Drug and Alcohol Dependence

Objectives: Non-suicidal self-injury (NSSI) and self-harming sexual behaviours share functional and behavioural overlaps. However, the relationship between NSSI and problematic sexual behaviour (PSB) remains underexplored. This study aimed to investigate the association between NSSI and PSB in two cohorts - a non-clinical university cohort and a clinical PSB patient cohort. Methods: Data were collected from 2,189 university participants and 477 clinical PSB patients. NSSI was assessed via self-report, and PSB was measured with the Sexual Addiction Screening Test-Revised (SAST-R) Core. The four core addictive dimensions of PSB: relationship disturbance, loss of control, preoccupation, and affect disturbance, were also evaluated. Logistic regression analyses were conducted to examine the association between PSB (presence/absence and severity) and NSSI, looking at effects of gender and contributions of addictive dimensions of PSB. Results: Rates of NSSI were similar in the university (7.1%) and patient (5.7%) cohorts; stratified by gender, a higher proportion of women PSB patients had NSSI compared to in the university cohort (29.3% vs 9.3%). In the university group, who had milder PSB than patients, PSB was associated with NSSI (OR=2.11, p<0.001); a significant gender by PSB interaction was found showing that women with PSB were over four times more likely to have NSSI than men without PSB (OR=4.44, p=0.037). In contrast, PSB severity was not associated with NSSI in PSB patients (OR=1.10, p=0.25). Associations of the addictive dimensions of PSB with NSSI were observed only in the subgroup of university women, in the 'preoccupation' dimension (p<0.001). Conclusions: Our findings highlight gender-specific patterns in the association between PSB and NSSI, suggesting the need for further research and possibly targeted prevention and intervention strategies in women.

Regular cannabis use has been associated with alterations in reward-related neural processes, yet findings remain inconsistent and the relationship between neural activity and behavioural performance is not fully understood. The present study aimed to characterise neural and behavioural correlates of reward processing in regular cannabis users (CU) compared with matched non-users (NU) using the Monetary Incentive Delay Task (MIDT). Firstly, we assessed behavioural performance through reaction times, accuracy and monetary earnings to determine whether potential neural alterations were reflected in task performance. Secondly, focusing on reward-related brain regions, we examined group differences in BOLD functional MRI activity during anticipation and outcome phases separately for monetary win and loss conditions. Finally, we explored the association between behavioural performance and neural activation. Our findings indicate that regular cannabis use is associated with altered engagement of key nodes within the mesocorticolimbic circuit during both anticipatory and outcome phases of reward processing, accompanied by impaired behavioural performance. Particularly, compared with NU, CU showed (I) lower striatal activity during anticipation of monetary win and higher ventral striatum and frontal pole activity during anticipation of monetary loss; (II) greater VTA activation during outcome of successful monetary win and loss avoidance and lower frontal pole activity during outcome of unsuccessful loss avoidance; (III) impaired behavioural performance, reflected in lower monetary rewards and a trend towards slower reaction times and reduced accuracy; (IV) disrupted brain-behaviour coupling. Results from this study may help inform future research on the neurobiological mechanisms underlying changes in reward function and the resultant behavioural consequences of cannabis use.

Substance use disorders run in families, yet the mechanisms underlying intergenerational transmission remain unclear. We investigated indirect genetic effects, pathways through which parental genotypes influence offspring phenotypes via the family environment, for alcohol use disorder (AUD), nicotine dependence (ND), and related quantitative outcomes, and aimed to identify family environmental factors through which such effects may operate. Using transmitted and non-transmitted polygenic scores (PGS) constructed for problematic alcohol use, tobacco use disorder, and general addiction liability, we analyzed 5972 European-ancestry adult offspring with at least one genotyped parent from the population-based Lifelines cohort (Netherlands). Offspring outcomes included lifetime DSM-5 AUD diagnosis, AUD symptom count, maximum drinks in 24 hours, Fagerstrom Test for Nicotine Dependence score, and cigarettes per day. AUD findings were meta-analyzed with data from the Brisbane Longitudinal Twin Study (N = 1368; Australia). We also examined parent-of-origin effects and mediation by parental substance use and socioeconomic status using structural equation modeling. Transmitted PGS robustly predicted all AUD and ND outcomes ({beta} = 0.07-0.16; OR = 1.20 for AUD diagnosis). Non-transmitted PGS, indexing indirect genetic effects, were negligible for all clinical syndrome outcomes. The only significant indirect genetic effect was on cigarettes per day ({beta} = 0.03, p = 0.01), mediated by parental smoking behavior but not socioeconomic status. These findings indicate that intergenerational transmission of risk for AUD and ND is driven primarily by direct genetic effects, with modest indirect genetic effects on smoking quantity. Larger samples and cross-trait analyses are needed to further elucidate these mechanisms.

