American Journal of Medical Genetics Part A

Individuals with inherited retinal dystrophies (IRDs) undergo a slow, genetically heterogeneous loss of vision, yet how the visual cortex and non-visual sensory, motor, and psychological systems adapt to this deprivation remains poorly characterized. Existing evidence comes mainly from single-modality, cross-sectional studies that rarely account for genetic heterogeneity, making it hard to distinguish adaptive change from a direct, non-retinal mutation effect, since several IRD genes are not retina-specific. To address this gap, we designed an observational, longitudinal, multimodal protocol that combines ophthalmological, genetic, and in silico characterization with electrophysiological (steady-state visual evoked potentials and TMS-EEG), chemosensory, sensorimotor, and psycho-personological assessments. Patients aged 18 to 75 years with rod-cone (retinitis pigmentosa, Usher syndrome) or cone and cone-rod dystrophies will be assessed at baseline (T0) and at an 18-month follow-up (T1); sighted controls, matched for age, sex, and handedness, will complete the same battery once. Importantly, pairing genotypic with phenotypic data allows changes in non-visual domains to be interpreted against, rather than independently of, each patient's molecular background. We expect individuals with IRDs to differ from controls in visual cortical responsiveness and in selected non-visual sensory and sensorimotor measures, with genotype-related differences explored where sample size permits. Given the rarity of IRDs, the design is exploratory and emphasizes effect sizes and individual variability over large-sample inference. The protocol was approved by the Ethics Committee of the University of Verona (CARP 08.R1/2024) and follows the Declaration of Helsinki and the GDPR; findings will be disseminated through peer-reviewed publications and shared with patients and IRD patient associations.

Objective: The objective of this study was to detect genetic factors associated with dermatochalasis using a genome-wide association study (GWAS) across three large cohorts. Design: GWAS meta-analysis Participants: A total of 13,200 dermatochalasis cases and 962,513 controls were included. Methods: A GWAS meta-analysis of dermatochalasis combining data from the FinnGen, the Estonian Biobank and the UK Biobank was conducted. We also performed colocalization analyses, a phenome-wide association study and age-at-onset analysis, and assessed genetic correlations with various diseases and traits. Main outcome measures: Identification of genetic variants associated with dermatochalasis. Results: We identified 18 loci associated with dermatochalasis at genome-wide significance, 16 of which were novel. Most of these loci had genes involved in skin biology and cutaneous diseases, such as the genes encoding elastin (ELN) and Latent TGF-{beta} binding protein 1 (LTBP1). Phenome-wide association study revealed previous associations with morphology-related traits, while genetic correlation analysis highlighted multiple genetic correlations, especially with smoking and pain. Conclusions: We detected 18 genetic loci associated with dermatochalasis, characterized these loci in detail and demonstrated their relevance in skin biology and related processes. These findings give novel information on the genetic background of dermatochalasis and provide a solid basis for further research.

Various professional organizations recommend screening prospective parents for autosomal recessive (AR) and X-linked (XL) conditions, which is reflected in commercial screening panels. There is merit to developing a distinct reproductive gene-list and analytic framework inclusive of genes based on available perinatal intervention, defined as possible prenatal intervention (including investigational) for the fetus or necessary early initiation of approved postnatal treatments. We evaluated a reproductive genetic screening framework that incorporates perinatal actionability across AR, XL, and selected autosomal dominant (AD) genes. Using a curated list of genetic conditions with perinatal intervention, we evaluated five subset gene lists to determine the individual-level number-needed-to-screen (NNS) to identify one individual with at least one qualifying heterozygous variant, defined as a heterozygous pathogenic or likely pathogenic (P/LP) variant in a gene on the specified list. To conduct NNS analyses, we sourced carrier frequency and allele frequency data for each gene and their respective ClinVar-curated high-confidence (>=2 star) P/LP variants, from two population databases -- gnomAD v4.1 and All of Us (AoU) v8. The analyses produced an individual-level NNS of 3.20 (CI: 3.193, 3.212) using gnomAD and 3.62 (CI: 3.606, 3.640) using AoU. These estimates do not represent couple-level reproductive risk, affected-pregnancy yield, clinical diagnostic yield, or validation of a clinical screening test. These findings support further evaluation of a perinatal-actionability framework, with clinical value dependent on which genes drive yield, and whether the relevant gene, variant, mechanism, and phenotype combinations are actionable in a reproductive or perinatal context for both the pregnant woman and her future offspring.

