Archives of Disease in Childhood

Background: 48,XXYY syndrome is a rare sex chromosome aneuploidy (SCA) characterized by neurodevelopmental deficits and medical comorbidities. The limited information available in the literature is almost exclusively limited to postnatally diagnosed cases. This study aims to describe the early medical and developmental features of prenatally identified 48,XXYY infants, with comparisons to 47,XYY, 47,XXY cohorts, and typical populations, as well as previously reported postnatally diagnosed 48,XXYY cases. Methods: The eXtraordinarY Babies Study prospectively follows children prenatally identified to be at high risk for SCA with annual medical and neurodevelopmental evaluations. Data presented herein include the prevalence of medical conditions, developmental milestones, developmental and adaptive functioning assessment scores, and therapy utilization in participants confirmed to have 48,XXYY. Comparisons were made between this cohort and the typical population, infants with 47,XYY and 47,XXY also enrolled in the eXtraordinarY Babies Study, and a 2008 cohort of individuals postnatally identified 48,XXYY. Results: Infants with 48,XXYY exhibited a range of early medical features, including high rates of feeding and GI disorders (breastfeeding difficulties, gastroesophageal reflux, and eosinophilic esophagitis), allergic disorders (food allergies and environmental allergies), and hypotonia. Developmental and adaptive functioning scores indicated delays in motor, communication, and social domains, with nearly all infants receiving speech therapy, physical and/or occupational therapy. Comparisons with the 47,XYY and 47,XXY cohorts revealed more medical and developmental challenges in the 48,XXYY group, however there was variability and some overlap with both the general population and sex chromosome trisomy conditions. Additionally, comparison to the 2008 postnatally identified 48,XXYY cohort indicated that while prenatal diagnosis allowed for earlier intervention, developmental outcomes in the first years of life were similar between the two groups. Conclusions: 48,XXYY diagnosed prenatally facilitates early monitoring, anticipatory guidance, and proactive referrals for medical evaluations and intervention, given developmental delays and medical challenges are more common in infancy and early childhood compared to the general population and trisomy SCAs. These findings provide valuable insights for genetic counselors and healthcare providers, emphasizing the spectrum of medical and developmental findings and importance of early and proactive care to support individual outcomes. Prospective study of this prenatally identified cohort will provide important natural history and phenotypic variability in XXYY, as well as identification of predictors of health and developmental outcomes.

Background Sierra Leones neonatal mortality rate is among the highest in the world. Koidu Government Hospital opened a Special Care Baby Unit (SCBU) in 2020. To increase knowledge of the SCBU health care providers (HCPs), a neonatal curriculum was implemented to facilitate HCP education on management of neonatal conditions. The aim of this study was to understand the effect of the curriculum on knowledge acquisition and the perception of the teaching methodologies among participating HCPs. Methods US-based mentors facilitated a two-phase, flipped classroom, virtual neonatal medicine curriculum between October 2024 and April 2025, followed by one-week in-person education sessions with SCBU HCPs. With each phase, participants completed pre- and post-test educational assessments. At the end of the curriculum, they completed a subjective assessment to capture perceptions related to the quality of teaching methodologies integrated within the curriculum. Wilcoxon signed rank test was used to assess pre- versus post-test change. Descriptive statistics were used to analyse the subjective assessment. Results Thirty-eight participants completed the educational assessments, 30 (79%) took all four pre- and post-tests; 25/38 (65.8%) were female, 27 (71.1%) were nurses. Median correct answers for both phases increased from the pre- to post-test for individual learners [Phase 1, pre-test 14/27 (51.9%), post-test 23/27 (85.2%), p<0.001], [Phase 2, pre-test 14/25 (56.0%), post-test 23/25 (92.0%), p <0.001]. Thirty-one participants completed the subjective assessment, of whom 96.8% (30/31) rated the curriculum to be "very effective." All 31 participants indicated that the in-person instruction was "very helpful." Through open text responses, they offered valuable insight into challenges, strengths, and next steps. Conclusion This neonatal curriculum resulted in significantly increased knowledge and was well regarded. Adapting this curriculum or similar curricula show promise to improve the quality of care for small and/or sick neonates in low resource settings.

