Schizophrenia Research

Objective: This study examined the prevalence of psychotic experiences (PE) and how early onset and persistence of PE contribute to risk and severity of mental disorders in adolescents at familial high-risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) and adolescents from a population-based control group (PBC). Methods: This is the second follow-up of a nationwide cohort study including 522 children at FHR-SZ (N=202), FHR-BP (N=120), and PBC (N=200). Participants were assessed at ages 7, 11, and 15 using a semi-structured interview to evaluate PE and mental disorders. Results: At age 15, adolescents at FHR-SZ reported more PE than PBC over the past six months (current) and the past four years, while adolescents at FHR-BP only reported more current PE. PE reported at two or three timepoints (persistent PE) predicted any Axis I disorder in mid-adolescence, corresponding to three- (OR 2.9, 95% CI [1.5-5.7]) and 21-fold (OR 21.4, 95% CI [2.8-162.3]) increased risks, respectively. Persistent PE also predicted multimorbidity, with three- (OR 2.8, 95% CI [1.0-7.6]) and four-fold (OR 4.1, 95% CI [1.2-14.1]) increased risks, respectively. This was after adjustment for sex, early mental disorders, and familial risk. Conclusions: This study demonstrates a strong link between persistent PE and mid-adolescence mental disorders. Our findings emphasize PE as important risk markers for mental disorders during mid-adolescence and highlight the importance of monitoring children with PE before age 7 who develop persistent symptoms.

Background: Cognitive impairment is the leading cause of disability in schizophrenia with limited treatments. A major barrier to treatment development is the absence of reproducible, mechanistically grounded neural targets. Cross-sectional studies have identified dorsomedial prefrontal cortex (DMPFC)-somatomotor connectivity as a neural marker of cognitive performance on the Auditory Continuous performance task (ACPT), a measure of attention. To test the stability of this marker, we tested the relationship between DMPFC-somatomotor connectivity and ACPT performance in a longitudinal psychosis sample. Methods: Individuals with early psychosis (n=251) and matched controls (n=90) were enrolled and underwent resting-state neuroimaging and neurocognitive assessment. A subset completed longitudinal assessments over 2-4 years. We calculated DMPFC-somatomotor resting-state functional connectivity using a previously identified DMPFC region and a seed in the somatomotor cortex. We performed linear mixed effects models to predict ACPT performance based on connectivity, time, psychosis type, and their interaction. Results: In the psychosis sample, time (p=.0037) and affective psychosis diagnosis (p<.0001) predicted better ACPT performance. In a model predicting ACPT performance, we observed a significant interaction effect of DMPFC-somatomotor connectivity*psychosis subtype (p=.0079) such that DMPFC-somatomotor connectivity predicted ACPT performance only in individuals with non-affective psychosis (p=.0051). We then tested the specificity of this connectivity-cognitive performance relationship. In a model predicting DMPFC-somatomotor connectivity, only ACPT performance (p=.017), but not fluid cognition, was a significant predictor. Conclusions: DMPFC-somatomotor connectivity is longitudinally associated with cognitive performance in early psychosis. This relationship is strongest in nonaffective psychosis, suggesting a novel, reliable target for intervention for cognitive deficits in early psychosis.

Psychosis has long been conceptualized as a disorder of disrupted hierarchical integration across distributed brain systems, yet it remains unclear whether alterations in macroscale cortical hierarchy are already present before illness onset and are associated with subsequent transition to psychosis. Using connectome gradient mapping, we characterized baseline cortical hierarchical architecture along the unimodal-to-transmodal axis in 580 participants from the NAPLS-3 cohort, including converters (CHR-C, n = 56), non-converters (CHR-NC, n = 434), and healthy controls (HC, n = 90). Group differences were assessed at regional, network, and global levels. Group comparisons revealed that CHR-C individuals, relative to the other two groups, exhibited bidirectional alterations selectively along the sensorimotor-to-association gradient, with reduced values in the visual network alongside elevated values in the default mode network, indicating greater separation between sensory and transmodal systems along the gradient. At the global level, CHR-C showed increased explained variance, range, and variation of this gradient, collectively indicating hierarchical expansion. Notably, greater explained variance of this gradient was associated with a shorter time to conversion to psychosis, while increased gradient range and variation were associated with higher positive symptom severity across CHR individuals. These findings indicate that expansion of the sensorimotor-to-association connectome hierarchy is already present before psychosis onset in individuals who subsequently convert to psychosis. This altered hierarchical organization may reflect greater decoupling between sensory and transmodal systems and may characterize neurobiological changes associated with progression from a clinical high-risk state to psychotic illness.