BackgroundAcrodysostosis type 2 (ACRDYS2) is a rare autosomal dominant disease characterized by skeletal defects and cognitive deficit, with clinical symptoms observed in multiple other tissues including the skin. It is caused by mutations in a phosphodiesterase, PDE4D, a key regulator of cAMP/PKA (cyclic adenosine monophosphate / protein kinase A) signalling. Despite its well-defined genetic causes, the molecular mechanisms underlying the disease remain poorly understood, with studies based largely on engineered cellular models reaching conflicting interpretations. MethodsTo investigate how endogenous dynamics are affected by PDE4D mutations in unmanipulated cells, we studied PDE4D transcript and protein expression, activity and downstream signalling in native dermal fibroblast from ACRDYS2 patients and healthy controls. ResultsSignificant reduction in total PDE4D expression in patient cells was observed both at the transcript and protein level, with marked decreases in the long isoforms PDE4D4 and PDE4D7; a reduction in PDE4D9 mRNA was also observed. PDE4D enzymatic activity was reduced in ACRDYS2 fibroblasts, though total PDE activity was largely preserved. Reduced PDE4D expression was associated with an increase in the phosphorylated form of the cAMP-responsive transcription factor CREB and elevated PRKAR1A (PKA type 1 regulatory subunit alpha) transcript levels, suggesting altered downstream signalling. Interestingly, expression of the related phosphodiesterase family member PDE4B was increased, consistent with a compensatory response to reduced PDE4D function. ConclusionsThis is the first study demonstrating reduced PDE4D expression and isoform-specific dysregulation in native ACRDYS2 cells. Together, our results support a model in which reduction in PDE4D activity and compensatory changes in other PDE4 family members contribute to the molecular pathology of ACRDYS2, providing new insights into the molecular mechanisms underlying this disorder.

Congenital NAD deficiency disorder (CNDD) is a gene x environment disorder caused by disruptions of the kynurenine pathway. To date, CNDD has been associated with biallelic variants in three kynurenine pathway genes: KYNU, HAAO, and NADSYN1. We identified two sisters with congenital anomalies overlapping with CNDD who have biallelic variants in a gene encoding a different kynurenine pathway enzyme, KMO. The surviving child also has elevated levels of metabolites upstream of KMO with low NAD+ levels in plasma, suggesting that KMO deficiency is a novel CNDD. To explore the pathogenicity of KMO deficiency, we generated a global Kmo knockout mouse model (Kmo-/-) and utilized dietary interventions to better model human gene x environment interactions. Although Kmo-/- mice are viable and fertile on typical breeder chow, they exhibit elevated serum kynurenine and are functionally vitamin B3-dependent. Under conditions of limited maternal vitamin B3 intake, a greater proportion of Kmo-/- embryos develop congenital anomalies and have significantly lower NAD+ levels than Kmo+/- littermates. Exploratory untargeted metabolomics performed in Kmo-/- embryos suggested that NAD+ deficiency may perturb the pyrimidine, purine, and pentose phosphate pathways. These findings establish KMO deficiency as a new cause of CNDD and highlight a critical gene x environment interaction influencing NAD metabolism and congenital anomalies.

