European Child & Adolescent Psychiatry

Objectives To explore caregiver and clinicians perspectives on implementing mental health conversations and supports for caregivers of children with chronic conditions in paediatric outpatient clinics. Specifically, views were sought on (a) screening approaches and measures (phase 1) and (b) how feedback and support could be provided to caregivers experiencing mental health difficulties (phase 2). Methods Caregivers and clinicians from two outpatient clinics (neuromuscular and diabetes) at a tertiary paediatric hospital in Melbourne, Australia participated in online focus groups in July and August 2024. Caregivers were recruited from outpatient clinics and clinicians were recruited via email. Both groups were combined for phase 1 before separating into breakout rooms for phase 2. Two authors conducted reflexive thematic analysis of transcripts using NVivo. Results Sixteen participants (caregivers n = 8; and clinicians n = 8) took part in in two semi-structured focus groups. Analysis generated two overarching domains, each comprising multiple themes. Domain 1, Addressing caregiver mental health, captured themes of overwhelm and invisibility, diverse caregiving roles, and the need for time and resources to support wellbeing conversations. Domain 2, Housing the mental health conversation, encompassed themes of screening preferences, caregiver agency in confidentiality, delivery of feedback, and access to tailored supports. Conclusions Caregivers and clinicians support routine caregiver mental health discussions in paediatric outpatient settings. Caregivers favour screening at diagnosis and key transitions, with clear, and actionable feedback delivered away from the child. Questions about record-keeping warrant further exploration, as do the perspectives of fathers.

Background. Psychotic-like experiences (PLEs) index early risk for psychotic disorders and are consistently associated with childhood trauma, yet underlying biological mechanisms remain poorly understood. DNA methylation (DNAm) may capture the biological embedding of early adversity, while adolescent exposures such as cannabis use may modify these processes. We examined epigenome-wide associations of childhood trauma and PLEs, tested the moderating role of early cannabis use, and evaluated DNAm as a potential mediator. Methods. We analysed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK population-based birth cohort. Childhood trauma was assessed prospectively and retrospectively. Epigenome-wide DNAm was measured in peripheral blood at ~17 years using the Illumina 450K array, and PLEs were assessed at 18 using a structured interview. Epigenome-wide association studies were conducted for trauma-DNAm and DNAm-PLEs associations in the final sample (n = 1,457), adjusting for demographic, biological, and technical covariates. Differentially methylated regions (DMRs) were identified using DMRff, followed by functional enrichment analyses. Cannabis use at 15.5 was modelled as a moderator with multiple imputation for missing data. Mediation was tested using the Divide-Aggregate Composite-null Test (DACT). Results. Childhood trauma was associated with widespread DNAm differences, primarily at the regional level, with enrichment in pathways related to cellular stress responses. In contrast, DNAm associated with PLEs was more limited and implicated loci involved in epigenetic regulatory processes. These signatures were largely distinct, and there was no evidence supporting mediation after multiple testing correction. Incorporating cannabis use altered the pattern and extent of DNAm associations, with stronger and more significant signals observed at both CpG and regional levels, although these did not translate into evidence of mediation. Conclusion. Childhood trauma and PLEs show distinct DNAm signatures in adolescence, with trauma-related DNAm reflecting broad stress-related processes and PLE-associated DNAm implicating regulatory mechanisms. We found little evidence that DNAm mediates the trauma-PLE association. Instead, adolescent exposures, particularly cannabis use, may distinctly influence trauma-related epigenetic variation with limited detectable downstream effects on PLEs. These findings support a context-dependent model of epigenetic risk and highlight the need for larger longitudinal studies to clarify causal pathways linking early adversity to psychosis.

