Although adverse childhood experiences (ACEs) have been related to poorer lifespan health, their association with DNA methylation-based indicators of biological aging during adolescence remains incompletely understood, particularly across intersecting social positions. To address this gap, we used an intersectional race–sex approach to identify ACE patterns and examine their associations with biological aging in adolescence.

Participants (n = 1,655) were drawn from the Future of Families and Child Wellbeing Study, a racially diverse urban U.S. birth cohort. ACEs were measured prospectively from ages 3 to 9 and modeled using latent class analysis with measurement invariance testing across six intersecting race–sex groups. Biological aging was assessed using saliva-derived DNA methylation measures at ages 9 and 15, and for change from age 9 to 15 using PhenoAge, GrimAge, and DunedinPACE.

Two ACE classes emerged within each racial/ethnic group. Among Black participants, females showed higher PhenoAge estimates than males across classes at ages 9 and 15 and for longitudinal change. Among White participants, females in the Single-Parent Poverty & Maternal Substance Use class showed higher PhenoAge estimates at age 9 than females in the Maternal Substance Use class, although this difference was not observed at age 15 or for longitudinal change. Findings for GrimAge and DunedinPACE were less consistent.

Prospectively measured ACE configurations showed selective associations with adolescent DNA methylation–based aging measures, most consistently for PhenoAge. Findings support intersectional, person-centered approaches to identifying heterogeneity in early biological risk and underscore the need for caution in interpreting clock-specific findings in youth.

Anxiety disorders show striking sex differences in prevalence, symptoms, and clinical characteristics, shaping how they manifest and are experienced.

Here, we report the first sex-specific meta-analysis of genome-wide association studies (GWAS) of anxiety, leveraging two of the largest biobank datasets, UK Biobank and All of Us, comprising 85,042 female cases with 196,789 controls and 36,732 male cases with 136,924 controls. Functional annotation, sex-specific polygenic scores (PGS), and genetic correlations were performed to assess genetic differences and functional implications.

In females, 21 lead SNPs were significantly associated with anxiety, compared to five in males. Although the genetic correlation between sexes was high, it was significantly different from one, indicating partially distinct genetic architectures. In addition, both the SNP-based observed and liability-scale heritabilities (assuming a 2:1 female-to-male prevalence ratio) were significantly higher in females. Gene-based tests and functional prioritization identified different genes associated with anxiety in females and males. Moreover, genetic correlation analyses revealed stronger associations of female anxiety with attention-deficit/hyperactivity disorder (ADHD) and body mass index (BMI), whereas male anxiety showed stronger correlations with waist-hip-ratio-adjusted BMI.

While the overall genetic architecture of anxiety is largely shared, our findings reveal distinct sex-specific genetic associations and correlations, highlighting the value of analyzing the sexes separately to uncover genetic signals that may be masked in sex-combined samples.

This study examined age-specific associations between parent-reported executive function (EF) difficulties and internalizing/externalizing symptoms in children with neurofibromatosis type 1 (NF1), a genetic condition underrepresented in psychiatric research.

Cross-sectional data of 1,049 observations from 803 children with NF1 (Mage = 10.58 years, SD = 3.84, range = 3–18; 47.5% female; 67.5% from higher-education households; 36.6% with familial NF1) across nine U.S. and Australian institutions were integrated. Parents rated EF difficulties using the Behavior Rating Inventory of Executive Function and internalizing/externalizing symptoms using the Child Behavior Checklist and the Behavior Assessment System for Children. Time-varying effect modeling estimated age-specific associations between EF and internalizing/externalizing symptoms and tested moderation by sex and parental education.

Poorer functioning in all EF domains was associated with greater internalizing and externalizing symptoms from ages 3 to 18. The associations were largely consistent across ages as well as sex and parental education subgroups with a few differences: (1) emotional control and cognitive flexibility problems were more strongly associated with internalizing symptoms during middle and late adolescence; (2) inhibitory control was more strongly linked to externalizing symptoms in childhood; (3) stronger associations between EF and internalizing symptoms were observed among males in early adolescence.

