Background: Prenatal substance exposure (PSE) occurs when an individual is exposed to substances in utero. PSEs may have lasting effects on mental health. We tested whether PSEs show threshold, cumulative, or individual substance associations with childhood psychiatric diagnoses. Methods: Clinical variables (demographics, ICD-9/10 diagnoses, PSE history) were extracted from electronic health records from the University of Minnesota Adoption Medicine Clinic. PSEs were identified from caregiver and child-protective-services narratives and/or toxicology (cord tissue/blood, meconium). For each ICD-9/10 diagnostic category, we fit logistic regression models comparing (1) exposure thresholds (0, 1, 2, 3, 4+ exposures), (2) a cumulative exposure count, and (3) individual substances to estimate marginal odds ratios (ORs) with 95% Confidence Intervals (CIs). Results: Psychiatric diagnoses increased with the number of PSEs. Relative to no exposure, odds of an Anxiety Disorder rose from OR 1.47 (95% CI 1.16-1.87) with one exposure to OR 2.03 (1.64-2.52) with >=4 exposures. Higher cumulative exposure scores were associated with Anxiety Disorders (OR 1.28, 1.18-1.38), Behavioral and Emotional Disorders (OR 1.42, 1.31-1.54), Substance Use Disorders (OR 1.52, 1.29-1.79), and Mood Disorders (OR 1.16, 1.04-1.30). Alcohol, tobacco, and marijuana exposures were associated with increased odds of at least one psychiatric diagnosis, and each substance showed at least one significant diagnostic cluster when modeled independently. Conclusion: Increasing numbers of PSEs were associated with higher odds of psychiatric diagnoses, with patterns varying by substance and outcome. These findings motivate research on exposure timing and combinations to support earlier identification and intervention for at-risk children.

Background: Cannabis use is highly prevalent among emerging adults (18-25 years), a developmental period marked by ongoing neurodevelopment and heightened risk for cannabis use disorder (CUD). Structural alterations in the orbitofrontal cortex (OFC) and medial prefrontal/anterior cingulate cortex (mPFC/ACC) have been linked to cannabis use, though findings remain inconsistent in directionality. To address this, we examined cortical thickness and surface area of the OFC and mPFC/ACC subregions using the high-resolution Glasser atlas, allowing for more granular characterization of associations with CUD severity. Method: One hundred eleven emerging adults (41% male, aged=20.6{+/-}1.1 years) reporting significant alcohol and/or cannabis use completed clinical assessments and structural MRI. The OFC and mPFC/ACC were segmented into seven and six subregions per hemisphere, respectively. Multiple linear regressions tested associations between cortical thickness or surface area and DSM-5 CUD symptom count, controlling for alcohol use and intracranial volume. Subregions surviving false discovery rate correction were examined in relation to depression, trauma-related symptoms, impulsivity, and cannabis use motives. Results: Greater CUD severity was associated with lower cortical surface area and greater cortical thickness in OFC and mPFC/ACC subregions. Lower OFC surface area was correlated with coping- and enhancement-related cannabis use motives. Lower mPFC/ACC surface area and greater thickness were associated with more severe depression, trauma-related symptoms, and impulsivity. Conclusion: In high-risk emerging adults, greater CUD symptom burden is associated with lower surface area and greater thickness in OFC and mPFC/ACC subregions. Using the high-resolution Glasser atlas, these findings provide a more precise characterization of structural correlates of CUD and highlight potential neurobiological markers linked to affective and motivational processes underlying cannabis use.