Introduction Gender norms and roles are important determinants of physical and mental health in the key period of adolescence. Yet, the gendered pathways to mental health in adolescents are not fully understood. Using a conceptual framework for global adolescent mental health that we developed based on a Delphi process, we empirically investigated the associations between six gender-related constructs and adolescent mental health. Methods We used cross-sectional Gender and Adolescence: Global Evidence (GAGE) data from Ethiopia (2020) to explore the associations between sex, gender norms, psychological competencies, gender attitudes, gender roles, with the latter two also serving as mediators, and psychological distress (GHQ-12), using Structural Equation Modelling (SEM). Results The SEM model contained measurements from 1,584 adolescents, including 843 girls and 741 boys, with a median age of 13 years. Out of 14 pathways tested, we found statistically significant associations between psychological competencies and psychological distress; sex and gender attitudes; and between gender norms and psychological competencies, gender attitudes, and gender roles. Hence, the gender-related constructs were mostly associated with each other, rather than with psychological distress. Conclusion The gender-related constructs are strongly interrelated, thereby attenuating their individual effects on psychological distress. The interplay of gender-related constructs should be considered when developing interventions to promote mental health in adolescents.

Background. Nascent findings suggest that people with attention-deficit/hyperactivity disorder (ADHD) experience higher rates of mortality. To date, study samples have been insufficiently well-characterized to examine the mechanisms via which this neurodevelopmental condition elevates mortality risk. Methods. We used data from the 2007 and 2011 waves of the US National Health Interview Survey, a general population-based cohort study comprising 52097 adults (28675 women) aged 18 years or older at baseline. ADHD diagnosis and an array of demographic, socioeconomic, lifestyle, and co-morbidity (somatic and psychiatric) covariates were self-reported. Findings. At baseline, compared with unaffected individuals, participants with ADHD were more likely to be socioeconomically disadvantaged, smoke cigarettes, consume alcohol, and report symptoms of psychological distress. A median 7.75 years of mortality surveillance (range: 7.25-12.25) gave rise to 6597 deaths from all-causes. After adjustment for age, sex, ethnicity, and survey year, ADHD was associated with a markedly elevated risk of death (hazard ratio [95% confidence interval]: 1.58 [1.20-2.09]). Statistical adjustment for socioeconomic circumstances (11% attenuation), physical co-morbidities (15%), and lifestyle factors (17%) had only a modest impact on the ADHD-death gradient, with the greatest explanatory power apparent for symptoms of depression and anxiety (58%). The magnitude of the association of ADHD with mortality was commensurate to that for several well-established risk factors such as poverty (1.66 [1.55-1.78]), hypertension (1.41 [1.32-1.51]), and diabetes (1.71 [1.59-1.85]) but somewhat lower than cigarette smoking (2.51 [2.29-2.76]) after controlling for age, sex, ethnicity, and survey year. Associations between ADHD and cause-specific mortality from cardiovascular disease, cancer, and chronic respiratory disease were inconclusive. Interpretation. In the present study, the influence of ADHD on total mortality appears to be largely embodied via a series of malleable characteristics, particularly mental illness. If confirmed elsewhere, these results raise the possibility that risk factor modification via standard pharmacological and behavioral interventions could help reduce rates of premature mortality in this patient group. Funding. This paper received no direct funding. GDB is supported by the UK Medical Research Council (MR/P023444/1) and the US National Institute on Aging (1R56AG052519-01, 1R01AG052519-01A1).

Background: In prospective cohort studies, where an exposure is collected repeatedly, interest often lies in determining whether the timing of that exposure has a differential effect on a later outcome. The Structured Life Course Modeling Approach (SLCMA), where users select between temporal hypotheses of exposure specified a priori, provides one way to analyse such longitudinal data. However, few studies using SLCMA consider the effect of time-varying covariates (TVC) which may impact associations. Methods: We present a modified version of the SLCMA - called direct and mediated effects (DME)-SLCMA - which corrects for TVC. We first develop the DME-SLCMA method, test it through simulation, and apply it to psychosocial data from the Drakenstein Child Health Study (DCHS, n=336) to investigate relationships between maternal psychopathology, TVC of socioeconomic status, and offspring depressive symptoms. Results: We found that, on average, offspring depressive symptoms score increased by 3.9% (95% CI: 1.0%-6.9%, p = 0.039) for each unit of maternal psychopathology (SRQ) at 48 months whilst adjusting for time-varying socioeconomic status (at 18, 30, 42 and 54 months). Our simulations identified several realistic scenarios where selections ignoring TVC - with TVC mediated exposure effects present - were prone to be incorrect, including our DCHS example. Conclusion: DME-SLCMA is a robust new approach for life course modelling in the presence of time-varying covariates. We recommend adjusting for TVC whenever possible, and, when not possible, our simulation study identified that scenarios where mediated effects are comparable, or greater, in magnitude to direct effects are most prone to confounding.

