Investigative Ophthalmology & Visual Science

Purpose: To develop and evaluate deep learning models for automated detection of corneal perforation in microbial keratitis using anterior segment optical coherence tomography (ASOCT) images. Methods: We enrolled 150 patients with microbiologically confirmed keratitis. Contralateral healthy eyes served as controls. Four convolutional neural network models using ResNet architecture were trained and evaluated using ASOCT images to classify the presence or absence of corneal perforation at the eye level. Ground truth labels for perforation were established following consensus grading by two masked ophthalmologist graders. Models differed in inclusion of healthy controls and masking of non-corneal anterior segment anatomy. Results: The best-performing model (Model 1), which included healthy controls and randomly applied masking of the inferior image portion during training, achieved an AUC of 0.965 (95% CI, 0.911-0.995), sensitivity of 84.0% (95% CI, 70.0%-97.1%), and specificity of 97.8% (95% CI, 96.1%-99.3%) for detection of corneal perforation. Models including healthy controls outperformed those without, and lens masking improved discrimination. Conclusions: Deep learning models achieved high diagnostic accuracy for detecting corneal perforation on ASOCT imaging in eyes with microbial keratitis. These findings support the potential role of automated ASOCT analysis as a clinical decision support tool for identifying this vision-threatening complication.

Purpose: To highlight the roles of intraoperative optical coherence tomography (iOCT) in managing acute corneal hydrops (ACH) and outcomes of iOCT-guided pneumodescemetopexy and corneal compression sutures. Methods: This was a retrospective, consecutive, interventional case series of patients with keratoconus who presented with significant ACH and underwent iOCT-guided pneumodescemetopexy (18% sulfur hexafluoride gas) and compression sutures at Birmingham and Midland Eye Centre, UK, between Aug 2023 and May 2025. Results: Five patients were included; mean age was 32.3+/-6.6 years old and 3 (60%) were male. The mean follow-up duration was 16.3+/-5.6 months. At presentation, the mean corrected-distance-visual-acuity (CDVA) was 1.90+/-0.67 logMAR, central corneal thickness (CCT) was 1187.6+/-372.6um, maximal corneal thickness was 1624.0+/-383.5um and maximal height and diameter of pre-Descemet layer/Descemet membrane (PDL/DM) detachment was 1014.6+/-366.4um and 4456.0+/-839.4um, respectively. The surgery successfully achieved complete PDL/DM attachment in all cases, with a mean time from surgery to ACH resolution of 17.8+/-8.0 days. iOCT successfully visualized the area of PDL/DM break/detachment, revealed the involvement of PDL (evidenced by a persistent taut type 1 DM detachment after gas tamponade), and guided the placement of compression sutures. Compared to preoperative, there was a significant improvement in the mean CDVA (0.52+/-0.32 logMAR; p=0.014) at last follow-up. One patient required a repeat procedure to fully attach the PDL/DM. Conclusions: This study demonstrated favorable outcomes of iOCT-guided pneumodescemetopexy and corneal compression sutures. iOCT revealed the involvement of PDL in ACH and provided plausible explanations why pneumodescemetopexy alone may not be able to resolve significant ACH rapidly in certain cases.

Purpose: To compare hypopyon detection using anterior segment optical coherence tomography (ASOCT) versus slit lamp examination (SLE) in microbial keratitis, and to evaluate intra-and inter-grader agreement for ASOCT hypopyon measurement. Methods: Two masked graders independently evaluated ASOCT images for hypopyon presence or absence in eyes with microbial keratitis, with disagreements resolved by consensus. A subset of hypopyon eyes underwent triplicate height measurement using two methods (endothelial length, vertical height). Cohen's kappa, intraclass correlation coefficients (ICC), sensitivity, and specificity were calculated comparing diagnostic performance of ASOCT versus SLE. Results: Inter-grader agreement for hypopyon detection on ASOCT was excellent (k=0.94; 95% CI 0.84-1.00) and intra-grader agreement was excellent (k=0.89-1.00). ASOCT detected hypopyon in 67.1% of eyes versus 57.0% by SLE (sensitivity 83.0%, specificity 96.2% using ASOCT as reference). Intra-grader reproducibility was excellent for both endothelial length and vertical height measurements (ICC 0.977-0.996). Inter-grader agreement was good for endothelial length (ICC 0.831) and vertical height (ICC 0.827), though a statistically significant inter-grader bias was identified for vertical height only (Wilcoxon p=0.008). Conclusions: ASOCT detected hypopyon with greater sensitivity than SLE and demonstrated excellent intra-grader and good inter-grader measurement reproducibility. Endothelial length showed slightly superior inter-grader concordance to vertical height measurement.