Parental complaints of EF difficulties are robustly linked to internalizing and externalizing problems from early childhood to late adolescence in children with NF1. Further longitudinal and experimental studies are needed to determine the directionality of these associations and whether EF represents a viable target for intervention.

Sex differences in psychosis pathoetiology are insufficiently understood. This study explores how childhood adversity (CA) and coping mechanisms relate to psychosis expression (PE) across males and females in the general population.

Data from the TwinssCan project (males: n = 312; females: n = 478) were used. The Childhood Trauma Questionnaire assessed CA domains. The Utrecht Coping List assessed coping strategies. Psychosis expression was assessed using the Community Assessment of Psychic Experiences (CAPE). Mixed linear regression analyses examined sex-stratified associations of CAPE scores with CA, coping strategies, and their interactions.

Emotional abuse (EA) was associated with increased total CAPE scores (T-CAPE), explaining the greatest variance among CA across sexes. Sex-specific effects showed that sexual abuse (SA) and physical abuse (PA) were linked to higher T-CAPE in females, whereas physical neglect (PN) was linked to higher T-CAPE in males. Passive-reacting was associated with increased T-CAPE, explaining the greatest variance among coping styles across both sexes. Sex-specific effects showed that, in females, seeking social support was linked to decreased T-CAPE, while emotional expression increased it. The only sex-shared interaction effect was between reassuring thoughts and emotional neglect (EN), associated with decreased T-CAPE. In females, social support (× PA/PN/EA), reassuring thoughts (× PA/PN), and palliative-reacting (× PN/PA) were associated with decreased T-CAPE, while passive-reacting (× EN) increased it. In males, avoidance (× SA/PA) and passive-reacting (× PN) were associated with increased T-CAPE.

Sex differences in the associations of PE with CA and coping underscore the necessity for sex-specific interventions that promote adaptive coping strategies.

Depression is often comorbid with alcohol use problems, and sex differences may further complicate this interplay.

We conducted a longitudinal study using a large European adolescent cohort assessed at ages 14 (baseline, BL), 16 (follow-up 1, FU1), 19 (follow-up 2, FU2), and 23 (follow-up 3, FU3). Depression and alcohol use were measured using standardized behavioral scales. Cross-lagged analysis, improved Mendelian randomization (MR) analysis, and mediation analysis were conducted to infer the causal interplay.

2110 adolescents were included at baseline (49% male). Depression and alcohol consumption demonstrated a significant positive correlation (rBL = 0.094, pBL = 1.58E-05, 95% CI = [0.052, 0.137]), which gradually diminished over time and eventually became significantly negative. Depression and alcohol use problems remained strongly correlated across three timepoints (r > 0.074, p < 6.76E-03). Cross-lagged analysis suggested that depression predicted future alcohol use problems: βBL-FU1 = 0.058, p = 0.021, 95% CI = [0.009, 0.108]; βFU2-FU3 = 0.142, p = 8.34E-07, 95% CI = [0.113, 0.263]. MR analyses confirmed this causal interplay (rmean = 0.043, longitudinal ppermuation < 0.001). Interestingly, MR analyses also indicated that alcohol consumption might alleviate depression (rmean = −0.022, longitudinal ppermutation = 0.043), particularly in females at FU3, of which the anxiety status and the personality trait neuroticism largely mediated the effect. These findings were validated in an independent matched sample (N = 562) from Human Connectome Project.

Depression may predict future alcohol use problems, whereas moderate alcohol consumption might alleviate depressive symptoms, especially in females.

This study aimed to explore the correlates of zero, one, and multiple performance validity test (PVT) failures on cognitive test performance in patients with various degrees of severity of traumatic brain injury.