Background: Childhood and adolescent hearing loss affects not only communication and cognitive development but also motor skills and school participation. Consequently, it generates inequalities in learning and educational inclusion. Nevertheless, no systematic review has yet analyzed these differences from an inclusive education perspective. Methods: A systematic review with meta-analysis was conducted following PRISMA guidelines and registered in PROSPERO. Observational studies comparing physical fitness between children and adolescents with hearing loss and their hearing peers were included. Methodological quality was assessed using the Newcastle--Ottawa Scale, and standardized effect sizes were calculated with a random-effects model. Results: Five studies (n=404) were analyzed. Findings revealed significant differences in strength, agility, speed, and balance. Moreover, the meta-analysis showed a large standardized effect favoring hearing children (ES=-2.35; 95% CI: -3.34 to -1.37). Conclusions: Children and adolescents with hearing loss present significantly lower physical fitness, which may affect the planning of physical education activities if their capacities are misinterpreted. Implementing inclusive and adapted strategies within the school curriculum is essential to ensure equal opportunities, improve physical fitness, and promote educational equity.

Background Evidence on factors associated with cannabis for medical purposes (CMP) authorizations among Veterans Affairs Canada (VAC) clients remains limited and inconsistent, particularly concerning mental health and posttraumatic stress disorder (PTSD), a leading indication for use. We investigated demographic, clinical and service characteristics associated with VAC authorizations for CMP reimbursement. Method We linked VAC administrative CMP program data with responses from the 2019 Life After Services Studies cross-sectional survey of Regular Force veterans released between 1998 and 2018. Multivariable logistic regressions examined associations between CMP reimbursement (yes/no) and demographic, clinical and well-being factors, with analyses stratified by PTSD status. Results Among 1,289 respondents (weighted n=33,131), 18.4% were authorized for CMP reimbursement. Younger age (<40 vs. [&ge;]60 years: OR 4.78, 95% CI: 2.24-10.21), unemployment with inability to work vs. employed (OR 3.10, 95% CI: 1.78-5.40), land service vs. air (OR 2.07, 95% CI: 1.22-3.50), PTSD (OR 2.81, 95% CI: 1.69-4.66), anxiety (OR 2.32, 95% CI: 1.45-3.70), and severe pain vs. no pain (OR 3.61, 95% CI: 1.97-6.60) were independently associated with authorization. Unemployment and severe pain were consistent correlates across PTSD strata. Among those without PTSD, younger age, multiple physical conditions, and frequent mental health visits were significant; among those with PTSD, shorter service, witnessing destruction, and suicidal ideation were additional factors. Conclusions CMP authorization patterns among Canadian veterans reflect the intersection of mental health, pain, and functional impairment, with variation by PTSD status. These findings underscore the need for longitudinal research on CMP mechanisms, effectiveness and safety.

Introduction Education is a core social determinant of health for children and adolescents. Unfortunately, academic achievement, health, and wellbeing of adolescents have decreased in many developed countries in the past decade. The purpose of the Wellbeing and Education linkages in school-aged children (WELL-ED) study is to examine associations of school absences and academic achievement with use of school-based and community-based health and social welfare services. In addition, we will assess user experiences and multi-sector services pathways of school-aged children for a better understanding of how the service system could respond to the needs of children. Methods and analysis WELL-ED is a large population-based study that combines register data on school absences and educational support from municipalities with register data on healthcare and social service use collected from wellbeing services counties in Finland. The study cohort includes all children who attended mandatory education in public schools in Southern Finland in school year 2023-2024. A smaller cohort of adolescents in school year 8 was invited to complete a user experience survey. The primary outcomes of this study are related to equity of service use. Ethics and dissemination The Regional Committee on Medical Research Ethics of the Helsinki and Uusimaa Hospital District (2803/2024) has approved the WELL-ED study protocol. For the survey, adolescents in year 8 and parents of adolescents younger than 15 provided informed consent. Results will be published in peer-reviewed journals, summaries will be sent to participating municipalities and wellbeing services counties and press releases will be written on key findings.