Chronic pain and nicotine use frequently co-occur, and individuals with chronic pain often experience greater difficulty quitting. Therefore, we examined nicotine withdrawal behaviors and analgesic-like effects in pain-naive and chronic pain conditions. Adult male and female rats underwent chronic constriction injury or sham surgery. After pain establishment, rats received twice-daily subcutaneous nicotine (0.3 or 0.7 mg/kg) or saline for 14 days. 24 h after the final injection, withdrawal was assessed, including physical signs and anxiety-like behavior. Depressive-like responses were evaluated at 72 h. Pain sensitivity and nicotines analgesic-like effects were assessed throughout. Chronic pain increased physical signs of withdrawal in both sexes, with greater effects in females. It also induced anxiety-like behavior in controls of both sexes. In rats with comorbid chronic pain and withdrawal, anxiety-like behavior was further enhanced in males, whereas females showed variable responses across assays, with increases or decreases depending on the test. Chronic pain induced depressive-like behavior in males but not in females. During withdrawal, depressive-like responses in males with chronic pain were not greater than those in the chronic pain alone group, while chronic nicotine exposure reduced depressive-like behavior in females. Nicotine produced acute analgesic-like effects that diminished over time in both pain-naive and chronic pain conditions, indicating tolerance. In pain-naive rats, repeated nicotine exposure induced mechanical hypersensitivity. Chronic pain intensified nicotine withdrawal severity in a nicotine concentration- and sex-dependent manner. These findings highlight the importance of considering pain status and sex when developing effective cessation strategies, particularly for individuals with comorbid chronic pain. SummaryChronic pain exacerbates nicotine withdrawal severity. Chronic nicotine exposure induces pain hypersensitivity and tolerance to analgesic effects. These effects vary by nicotine concentration and sex.

Sweetened alcoholic beverages are thought to contribute to developing Alcohol Use Disorder by increasing palatability. One monosaccharide, glucose, readily enters the brain more than fructose and directly impacts the activity of central neurons. The objective of this study is to determine the impact of glucose versus fructose on alcohol drinking patterns in female and male rats. Rats drank alcohol cocktails (1.25%-10%) containing either glucose or fructose (10%) in 4-hour sessions. We sought to parse orosensory effects from post-ingestive central effects by analyzing drinking microstructure. We compared measures of palatability and post-ingestive feedback between early and later in the session when brain levels of alcohol and glucose are different. We found that rats of both sexes drank more low alcohol glucose cocktails than cocktails containing fructose by volume and by overall calories. When considering the dose of alcohol, glucose potentiated alcohol intake by shifting the dose-response curve leftward compared to similar fructose cocktails. We found that drinking patterns associated with palatability remained stable for both types of cocktails over the entire drinking session. In contrast, post-ingestive behavior related to brain mediated satiety or positive feedback showed a greater influence of the session time, as well as a greater interaction with sex. Overall, our results suggest that glucose and alcohol interact to impact central regulation of cocktail drinking. This highlights that the type of sugar within cocktails interacts and ultimately have different effects on brain regulated alcohol drinking.

Drug overdose deaths in the United States reached record levels during the fentanyl era before recently declining. A plausible hypothesis is that a sudden drop in fentanyl purity beginning in 2023 caused the downturn in overdose mortality. We evaluated this hypothesis by replicating a published analysis with regional overdose data, using models that account for time trends and autocorrelation, and negative control indicators to test for spurious correlation. When fentanyl purity was rising, the national purity series did not track overdose increases in most regions and showed only a modest association in the West. When both purity and mortality later declined, the observed associations were also seen with unrelated macroeconomic indicators that shared the same time pattern. National fentanyl purity alone does not provide a sufficient explanation for recent overdose declines.