Background Large-for-gestational-age (LGA) and macrosomic newborns are at increased risk of adverse perinatal outcomes, including death, yet the burden of neonatal mortality associated with these conditions in low- and middle-income countries (LMICs), where ongoing nutritional and epidemiological transitions suggest their prevalence will rise, remains poorly quantified. In this study, we quantify the neonatal mortality risk associated with LGA and macrosomia from 16 subnational birth cohorts in low- and middle-income countries between 2000 and 2017. Methods and findings This is an individual-participant meta-analysis to estimate neonatal mortality rates (NMRs) and relative risks among LGA infants (>90th and >97th percentile birth weight-for-gestational-age using INTERGROWTH-21st) versus appropriate-for-gestational-age (AGA, 10th-90th percentile) infants. Macrosomic ([&ge;]4000 g and [&ge;]4500 g) neonates were compared with those weighing 2500 g-3999g. Missing birth weights were imputed using recalibration and multiple imputation methods. We used random effects meta-analysis to pool relative risks. Median prevalences of LGA >90th and >97th percentile were 5.3% (interquartile range 3.6-8.2) and 2.6% (IQR 1.3-4.5), respectively; macrosomia ([&ge;]4000 g and [&ge;]4500 g) prevalences were 1.0% (IQR 0.3-3.1) and 0.06% (IQR 0.0, 0.30), respectively. Mortality was highest among preterm plus LGA infants (61.3 per 1000). LGA infants in the >90th percentile had over twofold increased mortality compared with appropriate-for-gestational-age infants (RR: 2.46; 95% CI: 1.86-3.25), while >97th percentile infants had a higher risk (RR: 3.77; 95% CI: 2.50-5.69). Term LGA >97th percentile infants also showed elevated mortality (RR: 3.14; 95% CI: 1.58-6.22). For LGA >97th percentile, the risk was higher in the early neonatal period (RR: 2.71; 95% CI: 1.92-3.82) than late (RR: 1.69; 95% CI: 1.22-2.34). There was no overall association between macrosomia ([&ge;]4000 g) and neonatal mortality. Population attributable fractions were 7.2% for LGA >90th percentile and 0.4% for macrosomia ([&ge;]4000 g). Conclusions Neonatal mortality risks were elevated among LGA infants in low- and middle-income countries, particularly at extreme values (>97th percentile) and during the early neonatal period. Macrosomia showed weaker, less robust associations. Although LGA prevalence is currently low ([~]5%) and contributes less to neonatal mortality than small newborns, ongoing nutritional and epidemiological transitions suggest increasing prevalence. This highlights the need for strengthened surveillance, monitoring, and improved delivery planning to ensure that no population is left behind.

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 One in four surgical patients carries a drug allergy label, of which an estimated 90% are incorrect. Avoidance of first-choice drug therapies may lead to worse postoperative outcomes. We sought to determine the nature and extent of any association between drug allergy labels and postoperative complications. Methods A multicentre observational study in 21 NHS hospitals. Eligible patients were 18 years or older, undergoing common surgical procedures: primary hip or knee replacement; internal fixation of closed long bone fracture; colorectal resection; trans-urethral resection of prostate or bladder tumour; caesarean section; hysterectomy. Exclusion criteria: use of antibiotics in the two weeks prior to surgery, previous participation in the study. Primary outcome was postoperative complications within 30 days following surgery, a composite outcome comprising: all postoperative infections, anastomotic leak, acute respiratory distress syndrome, myocardial infarction, postoperative bleed, pulmonary embolism, stroke, antimicrobial side effects, death. Results Among 13,646 patients, 3924 (29%) carried greater than or equal to1 drug allergy labels. Labelled patients were more likely to develop postoperative complications (989/3924 (25%) vs 1926/9722 (20%); OR 1.21 [1.10-1.34]; p<0.001). They were more likely to develop surgical site infections (337/3924 (9%) vs 760/9722 (8%); OR 1.19 [1.03 -1.38]; p<0.018), and any postoperative infection (750/3924 (19%) vs 1472/9722 (15%); OR 1.24 [1.11-1.38] p<0.001). Labelled patients experienced increased risk of allergic drug reactions (31/3924 (0.01%) vs 29/9722 (<0.01%); OR 3.00 [1.77-5.09]; p<0.001), but no increase in mortality. Conclusions Drug allergy labels are common, but often incorrect. Labelled patients experience worse postoperative outcomes, including infective and non-infective complications and increased risk of allergic drug reactions. Trial registration Registered with ISRCTN registry, ISRCTN15775657.