Background Ocular injuries concomitantly occur among patients with head trauma because of the close anatomical relationship between the cranium and the orbit. Unfortunately, they are often overlooked during acute trauma care and may result in preventable visual loss. There is a dearth of data describing the burden and spectrum of ocular injury among head injury patients in sub-Saharan Africa. We conducted a hospital-based cross-sectional study to determine the prevalence and describe the patterns of ocular injury among adults admitted with head injury at the Accidents and Emergency Unit of Mulago National Referral Hospital, Uganda, from 1st May 2025 to 30th July 2025. Methods Consecutive patients aged 18 years and above with a confirmed head injury diagnosis underwent a structured ophthalmic evaluation comprising visual acuity testing, tonometry, slit-lamp and dilated fundus examination, pupillary and ocular motility assessment, confrontation visual fields, and review of craniofacial computed tomography. Ocular injuries were classified by anatomical site and injury type, and the prevalence was reported with a 95% confidence interval. Results Of 383 patients evaluated (mean age 32.7 {+/-} 12.3 years; 89.3% male), road traffic accidents were the leading mechanism of injury (68.9%) and most patients had mild head injury (72.3%). Overall, 268 patients (70.0%; 95% CI 65.1-74.5) sustained at least one ocular injury. Adnexal injuries were most frequent (64.0%), dominated by periorbital oedema (45.2%), subconjunctival haemorrhage (42.3%) and eyelid ecchymosis (33.2%); orbital fractures occurred in 27.4%. Closed and open globe injuries were present in 13.8% and 0.8% of patients, respectively, and abnormal confrontation visual fields in 28.2%. Conclusion Ocular injury is highly prevalent among patients admitted with head injury in this setting, with adnexal and orbital structures most commonly affected. Routine ophthalmic assessment should be integrated into the initial evaluation of all head injury patients to reduce missed injuries and prevent avoidable visual morbidity.

Background and Objectives: Genetic causes of epilepsy are well-established in children, but the genetics of adult-onset epilepsy is not well understood. There are few studies of epilepsy genetics in older adults, U.S. military Veterans, and people with acquired causes of epilepsy like traumatic brain injury (TBI) and stroke. To test if rare gene variants that cause pediatric epilepsy are associated with adult-onset epilepsy, we determined the prevalence of pathogenic germline variants (PGVs) in epilepsy-associated genes in an ancestrally diverse cohort of older Veterans and examined the penetrance of epilepsy among PGV carriers. We evaluated the effect of mode of inheritance (MOI), variant selection, single gene-level factors, and gene-disease relationship validity on prevalence and penetrance estimates. Methods: This retrospective cohort study used electronic health record (EHR) data from Veterans enrolled in the Million Veteran Program (MVP) biobank who had whole genome sequencing (WGS) data available. We identified Veterans with one or more rare (variant allele frequency [VAF] <0.01) pathogenic/likely pathogenic single nucleotide variants (SNVs) within one or more of 165 expert-curated epilepsy genes. Epilepsy phenotype was defined using a validated algorithm, and penetrance estimates were calculated using Bayes theorem and compared to civilian cohorts. Results: There were 102,624 MVP participants with WGS data. Mean age at censorship or death was 74.6 years, 6.1% were female and 6.3% had epilepsy. Among participants, 1.9% (n=1,955) carried at least 1 rare PGVs and 1.0% (n=1,041) carried ultrarare PGVs. Most carriers of autosomal dominant (AD) PGVs (89.7%) were not diagnosed with epilepsy, though carriers of both AD and autosomal recessive (AR) ultrarare PGVs had increased odds of epilepsy (odds ratios of 1.72 and 1.45, respectively) compared to non-carriers. Penetrance estimates were low for AD PGVs (8.2%), but similar to estimates from civilian biobanks. Discussion: Veterans carrying PGVs in AD-labeled epilepsy genes had increased risk for epilepsy, but only 10.3% were diagnosed. Unexpectedly, Veterans heterozygous for AR-labeled PGVs also had increased risk of epilepsy. Potential reasons for this include latent compound heterozygosity, misclassification of variant pathogenicity or gene MOI, or the possibility that PGVs in AR genes may be risk alleles for adult-onset epilepsy.

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

Studies of resemblance for disorders and other traits measured at the binary (yes/no) level between relatives frequently contain individuals who are currently in the negative category but who will become positive in future. For example, a 10-year-old may develop depression in the future, but is as yet unaffected. Such censoring can substantially bias estimates of correlation between relatives. To overcome this problem we develop a model for the association between liability to a disorder, and its age at onset. The model is designed for data from pairs of relatives to enable estimation of the correlation between an individuals' liability to disorder and their age at onset. Usually, such information is not available at the individual level, because age at onset is uniquely available when onset has occurred. Lacking variation in disorder status, data from non-related persons cannot estimate the covariance between liability and age at onset. Data from relatives can resolve this issue when there is a correlation in liability between the relatives, because different age at onset distributions would be expected in concordant vs. discordant pairs of relatives. Greater severity and worse outcomes are often observed among those with earlier onset, so a correlation between disorder liability and age at onset seems likely in many cases. In this article we present the basic theory of the model, implemented as a mixture distribution, and an application to cannabis use in a Virginia Twin Study of Adolescent Behavioral Development. A negative association of (-.212) between age at onset an liability was found, with confidence intervals of -.263 to -.152, which do not cross zero. The method contrasts with Cox Proportional Hazards, in which disorder liability and onset timing are treated as a single dimension.