PurposeAnti-vascular endothelial growth factor (anti-VEGF) therapy is the standard of care for neovascular age-related macular degeneration (AMD), yet many patients exhibit persistent retinal degeneration, fibrosis, and incomplete therapeutic response. The molecular pathways underlying this incomplete response remain poorly understood. We sought to identify VEGF-independent signaling pathways active in the vitreous of anti-VEGF-treated AMD patients. MethodsWe performed multiplex antibody-based proteomic profiling of 1,000 human proteins in vitreous samples from patients with neovascular AMD receiving anti-VEGF therapy (n=8) and comparative controls (n=6). Differential protein expression was assessed using one-way ANOVA, followed by gene ontology and pathway enrichment analyses. Drug-target relationships were evaluated to identify potential opportunities for therapeutic repositioning. ResultsWe identified 107 differentially expressed proteins (p<0.05), including key regulators of immune signaling, angiogenesis, and metabolism. Notably, multiple components of cytotoxic lymphocyte pathways were dysregulated, including IL-21R, SIGLEC-7, CTLA4, and IL-2-associated signaling. Enrichment analyses revealed significant activation of pathways related to T-cell activation, interleukin signaling, and leukocyte-mediated cytotoxicity. These immune signatures persisted despite suppression of VEGF signaling. Several clinically available immunomodulatory agents--including abatacept, sirolimus, and dupilumab--targeted pathways identified in this dataset. ConclusionsAnti-VEGF-treated neovascular AMD exhibits persistent cytotoxic immune signaling in the vitreous, suggesting that VEGF-independent immune mechanisms may contribute to ongoing retinal damage and incomplete therapeutic response. These findings provide a rationale for combination therapeutic strategies targeting both angiogenic and immune pathways in AMD.

Purpose: To determine whether spatial decomposition of longitudinal retinal nerve fiber layer (RNFL) change maps reveals distinct modes of glaucomatous progression masked by conventional averaging, and to validate these modes through structure function mapping and genetic association analysis. Methods: Pixel wise RNFL rates of change were computed from longitudinal optic disc OCT scans of 15,242 eyes (8,419 adults with primary open angle glaucoma [POAG]; Massachusetts Eye and Ear, 1998 to 2023). A loss only constraint zeroed all thickening values, reflecting the biological prior that adult RNFL does not regenerate. Nonnegative matrix factorization decomposed these maps into spatial progression components (80% training set). Components were evaluated in a heldout set (20%) for retinotopic structure function concordance, visual field (VF) progressor classification against global and quadrant RNFL rates, and enrichment of genetic association signals at established POAG loci. Results: Six anatomically distinct progression patterns emerged, including diffuse circumferential loss, focal peripapillary defects, and arcuate bundle degeneration. Pattern based models significantly outperformed global RNFL rate for classifying VF progressors (area under the curve, 0.750 [95% CI, 0.709 to 0.790] vs. 0.702; P = .0096) and explained additional variance in functional decline (Nagelkerke pseudoR2, 0.301 vs. 0.198; P = .0011). Structure function mapping confirmed retinotopic coherence. Spatial phenotypes recovered stronger genetic signals than global rates at 85.3% of established POAG loci, suggesting they capture more biologically homogeneous endophenotypes of progression. Conclusions: Glaucomatous structural progression occurs through spatially distinct modes with independent structure function and genetic signatures that conventional RNFL averaging obscures.