Background: Artemisinin-based combination therapies remain the mainstay of malaria control strategies; nevertheless, the advent of genetic markers linked to partial artemisinin resistance in Plasmodium falciparum has elicited substantial concern across African settings. To assess the prevalence, geographic distribution, and clinical associations of these molecular markers, we undertook a systematic review and meta-analysis of observational cohort studies.Methods: We conducted a search of cohort studies published between January 2015 and June 2025, following PRISMA 2020 guidelines. We queried databases including PubMed/MEDLINE, Scopus, Web of Science, and CINAHL. Eligibility required prospective enrollment of patients, longitudinal monitoring (therapeutic efficacy studies), and pfkelch13 propeller domain genotyping.Results: A meta-analytical synthesis of 888 isolates from six core prospective cohorts revealed a pooled prevalence of 6% (95% CI: 2.1%-11.8%) for validated pfkelch13 mutations. A profound geographic dichotomy was identified: while West and Central African cohorts maintained a 0% prevalence, East African hotspots showed significant expansion, with prevalence reaching 12.8% in Rwanda and up to 25.5% in Northern Uganda; high statistical heterogeneity (, ) reflects this biological divergence. Conclusions: These findings highlight the established and expanding presence of artemisinin partial resistance in East Africa. Standardized surveillance is essential to adapt malaria control policies across the continent. Keywords: Africa; artemisinin resistance; clinical indicators; pfkelch13 gene; molecular markers; partial resistance; Plasmodium falciparum.

Abstract Purpose: Published clinical outcome data on preconception carrier screening (PCS) in Central Asia are limited. We report the first clinical implementation study from Uzbekistan of a whole-exome sequencing (WES)-based multi-platform PCS program combining exome sequencing with targeted SMA, FMR1, and DMD assays. Methods: We retrospectively analyzed anonymized data from 65 individuals (19 couples, 27 singletons) screened at IMC Genomics, Tashkent, between January 2024 and May 2026. WES covering the protein-coding regions of approximately 20,000 genes was followed by exome-wide bioinformatics filtering and clinical geneticist interpretation. Partly overlapping cohorts underwent SMA carrier screening (n=179), FMR1 CGG-repeat analysis in females (n=155), and DMD deletion/duplication testing in preconception females (n=29). Variants were classified by ACMG/AMP criteria against gnomAD v4.1. Results: Sixty-one of 65 WES-screened individuals (93.8%; 95% CI 85.2 - 97.6%) carried at least one reportable variant (152 instances across 126 genes). Four of 19 couples (21.1%; 95% CI 8.5 - 43.3%) were concordant for pathogenic or likely pathogenic variants in the same autosomal recessive gene; two were referred for preimplantation genetic testing for monogenic disease. SMA screening identified four carriers, including two 2+0 silent carriers; FMR1 analysis identified one intermediate allele; DMD MLPA identified no exonic rearrangements. Conclusion: This first reported WES-based multi-platform PCS program in Uzbekistan was feasible and clinically informative, identifying actionable couple-level reproductive risks and supporting structured implementation of reproductive genetic screening in Central Asia.