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

Major depressive disorder (MDD) has been associated with accelerated structural brain aging, yet whether this reflects a pre-existing neurobiological vulnerability, a dynamic acute state effect, or an accumulating biological residual remains unresolved. Across two longitudinal cohorts (N=3220), including a unique sample of 78 initially healthy individuals who transitioned into their first depressive episode during the study course, we systematically tested all three hypotheses. Patients with diagnosed MDD showed elevated MRI-derived brain age relative to healthy controls (1.4 and 2.5 years across cohorts). For the vulnerability hypothesis, individuals scanned prior to their first episode showed no baseline elevation, despite already demonstrating subclinical elevations in self-reported symptom severity, indicating that advanced brain age does not precede illness onset. For the state hypothesis, we found no acceleration of brain aging following the first depressive episode, and longitudinal brain age trajectories were independent of acute clinical symptom severity. Finally, neither episode duration nor recurrence scaled with brain age. Accelerated brain aging in depression is therefore neither an antecedent vulnerability nor an acute state marker of the first episode, but rather a stable biological feature of a long term illness course.

Background: Bipolar disorder is associated with persistent social, cognitive, and functional impairment during euthymia, yet the neural mechanisms underlying these deficits remain unclear. Alterations to self-referential processing are a candidate mechanism, but existing electrophysiological studies rely on emotionally valenced paradigms that potentially confound self-processing with emotional biases. Methods: We analysed electroencephalography from 28 patients with bipolar disorder (type I or II) and 28 age- and sex-matched healthy controls during an emotionally neutral colour judgment task with self-related (preference) and non-self-related (similarity) conditions. Late positive potentials, temporal generalisation decoding, and frequency band decoding (theta, alpha, beta) were used to characterise the temporal dynamics and oscillatory correlates of self versus non-self processing. Results: Controls showed higher overall event-related potential amplitudes and greater self versus non-self differentiation than patients (condition by group interaction, 337 to 946 ms). Broadband temporal generalisation decoding revealed extensive cross-temporal generalisation of the self versus non-self representation in controls, spanning most of the trial, but no significant generalisation in patients. Frequency analyses showed that alpha and beta carried self versus non-self information in both groups, with broader extent in controls, and that anterior theta carried this information in patients but not controls. Exploratory correlations linked decoding measures to rumination and anxiety but not to manic symptoms. Conclusions: The neural representation distinguishing self-referential from externally guided processing was both smaller in amplitude and less temporally sustained in bipolar disorder. Reduced persistence is not detectable by conventional amplitude analyses, and may bear on the self-related and social cognitive difficulties reported in this population.

Major depressive disorder (MDD) is strongly associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, systemic inflammation, and gut microbiota dysbiosis. Although selective serotonin reuptake inhibitors such as escitalopram are standard treatments, their efficacy is often constrained by partial response and gastrointestinal adverse effects. In this 12-week, randomized, double-blind, placebo-controlled trial, we evaluated the clinical efficacy and microecological mechanisms of adjunctive Lactiplantibacillus plantarum PS128 (PS128; 6*1010CFU/day) in MDD patients on stable escitalopram therapy. Adjunctive PS128 significantly enhanced clinical response compared to placebo, yielding substantial reductions in HAMD-17 and MADRS, alongside a higher remission rate. 16S rRNA sequencing and PICRUSt2 profiling revealed that PS128 enriched key short-chain fatty acid producers (Faecalibacterium, Coprococcus), counteracting the Klebsiella expansion seen in placebo. Functionally, PS128 up-regulated neuroprotective cofactor, B vitamins, biosynthesis and down-regulated the neurotoxic kynurenine pathway. Network analysis demonstrated that PS128 maintained a resilient, integrated microbial co-occurrence topology, whereas the placebo network showed structural segregation. This stabilized ecosystem attenuated peripheral inflammatory signaling and normalized salivary cortisol levels. Overall, adjunctive PS128 augments escitalopram efficacy by enhancing gut network stability, supporting cellular energetics, and modulating neuroendocrine activity, offering a promising multimodal strategy for MDD.