BackgroundPractical alcohol risk-reduction strategies are widely recommended in public-facing alcohol guidance, but randomized evidence from socially interactive drinking episodes remains limited. We conducted a pilot cluster randomized trial to evaluate the feasibility and preliminary effects of a package intervention comprising practical drinking-strategy information, participant self-selection of same-day strategies, and a brief commitment declaration in a social drinking laboratory. MethodsThis single-center, parallel-group pilot trial was conducted in Japan. Pre-existing social groups participated. One or two groups scheduled in the same session slot were combined into a time-slot allocation unit, which was randomized 1:1 either to the package intervention or to alcohol-related knowledge only. The primary outcome was total pure alcohol intake during the first 120 min. Session satisfaction on a Visual Analog Scale (VAS) was a prespecified secondary participant-experience outcome. ResultsOf 83 interested individuals, 63 were randomized and 59 participants in 17 social groups and 12 allocation units were included in the modified intention-to-treat analysis. The mean paired intervention-control difference for 120-min alcohol intake was-8.84 g (95% confidence interval [CI]-27.92 to 10.23; exact sign-flip p = 0.281). The corresponding exploratory 0-30 min difference was-4.90 g (95% CI-10.48 to 0.68; exact sign-flip p = 0.094). In a genotype-adjusted participant-level sensitivity analysis, the intervention coefficient for 120-min intake was-16.0 g (95% CI-30.9 to-1.1; p = 0.036). Session satisfaction was high in both arms with no clear between-arm difference. Next-day follow-up was 100%, and no adverse-event-related discontinuations occurred. ConclusionsThe intervention was feasible to deliver in a socially interactive drinking setting, and session satisfaction was high in both arms. Primary allocation-unit estimates favored lower alcohol intake but were imprecise. Larger trials are needed to estimate effects more precisely, while considering the potential influence of genotype imbalance on effect estimation in East Asian samples. Trial registrationUniversity Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) UMIN000060685. Registered 17 February 2026.

Background: Substance use disorders (SUDs), including alcohol and drug dependence, and smoking, pose a public health threat with their high prevalence and comorbidity with other diseases, and contribution to mortality. SUDs are highly correlated, and their genetic background is shared to some degree. Objectives: We aimed to investigate the genetic associations of previously reported loci for a wide range of SUDs in an unstudied Ukrainian population. Methods: We collected data from 595 individuals (339 women, 253 men), including 321 participants from two rehab centres. Based on clinical review and questionnaire data we defined drug dependence, alcohol dependence, alcohol abuse, binge drinking, smoking, opiate, amphetamine, cannabis, and hallucinogen use, along with several intermediary alcohol use and smoking variables considering the amount of use and the level of dependence. We genotyped COMT-rs4680, ADH1B-ADH1C-rs1789891, and HTR2A-rs6313, and applied logistic and ordered logistic regression assuming an additive inheritance model, controlling for the recruitment group, other substance uses, age, and sex, in the association analyses. Results: We replicate (P<0.05) the associations at COMT-rs4680 with smoking status (OR[95% CI]=1.56[1.01-2.41], P=0.047) and heaviness (1.37[1.04-1.80], P=0.026), and at ADH1B-ADH1C-rs1789891 and HTR2A-rs6313 with alcohol dependence (1.69[1.03-2.76], P=0.038 and 0.66[0.47-0.92, P=0.016], respectively). Furthermore, we provide evidence for an association at HTR2A-rs6313 with hallucinogen use (0.58[0.35-0.98], P=0.040). Conclusion: In this study on multiple SUDs we shed light on the genetic background of SUDs in Ukrainians and provide further evidence that variation at COMT is mainly associated with smoking, at ADH1B-ADH1C with alcohol-related variables, whereas HTR2A is a more general SUD-associated locus.