Background: Tobacco use is prevalent in clinical high risk for psychosis (CHR-P) population and has widespread negative health consequences, but understanding of its neural substrates is limited. Abnormal default mode network (DMN) may underlie tobacco dependence in CHR-P. We investigated how tobacco use relates to DMN connectivity and how CHR-P status impacts this relationship. Methods: We used baseline substance use and resting-state functional magnetic resonance imaging data from the North American Prodrome Longitudinal Study (NAPLS2; CHR-P: n=211, mean age 19.2, 37.9% female; healthy control: n=132, mean age 19.9, 47.7% female). Voxel-wise connectivity was calculated from the left lateral parietal (LLP) node of the DMN to the rest of the brain. We regressed LLP-brainwide connectivity against tobacco use frequency in the past month to generate a spatial map of how connectivity relates to current tobacco use. Results: Brainwide connectivity analysis identified two clusters in R hippocampus (peak voxel at MNI [+30,-12,-27]) and in L parahippocampus (peak voxel at MNI [-27,-27,-27]), where higher LLP-cluster connectivity was associated with more frequent tobacco use. LLP - R hippocampus connectivity was higher in current tobacco users compared to non-tobacco users (t=-3.5466, df=101.88, p=0.0006), and higher in CHR-P than controls (t=-2.8651, df=279.47, p=0.0049). Among current tobacco users, there was a significant tobacco-by-diagnosis interaction on LLP - R hippocampus connectivity (estimate=0.306, SE=0.149, t=2.051, p=0.045) such that heavier tobacco use predicted hyperconnectivity only in CHR. Conclusions: More frequent tobacco use was associated with higher DMN-hippocampal connectivity in both CHR-P and controls. CHR-P diagnosis enhanced this relationship.

Abstract Schizophrenia (SCZ) and bipolar disorder (BPD) are highly heritable psychiatric disorders with complex polygenic architectures. Genome-wide association studies (GWASs) have identified numerous common variant associations, but rarer variants detectable through whole-genome sequencing (WGS) remain underexplored. We conducted rare variant association analysis using WGS data from the Portuguese Island Collection (PIC), including 28 families with SCZ (n = 53) and 41 families with BPD (n = 83) cases, and population controls (n = 62). Following ANNOVAR and CADD annotation, burden analysis of deleterious variants showed that both affected and unaffected family members from SCZ and BPD pedigrees had significantly higher burdens of rare deleterious variants compared to controls (p < 0.0001), with no significant differences observed between affected and unaffected relatives, consistent with shared familial genetic liability. Polygenic Risk Score (PRS) analysis confirmed significant genetic contributions to both disorders within PIC. Association analyses were subsequently performed using SAIGE-GENE+ identifying 483 and 583 nominally significant (suggestive associations) gene sets (p-value [&le;] 0.05; FDR > 0.05) for SCZ and BPD, respectively, including gene sets related to neurotransmission, synaptic function and structure, neurodevelopment, and neuroinflammation as well as major signaling pathways. Cross disorder overlaps also identified shared suggestive enrichment of GABA and glutamate signaling, synaptic signaling, and Wnt signaling gene sets in both SCZ and BPD. These findings support shared rare variant burden within multiplex psychiatric families and highlight the role of gene-set based rare variant analysis in identifying neurobiological pathways relevant to SCZ and BPD. Keywords: WGS, Rare Variants, Schizophrenia, Bipolar Disorder