Clinical relevance: Validated virtual control arms may provide population-level estimates of treatment effect and reduce reliance on untreated control allocations in myopia trials. Background: Untreated single-vision control arms in paediatric myopia efficacy trials are increasingly difficult to justify and retain. Several published models predict untreated childhood axial elongation by region or ethnicity. Here they are implemented unchanged in an open-source tool and validated against an untreated multi-ethnic cohort. Methods: Five published models predicted untreated elongation from baseline age, cycloplegic spherical equivalent, sex, and ethnicity, anchored at baseline axial length (AL) and evaluated at actual follow-up. Predictions were compared with 242 untreated myopic children (Chinese, Vietnamese, Indian) with AL measured at approximately 6 and 12 months, assessing bias, root-mean-square error, and prediction-interval coverage against pre-specified thresholds (bias <0.03 mm; coverage greater than or equal to 0.90). Results: The regional generalised estimating equation (GEE) and meta-regression models reproduced mean East Asian elongation without meaningful bias at 6 months (GEE bias -0.013 mm; equivalence to plus-or-minus 0.03 mm, p = 0.014) and at 12 months (-0.004 mm), although equivalence was not established at 12 months in an underpowered subgroup (n = 71, all Vietnamese; p = 0.068). Older age-only models under-predicted by 0.07 to 0.12 mm. Published individual prediction intervals were too narrow (coverage 0.77): the means were accurate, the individual uncertainty was not. Indian elongation fell between strata and was matched by no existing model. Conclusions: The models reproduce mean untreated East Asian elongation at 6 months, conditional on cohort independence; South Asian children remain unserved by any existing stratum. The tool is a group-level instrument, not an individual predictor, and a transparent unification of published models in open-source code. Its value for estimating treatment effect awaits back-testing against a trial with a known untreated arm, ideally over 24 to 36 months.

Gastrointestinal (GI) conditions are common among children with neurodevelopmental disabilities (NDDs), and are associated with functional impairment, behavioral symptoms, and increased health care utilization. A unique relationship between autism and GI dysfunction has been proposed, leading to a focus on autism in GI research, management guidelines, and clinical tool development. Leveraging >20 years of electronic health record data and a cohort of 42,204 cases with attention-deficit/hyperactivity disorder, autism, cerebral palsy, epilepsy, or intellectual disability and 297,402 controls without NDDs, we quantified associations between NDDs and GI conditions in children. GI conditions were more common in cases than controls across all individual NDDs; intellectual disability and cerebral palsy were most strongly associated with having a GI condition. In this work, clinically recognized GI morbidity was elevated across all NDDs and not unique to autism, suggesting that a broader, transdiagnostic approach to GI dysfunction in children with NDDs is warranted.

Despite substantial advances in diagnostic testing, 10-15% of Usher syndrome patients remain without a genetic diagnosis, having significant implications for genetic counseling and potential future therapeutic interventions. In this study, genome sequencing data from probands clinically presenting with Usher syndrome were analyzed. Two novel deep-intronic variants were identified in PCDH15, c.3983+3635A>G and c.3123-1728A>G, in two independent patients. Both deep-intronic variants were classified as likely pathogenic and predicted to alter PCDH15 pre-mRNA splicing. Using a minigene splice assay and iPSC-derived photoreceptor precursor cells from patients, we confirmed that both variants lead to the inclusion of a pseudoexon in the PCDH15 transcript introducing a stop codon and subsequent premature termination of protein translation. We designed and evaluated antisense oligonucleotides (ASOs) with the purpose of redirecting aberrant pre-mRNA splicing caused by both deep-intronic variants. For both variants, designed ASOs were successful in restoring normal splicing patterns, highlighting their potential as a future therapeutic intervention strategy to halt the progression of retinitis pigmentosa caused by these novel variants. Overall, these findings contribute to the understanding of Usher syndrome caused by deep-intronic pathogenic variants in PCDH15 and describe for the first time the use of an ASO-mediated splice correction strategy for individuals diagnosed with these variants.

Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder caused by a microdeletion within chromosome 22q13.3 1-6, and accounts for [~]1-3% of cases of autism spectrum disorders (ASD). Individuals with PMS typically present with neonatal hypotonia, severe speech delay, intellectual disability, motor impairments, and autism-related features, although additional manifestations such as epilepsy, sleep disturbances, and developmental regression are common. As in ASD, there is considerable heterogeneity in cognitive and behavioral impairments in PMS, making it difficult to determine which features arise directly from SHANK3/Shank3 deficiency and how deficits manifest across development. In the present study, we transferred the targeted Shank3 mutation, previously characterized on the Sprague Dawley background, onto the Long-Evans strain and performed a longitudinal behavioral assessment of Shank3-deficient rats from infancy to adulthood. The rats were evaluated for delays in early sensory and motor development, and ultrasonic vocalizations as neonates, social behavior, short term memory and gait as juveniles, and cognitive-executive dysfunction using a touchscreen-based visual discrimination and reversal learning task as adults. Despite profound reductions and/or complete loss of Shank3 protein expression, heterozygous and homozygous male and female rats showed normal physical and neurological reflexes across development, yet female Shank3 knockout pups showed a selective reduction in distress-associated ultrasonic vocalizations. As juveniles, subtle abnormalities emerged in short-term memory and limb coordination, while social preference for novelty and recognition was normal. Prominent behavioral abnormalities were observed in adults characterized by rapid and error-prone responding to visual stimuli during discrimination learning and reversal. These data suggest that rats with complete or partial Shank3 deficiency produce a selective behavioral profile in which high-order cognitive dysfunction is more pronounced than deficits in basic sensorimotor or select social behaviors. More broadly, these findings highlight executive dysfunction as a key consequence of the loss of Shank3. For the first time, we report the loss of Shank3 expression on a Long-Evans background strain as a valuable translational tool for investigating cognitive dysfunction and therapeutic windows in Shank3-associated disorders.