This study evaluated the feasibility of collecting passive and active digital phenotyping data using the OverSight iOS application in individuals with inherited retinal diseases (IRDs), and explored associations between digital behavioural markers, visual function, and mental health. Participants with IRDs were recruited from Moorfields Eye Hospital (UK) and followed for 12 months. OverSight passively captures mobility data through HealthKit and typing-derived metrics through SensorKit. Participants completed patient-reported outcome measures (EQ-5D, NEI-VFQ-25, HADS, and MRDQ) within the app. Passive data included step count, walking speed, typing speed, total words typed, autocorrections, and sentiment word categories (anxiety, down, and health-related terms). Feasibility indices included enrolment, retention, and completeness of passive datastreams. Twenty-five participants were enrolled and 92% were retained at 12 months. Seventeen participants met the validity threshold for HealthKit data and 16 also met SensorKit thresholds. Median daily step count was 6,087, walking speed 1.18 m/s, and typing speed 2.19 characters/s. Age was negatively correlated with typing speed and anxiety-related word use, and photopic peripheral visual difficulty was negatively correlated with anxiety- and down-related word use. Digital phenotyping using OverSight was feasible over 12 months. Exploratory analysis suggest mobility, typing behaviour and sentiment markers may represent useful adjunctive indicators of functional vision and psychological outcomes in patients with IRDs.

Objective: The study aims to evaluate the real-world effectiveness of Highly Aspherical Lenslets spectacle (HAL; Essilor(R) Stellest(R)) in slowing myopia progression among Indian children and adolescents aged between 4 and 16 years. Methods and analysis: This was a multicentre retrospective study conducted across 10 leading ophthalmic centers. The study participants comprised children aged between 4 and 16 years who were prescribed HAL spectacles (Essilor(R) Stellest(R)). Data were extracted from electronic medical records at three time points: T1: One year prior to intervention; T2: Baseline at HAL spectacle prescription; T3: 6 to 24 months after prescription. The primary endpoint was the myopia progression and axial elongation in the year following prescription, compared with the untreated year and with published meta-regression models. Only data from the right eye were analysed, with the expected physiological progression estimated based on the individual progression trajectory after adjusting for age-related slowing as reported in published meta-regression models. Results: A total of 372 myopic children were included in the study. The annual myopia progression was -0.72 {+/-} 0.47 D/year during the untreated period, reducing to -0.11 {+/-} 0.29 D/year with HAL spectacle wear. The expected progression without treatment was -0.65 D/year, based on trajectory-adjusted modelling, indicating a treatment effect of 0.54 D/years and an estimated 83% slowing in myopia progression compared to expected progression. The expected axial elongation under physiological conditions was 0.29 mm/year, estimated using age-adjusted meta-regression models; with HAL lens wear, axial elongation was 0.11 {+/-} 0.16 mm/year, corresponding to a [~]62% relative slowing of elongation. Conclusion: The present study demonstrates the real-world evidence validating the efficacy of HAL lenses as an effective myopia control intervention in Indian children and adolescents. The retrospective design and limited follow-up period warrant future prospective, long-term studies to validate these findings.