Background: Childhood adversity (CA) is recognized as a distal risk-factor for suicide attempts (SA) in individuals with psychiatric disorders. However, not all individuals with experiences of CA will engage in SA. Contributing to this relationship may be proximal factors such as impulsivity, inward anger and self-aggression. However, these factors are often conceptually blended and measured in different samples. We sought to clarify association among CA and personality factors in persons with SA. Methods: Participants from two studies comprised individuals with a diagnosed psychiatric disorder and history of SA (n= 139) and individuals with depressive disorder (clinical controls, CC; n= 24). We investigated self-reported levels of CA, impulsivity, inward anger, and self-aggression between the SA and CC (pcorr< .012). We tested the relationship among the factors using regression (pcorr<.017) and mediation model (indirect effects, p<.05) within the SA group. Sensitivity models were run controlling for age, gender, symptom severity, trait anger, and externally oriented aggression. Results: SA group had higher impulsivity (pcorr=.067) in a model controlled for age and gender. Other factors did not differ among groups. Within the SA group the analyses revealed positive association among CA and personality factors (pcorr<.06) in basic and model with age and gender, however the association was not specific for internally (self) oriented factors (coefficient comparison, p<.07). Parallel mediation model indicated that CA had indirect effect on self-aggression through impulsivity (p=.001) and to a lesser extent through inward anger (p=.066). Generally, models controlling for cognitive depression symptoms showed less prominent effects (pcorr>.1). Limitations: The study was cross-sectional and did not include behavioral tasks (state) measures of proximal factors. Conclusions: CA and personality factors showed similar severity levels among the SA and CC groups suggesting they may relate to broader psychopathologies, rather than specifically to SA. The association of CA with anger and aggression was unspecific to internally oriented factors indicating the need for more precise measuring instruments developed specifically for individuals with SA. Overall, the study highlights personality factors as being associated with risk in broader vulnerable populations.

Background: Attention Deficit Hyperactivity Disorder (ADHD) is characterized by persistent inattention, hyperactivity, and impulsivity. While documented in children, research on its persistence into young adulthood in Jordan remains scarce. This gap is critical given the cognitive demands of higher education. This study estimated attention deficit hyperactivity disorder (ADHD) symptom prevalence among Jordanian university students, examined associations with gender and academic performance, and identified barriers to mental health service accessibility. Methods: A descriptive cross-sectional study using web-based sampling recruited 389 university students (aged [&ge;] 18 years) from various Jordanian universities. Participants completed an online survey, incorporating the validated English and Arabic versions of the Adult ADHD Self-Report Scale (ASRS-v1.1) to assess symptom prevalence, alongside inquiries regarding demographics, academic history, and barriers to care. Results: The prevalence of probable ADHD was 37.5% (n=146). Males constituted a significantly higher proportion of positive cases (69.9%) compared to females (30.1%). A strong statistical association was found between positive ADHD screening and negative academic impact (p<0.001), as well as negative effects on emotional well-being (p<0.001). Comorbidities including anxiety disorders and emotional abuse were significantly linked to probable ADHD (p=0.019). Notably, positive-screened participants were significantly more likely to cite social stigma as a primary barrier to seeking professional help (p=0.024). Conclusion: Self-reported ADHD symptoms are highly prevalent among Jordanian university students, correlating with substantial academic underachievement and emotional dysfunction. These findings highlight an urgent need for targeted university-based screening programs, academic accommodations, and de-stigmatization campaigns to facilitate early intervention and improve educational outcomes in this population.

Background Treatment guidelines for borderline personality disorder (BPD) recommend assessment, diagnosis, and psychoeducation. We report on the feasibility and safety of a randomized controlled trial protocol of online psychoeducation, assessment, and personalized feedback as an immediate first step of care for BPD. Methods Newly diagnosed participants were randomized to receive 10 videos about BPD or general mental health for two weeks. Half the participants receiving BPD videos were randomized to receive personalized feedback on changes in symptom ratings and cognitive performance. Ecological momentary assessment (EMA) evaluated interpersonal interactions, emotions, and behaviors for 30 days. BPD symptoms, depression, and personality functioning were assessed at baseline, after videos, after feedback, and one month later. Results Eighty-two participants were randomized into three conditions that did not differ significantly in terms of demographics or baseline variables. Dropout occurred for 32.9% of the sample. No differences in rate of emergency room visits, hospitalizations, or other escalations in level of care were reported among groups. Satisfaction was higher for those receiving psychoeducational videos about BPD. Improvement in BPD knowledge in the psychoeducation conditions was significantly greater than the control condition. No statistically significant differences were found regarding reduction of BPD symptoms. The psychoeducation with feedback arm showed significantly greater improvements in self-impairment compared to controls with medium effect size at the final timepoint. Modeling of the relationship between time spent alone and BPD symptoms showed a positive correlation in the control condition, but in the group receiving both psychoeducation about BPD and feedback, this relationship was negative. Conclusion Online psychoeducational videos and assessment were safe, feasible, and acceptable to participants with newly diagnosed BPD. Psychoeducation with personalized feedback appears to be more effective than either BPD or general psychoeducation alone in improving deficits in self-functioning, which may relate to an increased capacity to be alone with fewer symptoms. The protocol was registered with ClinicalTrials.gov (NCT05358925, https://clinicaltrials.gov/study/NCT05358925) on April 28th, 2022.