Background: Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition for which timely diagnosis is critical to early intervention, family support, and equitable access to care. However, substantial disparities in access to ASD diagnostic services persist across socioeconomic, geographic, clinical, and health-system contexts. This systematic review and meta-analysis synthesized evidence on determinants of access across the ASD diagnostic pathway, from recognition and referral to diagnostic completion and timely diagnosis. Methods: We systematically searched MEDLINE/PubMed, Embase, Scopus, Web of Science, Global Health, and grey-literature sources for studies published between January 2004 and December 2024. Eligible studies examined determinants of ASD diagnostic completion, diagnostic pathways, diagnostic timeliness, or barriers and facilitators to diagnostic access. Two reviewers independently extracted data and assessed methodological quality using the Mixed Methods Appraisal Tool (MMAT). Quantitatively comparable estimates were synthesized using random-effects models with restricted maximum likelihood estimation. Heterogeneity was assessed using Cochran's Q, I2, tau2, and 95% prediction intervals. Pre-specified subgroup analyses, meta-regression, sensitivity analyses, funnel-plot assessments, and Bayesian random-effects analyses were undertaken. Results: The search identified 4,899 records; after removal of 537 records without associated data, 4,362 records underwent title/abstract screening. 3,800 records were excluded, 562 reports were sought for retrieval, and 450 full-text reports were assessed after 112 could not be retrieved. Ultimately, 22 unique studies met the inclusion criteria. Nine unique studies contributed 23 quantitative effect estimates, while the remaining studies contributed to the narrative synthesis. The evidence covered socioeconomic, geographic, family, communication, screening, child developmental, provider, and health-system determinants. The overall random-effects meta-analysis yielded a pooled diagnostic access outcome of 74.1% (95% CI 65.8-81.1%), with substantial heterogeneity (Qe=209.95, p<0.001; I2=88.4%, 95% CI 79.1-94.4%; tau2=0.691) and a wide 95% prediction interval of 32.8-94.4%. Bayesian analysis produced a highly concordant pooled estimate of 73.3% (95% CrI 65.3-80.2%), with I2=87.5% and tau=0.833, and satisfactory MCMC convergence (R-hat=1.000). By outcome domain, pooled successful outcomes were highest for diagnostic pathways (89.3%, 95% CI 70.1-96.7%), followed by timely diagnosis (76.3%, 95% CI 62.9-86.0%), and lowest for diagnostic completion (67.1%, 95% CI 61.8-72.0%) (Qm=5.98, p=0.050). Timely diagnosis demonstrated particularly high heterogeneity (I2=91.2%), whereas diagnostic completion showed moderate heterogeneity (I2=40.6%). Across determinant domains, frequentist pooled estimates were 79.5% for child developmental/neurobehavioral factors, 74.2% for family/socioeconomic/perceptual factors, 68.0% for intervention/care-navigation factors, and 63.6% for provider/clinical recognition factors. Bayesian estimates were 76.7% (BF=53.76), 72.9% (BF=226.32), 64.3% (BF=25.60), and 53.7% (BF=0.684), respectively. Meta-regression indicated that determinant category (Qm=13.48, p=0.004) and effect measure (Qm=7.81, p=0.020) significantly explained between-study variation, whereas age group (p=0.203) and geographic region (p=0.453) did not. Family/socioeconomic factors had significantly larger effect sizes (B=2.703, 95% CI 0.661-4.744; p=0.009), as did child developmental/neurobehavioral factors (B=1.516, 95% CI 0.047-2.985; p=0.043). Potential small-study effects were detected by two of three asymmetry tests, although the Rosenthal fail-safe N was 1,723. Trim-and-fill identified seven potentially missing estimates, with an adjusted pooled effect of 68.4% (95% CI 27.7-109.1%). Importantly, exclusion of two influential outlying estimates produced a pooled outcome of 77.1% (95% CI 71.6-81.9%), indicating that the principal finding was robust. Conclusions: Approximately three-quarters of observed ASD diagnostic outcomes represented successful access, but the substantial heterogeneity indicates that diagnostic access is highly context-dependent. Families were more likely to successfully navigate diagnostic pathways than to complete diagnostic assessment, while timely diagnosis showed the greatest variability across settings. Family and socioeconomic circumstances and child developmental characteristics emerged as particularly important determinants, whereas provider-related effects were more heterogeneous and uncertain. Improving equitable ASD diagnosis requires interventions spanning the entire diagnostic pathway, including developmental surveillance, screening, referral coordination, family navigation, provider capacity, specialist availability, and mechanisms to ensure completion of diagnostic assessment. Greater longitudinal and implementation research is particularly needed in low- and middle-income countries, where diagnostic infrastructure and specialist capacity remain limited.

Background Oral contraceptive (OC) use, particularly during adolescence, may increase depression risk in some individuals, but it remains unclear who is susceptible to mood-related side effects and who is not. We aimed to detect single nucleotide polymorphisms (SNPs) and genes that moderate the effect of OC use on depression in young adulthood using data from the UK Biobank. Methods N=202,243 participants were followed from birth to age 23.29 (SD: 2.58) years. We used Cox models for counting processes to test the association between OC use and incident depression in young adulthood, and conducted a genome-wide-by-drug-interaction study (GWDIS) of SNP by OC use interactions alongside a standard genome-wide association study (GWAS) on incident depression in young adulthood. Results Over half of all participants (57.5%) initiated OC and 1.0% received a depression diagnosis during follow up. OC initiators had a 20% higher hazard of incident depression than non-initiators (HR=1.20, 95% CI=1.04-1.37). No SNPs reached genome-wide significance in the GWDIS, though eight showed suggestive interaction signals (p<1e-5). At the gene level, FSIP1 (p=5.90e-5) and EHBP1 (p=6.47e-5) showed suggestive signals, but none passed the genome-wide threshold. No SNPs reached genome-wide significance in the GWAS. Conclusions We did not find evidence for genetic variants that moderate the association between OC initiation and depression. If such effects exist, they are likely to be small and polygenic, suggesting there is currently no solid basis for using genetic data for individualised contraception counselling concerning mood-based side effects.