Mitochondria are central hubs for cellular metabolism and mitochondrial dysfunction is a hallmark of many chronic diseases. Consequently, changes in mitochondrial DNA copy number (mtDNA-CN), the number of mtDNA genomes per cell or tissue sample, are associated with diseases ranging from cancer and obesity to psoriasis and all-cause mortality. MtDNA-CN especially holds promise as a biomarker for neurodegenerative diseases, but whether and how mtDNA-CN changes with neurodegeneration is controversial. Here, we performed a systematic review and meta-analysis of 76 studies including 156 comparisons of mtDNA-CN in populations with or without a neurodegenerative disease to identify overall trends and potential moderators that explain variation among studies. Overall, mtDNA-CN was not statistically different with neurodegeneration, but heterogeneity among studies was extreme (I2 = 99.5%). The diagnosed disease explained the most variation. For example, Alzheimer's patients showed a 21% decrease in mtDNA-CN, but there was no change in mtDNA-CN with Parkinson's disease. Decreases in mtDNA-CN during neurodegeneration were also more extreme at older ages. Surprisingly, the tissue sampled for mtDNA-CN was not particularly influential, except for certain diseases. Studies published in earlier years also showed more extreme decreases in mtDNA-CN with neurodegeneration. Excessive heterogeneity persisted even after accounting for all moderators and their interactions (I2 = 85.7%). We conclude that the general perception of decreased mtDNA-CN with neurodegeneration is a vast oversimplification that may stem from legacy effects of early studies. However, mtDNA levels offer great promise as biomarkers for neurodegeneration, other diseases, and general health metrics, assuming appropriate complications can be considered.

Background: Major depressive disorder (MDD) is a severe mental illness associated with severe clinical consequences and substantial societal burden. It's characterized by immune-inflammatory dysregulation and immune sensitization. Objective: To determine whether in vitro ketamine attenuates phytohemagglutinin (PHA)/lipopolysaccharide (LPS)-induced immune sensitization in patients with MDD and healthy controls (HCs). Methods: Whole blood from 18 patients with MDD and 18 HCs was stimulated with PHA/LPS and exposed to ketamine (0.3 M, 0.6 M, and 6 M) for 72 hours. Cytokines, chemokines, growth factors, and composite immune profiles, including M1/M2 macrophages, T helper (Th)1/2/17, the immune-inflammatory response system (IRS), and compensatory immunoregulatory system (CIRS), were synthesized and determined. Results: Under PHA and LPS stimulation in vitro, the MDD group exhibited markedly elevated immune profiles, including M1, M2, Th1, Th2, Th17, IRS, CIRS, chemokines, and growth factors, consistent with immune sensitization. Significant group-by-treatment interactions were observed for Th1-Th2, M2, growth factors, IL-12(p70), M1, and chemokines. Ketamine produced minimal changes in HCs but broader suppression in MDD, particularly at the highest concentration, without normalizing the sensitized immune phenotype. Among the immune markers with no notable group-by-treatment interactions, ketamine exerted diagnosis-independent effects, decreasing MIP-1{beta}, IL-1&{beta}, Th1, TNF-{beta} IRS, IFN-{gamma}, and IL-2 compared to the control condition. Conclusions: Ketamine exhibited two distinct immunoregulatory patterns: selective, disease-dependent attenuation of sensitized immune pathways and broader, diagnosis-independent suppression of the stimulated immune response, predominantly at higher concentrations. However, these effects were insufficient to normalize the immune-sensitized phenotype of MDD.

Aim: The Patient Safety Screener-3 (PSS-3) is a brief suicide-risk screening tool. Item 1 of this scale assesses depressive mood but is not included in the total score. We examined the association of item 1 with depressive symptom severity and characterized the suicide-related risk captured by PSS-3 total positivity. Methods: We conducted a nationwide cross-sectional survey among resident physicians in Japan. Associations between PSS-3 item 1 endorsement and Patient Health Questionnaire-9 (PHQ-9) scores were evaluated using the Wilcoxon rank-sum test. Diagnostic performance of item 1 was evaluated using PHQ-9 positivity ([&ge;]10) as reference standard. We also compared Short-form Scale for Suicide Ideation (SIS-6) scores according to PSS-3 total positivity and PHQ-9 item 9 positivity. Results: A total of 1,844 participants were included. PSS-3 item 1 was endorsed by 443 physicians (24.0%), and 47 (2.5%) met the criteria for PSS-3 total positivity. Item 1 showed 79.3% sensitivity and 79.5% specificity for PHQ-9 positivity. SIS-6 scores were higher in the PSS-3 total-positive group than in the total-negative group (median [IQR], 6 [5-9] vs 0 [0-1]; p<0.001). The SIS-6 showed a higher area under the receiver operating characteristic curve (AUC) and Youden index using PSS-3 total positivity (AUC, 0.961; optimal cutoff, 3) than PHQ-9 item 9 positivity (AUC, 0.907; optimal cutoff, 2). Discussion: PSS-3 may support brief, simultaneous screening for depressive symptoms and suicide-related risk. Compared with PHQ-9 item 9, PSS-3 may capture a more severe spectrum of suicide-related risk. PSS-3 may facilitate identification of individuals requiring further mental health assessment.