Background: Adverse childhood experiences (ACEs) are traumatic or adverse events in early life that can have lasting effects on behavioral, emotional, and psychological functioning. Prior research suggests ACEs relate to later psychiatric outcomes through threshold, cumulative, and individual-specific risk patterns. Few studies, however, have operationalized all three models to test ACE-specific associations with diagnosed psychiatric disorders in individuals who are adopted or with foster care histories. Methods: We conducted a cross-sectional retrospective study using electronic health record data from foster care and adopted patients aged 0-21 years old seen at the University of Minnesota Adoption Medicine Clinic (UMN-AMC) between 2014-2024. Extracted measures included ACE history, demographics, and psychiatric diagnoses. We used latent class analysis and logistic regression to identify clusters of adversity and estimate associations with psychiatric diagnosis domains, adjusting for Sex and Age at Initial Visit. Results: ACEs showed a threshold pattern across psychiatric domains, with higher ACE counts associated with greater odds of psychiatric diagnoses. Individual risk modeling indicated that exposure to abuse or violence was associated with higher odds of psychiatric diagnoses. Across cumulative and individual risk approaches, Anxiety Disorders, Mood Disorders, and Behavioral or Emotional Disorders showed the greatest sensitivity to adversity. Conclusion: Current ACE models may not fully capture neurodevelopmental impacts reflected in diagnosed psychiatric disorders among adolescents, particularly in high-risk groups such as foster and adopted individuals. In a large clinic sample our findings support a nuanced association between ACEs and later psychiatric diagnoses and highlight the need for ACE-focused assessment, prevention, and treatment strategies tailored to foster care and adopted populations.

Background & Aims: Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) is the leading cause of chronic liver disease in children. However, accurate, noninvasive diagnostic tools remain limited. Current screening methods are invasive or lack sensitivity. Breath-based volatile organic compound (VOC) analysis offers a simple approach with potential for point of care screening. This study aimed to identify and validate breath VOC signatures of pediatric MASLD. Approach & Results: We conducted a prospective IRB approved cohort study at the Childrens Hospital of Philadelphia (CHOP). Children aged between 7 and 20 years with MASLD (n=22), as defined by hepatic steatosis either by liver biopsy or imaging and 1 cardiometabolic risk factor, and a control group without MASLD (n=20) were enrolled. Breath samples were collected using a standardized protocol and analyzed by untargeted comprehensive two-dimensional gas chromatography-mass spectrometry (GCGCMS). Machine learning and unsupervised clustering were applied to identify discriminatory VOCs and assess heterogeneity. Untargeted GCGCMS analysis identified a distinct breath VOC signature in children with MASLD compared with non MASLD controls. A Random Forest model achieved a sensitivity of 73% and specificity of 65%, with AUC of 0.84. The VOC 2,4-dimethyl-1-heptene demonstrated strong diagnostic performance in the discovery cohort with a sensitivity of 85%, specificity of 77% and an AUC of 0.81. Unsupervised clustering revealed four MASLD subgroups with distinct volatile phenotypes associated with differences in liver enzymes and metabolic parameters. External validation in a second pediatric cohort confirmed reproducible reductions in o/p-xylene in subjects with MASLD. Conclusions: Pediatric MASLD is associated with a reproducible breath VOC signature identified by untargeted GCGCMS. These findings support breath analysis as a scalable, noninvasive screening and stratification tool for pediatric MASLD and warrant validation in larger, longitudinal studies.