Background: Lung cancer screening can reduce lung cancer mortality through early detection, but uptake of the NHS Targeted Lung Health Check (TLHC) programme remains low. Behaviourally informed invitation messages have been proposed as a low-cost approach to increase attendance, but evidence of their effectiveness in lung cancer screening is mixed. Few intervention studies used evidence-based behaviour change frameworks, and rarely tailored invitation strategies to empirically identified barriers and enablers. Methods: In an online experiment, 3,274 adults aged 55-74 years and with a history of smoking were randomised to see one of four behaviourally informed invitation messages or a control message. Participants then rated their intention to attend a TLHC appointment, and selected barriers and enablers to attending from a pre-defined list, which were classified according to the Theoretical Domains Framework. Invitation messages were mapped to Behaviour Change Techniques using the Theory and Techniques Tool. Message conditions were compared on intention to attend TLHC using bootstrapped ANOVA followed by pairwise comparisons. Exploratory counterfactual mediation analyses examined the role of fear in intention to attend. Results: Behaviourally informed invitation messages did not meaningfully increase intention to attend TLHC compared with the control message. While a GP-endorsed message showed a small potential benefit relative to the other conditions, this finding was not robust after adjustment for multiple comparisons. Participants most frequently reported barriers related to Emotion (particularly fear), Social Influence, and Knowledge, while Beliefs about Consequences emerged as the primary enabler of attendance. Only around half of reported barriers and enablers were addressed by the invitation messages. Exploratory analyses found that fear was associated with lower intention to attend a TLHC appointment, yet none of the behaviourally informed messages appeared to reduce fear compared to the control message. Conclusions: Improving lung cancer screening uptake will likely require invitation messages that directly address emotional concerns, particularly fear, alongside credible recommendations. These findings highlight the importance of systematically aligning invitation message content with empirically identified behavioural influences when designing scalable interventions to improve lung cancer screening uptake.

BackgroundPsilocybin is a classic psychedelic that acutely alters brain functional connectivity. These changes are linked to therapeutic doses and subjective effects, with some evidence that changes persist beyond acute drug administration. However, the effects of lower doses on sustained connectivity changes remain unclear. MethodsTen healthy volunteers received three psilocybin doses (between 5 and 20 mg) in a randomized and blinded order, with at least one week between doses. Resting-state functional magnetic resonance imaging was completed at baseline and one week after a single dose. Functional connectivity changes were analyzed in relation to dose and altered conscious states at both the level of individual brain region connections (edges) and resting-state networks. ResultsDose-dependent changes in 77 edges (76 increases, 1 decrease, of 1275 possible) were observed, but none survived multiple-comparison correction. At the network level, we observed one dose-dependent between-network increase (of 21 possible), and one dose-dependent within-network increase (of seven possible); the latter surviving correction. Alterations in conscious state were positively associated with widespread connectivity changes (dose-adjusted), with many network-level associations surviving correction. These directional patterns showed that lower doses and smaller conscious state alterations were linked to decreased connectivity, whereas higher doses and greater conscious state alterations were linked to increased connectivity. ConclusionsDose level and acute subjective effects were positively associated with multiple functional connectivity changes one week after a low-to-moderate psilocybin dose. Further research is warranted to characterize these sustained effects and their therapeutic relevance to inform studies adopting similar dosing regimens in clinical cohorts. Trial RegistrationAustralian New Zealand Clinical Trials Registry: ACTRN12621000560897 Date registered: 12 May 2021 URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381526&isReview=true

Abstract Importance Stigma and discrimination against transgender and gender-diverse people are prevalent across many settings and may contribute to substantial health disparities. Objective To synthesize global evidence on the prevalence of stigma, discrimination, and resilience among transgender (trans) and gender-diverse adults. Data Sources A systematic search was conducted in PubMed, Embase, CINAHL, Cochrane Central, LILACS, and PsycInfo for articles published between January 1, 2010 and January 2, 2023. This database search was supplemented by grey literature and secondary reference searches. Article Selection Studies were eligible if they presented primary quantitative data on prevalence of stigma, discrimination, and/or resilience among trans and gender-diverse adults (aged 18 and over), with no restrictions on study design, language, or geographic region. Data Extraction and Synthesis Two independent reviewers extracted data using standardized forms, with discrepancies resolved by consensus. The JBI Critical Appraisal Checklist for Prevalence Articles was used to assess risk of bias. Random effects meta-analysis was conducted for dichotomous prevalence measures using inverse variance weighting and logit transformation; non-dichotomous prevalence data were summarized descriptively. Main Outcomes and Measures Outcomes included prevalence estimates for various forms of stigma (anticipated, perceived, internalized, and experienced), discrimination in legal/institutional settings (housing, healthcare, employment, police/prison), and resilience. Results A total of 97 articles, with data from 72,158 unique trans and gender-diverse participants across 26 countries, met inclusion criteria. Studies showed moderate levels of anticipated stigma, perceived stigma, and internalized stigma. Meta-analyses of 36 studies provided pooled estimates of discrimination prevalence across multiple domains: 21.4% in housing (e.g., eviction, rental denial), 24.6% in healthcare (e.g., denial of care, mistreatment), 32.8% in employment (e.g., hiring bias, workplace harassment), and 39.1% in police/prison settings (e.g., profiling, mistreatment). High heterogeneity was observed across studies, reflecting regional and methodological differences. Resilience scores ranged from moderate to high, indicating variation within trans and gender-diverse communities. Conclusions and Relevance This systematic review and meta-analysis found that stigma and discrimination against trans and gender-diverse adults are pervasive globally. Variation in stigma and discrimination across settings and regions underscores the need for targeted interventions and policy reforms. Funding World Health Organization through a grant from the Elton John AIDS Foundation and the Bill and Melinda Gates Foundation.