Although language acquisition delays are frequently observed in children with autism spectrum disorder (autism), our current understanding of the neurobiological mechanisms underlying language development in autism is sparse. Previous studies have found resting-state electroencephalography (EEG) power to be associated with language abilities in autistic children. However, longitudinal studies examining resting-state EEG phase coherence in relation to language development in preschool-aged children with autism are limited. This study aimed to characterize age- and group-related changes in whole-brain coherence in neurotypical children and in autistic children with and without language delay. Resting-state EEG and language data were collected at 2, 3, and 4 years of age. Peak phase coherence within the alpha band (6-11 Hz) was calculated at each timepoint and differences in the developmental trajectory of peak alpha coherence (PAC) were analyzed. In neurotypical children, PAC increased between 2 and 4 years of age. In contrast, PAC did not significantly change with age in children with autism. However, when examining autistic children based on language delay status, PAC increased with age in autistic children without language delay, but not in children with language delay. Exploratory analysis revealed evidence for an interaction between PAC and age, suggesting that the direction of the association between PAC and VDQ varied across age. Overall, these results support previous findings of altered oscillatory connectivity in autism and suggest that differences become apparent early in development. Importantly, phase coherence may not only differentiate diagnostic groups but also capture meaningful variability within the autism group. Future research should further investigate the use of EEG coherence as a biomarker of language development in autism.

Background: Pregnancy loss has important implications for womens health. Although maternal age is a well-established risk factor, the contribution of routinely measured cardiometabolic and behavioral markers at population-scale remains incompletely characterized. Objective: To examine associations between cardiometabolic, nutritional, and behavioral risk markers and pregnancy loss among U.S. women of reproductive age. Methods: We conducted a cross-sectional analysis of 4,842 U.S. women aged 20-44 years with [&ge;]1 pregnancy using the National Health and Nutrition Examination Survey data (2013-2023). Pregnancy loss was defined as [&ge;]1 prior miscarriages. Exposures included body mass index, smoking exposure (cotinine), lipid biomarkers, vitamin D and folate, and a composite cardiometabolic-nutritional risk score. Survey-weighted logistic regression estimated adjusted odds ratios (aORs) and 95% confidence intervals, with bootstrap resampling for predictor robustness. Results: The weighted prevalence of pregnancy loss was 23%. Higher odds of pregnancy loss were associated with increasing age (aOR per year=1.02; 95% CI: 1.00-1.04), Non-Hispanic Black race (aOR=1.32; 95% CI: 1.00-1.74), overweight (aOR=1.56; 95% CI: 1.16-2.11), obesity (aOR=2.06; 95% CI: 1.39-3.05), and smoking (aOR=1.58; 95% CI: 1.19-2.10). Adverse lipid profiles, particularly elevated triglycerides (aOR=1.83; 95% CI: 1.16-2.90) and high low-density lipoprotein (aOR=2.97; 95% CI: 1.45-6.61), were independently associated with pregnancy loss. Vitamin D/folate were not stable predictors. Higher composite cardiometabolic-nutritional risk scores were observed among women with pregnancy loss (P=0.026). Conclusion: Pregnancy loss clustered with adverse cardiometabolic and behavioral risk markers in a nationally representative population. These findings highlight pregnancy loss as a marker of broader metabolic vulnerability supporting the need for longitudinal studies and cardiometabolic profiling to inform preconception care and risk stratification.