Forensic patients often have complex and costly healthcare needs, even following discharge from secure care. However, little is known about their health and justice outcomes after community reintegration. To address this gap in the literature, we conducted a systematic review and meta-analysis to estimate the incidence of key post-discharge outcomes among community-discharged forensic patients, including any reoffending, violent reoffending, reconvictions, readmissions, all-cause mortality, and suicide. We systematically searched PsycINFO, Embase, CINAHL, Medline, PubMed, and ProQuest Dissertations from database inception to May 2025 (PROSPERO CRD42024529265). Random-effect meta-analyses were used to generate pooled incidence estimates, with heterogeneity quantified using prediction intervals. A total of 49 studies met inclusion criteria (total patient n = 18,871) and contributed to the meta-analyses. The pooled incidence rate per 100,000 person-years was: any reoffending 3,889 (95% CI 2,055, 7,359; 95% PI 290, 52,136); violent reoffending 1,851 (95% CI 1,229, 2,789; 95% PI 201, 17,068); reconvictions 3,291 (95% CI 2,591, 4,179; 95% PI 950, 11,394); readmissions 7,945 (95% CI 5,507, 11,463; 95% PI 1,225, 51,548); all-cause mortality 1,789 (95% CI 1,341, 2,388; 95% PI 673, 4,756); and suicide 407 (95% CI 319, 519; 95% PI 225, 735). Overall, the reoffending rate for forensic patients discharged to the community was lower than that reported for other cohorts of people charged with general and violent offences. However, despite typically receiving long admission periods, discharged forensic patients continue to experience high rates of readmission, all-cause mortality, and suicide relative to other psychiatric patient groups in the community. Together, our findings highlight a need for enhanced post-discharge suicide support for forensic patients living in the community to better facilitate successful, long-term reintegration.

Background Preterm birth (PTB) rates among Hispanic/Latina individuals in the United States have risen over the past decade. Data suggests this rise may be driven in part by psychosocial stress. Leukocyte telomere length (LTL), a marker of cumulative cellular aging that shortens under chronic stress, may capture stress-related biological vulnerability, but has not been examined as a potential population-level contributor to PTB in Hispanic/Latina pregnancies. Objective To examine the association between mid-pregnancy maternal LTL and PTB in a population-based Hispanic/Latina cohort. Methods In a case-control study nested within a California singleton birth cohort (n = 436 Hispanic/Latina individuals; 215 PTB, 221 term births), LTL was measured by quantitative PCR from biobank specimens collected from 15 to 20 weeks of gestation. Covariates from linked birth certificate and hospital discharge records were included. Logistic regression estimated ORs and 95% CIs of PTB by LTL examined continuously and by percentile category (<=10th, 11th-89th, >=90th) with and without adjustment for covariates. Results Mean and median LTL did not differ between PTB and term births. LTL at or below the 10th percentile was associated with elevated odds of PTB relative to full-term birth (12.6% versus 4.3%; ORc = 3.2, 95% CI 1.3-7.9), persisting after partial (ORadj1 = 3.2, 95% CI 1.3-8.3) and full covariate adjustment (ORadj2 = 3.4, 95% CI 1.3-9.3). Subgroup analyses showed consistent directional patterns across PTB subgroups and for early term birth (ORadj2 = 5.1, 95% CI 1.5-17.0). Conclusions Mid-pregnancy maternal LTL <=10th percentile was associated with more than three times the odds of PTB, with risk concentrated at the extreme low tail of the distribution. Consistent with a cumulative allostatic load model, markedly short LTL at mid-gestation may reflect elevated stress-related biological risk for preterm delivery. These findings support upstream investment in stress reduction and prospective LTL research in high-burden populations.