Targeted precision therapies are increasingly used in the treatment of individuals with vascular anomalies (VAs). This increases the need for rapid, accurate and inexpensive genetic diagnosis. Droplet digital polymerase chain reaction (ddPCR) is an alternative to next-generation sequencing (NGS), permitting rapid, highly sensitive interrogation of recurrent pathogenic mosaic variants. We examined the feasibility of ddPCR as a primary diagnostic tool in a large cohort of individuals with VAs. Lesional tissue was collected for ddPCR of up to 46 recurrent pathogenic variants across 16 genes associated with VAs. Specimens were assessed on a subset of assays for each individual based on clinical phenotype. Most individuals who had negative ddPCR results went on to high-depth gene panel or deep exome NGS, or Sanger sequencing. Here we report the phenotypic and molecular findings for 78 newly recruited and tested individuals in addition to the 60 individuals already reported from our cohort. The overall diagnostic yield for our cohort when combined with individuals previously reported was 104/138 (75%). Of 138 individuals tested, recurrent pathogenic variants were detected in 71 (51%) on ddPCR. Variants were most frequently identified in PIK3CA (n=28), TEK (n=18), GNAQ (n=12), or MAP2K1 (n=7). In a further 33 individuals, pathogenic variants were identified on NGS or Sanger sequencing. Our findings indicate that ddPCR is an efficient method achieving a high diagnostic yield in our cohort when used prior to sequencing.

Background Given the close anatomical proximity of the eye and its adnexae to the cranium, ocular injury frequently coexists with head trauma. However, specific factors predisposing patients with head injury to ocular involvement in Uganda remain poorly defined. Objective This study aimed to determine the factors associated with ocular injury among patients with head injury at Mulago National Referral Hospital (MNRH), a tertiary referral facility in Kampala, Uganda. Methods We conducted a cross-sectional study among 383 adult patients admitted with head injury to the Accidents and Emergency Department of MNRH from 15/05/2025 to 30/07/2025. All participants underwent a standardized ophthalmic evaluation. Bivariable and multivariable Poisson regression analyses were used to identify factors associated with ocular injury, reported as adjusted prevalence ratios (APR). Results Ocular injury was identified in 268 of 383 patients (70.0%; 95% CI: 65.1-74.5). On multivariable analysis, age 26-44 years (APR 1.18; 95% CI: 1.11-1.43; p=0.013), commercial motorcyclist (boda-boda rider) occupation (APR 1.25; 95% CI: 1.06-1.47; p=0.007), road traffic accident mechanism of injury (APR 1.19; 95% CI: 1.02-1.38; p=0.03), severe head injury (APR 1.70; 95% CI: 1.44-2.01; p<0.0001), and the presence of facial fractures (APR 1.61; 95% CI: 1.44-1.81; p<0.0001) significantly increased the likelihood of ocular injury. Conversely, intracranial hemorrhagic lesions were inversely associated with ocular injury (APR 0.80; 95% CI: 0.68-0.93; p=0.004). Conclusion Ocular injuries are common among patients with head injury. Patients aged 26 to 44 years, commercial motorcyclist occupation, road traffic injury, severe head injury, and facial fractures have a higher risk of ocular injury. We recommend prioritizing ophthalmic evaluation of for patients admitted with head injury to minimize preventable visual impairment.