Introduction Care home (CH) influenza vaccination of staff improves resident health, yet uptake remains low at just over 11% (England, 2025/2026). We report an economic evaluation (EE) of "FluCare", an intervention to increase staff influenza vaccination through: vaccination clinics at CHs; promotional materials; and CH financial incentives. Method Seventy-five CHs were randomised to FluCare or control. A cost-consequence analysis took the influenza vaccination programme funder perspective, but also extended to the National Health Service (NHS) and CH perspective. Costs included: influenza vaccination; administration fee; FluCare components; CH resident NHS utilisation. Outcomes were: staff influenza vaccination rates; staff sickness; and resident mortality. Sensitivity analyses excluded intervention CHs that did not host vaccination clinics. Results Compared to control CHs, adjusted analysis found intervention homes with a mean absolute increase in vaccination rates of 1.8% (95% CI: -6.0%, 10.8%; p=0.572) at an increased cost of {pound}451 (95% CI: {pound}239, {pound}675; p<0.001) to the vaccination programme funders: {pound}249 per additional percentage point (PAPP) per CH. Vaccination clinics were delivered late in the influenza season, with 80% taking place from February 2023. Including only intervention CHs that hosted staff flu vaccination clinics (23/35), increases the mean difference to 10.1% (95% CI: 0.9%, 21.9%; p=0.018) and costs to {pound}805 (95% CI: {pound}603, {pound}1,079; p<0.001): {pound}79 PAPP per CH. Differences between trial arms in other costs and outcomes were marginal and generally non-significant. Conclusions FluCare delivered little improvement when staff flu vaccination clinics did not occur and had little impact on other costs/outcomes. Cost-effectiveness depends on willingness-to-pay for increased staff vaccination, but cost PAPP per CH improved from {pound}249 to {pound}79 when only CHs hosting clinics were considered. Late implementation, likely reduced impact by limiting clinic delivery, as reflected in sensitivity analysis. Future evaluations should implement FluCare earlier in the season.

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.

Background The European Association for the Study of the Liver (ESAL) - Steatotic Liver Disease (SLD) screening algorithm involves two steps; initial screening with FIB-4 followed by referral for vibration-controlled transient elastography (VCTE) in patients likely to have significant fibrosis (SF). However, VCTE is not widely available in resource-limited settings. Aim To optimise the EASL SLD screening algorithm for resource-poor settings using machine learning (ML). Methods We analysed data from 964 adults aged [&ge;]35 years who underwent VCTE at a tertiary referral centre in Sri Lanka between November 2024 and 2025. Multiple ML models using different methods and variable combinations were trained on 80% of the dataset and tested on the remaining 20%. Best models were selected based on performance and externally validated using data from 430 patients who underwent VCTE before November 2024. Model performance was compared with the FIB-4 using confusion matrices. Results A Random Forest model incorporating age, AST, ALT, and platelet count separately, rather than using FIB-4, outperformed. The all-variable ML model showed the best predictive performance for SF, with accuracy of 77.2%, recall of 0.762, precision of 0.778, and AUC-ROC of 0.818. The variables used in the model, in descending order of feature importance, were AST, platelet count, BMI, ALT, age, diabetes mellitus, hypertension, dyslipidaemia, sex, family history, hypothyroidism, diabetes complication and smoking. External validation demonstrated 75.1% accuracy and an AUC of 0.779. When used as the first step of the SLD screening algorithm, the all-variable ML model identified 37 (17.1%) additional true positives and reduced false-negative diagnoses by 50% compared with FIB-4. Conclusions ML-based models were more effective than the FIB-4 score as the first-line screening tool for VCTE referral, substantially improving the identification of patients with significant fibrosis in this South Asian cohort.