Background and Aims: The North American overdose crisis is increasingly characterized by complex polysubstance use alongside a transition from injecting to smoking unregulated opioids. However, transitions involving multiple substances remain understudied. We characterized longitudinal transitions in the route of administration and frequency of heroin, fentanyl, and methamphetamine use and examined whether these transitions differed by multilevel factors hypothesized to influence patterns of polysubstance use and routes of administration over time. Design: People who inject drugs (PWID) enrolled in a cohort study completed baseline surveys (October 2020-2021) and three biannual follow-up visits (through April 2023). Setting: San Diego, California, and Tijuana, Baja California. Participants: Among 612 PWID, median age was 43 years; most were male (74%), Hispanic, Latino, or Mexican (72%), and San Diego residents (67%). Measurements: Based on past six-month substance use behaviors reported at each visit, we categorized participants according to six indicators over time: low- (< weekly) and high-frequency ([&ge;] weekly) smoking and injecting of heroin, fentanyl, and methamphetamine. We then used latent transition analysis (LTA) to identify distinct subgroups of participants with respect to these indicators at baseline and examine transitions between them over 18 months. We fit models with 2-5 subgroups, selecting the final model based on fit and interpretability and used multiple-groups LTA to examine differences in subgroup transitions by multilevel factors. Findings: We identified four subgroups: Subgroup 1 (Heroin-Methamphetamine Polyroute), characterized by high-frequency heroin and methamphetamine smoking and injection, included 22% of participants at baseline but 0% at 18 months. Subgroup 2 (Methamphetamine-dominant Smoking), characterized by high-frequency methamphetamine smoking, accounted for 14% of participants at baseline and 18 months. Subgroup 3 (Fentanyl-Methamphetamine Smoking), characterized by high-frequency fentanyl and methamphetamine smoking, included 4% of participants at baseline and 21% at 18 months. Subgroup 4 (Heroin-dominant Injecting), characterized by high-frequency heroin injection, included 61% of participants at baseline and 65% at 18 months. Participants in Subgroup 1 primarily transitioned to Subgroups 3 and 4 over time. Larger increases in Subgroup 3 prevalence occurred for participants who, at baseline, experienced homelessness, resided in San Diego (vs. Tijuana), received syringes from a syringe services program, and overdosed in the past six months. Conclusions: PWID in this region increasingly transitioned from high-frequency heroin and methamphetamine injection toward fentanyl and methamphetamine smoking, likely reflecting shifts in drug availability. Results highlight the need for multilevel interventions that address health harms resulting from polysubstance smoking alongside continued injection.

Background: Sleep debt and irregular sleep patterns are highly prevalent amongst adolescents. However, whether the absence of these sleep behaviours protects against subsequent depression remains unclear. Here, we examined the association of sleep debt, weekend catch-up sleep (WCS), and social jetlag (SJL) in adolescence with depression in young adulthood and identified underlying biopsychosocial mechanisms. Methods: Secondary data analyses were conducted using the Avon Longitudinal Study of Parents and Children. Bedtimes and wake-up times on school days and weekends (i.e., sleep duration) and sleep need were self-reported at 15 years. This was used to generate sleep debt (sleep need minus school day sleep duration), WCS (weekend sleep duration minus school day sleep duration), and SJL (absolute difference in the midpoint of sleep times between school days and weekends). Depression was assessed at 24 years with the Clinical Interview Schedule-Revised. Common mental health symptoms, biological, and school-related factors at 17 years were the mediators. Results: Logistic regression analyses revealed that greater WCS (adjusted odds ratio [AOR]=0.90; 95% CI=0.84-0.97; p=0.004) and lower sleep debt (AOR=1.10; 95% confidence interval [CI]=1.03-1.18; p=0.005) at age 15 reduced the likelihood of depression at 24 years. Irritability at 17 years partially mediated the relationship between sleep debt and depression (bias-corrected estimate=0.003; 95% CI=0.002-0.004; p<0.001). Conclusions: Adolescents who experience less sleep debt (i.e., less discrepancies between their actual sleep and their perceived sleep need) and those who extend their sleep duration on weekends are at reduced risk for depression in young adulthood. These findings underscore the need for greater opportunities for adolescents to obtain more hours of sleep to protect them against later poor mental health outcomes, such as depression. Keywords: Sleep; longitudinal studies; depression; ALSPAC