Objectives: The primary aim of this study was to assess the feasibility of delivering an adapted problem-solving skills (PSS) intervention by quantifying the recruitment, follow-up and completion rates using a brief problem-solving intervention for people with a mental health diagnosis in two Polish prisons. Design: IAPPS is an open, multi-centred, parallel group feasibility randomised controlled trial (RCT). Setting: Two prisons in Poland. Participants: Men in custody aged 18 years and older, having a mental illness and living within the prison therapeutic unit. Interventions: The intervention consisted of an adapted PSS skills intervention plus care as usual (CAU) or care as usual only. Delivered in groups of up to five people in 1.5-hour sessions over the course of two weeks. Main outcome measures: Primary outcomes - rate of recruitment, follow-up, and feasibility to deliver the intervention. Secondary outcomes included measures of depression, general mental health, and coping strategies. Results: 129 male prisoners were screened, 64 were randomly allocated, with a mean age of 53.5 years (SD 14, range 23-84). 59 (95%) prisoners were of Polish origin. Our recruitment rate was 48%. There was differential follow up with those in the intervention group less likely to complete the post-test battery versus those who received care as usual. Outcome measures were successfully collected at both time points. Conclusions We were able to recruit, retain and deliver the intervention within the prison setting; some logistical challenges limited our assessment of intervention engagement. Our data helps to demonstrate how use of the RCT study design can be implemented and delivered within the complex prison environment. Trial registration number ISRCTN 70138247, protocol registration date May 2021

BackgroundThe severity of positive psychotic symptoms largely defines emerging psychosis syndromes. However, depressive and negative symptoms are strongly psychologically and biologically interlinked. A transdiagnostic exploration of symptom severity across early illness syndromes could enhance the understanding of shared common factors and future trajectories of mental illness. We aimed to identify subgroups based on the severity of positive, negative, and depressive symptoms and assess relationships with: 1) premorbid functioning, 2) longitudinal illness course, 3) genetic risk, and 4) brain volume differences. MethodsWe analysed 749 participants from a multisite, naturalistic, longitudinal (18 months) cohort study of: clinical high risk for psychosis (n=147), recent onset psychosis (n=161), and healthy controls (n=286), and recent onset depression (n=155). Participants were stratified into subgroups based on severity of baseline positive, negative, and depression symptoms. Baseline and longitudinal differences between groups for clinical, functioning, and polygenic risk scores (schizophrenia, depression, cross-disorder) were assessed with ANOVAs and linear mixed models. Voxel-based morphometry was used to examine whole-brain grey matter volume differences. Discovery findings were replicated in a held-out sample (n=610). ResultsParticipants were stratified into no (n=241), mild (n=50), moderate (n=182), and severe symptom (n=254) subgroups. The mean (SD) age was 25.3 (6.0) and 344 (47.3%) were male. Symptom severity was associated with poorer premorbid functioning and illness trajectory, greater genetic risk, and lower brain volume. Findings were not confounded by the original study groups or symptoms and were largely replicated. Conclusions and relevanceTransdiagnostic symptom severity is linked to shared aetiologies, prognoses, and biological markers across diagnoses and illness stages. Such commonalities could guide therapeutic selection and future research aiming to detect unique contributions to specific psychopathologies.