Abstract Importance: Access to eye care is increasingly constrained by declining ophthalmologist workforce density, particularly in rural areas, while optometrist workforce is projected to exceed demand. Numerous state legislatures have expanded optometrist scope of practice (SOP), but the workforce effects of these policies have not been evaluated.. Objective: To evaluate changes in optometrist and ophthalmologist workforce density following state-level expansion of optometrist scope of practice. Design: This retrospective ecological study analyzed workforce density across 50 states and the District of Columbia. Between 2008 - 2019, nine states expanded SOPs for optometrists. We used interrupted time-series regression to estimate associations between these policy changes and provider density from 2010-2021, adjusting for covariates. Setting: Population-based analysis of all 50 US states and the District of Columbia, 2010 - 2021. Participants: State-level workforce data were derived from Bureau of Labor Statistics and US Census data (optometrists) and the American Medical Association Physician Masterfile (ophthalmologists). Socioeconomic covariates were obtained from the American Community Survey. Exposure: State-level legislative expansion of optometrist SOPs to allow injections beyond anti-anaphylaxis treatment, lesion removal, and/or laser procedures. SOP changes were identified through systematic review of legislative and regulatory records. Main Outcomes and Measures: Annual change in optometrist and ophthalmologist workforce density (providers per 100,000 population) following SOP expansion, adjusted for age, income, rates of vision difficulty, diabetes, poverty, and uninsured status. Results: Nine states met inclusion criteria for SOP expansion between 2008 and 2019. Analysis of national data showed that among all 50 US states and the District of Columbia, SOP expansion was associated with a non-significant change in optometrist density (-0.65 per 100,000; 95% CI, -1.87 to 0.57) and ophthalmologist density (+0.09; 95% CI, -0.10 to 0.28). Results were consistent in the 9-state subgroup (optometrists: -0.60, 95% CI -2.90 to 1.70; ophthalmologists: +0.02, 95% CI -0.13 to 0.18). Conclusions and Relevance: Our population-level data suggest that, in the US, state legislation expanding optometrist scope of practice has not been associated with increased workforce density. As numerous state legislatures continue to consider such policies, these findings can inform efforts to balance access to eye care with patient safety.

Background: Reducing maternal mortality and improving newborn and child outcomes are targets of the Sustainable Development Goals. Evidence on how these efforts are reaching women with disabilities is lacking. Objectives: to estimate global, relative inequalities in stillbirth, neonatal, infant, and maternal mortality for women with disabilities compared to women without disabilities. Methods: We searched MEDLINE, Global Health, PsycINFO, and Embase from 1 January 2015 to 28 January 2026, to identify articles on disability and stillbirth, neonatal, infant, and maternal mortality. We included studies that had a recognised measure of disability as an exposure, a control group of women without disabilities and at least one of the four outcomes. A pooled estimate for each outcome was done using a random-effects meta-analysis of the minimally adjusted results. Results: We identified over 4,300 titles, of which 17 papers were eligible for inclusion. Almost all data came from nationally-representative data sources in high-income countries. We found that women with disabilities were 4.66 times more likely (95% C.I. 1.70-12.75) to experience maternal mortality compared to women without disabilities. Women with disabilities were also 37% more likely to have a stillbirth and 27% and 48% more likely to have a neonatal or infant death compared to women without disabilities, respectively. Conclusions: Women with disabilities consistently have higher incidence of maternal, stillbirth, neonatal, and infant mortality, even in countries that have relatively low incidence of these outcomes. There is a lack of evidence globally and particularly from LMICs, and on effective interventions to improve maternal and infant outcomes for women with disabilities.

Objective: The purpose of this study was to estimate the negative predictive value (NPV) of screening for group B streptococcus (GBS) colonization in pregnant patients undergoing antepartum hospitalization for GBS colonization status at the time of preterm delivery. Study Design: This prospective, observational cohort study compared GBS colonization status upon initial hospital admission to that at the time of delivery. Pregnant patients at 22 to 35 weeks gestation admitted to the antepartum unit at a tertiary care hospital underwent standard screening for GBS colonization. When preterm labor progressed or iatrogenic preterm delivery was indicated, the GBS colonization test was repeated. Comparison of the sequential test results was performed to determine the NPV of the antepartum screening test for the intrapartum status. Results: 159 eligible patients were enrolled in the study, and 100 completed the study and were included in the analysis. The average gestational age at admission was 30 weeks 1 day (95% confidence interval [CI] 29w4d to 30w6d) and the average duration of pregnancy latency in the study group was 17.5 days (95% CI 15.1 to 19.8). GBS colonization rate at the time of admission was 18% and at the time of delivery was 20%. The NPV of GBS screening at admission was 91.5% (95% CI 83.2 to 96.5%) and the positive predictive value (PPV) was 72.2% (95% CI 46.4 to 90.3%). Conclusion: In a cohort of pregnant patients with preterm pregnancy complications, GBS screening at the time of antepartum hospital admission has an NPV of 91.5% (95% CI 83.2 to 96.5%) for GBS colonization at the time of preterm delivery. This is comparable to the published NPV of routine GBS screening for colonization status at term delivery.