Introduction: Respiratory infections are a leading cause of morbidity. Newly available vaccines to prevent respiratory syncytial virus (RSV) disease and encouraging clinical progress on vaccines for human metapneumovirus (hMPV) and parainfluenza (PIV) could reduce the disease burden beyond existing influenza and SARS-CoV-2 immunisation programs. However, evidence on the contribution of these viruses to respiratory disease burden across the lifespan remains limited. Methods: We reviewed studies from 01/2002-11/2025 reporting age-stratified, medically attended cases of influenza, and at least one of RSV, hMPV, or PIV, in high-income countries, excluding periods substantially overlapping with the COVID-19 pandemic. Using only studies that tested for all four viruses, we estimated the age-specific proportion of cases that were non-influenza (total across RSV, hMPV and PIV) compared to influenza using a mixed-effects logistic regression model. Results: Following exclusions and screening, 61 studies were included in the primary analysis comprising >500,000 detections of the four viruses. We found that a substantial proportion of medically attended respiratory illness in infants and young children was due to PIV, hMPV and RSV, rather than influenza, with a non-influenza virus proportion of 90.2% (95% CI 85.9-93.2%) in young infants aged 0-6 months. The converse was true for school-aged children, with a non-influenza virus proportion of 34.8% (95% CI 26.5-44.2%) in children aged 5-18 years. In adults aged 65+ years, non-influenza causes of medically attended disease were common at 60.2% (95% CI 50.0-69.5%). Restricting to studies reporting hospitalised cases (n=19) produced broadly similar age-specific trends in relative virus burden contributions. Discussion: We highlight the significant burden of medically attended illness due to PIV, hMPV and RSV across ages, particularly in infant and preschool-aged children and older adults, supporting the need for effective vaccines targeting this burden.

Background Coeliac disease (CD) diagnosis on duodenal biopsies is limited by interobserver variability. We have previously demonstrated pathologist-level performance with our artificial intelligence (AI) model for the histopathological diagnosis of adult CD, but not in paediatric practice. As paediatric CD screening programmes expand internationally, accurate and scalable diagnostic tools are needed. We investigated whether an AI model trained exclusively on adult whole-slide images (WSIs) can generalise to paediatric CD diagnosis across independent centres. Methods A training and validation dataset of 9,958 WSIs from 8,421 adult patients (961 CD) from five centres was used to develop an ensemble of multiple-instance learning models using features from a foundation model. Testing was performed on 708 consecutive paediatric patients (86 CD) from two centres (Edinburgh and Southampton) not included in training. Model calibration was assessed, and probability outputs were grouped into clinically interpretable categories. Findings In adult cross-validation, the AI model achieved an area under the receiver operating characteristic curve (AUC) of 98.7%, sensitivity of 84.9%, specificity of 99.0%, and negative predictive value (NPV) of 98.1%. On testing (paediatric) datasets, performance remained high (AUC 98.8%, sensitivity 80.2%, specificity 98.4%, NPV 97.3%). Restricting analysis to predictions outside the intermediate-probability range (predicted CD probability <10% or [&ge;]65%; 85.3% of cases) improved sensitivity to 100% and specificity to 98.7%. No misclassifications were observed among high-confidence predictions (<2% or [&ge;]85%; 66.0% of cases). The expected calibration error was 0.03. Performance improved significantly when biopsies from both duodenal sites (bulb [D1] and descending [D2/3]) were considered. Interpretation Our AI model, trained on adult biopsies, generalises to paediatric CD diagnosis across centres and scanner platforms. Well-calibrated probability outputs provide clinically interpretable measures of diagnostic confidence and could support safe identification of CD-negative biopsies within defined thresholds. These findings demonstrate the feasibility of applying adult-derived AI models in paediatric populations and reinforce the importance of multi-site (D1 & D2) biopsy sampling.