ImportanceBlood-based biomarkers hold promise for psychiatric diagnosis and prognosis, yet clinical translation is constrained by poor reproducibility. Psychiatric biomarker studies are typically small, and demographic, behavioral, and temporal covariates often go undetected or cannot be adequately modeled. This may lead to residual confounding and unstable associations. ObservationsLeveraging UK Biobank data (N=~500,000), we systematically quantified how technical, demographic, behavioral, and temporal covariates influence 29 blood biomarkers commonly measured in research studies in psychiatry. Variance analyses showed substantial differences across biomarkers. Technical factors explained 1-6% and demographic factors explained 5-15% of the variance, with pronounced age-by-sex interactions for lipids and sex hormones. Behavioral covariates, particularly body mass index (BMI) and smoking, strongly influenced inflammatory markers. Temporal factors introduced systematic confounding. Chronotype was associated with blood collection time, multiple biomarkers exhibited marked diurnal rhythms (including testosterone, triglycerides, and immune markers), and inflammatory markers showed seasonal peaks in winter. In association analysis of biomarkers with major depression, bipolar disorder and schizophrenia, covariate adjustments attenuated or eliminated a substantial proportion of the biomarker-disorder associations, with BMI emerging as the dominant confounder. These findings demonstrate that such confounding structures exist and can be characterized in large cohorts, though specific biomarker-disorder relationships require validation in clinical samples. Conclusions and RelevancePoor reproducibility of biomarkers may not only stem from insufficient biological signal but also from inconsistent handling of confounders. We propose a systematic framework distinguishing technical factors (to be removed), demographic factors (addressed through adjustment or stratification), temporal factors (ideally controlled at design stages), and behavioral factors (requiring explicit causal reasoning). Associations robust to multiple adjustment strategies should be prioritized for clinical biomarker development. Standardized collection protocols, comprehensive covariate measurement, and transparent reporting across models are essential to improve reproducibility and identify biomarkers that reflect genuine illness-related pathophysiology.

Objectives: In Latin America, up-to-date information to monitor UNAIDS 95-95-95 HIV targets in key populations, such as men who have sex with men, is limited. Elsewhere, structural homophobia restricts access to ART. Conceptual frameworks suggest that intersecting forms of violence and discrimination may negatively influence HIV care outcomes through psychosocial and structural pathways, although empirical evidence remains limited. The study aimed to assess whether sexual orientation outness and recent homophobic violence are associated with not being on ART among Latin American MSM living with HIV. Methods: This cross-sectional study is a secondary analysis of data from LAMIS-2018, including 7,609 MSM aged 18+ with an HIV diagnosis [&ge;]1 year prior from 18 Latin American countries. Participants self-reported ART status, sociodemographic characteristics, homophobic violence, and sexual orientation outness. Bivariate and multivariate logistic regressions identified those factors associated with not being on ART. Results: Nine percent of MSM with HIV were not on ART, 18% reported low sexual orientation outness, and 27% experienced homophobic violence, especially in Andean and Central American countries. Not being on ART was associated with recent homophobic violence (aPR=1.25), low outness (aPR=1.22), unemployment (aPR=1.27), and residence in the Andean subregion (aPR=1.87), Mexico (aPR=1.28), or the Southern Cone (aPR=1.45) versus Brazil. Protective factors included being older (25-39: aPR=0.72; >39: aPR=0.49), living in large cities (aPR=0.72), having a stable partner (aPR=0.78), and university education (aPR=0.74). Conclusions: Recent homophobic violence and low sexual orientation outness were associated with not being on ART among MSM in Latin America. While access varies across countries, structural factors such as stigma and violence may limit engagement in care. Addressing these barriers alongside strengthening health systems may be key to improving ART uptake and advancing progress toward the 95-95-95 targets.