Introduction: Blackpool, England's most deprived local authority, has the highest drug-related death rate in the country. People in police custody with problem substance use are a key Core20PLUS5 inclusion-health group, yet referral from the police into structured drug and alcohol treatment is fragmented and relies heavily on self-report. We evaluated the current police-to-treatment route in Blackpool and designed an evidence-informed unified pathway. Materials and Methods: A mixed-methods service evaluation and pathway-design project was conducted during a six-month General Practice / Public Health rotation. Routinely collected referral data from Horizon (the local specialist drug and alcohol service) covering the 47-month period from December 2019 to October 2023 were analysed. Findings were triangulated with national policy, the Project ADDER and Liaison and Diversion evaluations, and the international evidence on police-led pre-arrest diversion. Results: Of 5,900 total referrals into Horizon over 47 months, only 269 (4.56%) originated from the police. Police referrals accounted for fewer than 5% of monthly referrals in 30 of 47 months, for 5 to 9.9% in 16 months, and for >/= 10% in only one month (10.8%, December 2022). Blackpool recorded 76 drug-misuse deaths in 2019-21 (19.4 per 100,000, approximately four times the England rate). A six-step unified pathway is proposed: Initiate Referral (opt-out, from ADDER Police and Liaison and Diversion); Initial Assessment; Tailored Treatment Plan; Continuous Support; Collaboration and Monitoring; and Evaluation and Adjustment. Conclusions: Police contact is markedly under-used as a gateway to treatment despite Blackpool having the highest drug-related mortality in England. An opt-out, multi-agency pathway anchored in Core20PLUS5 has the potential to narrow the treatment gap, reduce re-offending, and address the structural health inequalities that drive premature mortality.

Objective: We examined the link between cohabitation with a partner and nighttime smartphone use through the social control of health behavior theory. Background: Nighttime smartphone use is a behavioral risk factor for sleep problems. While previous research has predominantly focused on individual-level risks of sleep disturbances, the role of social context remains underexplored. Theoretical frameworks, specifically the Social Control of Health Behavior, suggest that social relationships regulate health-related behaviors; however, it is unclear how far this regulation extends to modern digital behaviors among couples. Method: We analyzed survey data from three waves of the SmartSleep Study (2018, 2020, and 2023; total N = 25,028), including a longitudinal follow-up subset (N = 1,003). We tested multivariate associations between living with a partner, changes in cohabitation status and frequent nighttime smartphone use by fitting generalized linear mixed-effects models. Additionally, we mapped the complex interplay between indicators of social integration, social support, smartphone use, and sleep quality using hierarchical clustering of non-linear correlations. Results: Cohabiting participants had lower odds of frequent nighttime smartphone use compared to those living alone (OR = 0.66; 95% CI: 0.61, 0.72). This lower risk was driven primarily by cohabitation with a partner (OR = 0.49; 95% CI: 0.36, 0.66). Longitudinal analysis supported these findings, showing that sustained cohabitation was associated with less frequent nighttime use (OR = 0.56; 95% CI: 0.38, 0.82). Clustering analysis revealed that indicators of social integration and support clustered with favorable sleep quality. Conclusion: Our findings suggest that the health-protective effects of cohabitation with a partner extend to digital behaviors. Consistent with social control of health behavior theory, the presence of a partner appears to reduce frequent nighttime smartphone use, highlighting the critical importance of considering social context when addressing digital health hygiene and promoting sleep.

Background: Psychological distress is common in chronic kidney disease (CKD) and is associated with reduced quality of life, treatment non-adherence, and worse clinical outcomes. Distress in CKD is also linked to difficulties adjusting to the demands of illness management. Despite this, psychological support remains inconsistently integrated within kidney care pathways, and existing interventions often lack clear theoretical specification and explicit targeting of mechanisms underpinning adjustment to CKD. Objectives: To describe the systematic development of iADJUST, a theory-informed patient co-designed digital psychological intervention targeting key cognitive and behavioural mechanisms involved in adjustment to CKD. Methods: Intervention development was guided by the Medical Research Council framework for complex interventions. A structured, iterative process integrated empirical evidence, psychological theory, and patient and public involvement and engagement. The Common-Sense Model of Self-Regulation and cognitive behavioural theories informed the identification of modifiable maintaining mechanisms associated with adjustment to CKD. Intervention components were mapped onto these mechanisms and refined through co-design with people living with CKD. Results: iADJUST is a six-session self-guided digital psychological intervention delivered over 12 weeks and supplemented by therapist contact. The intervention targets illness-related uncertainty, fatigue-related activity dysregulation, catastrophic what-if thinking, self-critical evaluation, and behavioural withdrawal. It integrates psychoeducation, cognitive and behavioural strategies, maintenance planning, and elements from acceptance and commitment therapy and compassion-focused approaches. Content is delivered through video, audio, and guided tasks and activities. Conclusion: iADJUST provides a theory-informed, evidence-based psychological intervention for CKD explicitly mapping intervention components to maintaining cognitive and behavioural mechanisms implicated in adjustment. Feasibility evaluation is underway.