ImportanceAge-related eye diseases, such as cataract, glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR), are leading causes of irreversible vision loss globally. Chronic inflammation is a shared pathogenic pathway, but the role of systemic inflammatory drivers like clonal hematopoiesis of indeterminate potential (CHIP) is unknown. ObjectiveTo investigate the association of CHIP, including its major genetic subtypes and clone sizes, with the risk of four major age-related eye diseases. Design, Setting, and ParticipantsThis was a prospective cohort study conducted using data from the UK Biobank, a large-scale, population-based cohort. A total of 436,469 participants free of the four eye diseases at baseline were included in the analysis. Data were collected from 2006 to 2010, with follow-up extending to March 2022. ExposuresCHIP status was ascertained from whole-exome sequencing data, defined by the presence of a somatic driver mutation with a variant allele fraction of 2% or greater. Main Outcomes and MeasuresThe primary outcomes were incident cases of cataract, glaucoma, AMD, and DR, identified through linked electronic health records. Associations were assessed using multivariable Cox proportional hazards regression models. ResultsOf 436,469 participants (mean [SD] age, 56.4 [8.1] years; 54.5% women), 14,110 (3.2%) had CHIP. Over a median follow-up of 13.1 years, CHIP was significantly associated with an increased risk of incident cataract (Hazard Ratio [HR], 1.08; 95% CI, 1.03-1.14), AMD (HR, 1.12; 95% CI, 1.04-1.21), and DR (HR, 1.41; 95% CI, 1.20-1.64). No significant association was found with glaucoma (HR, 1.08; 95% CI, 0.99-1.17). The risk for AMD was primarily associated with smaller clones (VAF <10%), while the risk for DR was highest with non-DNMT3A mutations. Systemic inflammation, particularly neutrophil count, partially mediated the associations. Conclusions and RelevanceIn this study, CHIP was independently associated with a higher risk of developing cataract, AMD, and DR, but not glaucoma. These findings establish a link between hematopoietic somatic mutations and the pathogenesis of several major age-related eye diseases, suggesting that CHIP-driven inflammation is a potential target for risk stratification and prevention. Key PointsO_ST_ABSQuestionC_ST_ABSIs clonal hematopoiesis of indeterminate potential (CHIP) associated with the risk of major age-related eye diseases? FindingsIn this cohort study of 436,469 participants, CHIP was associated with an increased risk of incident cataract (HR, 1.08; 95% CI, 1.03-1.14), age-related macular degeneration (HR, 1.12; 95% CI, 1.04-1.21), and diabetic retinopathy (HR, 1.41; 95% CI, 1.20-1.64), but not glaucoma. MeaningThese findings identify CHIP as an independent, non-ocular risk factor for cataract, AMD, and diabetic retinopathy, suggesting that systemic inflammation driven by CHIP contributes to the pathogenesis of these conditions and may represent a novel target for preventive strategies.

Purpose: To identify the ocular biometric parameters associated with refractive outcomes in Chinese Primary angle closure glaucoma (PACG) patients receiving phacoemulsification and intraocular lens (IOL) implantation (PEI) surgery. Methods: 165 Chinese PACG patients receiving PEI and goniosynechialysis (GSL) and 53 cataract patients as controls only receiving PEI surgery were recruited. The prediction accuracy of IOL power calculation was assessed by the prediction error (PE), mean absolute error (MAE), median absolute error (MedAE), and proportions of eyes with a PE within {+/-} 0.25 diopters (D), {+/-} 0.50 D, {+/-} 0.75 D, and {+/-} 1.00 D. The association of different ocular biometric parameters with the PE of IOL calculation were evaluated. Results: The PACG patients had significantly higher absolute of PE as compared to the control subjects, especially the acute PACG patients. The axial length (AL), changes in aqueous depth pre- and post-surgery ({bigtriangleup}AD), and the ratio of {bigtriangleup}AD/AL were significantly associated with the PE in acute PACG patients. The association of {bigtriangleup}AD with the PE of IOL power calculation was found in PACG patients with AL [&ge;] 22 mm. Conclusions: This study revealed the association of AL and {bigtriangleup}AD with the PE of IOL calculation in Chinese PACG patients. Precisely predict the {bigtriangleup}AD is necessary for acute PACG patients, especially for those with AL [&ge;] 22 mm, to improve the refractive outcomes.