There is a dearth of information on how different cocktails sweetened with different sugars impact brain activity. Glucose enters the brain faster and in greater concentration than fructose and directly affects neuronal activity of melanin-concentrating hormone (MCH) neurons. MCH signaling promotes both glucose drinking and alcohol intake by integrating central and sensory inputs, but it is currently unknown how MCH neuronal activity relates to sweetened cocktail drinking. This study sought to investigate the relationship between MCH activity and sugar-sweetened alcoholic cocktail drinking. We also sought to compare MCH neuronal responses to the sugar solutions without alcohol as well as their response to sensory stimuli. In female and male rats, we used fiber photometry to monitor MCH neurons in response to sensory stimuli and during drinking of 10% glucose, 10% fructose, and glucose or fructose cocktails with 1.25% or 10% alcohol. We found that MCH activity rises in response to a variety of sensory stimuli and peaks before the start of drinking for all cocktails, before returning to baseline near the start of drinking. The cocktail type impacted the dynamics of MCH activity, where increased alcohol concentration resulted in earlier MCH activity for fructose but not glucose cocktails. Finally, we found that peak MCH activity during drinking is correlated with approach behavior for all sugar and cocktail types. These findings suggest that glucose and alcohol may interact to directly influence MCH activity. Further, MCH neurons may regulate cocktail drinking in response to sugar type and alcohol concentration. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/719280v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@b992c3org.highwire.dtl.DTLVardef@1526895org.highwire.dtl.DTLVardef@1504c6dorg.highwire.dtl.DTLVardef@c990fc_HPS_FORMAT_FIGEXP M_FIG C_FIG New and noteworthyFiber photometry was used to monitor lateral hypothalamic melanin-concentrating hormone (MCH) neurons in male and female rats during sensory stimuli and drinking of glucose, fructose, or glucose- or fructose-sweetened alcoholic cocktails. Subsecond-scale changes in MCH activity occurred after stimuli. Peak MCH activity during drinking was correlated with approach behavior. Alcohol concentration only impacted MCH activity with fructose cocktails. We discuss the implications of MCH dynamics towards brain function, associative learning, and alcohol use disorder.

Introduction Understanding provider preferences for the design of HIV treatment packages could enhance the implementation of programs to support the adoption of long-acting injectable antiretroviral therapy (LAI ART) by people living with HIV who are interested in initiating this treatment modality. Methods We recruited providers from New York City (NYC), Rockland, Putman, and Westchester County Ryan White Part A Medical Case Management (MCM) programs to complete a discrete choice experiment (DCE) containing twelve tasks with two alternatives and an opt-out option, with additional survey questions about implementation readiness and choice motivations. The alternatives included four attributes--Type of ART Medication (monthly or bimonthly LAI ART), Service Location and Mode, Support for Clients, and Rewards for Clients--with 2-4 levels each. We ran latent class multinomial logit analyses (LCA) with 1-5 classes to estimate preferences and explore hypothesis-free preference heterogeneity. We estimated attribute influence using relative importances and preferences using zero-centered part-worth utilities for each level. Results One hundred seventy-seven providers completed the survey (July 2022-January 2023). About half (52%) were 40-59 years old, 72% identified as women, and the plurality (41%) identified as Latino/a. We chose the two-group LCA solution. Bimonthly LAI ART was preferred over monthly LAI ART overall and in both groups. Group 1 (n=45) preferred more traditional adherence supports (e.g., injections at the clinic by appointment, injection appointment reminders) whereas Group 2 (n=132) preferred more client-centered supports (e.g., injections at home by appointment, free transportation to injection appointments if at a clinic). Both groups preferred higher monetary value gift cards for clients for every on-time injection. The top-ranking motivations indicated that participants prioritized patient convenience over job satisfaction and administrative or financial feasibility for the agency. The scores for all implementation measures indicate readiness to implement LAI ART in both groups. Conclusions Our implementation science-focused study suggests that providers of MCM services in NYC and surrounding counties are motivated to offer services to support clients' access and adherence to LAI ART. More work is needed to understand how programs have, in fact, integrated supports for LAI ART into their services.

Background and HypothesisClozapine is the only medication with proven efficacy for treatment-resistant schizophrenia, yet many patients experience delays of several years before initiation. Our aim was to develop and validate a dynamic prediction model for clozapine initiation among patients with schizophrenia trained solely on electronic health record (EHR) data from routine clinical practice. Study DesignEHR data from all adults ([&ge;] 18 years) with a schizophrenia (ICD10: F20) or schizoaffective disorder (ICD10: F25) diagnosis who had been in contact with the Psychiatric Services of the Central Denmark Region between 1 January 2013 and 1 June 2024 were retrieved. 179 structured predictors were engineered (covering, e.g.,diagnoses, medications, coercive measures) and 750 predictors derived from clinical notes. At every psychiatric hospital visit, we predicted if an incident clozapine prescription occured within the next 365 days. XGBoost and logistic regression models were trained on 85% of the data with 5-fold stratified cross-validation. Performance was evaluated on the remaining 15% of the data (held out) using the area under the receiver operating characteristic curve (AUROC). Study ResultsThe training/test set comprised of 194,234/35,527 hospital visits, distributed on 4928/878 unique patients. In the test set, the best XGBoost model achieved an AUROC of 0.81, sensitivity of 32%, positive predictive value of 23% at a 7.5% predicted positive rate. ConclusionsA dynamic prediction model based solely on EHR data predicts clozapine initiation with high discrimination. If implemented as a clinical decision support tool, this model may guide clinicians towards more timely initiation of clozapine treatment.