Background Tobacco smoking during pregnancy increases the risk of preterm birth, small for gestational age (SGA), stillbirth, and longer-term adverse health outcomes. Globally, reducing smoking in pregnancy is a key public health priority, yet the organisation, accessibility, and effectiveness of cessation support varies substantially between countries and healthcare systems. Differences in policy implementation, resource allocation, and integration of cessation services into antenatal care influence uptake and success rates across diverse settings. In England, pregnant women are entitled to free smoking cessation support, however, service delivery varies across regions with mixed efficacy. While tobacco smoking is more prevalent in deprived communities, there is limited understanding of how, why, for whom, and under what circumstances these services are most effective, particularly in areas of social deprivation, such as the North East and Yorkshire. Objective To conduct a realist evaluation to understand how smoking cessation services support pregnant women in areas of social deprivation to stop smoking and reduce adverse perinatal outcomes. Methods This multi-site realist evaluation will be conducted across three NHS maternity services in West Yorkshire, England. The study comprises four iterative stages: (1) development of initial programme theories through realist-informed literature scoping and stakeholder consultation; (2) case study data collection including qualitative interviews with pregnant women (approximately 15-30) and staff (approximately 15-30); (3) analysis of routine anonymised maternity and neonatal electronic data collected over a one-year period; and (4) realist analysis to refine context-mechanism-outcome (CMO) configurations. Qualitative data will be analysed using realist logic supported by NVivo software. Quantitative data will be analysed using descriptive and inferential statistics to explore associations between smoking cessation engagement and perinatal outcomes. Ethics and dissemination Ethical approval was obtained through the UK Health Research Authority and a Research Ethics Committee prior to study commencement (IRAS 364173; REC reference number 26/SC/0020). Findings will inform recommendations to improve smoking cessation support for pregnant women in deprived areas. Results will be disseminated through peer-reviewed publications, conference presentations, and stakeholder engagement.

Background Multimorbidity is increasingly prevalent, and associated with worse clinical and psychosocial burdens. Interoception, the brain's ability to sense and interpret internal bodily signals, may contribute to multimorbidity, through its link with health behaviors, stress regulation, and mental health. This study examines whether self-reported interoceptive accuracy and attention is associated with multimorbidity, by identifying multimorbid subgroups and their interoceptive profiles. Methods Morbidity classes were identified through latent class analyses in two Dutch survey datasets, focusing on depression and alexithymia (DA-dataset; N = 671) and lifestyle factors (L-dataset; N = 1022). Linear regression analyses were used to assess interoceptive accuracy and attention (by the Interoceptive Accuracy Scale and Interoceptive Attention Scale respectively) among different subgroups. Results Multimorbid subgroups were characterized by older age, low socioeconomic position, and elevated physical, psychological, and behavioral problems. Multimorbid classes exhibited lower interoceptive accuracy (DA-dataset: B = -1.14, 95% CI = [-2.89, 0.62]; L-dataset: B = -2.36, 95% CI = [-3.83, -0.89]) and higher attention (DA-dataset: B = 3.62, 95% CI = [0.97, 6.27]; L-dataset: B = 1.07, 95% CI = [-1.42, 3.56]) compared to healthier classes. Conclusion Multimorbid populations demonstrated lower interoceptive accuracy and higher interoceptive attention. This highlights the psychosocial complexity of multimorbid populations which may impact their self-management and health behavior. These findings underscore the need to expand treatments to include psychosocial domains for multimorbid patients.