Background: Substance use is common among individuals with depression. Transcranial magnetic stimulation (TMS) is an effective treatment for depression, but current clinical guidelines have discouraged TMS treatment for individuals with depression and co-occurring substance use given concerns for limited efficacy. However, limited data exists on whether substance use affects response to TMS. Methods: Using electronic health record data from patients who received a standard course of TMS for major depressive disorder at an academic medical center, we investigated associations between substance use frequency and response to TMS, defined as change in Patient Health Questionnaire-9 (PHQ-9) scores. Substance use frequency was extracted for alcohol, cannabis, nicotine, stimulants, benzodiazepines, opioids, inhalants, psychedelics, and other drugs. We performed ANCOVA and multiple regression analyses to predict change in PHQ-9 score based on substance use frequency, controlling for pre-TMS PHQ-9 score, age, sex, and number of TMS sessions received. Results: We extracted data from 219 TMS courses. Alcohol was the substance used most commonly (34.2%), followed by prescription benzodiazepines (28.3%), and prescription stimulants (21.0%). Across all substance categories, substance use was not associated with change in PHQ-9 score (all p > 0.05, Cohens d=0.00 to 0.30). In multiple regression models to compare individual levels of substance use frequency (e.g., daily use vs. no use), level of substance use was not associated with change in PHQ-9 score (all p > 0.05). The range of plausible effects of substance use frequency on PHQ-9 change was generally below the minimal clinically important difference for PHQ-9, suggesting substance use was unlikely to have a meaningful clinical effect on antidepressant response to TMS. Conclusions: Low to moderate substance use does not have a clinically significant effect on antidepressant response to TMS. Low-level substance use should not exclude individuals with depression from receiving TMS.

Children and adolescents with hearing loss frequently encounter reduced auditory access and delayed language development, factors that may influence the maturation of executive functions. This study examined developmental differences in planning, a core executive function, in 98 children and adolescents with hearing loss or normal hearing aged 7 to18 years using the Tower of London task. Compared to normal hearing peers, participants with hearing loss made more unnecessary moves and rule violations and initiated problem-solving more rapidly, suggesting reduced preplanning efficiency and increased impulsivity. These group differences were most pronounced in adolescents, who showed faster initiation and greater movement inefficiency than age-matched normal hearing participants. Within the hearing loss group, adolescents displayed higher accuracy and longer initiation times than children, reflecting developmental improvements despite persistent gaps relative to hearing peers. Language development age did not alter the main effects. Findings indicate that reduced early auditory and language access may contribute to differences in planning development, highlighting the need for targeted executive functions support in educational and clinical settings for youth with hearing loss.

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

Background: The Centiloid (CL) scale standardizes global amyloid PET quantification and is widely used to define amyloid positivity. As a global summary measure, however, CL may not fully reflect the regional distribution of amyloid deposition, which can carry additional prognostic information about the rate of cognitive decline. Objective: To develop and externally validate a fixed, regional amyloid PET composite score that complements CL for predicting cognitive decline in Alzheimer's disease. Methods: The Regional Amyloid PET Score (RAPS) was derived from 82 FreeSurfer regions using machine learning with bootstrap stability selection to predict the rate of change in CDR-Sum of Boxes (CDR-SB) in 433 amyloid-positive ADNI [18F]florbetapir participants. The fixed nine-region weights were applied without retraining in a cross-tracer ADNI [18F]florbetaben subset (N = 71; largely overlapping the discovery participants) and two external validation cohorts, NACC SCAN (N = 1531; four tracers) and OASIS-3 (N = 428). Results: RAPS comprised nine regions. In ADNI, RAPS correlated more strongly with CDR-SB slope than CL and showed higher discrimination of rapid decliners (AUC 0.813 vs 0.713). Performance was directionally consistent across validation cohorts; in NACC SCAN, RAPS and CL independently predicted clinical progression. Cross-cohort meta-analysis of the three independent cohorts supported incremental discrimination beyond CL (pooled {Delta}AUC +0.066; I2 = 0%). Conclusions: RAPS, a fixed regional amyloid PET-derived score, may complement CL for prognostic stratification in Alzheimer's disease research.