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: Olfactory dysfunction (OD) in children remains underdiagnosed and poorly characterised. Despite its known impacts on nutrition, quality of life, safety awareness, and psychosocial development, no standardised diagnostic or management pathway currently exists for paediatric OD. This study aimed to characterise global practice patterns and identify diagnostic and therapeutic challenges unique to paediatric care. Methodology/Principal: A 44-item cross-sectional online survey was distributed to a verified international network of paediatric otolaryngologists across 36 countries via a closed professional platform. The survey assessed five domains: diagnostic practices, management protocols, technology and innovation, education and training, and barriers to effective care. Regional grouping was used to facilitate meaningful statistical comparisons. Categorical variables were evaluated using chi-square tests, with odds ratios and 95% confidence intervals reported for significant findings. Results: Of 351 potential participants, 167 responded (47.6% response rate). Most respondents (83%) reported seeing children with OD, yet 95% saw fewer than ten such patients annually. Psychophysical testing was never performed by 54.8% of respondents, while 88.4% routinely ordered cross-sectional imaging. Testing frequency increased significantly with patient age (Cochran's Q p<0.001). The most common barriers to objective testing were insufficient training (44.3%), time constraints (29.9%), and funding limitations (28.1%). Multidisciplinary collaboration was negligible. Significant regional variation was observed across most practice domains. Conclusions: Paediatric OD care is characterised by functional underinvestigation, fragmented multidisciplinary collaboration, and systemic educational gaps. These findings support urgent development of standardised clinical guidelines, age-appropriate validated assessment tools, and formal interdisciplinary care pathways.

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.

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.

Background: Neurological, neuropsychiatric, and neurodevelopmental disorders cluster in ALS families, sharing a common genetic architecture with ALS. Pathogenic variants in genes associated with other neurological, neurodevelopmental, or neuropsychiatric disorders may also co-occur in ALS and modify phenotype. We have sought to determine the prevalence and clinical pattern of likely-pathogenic/pathogenic (LP/P) non-ALS neurological, neurodevelopmental, and neuropsychiatric variants, alone and in combination with ALS-gene variants, in two large ALS cohorts. Methods: Whole-genome sequencing (WGS) of 469 Irish and 774 Answer ALS people with ALS (pwALS) was analysed for ClinVar LP/P variants associated with other neurological (n = 15541), neurodevelopmental (n = 9761), and neuropsychiatric (n = 321) phenotypes. Inheritance patterns for associated genes (autosomal recessive/autosomal dominant) along with the associated phenotype were validated using OMIM. Standardised clinical data included family history, site and age of onset, El Escorial category, survival, motor decline, and cognitive and behavioural assessments. Known ALS-gene variants and C9orf72 repeat expansion status were included for each cohort. Results: Non-ALS neurological variants were identified in 47/469 (10.0%) Irish and 69/774 (8.9%) Answer ALS participants, most frequently in hereditary spastic paraplegia-associated genes (3.2% Irish; 2.8% Answer ALS). Irish neurological variant carriers showed higher frequency of respiratory onset (10.6% vs 1.2%, Fisher's exact p = 0.002, {Phi} = 0.20) and fewer premorbid behavioural symptoms (0.92 +/- 0.56 vs 3.08 +/- 0.97, Cohen's d = -0.40). Neurodevelopmental variants occurred in 12/469 (2.6%) Irish and 20/774 (2.6%) Answer ALS participants. In the Irish cohort, neurodevelopmental variant carriers had significantly shorter survival in Cox proportional hazards model (log-rank p = 0.005), corresponding to a more than two-fold increased hazard of death (HR = 2.25, 95% CI 1.26-4.00), and had significantly increased familial burden of neuropsychiatric disorders among first- and second-degree relatives (negative binomial IRR for carriers = 2.41, 95% CI: 1.12-5.18, p = 0.025). Across combined cohorts, 18 individuals (Irish n = 8; Answer ALS n = 10) carried [&ge;]2 LP/P variants spanning ALS and non-ALS genes. Conclusion: Rare LP/P variants in genes associated with other neurological and neurodevelopmental disorders occur in up to 12% of pwALS across two independent cohorts. Carriers show distinct phenotypes, shorter survival, and characteristic family history patterns. These findings suggest that extended pleiotropic and oligogenic architectures may contribute to ALS heterogeneity.