Background: Adults with severe mental health conditions (often referred to as severe mental illness, SMI) experience 15 to 20 year mortality gap relative to the general population, with lung cancer a significant contributor. National cancer policy targets earlier diagnosis but does not explicitly address how pathways function for this group. Aims: This study aimed to describe lung cancer risk, prevalence, screening eligibility, referral activity and diagnostic pathway performance for adults with SMI in South East London (SEL), and to examine where along the pathway inequalities arise. Methods: Co-designed with experts with lived experience and voluntary sector, this exploratory mixed-methods service evaluation combined quantitative analysis of routinely collected data from the Quality Outcomes Framework (QOF), SMI Register and Cancer Waiting Times Record (April 2023-March 2024) with semi-structured qualitative interviews (n=11 clinical staff) and focus groups (n=6 adults with lived experience of SMI). Quantitative and qualitative data were analysed using descriptive statistics and framework-based thematic analysis respectively, and findings were integrated using a joint display approach, organised by the Consolidated Framework for Implementation Research (CFIR). Results: Lung cancer prevalence was approximately double among adults with SMI (0.17% vs 0.09% in the general population). Despite Urgent Suspected Cancer (USC) referral rates being more than twice as high in the SMI population (63 vs 28 per 100,000), fewer cancers were detected via planned general practice (GP) routes (11% vs 20%), the 28-day Faster Diagnosis Standard was not met for any SMI patient diagnosed with lung cancer during the study period; overall FDS performance was 76% in the SMI population compared with 84% in the general population; and appointment non-attendance was more than double that in the general population (6% vs 3%). Qualitative findings identified individual, service and system-level mechanisms, including stigma, diagnostic overshadowing, fragmented coordination, and rigid pathway protocols, that compound disadvantage across lung cancer pathway stages. Conclusions: Inequality in lung cancer outcomes for adults with SMI accumulates across the pathway rather than arising at a single point of failure. Addressing this requires proportionate adaptations within existing cancer pathways, alongside routine reporting of cancer outcomes stratified by SMI population. Keywords: severe mental health conditions, lung cancer, health inequalities, cancer screening, diagnostic pathway, mixed methods

Background: Infants with critical congenital heart disease (CHD) are at high risk for abnormal brain development and later neurodevelopmental impairment. We hypothesized that the trajectory of perioperative whole-brain network development would predict neurodevelopmental outcomes in early childhood. Methods: This prospective longitudinal cohort of neonates with critical CHD (n = 97) underwent preoperative and/or postoperative brain MRI with diffusion imaging. Whole-brain network measures were derived from structural connectomes. Neurodevelopment was assessed between 1 and 4 years using the Bayley Scales of Infant and Toddler Development. Results: White matter injury was associated with slower perioperative growth in global efficiency (p = 0.013), a measure of network integration, whereas cardiac physiology was not associated with network development. Infants with greater perioperative increases in global efficiency had higher cognitive (p = 0.001), language (p < 0.001), and motor (p = 0.008) scores. For each 1-standard deviation increase in the trajectory of global efficiency, cognitive scores increased by 8.2 points (95% CI, 3.64-12.78), independent of brain injury and socioeconomic factors. Conclusion: In infants with critical CHD, longitudinal whole-brain network development was associated with neurodevelopment across multiple domains. Early network development may represent a candidate biomarker of neurodevelopmental risk and resilience in this population.

In the past two decades, the focus on genome-wide association studies in large samples of unrelated patients has overshadowed family genetic studies. Therefore, little is still known about the levels and effects of the transmission of polygenic risk scores (PRS) among familial cases of schizophrenia (SZ) or bipolar disorder (BD) and their unaffected relatives. Prior research has shown that PRS are elevated in both patients and young individuals at familial risk for BD and SZ. We sought to study the transmission of PRS in affected multigenerational families and non-affected adult relatives (NAARs) with or without other non-mood nonpsychotic DSM-IV diagnoses and unrelated non-affected individuals from the same population. We genotyped 1,117 participants divided in 48 families from the Eastern Quebec Schizophrenia and Bipolar Disorder Kindreds. PRSs for both SZ and BD were computed using Multivariate Lassosum. For both SZ PRS and BD PRS, SZ and BD cases present higher PRS compared to controls, replicating previous findings. Regardless of a diagnosis of other non-psychotic and non-mood conditions, NAARs presented higher PRS than the unrelated cohort. Crucially, a subset of families presented consistently low PRS transmission profiles across generations, falling below expectations from our polygenic inheritance model. When the effect of individual PRs is accounted for, we observed sex-specific associations between familial PRS and patients' symptom dimensions. Our results clearly demonstrate that polygenic inheritance alone does not adequately explain disease transmission in families. Such an approach may also clarify why some families exhibit dense clustering of cases despite minimal polygenic burden.