The global ambition to end the human immunodeficiency virus (HIV) epidemic requires understanding which system-level policy levers, enacted under the framework of Universal Health Coverage (UHC), are most effective in achieving both transmission reduction and diagnostic coverage. This study addresses an important evidence gap by quantifying the within-country association between measurable UHC policy indicators and the estimated rate of new HIV infections across nine Southeast Asian countries between 2013 and 2022. Employing a Fixed-Effects panel data methodology, the analysis controls for time-invariant national heterogeneity, ensuring reliable estimates of policy impact. We found that marginal changes in total current health expenditure (CHE) as a percentage of gross domestic product (GDP) were not statistically significantly associated with changes in HIV incidence. However, increases in the UHC Infectious Disease Service Coverage Index were statistically significantly associated with concurrent reductions in HIV incidence (p < 0.001), suggesting the efficacy of targeted service implementation as the principal driver of curbing new HIV infections. In addition, the UHC Reproductive, Maternal, Newborn, and Child Health Service Coverage Index exhibited a statistically significant positive association with changes in HIV incidence (p < 0.01), which is interpreted as a vital surveillance artefact resulting from expanded detection and reporting of previously undiagnosed HIV cases. Furthermore, out-of-pocket (OOP) health expenditure as a percentage of CHE showed a counter-intuitive negative association with changes in HIV incidence (p < 0.01), suggesting this metric primarily shows ongoing indirect cost burdens on the established patient cohort, or, alternatively, presents a diagnostic access barrier that results in lower case finding. These findings suggest that policymakers should prioritise investment in targeted infectious disease service efficacy over aggregate fiscal commitment and utilise integrated sexual health platforms for strengthened HIV surveillance and case identification.

Background Higher levels of sedentary behaviour, such as leisure screen time (LST), and lower levels of physical activity are associated with diseases across multiple body systems which contribute to a large global health burden. Whether these associations are causal is unclear. The primary aim of this study is to investigate the causal effects of higher LST (given greater power) and, secondarily, lower moderate-to-vigorous intensity physical activity (MVPA), on a wide range of diseases in a hypothesis-free approach. Methods A two-sample Mendelian randomisation phenome-wide association study was conducted for the main analyses. Genetic single nucleotide polymorphisms (SNPs) were first selected as exposure genetic instruments for LST (hours of television watched per day; 117 SNPs) and MVPA (higher vs. lower; 18 SNPs) based on the genome-wide significant threshold (p < 5*10-8) from the largest relevant genome-wide association study (GWAS). For disease outcomes, we used summary results from FinnGen GWAS, including 1,719 diseases defined by hospital discharge International Classification of Diseases (ICD) codes in 453,733 European participants. For the main analyses, we used the inverse-variance weighting method with a Bonferroni corrected p-value of p [&le;] 3.47*10-4. Sensitivity analyses included Steiger filtering, MR-Egger and weighted median analyses, and data from UK Biobank were used to explore replication. Findings Genetically predicted higher LST was associated with increased risk of 87 (5.1% of the 1,719) diseases. Most of these diseases were in musculoskeletal and connective tissue (n=37), genitourinary (n=12) and respiratory (n=8) systems. Genetic liability to lower MVPA was associated with six diseases: three in musculoskeletal and connective tissue and genitourinary systems (with greater risk of these diseases also identified with higher LST), and three in respiratory and genitourinary systems. Sensitivity analyses largely supported the main analyses. Results replicated in UK Biobank, where data available. Conclusions Higher levels of sedentary behaviour, and lower levels of physical activity, causally increase the risk of diseases across multiple body systems, making them promising targets for reducing multimorbidity.