306 participants completed the Trail Making Test as part of a neuropsychological evaluation within 1–36 months post-injury. They were assigned to zero, one, or ≥ two fail groups on the basis of at least two independent PVTs. Group differences in Trail Making Test performance were analyzed with analysis of variance, with post hoc contrasts with the Bonferroni correction for multiple comparisons. Groups were also compared on various background characteristics.

Participants who passed all PVTs had statistically significantly better performance on both parts of the Trail Making Test as compared to those who failed either one or multiple PVTs, with the latter two groups not differing statistically significantly from each other. PVT failure was relatively more common in participants who were female, had an uncomplicated mild TBI, were involved in financial compensation-seeking, and were seen at a longer time point since injury.

Failure of even only one PVT is associated with lower neuropsychological test performance in patients with traumatic brain injury, especially when empirically validated criteria are used that are stratified by injury severity. Such failure does not always reflect malingering but must be interpreted and addressed in the context of patient background characteristics.

Accumulating evidence suggests that stress, social relationships, and sex/gender differences in brain function, particularly of the orbitofrontal cortex (OFC), may drive problematic alcohol use. How these factors interact to effect alcohol use, and if they do so differently in men and women, has yet to be explored.

Using a subsample of the publicly available Human Connectome Project data consisting of young adults with problematic alcohol use (N = 491; 41.75% women, ≥1 symptom of alcohol abuse/dependence), we used a moderated moderation approach to test whether perceived stress and sex/gender moderated the effect of a multidimensional measure of social relationship quality on drinking levels. We subsequently tested whether OFC function moderated these effects.

We found that in women, higher friendship and companionship had a protective effect on drinking levels, particularly for women under high stress. In contrast, in men, higher friendship and companionship were linked to increased drinking levels under stress. Preliminary evidence suggested that this effect in men was driven by a subgroup of men with higher OFC reactivity to negative emotional faces.

Our findings suggest that women benefit from friendship and companionship as a form of stress-relief in the context of problematic drinking, whereas men do not, supporting the need of interventions that facilitate emotionally supportive, pro-recovery social environments particularly in men. Preliminary evidence further suggests a role of emotional dysregulation in men. Overall, our findings support the importance of developing sex/gender and neurobiologically informed interventions that target stress-related alcohol use.

Child video game playing (“gaming”) may lead to decreased child academic motivation. Conversely, children with low academic motivation may seek fulfillment through gaming. We examined bidirectional associations between child gaming and academic motivation across middle childhood.

Our analyses are based on 1,631 children (boys = 785) followed in the context of the Quebec Longitudinal Study of Child Development. Data on gaming and academic motivation were collected repeatedly at ages 7, 8, and 10. Measures of child gaming were parent-reported and reflect daily video game playing time. Measures of academic motivation were child self-reported and reflect enjoyment in learning mathematics, reading, and writing. To disentangle the directionality of associations, we estimated a random-intercept cross-lagged panel model to estimate bidirectional, within-person associations between gaming and academic motivation in a cohort of school-aged Canadian children.

Our results revealed unidirectional associations whereby more frequent gaming by boys at age 7 years predicted lower academic motivation at age 8 years (β = −.11, 95% confidence interval [CI]: −.22 to −.01), and similarly, gaming by boys at age 8 years predicted lower academic motivation at age 10 years (β = −.10, 95% CI: −.19 to −.01). Changes in boys’ academic motivation did not contribute to subsequent changes in gaming. There were no associations between gaming and academic motivation for girls.

More time devoted to gaming among school-aged boys is associated with reduced academic motivation during a critical developmental period for the development of academic skills. Fostering healthy gaming habits may help promote academic motivation and success.

To evaluate sex differences in the triage and assessment of chest pain in Dutch out-of-hours primary care (OOH-PC).

Prior research illustrated differences between women and men with confirmed cardiac ischemia. However, information on sex differences among patients with undifferentiated chest pain is limited and current protocols used to assess chest pain in urgent primary care in the Netherlands do not account for potential sex differences.