Recent large-scale studies have enabled new knowledge about genetic underpinnings of morphological and electrophysiological alterations of the retina. Variation in retinal traits, often of neurodevelopmental origin, have been linked to major psychiatric disorders (MPDs). Here, we investigate the genetic overlap between MPDs and key retinal traits to identify underlying molecular mechanisms. We obtained genome-wide associations studies data for bipolar disorder (BD), major depression (MD), schizophrenia (SCZ), and the retinal traits retinal nerve fibre layer thickness (RNFL), ganglion cell inner plexiform layer thickness (GCIPL), and vertical cup-disc ratio (VCDR). We estimated the number of trait-influencing variants shared between traits with MiXeR and identified shared genetic loci with condFDR. Subsequently, we examined the biological pathways of the genes mapped to shared loci. This revealed that GCIPL shared the most genetic variants with MPDs (~60%), followed by RNFL (~40%), and VCDR (~20%). The genetic variants shared between retinal traits and MPDs showed disorder-specific patterns with more pronounced overlaps of SCZ and BD with RNFL, and MD negatively correlated with GCIPL. Gene-pathway analysis highlighted the importance of GABAergic neurotransmission and a two-stage neurodevelopmental process in SCZ, whereas the role of mitochondria and a weaker developmental component were observed in BD. The results also implicated synaptic functioning and gene-expression processes in MD. Furthermore, polygenic analysis suggested that the genetic architecture of retinal traits can distinguish between MPDs. Our findings indicate shared genetic underpinnings between retinal traits and SCZ, BD, and MD, implicating altered neurodevelopment and neurotransmission underlying the retinal link to major psychiatric disorders.

Objective: To examine how medial plantar nerve shear wave speed (Cs) and viscosity coefficient (Vi) are associated with the severity of diabetic peripheral neuropathy (DPN), and to assess their ability to differentiate adjacent severity categories. Materials and Methods: Based on TCSS, the 113 patients with type 2 diabetes mellitus were assigned to the non-DPN (n = 33), mild DPN (n = 46), and moderate DPN (n = 34) groups. Medial plantar nerve Cs and Vi were measured using shear wave elastography and viscosity imaging. Receiver operating characteristic analysis evaluated Cs, Vi, and their logistic regression-based combination; areas under the curves (AUCs) were compared using DeLong tests. Results: Cs and Vi increased progressively across the three groups (both P < 0.001). For non-DPN versus mild DPN, the AUCs of Cs, Vi, and the combined model were 0.688 (95% CI, 0.604-0.772), 0.741 (0.660-0.822), and 0.745 (0.665-0.826), respectively, without significant pairwise differences. For mild versus moderate DPN, the corresponding AUCs were 0.707 (0.625-0.789), 0.794 (0.724-0.865), and 0.799 (0.731-0.867). The combined model outperformed Cs (P = 0.045), whereas Cs versus Vi and Vi versus the combined model did not differ significantly (P = 0.162 and 1.000, respectively). Conclusion: Medial plantar nerve Cs and Vi increased with DPN severity. Their combination improved discrimination between mild and moderate DPN compared with Cs alone but not with Vi alone. Quantitative medial plantar nerve viscoelastic assessment may complement clinical severity grading.

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

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

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

Disseminating study results to participants is an ethical responsibility for researchers but remains uncommon in low- and middle-income countries, and participants preferences for receiving study results are poorly understood. This study examined study result dissemination preferences among pregnant women in a phase III malaria prevention trial in Papua New Guinea (PNG). Participants completed an interviewer-administered questionnaire (survey) assessing their interest in and motivation for receiving trial results and preferences for dissemination methods and content. Associations between participants characteristics and dissemination preferences were explored using multivariable logistic regression analysis. Of 1172 trial participants, 96.0% (1125/1172) completed the survey, and of these 99.6% (1121/1125) wanted to learn about the trial results. The main motivation factors driving participants interest were an acknowledgment of their contribution to research (51.7%; n=579) and a better understanding of the study (45.0%; n=505). Most participants (78.9%; n=884) wanted to learn about the trial findings through written summary and a group meeting with other participants at the nearest clinic (31.1%, n=349). Multivariable regression analysis indicated that participants from rural/peri-urban clinics were more likely to choose non-electronic media dissemination approaches such as a group meeting as compared to urban-dwelling participants. Frequently selected items (>50% of participants) for content included information regarding good results of the study, purpose of the study, medical treatment advances, results specific to me, and how study was conducted. There was heterogenicity in the preference for dissemination content: compared to urban clinics rural clinics are less likely to want to learn about how and why study was conducted and medical and scientific advances. Overall, the majority wanted to learn about trial results, highlighting the importance of integrating dissemination into research activities in PNG. Variation in preferences for mode and content of dissemination between study clinics suggests that dissemination activities could be tailored to local context and preferences.