The Epic Sepsis Model version 2 (ESMv2) is a prediction model embedded into the electronic medical record used to warn clinicians which hospitalized patients are at risk for sepsis. We conducted a retrospective cohort study of 31,951 hospitalizations of 25,760 patients to compare analyses conducted at the commonly used patient-level (where a maximum prediction prior to the onset of sepsis is used to measure performance) vs novel prediction-level (where each prediction is used to measure performance). Sepsis, defined by the Sepsis 3 criteria occurred during 1,049 hospitalizations (3.3%). Patient-level analyses suggested excellent discrimination AUC 0.86; [IQR 0.85, 0.87], whereas prediction-level analyses demonstrated lower performance AUC 0.62; [IQR 0.57, 0.65]. Low estimates of the positive predictive value (14.5% at the patient level vs 4% at the prediction level) imply a high number of false alerts. Common evaluation approaches may overstate the performance of dynamic prediction models and mislead clinical decision-making.

Background Artificial intelligence-enhanced electrocardiography (AI-ECG) enables scalable, low-cost cardiac dysfunction screening, but existing models are annotation-intensive and predominantly adult-derived, leaving paediatric generalizability uncertain. Paediatric cohorts exhibit highly variable cardiac morphology and function compared to adults, which may be useful for learning generalizable AI-ECG models. Methods We pretrained ECG-Fyler on a predominantly paediatric, all-age cohort at Boston Children's Hospital (1992-2023), annotated with a cardiology-specific coding system (Fyler codes), and evaluated it on assessments from echocardiography (echo) and cardiac magnetic resonance (CMR) studies. We validated on an external adult cohort from Columbia University Irving Medical Center. Performance was benchmarked against several AI-ECG foundation models by AUROC across age groups, lesion types, and limited-data scenarios. Findings The pretraining cohort comprised 782,138 ECGs from 255,271 patients (median age: 10.9 years, IQR: [2.8-16.8]). Internal evaluation included 178,495 ECG-echo pairs (median age: 10.9 [3.7-17.0]) and 8,584 ECG-CMR pairs (median age: 20.7 [15.6-29.6]). External validation included 82,543 ECG-echo pairs from adults (median age: 64.0 [52.0-74.0]). ECG-Fyler improved AUROC across biventricular dysfunction and dilation tasks, with the largest gains in low-data settings. In internal validation, ECG-Fyler detected low left ventricular ejection fraction (LVEF [&le;] 40%) from only 100 fine-tuning samples (AUROC: 0.80, 95% CI: [0.78-0.80]), outperforming other models (AUROC < 0.65) and improving with additional fine-tuning (AUROC: 0.94 [0.93-0.94]). Similar improvements were observed for CMR-derived LVEF, RVEF, and ventricular dilation. In external validation on adults, ECG-Fyler exhibited an AUROC of 0.83 (CI: [0.82-0.85]) for LVEF [&le;] 40%. After fine-tuning on less than 10% of external data, LVEF [&le;] 45% performance (AUROC: 0.87 [0.86-0.88]) outperformed a fully trained, site-specific prior model (AUROC: 0.85 [0.84-0.87]). Interpretation Pretraining on richly annotated, paediatric-dominant ECGs yields models that transfer efficiently across institutions and ages, supporting AI-ECG screening and triage when labels or imaging access are limited. Funding National Institutes of Health (R01LM012973); Kostin Innovation Fund, Boston Children's Hospital