Electronic health record (EHR) prediction models often summarize longitudinal histories as static patient-level features, which may omit potentially informative event ordering. We developed a simplified spike-timing-dependent plasticity (STDP)-inspired framework that represents asynchronous EHR data as sparse, directional transition features. The approach encodes whether one clinical event precedes another within prespecified temporal windows, preserving event identity, directionality, and approximate timing while retaining feature-level interpretability. We evaluated this framework in two retrospective prediction tasks with different temporal scales: incident acute kidney injury (AKI) prediction in 17,351 MIMIC-IV ICU stays and early postoperative recurrence prediction in 713 CUMC patients with pancreatic ductal adenocarcinoma (PDAC). Models were compared with static burden features (demographics, comorbidities, raw lab measurements) and in addition with STDP transitional feature sets using patient-level cross-validation and rolling prediction horizons. In AKI, a calibrated STDP ensemble model showed higher discrimination than static burden alone at the 24-hour decision snapshot for AKI by 72 hours, with AUROC 0.838 versus 0.800, and at 48 hours for near-term AKI prediction, with AUROC 0.868 versus 0.827. In PDAC, STDP transition features modestly improved Day -30 preoperative recurrence prediction, with AUROC 0.611 versus 0.587 and AUPRC 0.323 versus 0.318 for static burden and showed similar performance at Day 0 (7 days before recorded surgery date), with AUROC 0.681 and AUPRC 0.363. Decision-curve and feature analyses suggested that selected temporal transitions were clinically interpretable across renal, inflammatory, hepatobiliary, hematologic, glycemic, and nutritional trajectories. These findings suggest that STDP-inspired transition features may provide a practical, interpretable way to incorporate temporal ordering into EHR-based risk prediction across both acute and longitudinal settings

Background Thalassemia is one of the most common monogenic disorders worldwide, current screening strategies combining hematological testing with molecular assays still carry a risk of missed diagnoses and undesirable efficiency, particularly for complex structural variants and rare mutations. Methods In this prospective double-blind, multicenter cohort study of 3,842 participants (3,362 pregnant women and 480 male partners), we conducted a head-to-head comparison to systematically evaluate the incremental clinical value and detection performance of single-molecule nanopore sequencing in thalassemia (SMITH) against conventional hematological testing and next-generation sequencing (NGS). Findings The overall concordance rate between NGS and SMITH was 98.6% (3789/3842). The discrepant cases (n=53) were directly attributed to the superior detection capabilities of SMITH, which successfully identified complex structural rearrangements-including 45 -globin gene triplications and four HK alleles-that were missed by NGS. Furthermore, SMITH accurately detected four rare variants (c.134_135insT/, c.-22(C>T)/, {beta}N/{beta}c.316-290delinsAGGGCAATAATTT and {beta}3.5 kb deletion/{beta}N ) and resolved ten trans and three cis configurations within the globin gene allele. Clinically, these technical advantages translated to a 9.3% (5/54) increase in the detection rate of high-risk prenatal couples, effectively preventing one birth affected by moderate-to-severe thalassemia. Additionally, SMITH corrected a diagnostic discrepancy in one case (HK vs. -3.7), sparing the couple from an unnecessary invasive procedure. Interpretation Our findings demonstrate that SMITH provides a powerful platform for resolving globin gene rearrangements, detecting rare variants, and enabling direct haplotype phasing. By effectively eliminating diagnostic blind spots, SMITH is expected to become an optimal method for thalassemia prevention programs. Funding This study was supported by Chinese National Natural Science Foundation Projects 81760037 and 82271894.