As genetic testing becomes increasingly integrated into Parkinson disease (PD) research, including targeted testing for variants in LRRK2 and GBA1, the return of individual research results is becoming more common. However, limited qualitative data exists regarding how research participants experience genetic results disclosure and post-test genetic counseling in PD research settings. We conducted semi-structured qualitative interviews with participants (n=13) enrolled in the Parkinson Precision Medicine Initiative (formerly Parkinson Progression Markers Initiative; PPMI) who had received PD-related genetic test results and post-test genetic counseling. Interviews were conducted 1 to 3 weeks following result disclosure and analyzed using thematic analysis with a primarily deductive coding approach informed by study aims and inductive identification of emergent themes. Four primary themes were identified: (1) personal connection and motivations for participation, (2) centrality of result disclosure and information preferences, (3) emotional experiences and support needs, and (4) communication quality and alignment with participant needs. Overall, our findings underscore the importance of person-centered genetic counseling within PD research. As return of genetic and biomarker results in research and clinical trial contexts expand, thoughtful integration of relational, informational, and communication-focused practices will be essential to support participant engagement and trust.

Large language models (LLMs) such as ChatGPT are rapidly reshaping healthcare education and simulation-based training in non-technical skills (NTS), yet no bibliometric analysis has mapped this landscape. We searched seven open-access databases (OpenAlex, PubMed, Europe PMC, Crossref, Semantic Scholar, CORE, DOAJ) for English-language publications from January 2020 to March 2026. From 100,277 initial records, a sequential keyword funnel yielded 830 candidate papers, which were screened by 83 independent Claude Sonnet 4.6 AI agents applying pre-specified inclusion criteria (PRISMA-trAIce compliant; Cohen's kappa = 0.86 pre-reconciliation, 1.0 post-reconciliation). The final AI-verified corpus comprised 551 papers with a compound annual growth rate of 109%, contributions from 2,398 authors across 279 journals in 58 countries, and an h-index of 41. ChatGPT dominated the model landscape (46% of papers), with open-source models virtually absent. Virtual patient chatbots were the leading simulation modality (106 papers). Among NTS domains, communication (145 papers) and decision-making (135 papers) were most studied, whereas teamwork, leadership, situational awareness, and crisis resource management were markedly underrepresented. Only 6 urology-relevant papers were identified, none examining LLM integration within boot camp training formats. The field is growing at extraordinary pace but remains concentrated in a narrow range of NTS domains and a single proprietary model. Critical gaps persist in team-based skills training, open-source model evaluation, and specialty-specific simulation. AI-assisted bibliometric screening using multiple independent agents is feasible, reliable, and scalable, offering a replicable methodology for mapping fast-evolving research fields.

Objectives People with mental health conditions experience increased rates of diagnostic errors and delays in acute treatment. While causes such as diagnostic overshadowing (misattribution of physical symptoms to mental health conditions) are well documented, less attention has been paid to the organisational and structural conditions that shape diagnostic work. This study examines how physical illness is diagnosed in patients with mental health conditions in emergency departments (EDs), with a focus on the structural conditions that enable or constrain safe diagnostic practice. Method We conducted a multi-site ethnography across three purposively selected EDs in England between April 2023 and April 2024, varying in size, population demographics, and local service configuration. Data were collected through 284 hours of non-participant observation and 20 semi-structured interviews with ED staff. Results Our analysis identified four recurring structural gaps that shaped the conditions under which physical health diagnosis took place for patients with mental health conditions: a design gap, whereby targets and physical layouts constrained diagnostic reasoning; a preparedness gap, reflecting the lack of structural support to allow staff to act on their existing knowledge and skills; a coordination gap, reflecting fragmented ownership and the challenges of joint assessment across mental and physical healthcare teams; and an expectation gap, whereby unmet need elsewhere in the system increased demand for ED services that were beyond its formal scope. These gaps made diagnostic errors and delay more likely for patients with mental health conditions seeking physical healthcare in the ED. Conclusions As new dedicated mental health EDs are introduced in England, there is an opportunity to avoid reproducing these structural gaps in new settings. Our study suggests that improving physical healthcare for patients with mental health conditions requires changes to how EDs are designed, resourced and supported, and how they connect with the wider health and care system. Keywords: mental health, diagnostic inequality, emergency departments