A retrospective cohort study of consecutive patients who contacted a large OOH-PC facility in the Netherlands in 2017 regarding chest pain. We performed descriptive analyses on sex differences in patient and symptom characteristics, triage assessment, and subsequent clinical outcomes, including acute coronary syndrome (ACS).

A total of 1,802 patients were included, the median age was 54 years, and 57.6% were female. Compared to men, women less often had a history of cardiovascular disease (CVD) (16.0% vs 25.8%, p < 0.001) or cardiovascular risk factors (49.3% vs 56.0%, p = 0.005). Symptom characteristics were comparable between sexes. While triage urgencies were more frequently altered in women, the resulting triage urgencies were comparable, including ambulance activation rates (31.1% and 33.5%, respectively, p = 0.33). Musculoskeletal causes were the most common in both sexes; but women were less likely to have an underlying cardiovascular condition (21.1% vs 29.6%, p < 0.001), including ACS (5.4% vs 8.5%, p = 0.019).

Women more frequently sought urgent primary care for chest pain than men. Despite a lower overall risk for cardiovascular events in women, triage assessment and ambulance activation rates were similar to those in men, indicating a potentially less efficient and overly conservative triage approach for women.

Depression is a complex mental health disorder with highly heterogeneous symptoms that vary significantly across individuals, influenced by various factors, including sex and regional contexts. Network analysis is an analytical method that provides a robust framework for evaluating the heterogeneity of depressive symptoms and identifying their potential clinical implications.

To investigate sex-specific differences in the network structures of depressive symptoms in Asian patients diagnosed with depressive disorders, using data from the Research on Asian Psychotropic Prescription Patterns for Antidepressants, Phase 3, which was conducted in 2023.

A network analysis of 10 depressive symptoms defined according to the National Institute for Health and Care Excellence guidelines was performed. The sex-specific differences in the network structures of the depressive symptoms were examined using the Network Comparison Test. Subgroup analysis of the sex-specific differences in the network structures was performed according to geographical region classifications, including East Asia, Southeast Asia, and South or West Asia.

A total of 998 men and 1,915 women with depression were analysed in this study. The analyses showed that all 10 depressive symptoms were grouped into a single cluster. Low self-confidence and loss of interest emerged as the most central nodes for men and women, respectively. In addition, a significant difference in global strength invariance was observed between the networks. In the regional subgroup analysis, only East Asian men showed two distinct clustering patterns. In addition, significant differences in global strength and network structure were observed only between East Asian men and women.

The study highlights the sex-specific differences in depressive symptom networks across Asian countries. The results revealed that low self-confidence and loss of interest are the main symptoms of depression in Asian men and women, respectively. The network connections were more localised in men, whereas women showed a more diverse network. Among the Asian subgroups analysed, only East Asians exhibited significant differences in network structure. The considerable effects of neurovegetative symptoms in men may indicate potential neurobiological underpinnings of depression in the East Asian population.

A key step toward understanding psychiatric disorders that disproportionately impact female mental health is delineating the emergence of sex-specific patterns of brain organisation at the critical transition from childhood to adolescence. Prior work suggests that individual differences in the spatial organisation of functional brain networks across the cortex are associated with psychopathology and differ systematically by sex.

We aimed to evaluate the impact of sex on the spatial organisation of person-specific functional brain networks.

We leveraged person-specific atlases of functional brain networks, defined using non-negative matrix factorisation, in a sample of n = 6437 youths from the Adolescent Brain Cognitive Development Study. Across independent discovery and replication samples, we used generalised additive models to uncover associations between sex and the spatial layout (topography) of personalised functional networks (PFNs). We also trained support vector machines to classify participants’ sex from multivariate patterns of PFN topography.

Sex differences in PFN topography were greatest in association networks including the frontoparietal, ventral attention and default mode networks. Machine learning models trained on participants’ PFNs were able to classify participant sex with high accuracy.

Sex differences in PFN topography are robust, and replicate across large-scale samples of youth. These results suggest a potential contributor to the female-biased risk in depressive and anxiety disorders that emerge at the transition from childhood to adolescence.