ABSTRACT OBJECTIVE: We performed a systematic review and meta-analysis (SRMA) of post-surgical outcomes, comparing chlorhexidine gluconate (CHG) versus povidone iodine (PI) for vaginal antisepsis of major gynecologic procedures. DATA SOURCES: Ovid Medline, Embase, Scopus, Embase, Cochrane, and Clinicaltrials.gov were searched between 1986 and December 2023, for studies comparing CHG with PI for vaginal antisepsis of major gynecologic operations. STUDY ELIGIBILITY CRITERIA: We included Randomized Controlled Trials (RCTs) and non-RCTs comparing CHG to PI for vaginal antisepsis of major gynecologic operations. The primary outcome was surgical site infections (SSIs) and the secondary outcome was urinary tract infections (UTIs) and vaginal irritation. METHODS: Summary estimates were calculated by fixed effects models when I2 [&le;] 25% and by random effects models when I2 > 25%. Statistical analysis was performed using RevMan 5.4.1. The protocol for this systematic review was registered on PROSPERO (ID CRD42022378101). RESULTS: Nine studies met the inclusion criteria, four of which were randomized controlled trials (RCTs). 9538 patients were included, 4300 (45%) of whom were allocated to CHG and 5238 (55%) to PI. No statistically significant difference in SSI incidence was found for vaginal antisepsis with CHG versus PI in pooled analyses (n= 9538 patients; RR 1.20; 95% CI 0.92-1.57; I2 =0%). In contrast, a significantly higher risk of UTIs was observed for vaginal antisepsis with CHG than with PI (n=6061 patients; RR 1.48 95% CI 1.03-2.14; I2 = 0%). CONCLUSION: In our SRMA, there were no significant differences in SSI risk when either CHG or PI was utilized for antiseptic vaginal preparation. Interestingly, vaginal antisepsis with PI was associated with a lower incidence of post-operative UTIs following major gynecologic surgery. Our findings support current guidelines that form of vaginal antisepsis can be used for SSI prevention. They also suggest that PI may result in fewer postoperative UTIs but further randomized studies are needed to support these findings. Key words: surgical site infection, surgical wound infection, urinary tract infection, urogynecologic surgery, Chlorhexidine, Povidone Iodine, surgical antiseptic,

Background: Frontotemporal dementia (FTD) lacks widely accessible disease-specific biomarkers. Optical coherence tomography (OCT) and OCT angiography (OCTA) may provide non-invasive measures of retinal changes associated with neurodegeneration. We conducted a systematic review and meta-analysis evaluating retinal biomarkers in FTD compared with Alzheimer disease (AD) and controls. Methods: A systematic search of PubMed and Embase was conducted through April 25, 2026 according to PRISMA guidelines. Studies evaluating OCT/OCTA biomarkers in FTD with comparator groups were included. Inverse weighted random-effects models, publication bias assessments, and meta-regressions were performed. Results: Ten studies involving 139 individuals with FTD, 87 with AD, 29 with mild cognitive impairment, 14 with TDP-43 proteinopathy, 5 with tauopathy, and 255 controls were included in the systematic review; five studies were eligible for meta-analysis. Compared with AD, individuals with FTD demonstrated significantly thinner retinal nerve fiber layer (RNFL) thickness (SMD = -0.61, 95% CI -0.98, -0.24). Compared with controls, individuals with FTD exhibited significantly thinner ganglion cell layer-inner plexiform layer (GCL-IPL) thickness (SMD = -0.55, 95% CI -1.02, -0.08), whereas pooled analyses across multiple retinal biomarkers were non-significant (SMD = -0.19, 95% CI -0.52, 0.14). RNFL thickness correlated negatively with female % in FTD and positively with age in both AD and controls. Conclusions: Individuals with FTD exhibit lower RNFL thickness than AD and lower GCL-IPL thickness than controls, suggesting retinal alterations may reflect neurodegeneration. However, larger longitudinal studies with standardized OCT/OCTA protocols are needed to determine the diagnostic and prognostic utility of retinal biomarkers in FTD