Progress in pharmacological treatment development for neurodevelopmental disorders is hindered by a misalignment between targeted mechanisms, outcome measures, and trial designs. This study was initiated as a post-trial access pathway for bumetanide and later expanded with treatment-naive participants. Within this framework, we implemented a parent-cocreated sensory outcome measure set (PROMset) in an unmasked, multiple-baseline single-case experimental design with randomized baseline periods of 2-12 weeks, followed by 6 months of bumetanide treatment (up to 1.5 mg twice daily). Participants (7-19 years) had atypical sensory reactivity and a diagnosis of ASD, ADHD, epilepsy, or TSC. The primary outcome was a PROMset comprising seven PROMIS item banks assessing anxiety, depressive symptoms, sleep disturbance, fatigue, sleep-related impairment, cognitive function, and peer relationships. Secondary outcomes included SSP, SRS-2, RBS-R, and ABC. Of 113 enrolled participants (mean age 13.2 [SD 2.7], 64% male), 102 completed the trial and 95 had analyzable PROMsets. At baseline, PROMset scores showed substantial impairment across domains (mean deviation =9.0 T-score points, p<.001) and correlated with sensory reactivity (SSP; r=-0.40, p<.001). Individual-level analyses showed improvement in 24-41% of participants per PROM domain, most frequently in anxiety and depressive symptoms (41% and 38%; mean across-case Cohen's d=-1). Overall, 83% improved on at least one domain. Group-level analyses showed improvement across all secondary outcomes (p<.001), with superiority over historic placebo for RBS-R and SSP. Integrating PROMsets with individualized trial designs can reveal clinically meaningful changes, supporting a more sensitive and patient-centered framework for treatment evaluation in heterogeneous populations.

Introduction: Smoking cessation after acute coronary syndrome (ACS) is a Class I recommendation, yet prescription pharmacotherapy use remains low and its real-world cardiovascular effectiveness when added to nicotine replacement therapy (NRT) is poorly characterized. Methods: We conducted a retrospective cohort study using the TriNetX US Collaborative Network (67 healthcare organizations). Adults hospitalized with ACS who received NRT within one month, serving as a proxy for active smoking status, were identified. Two co-primary propensity-matched (1:1, 50 covariates, caliper 0.10 SD) comparisons evaluated bupropion + NRT and varenicline + NRT individually versus NRT alone; a supportive analysis evaluated combined pharmacotherapy versus NRT alone. All-cause mortality was the primary endpoint. Secondary outcomes included MACE, heart failure exacerbations, major bleeding, TIA/stroke, emergency rehospitalizations, and cardiac rehabilitation utilization, assessed at 6 months and 1 year via Kaplan-Meier analysis. Hazard ratios (HRs) greater than 1.0 indicate higher hazard in the NRT-only group. Results: After matching, the combined analysis comprised 8,574 pairs, the bupropion analysis 4,654 pairs, and the varenicline analysis 2,126 pairs. At 1 year, the combined pharmacotherapy group had significantly lower all-cause mortality (HR 1.26, 95% CI 1.16-1.37), MACE (HR 1.16, 95% CI 1.12-1.21), heart failure exacerbations (HR 1.16, 95% CI 1.08-1.25), major bleeding (HR 1.18, 95% CI 1.08-1.28), and greater cardiac rehabilitation utilization (HR 0.82, 95% CI 0.74-0.92; all p < 0.001). TIA/stroke did not differ significantly. Six-month results were consistent. Both varenicline and bupropion individually showed lower mortality and MACE. A urinary tract infection falsification endpoint showed no between-group differences, supporting matching validity. The pharmacotherapy group had higher rates of new-onset depression, driven predominantly by bupropion recipients. Conclusions: In this propensity-matched real-world analysis, adding prescription smoking cessation pharmacotherapy to NRT after ACS was associated with lower mortality and fewer adverse cardiovascular events, supporting broader integration into post-ACS care pathways.