BackgroundNegative symptoms are core features of schizophrenia that relate strongly to functional impairment, yet interventions targeting these symptoms remain largely ineffective. Emerging theoretical work highlights how environmental factors may shape and maintain negative symptoms. Although racial disparities in schizophrenia diagnosis among Black Americans are well documented and linked to racial stress and psychosis, the impact of racial stress on negative symptoms has not been examined. This study provides an initial test of a novel theory proposing that racial stress - here measured by racial discrimination - influences negative symptom severity through exacerbation of negative cognitions about the self, particularly defeatist performance beliefs (DPB). Study DesignParticipants diagnosed with schizophrenia-spectrum disorder (SSD) (N = 208; 80 Black, 128 White) completed the Positive and Negative Syndrome Scale (PANSS), the Defeatist Beliefs Scale, and self-report measures of subjective racial and ethnic discrimination (Racial and Ethnic Minority Scale and General Ethnic Discrimination Scale). Relationships among variables were tested using linear regression and mediation analysis. Study ResultsBlack participants exhibited significantly greater total and experiential negative symptoms than White participants with no group difference in DPB. Racial discrimination explained 46% of the relationship between race and negative symptoms. Among Black participants, higher DPB were associated with greater negative symptom severity. Discrimination was positively related to both DPB and negative symptoms. DPB partially mediated the relationship between discrimination and negative symptoms. ConclusionsFindings suggest that racial stress contributes to negative symptom severity via defeatist beliefs among Black individuals, highlighting potential targets for culturally informed interventions.

BackgroundEarly-life adversity (ELA) is a risk factor for enduring pain in youth and is associated with alterations in brain morphology and function. However, it remains unclear whether ELA-related neurobiological changes contribute to the development of enduring pain in early adolescence. MethodsUsing data from the Adolescent Brain Cognitive Development (ABCD) Study, we examined multimodal magnetic resonance imaging (MRI) markers in children assessed at baseline (ages 9-11 years) and at 2-year follow-up (ages 11-13 years). ELA exposure was defined at baseline to maximise temporal separation between early adversity and later enduring pain. Participants with enduring pain at follow-up (n = 322) were compared to matched pain-free controls (n = 644). Structural MRI, diffusion MRI (fractional anisotropy, mean diffusivity), and resting-state functional connectivity data were analysed. Linear models tested main effects of enduring pain, ELA, and their interaction on brain metrics, controlling for relevant covariates. ResultsELA exposure was associated with smaller caudate and nucleus accumbens volumes, and reduced surface area of the left rostral middle frontal gyrus. No significant effects of enduring pain or ELA-by-enduring pain interaction were observed across grey matter, white matter, or functional connectivity measures. ConclusionsELA was associated with alterations in fronto-striatal regions in late childhood, but these changes were not linked to enduring pain in early adolescence. These findings suggest that ELA-related neurobiological alterations may represent early markers of vulnerability rather than concurrent correlates of enduring pain. Longitudinal follow-up is needed to determine whether these alterations contribute to later chronic pain risk.

Background: Gamma oscillation dysfunction has been implicated in neuropsychiatric disorders. Restoring gamma oscillations via brain stimulation represents an emerging therapeutic approach. However, the strength of its clinical effects and treatment moderators remain unclear. Method: We conducted a systematic review and meta-analysis to examine the clinical effects of gamma neuromodulation in neuropsychiatric disorders. A literature search for controlled trials using gamma stimulation was performed across five databases up until April 2025. Effect sizes were calculated using Hedge's g. Separate analyses using the random-effects model examined the clinical effects in schizophrenia (SZ), major depressive disorder (MDD), bipolar disorder, and autism spectrum disorder. For SZ and MDD, subgroup analyses evaluated the effects of stimulation modality, stimulation frequency, treatment duration, and pulses per session. Result: Fifty-six studies met the inclusion criteria (NSZ = 943, NMDD = 916, NBD = 175, NASD = 232). In SZ, gamma stimulation was associated with improvements in positive (k = 10, g = -0.60, p < 0.001), negative (k = 12, g = -0.37, p = 0.03), depressive (k = 8, g = -0.39, p < 0.001), anxious symptoms (k = 5, g = -0.59, p < 0.001), and overall cognitive function (k = 7, g = 0.55, p < 0.001). Stimulation frequency and treatment duration moderated therapeutic effects. In MDD, reductions in depressive symptoms were observed (k = 23, g = -0.34, p = 0.007). Conclusion: Gamma neuromodulation showed moderate therapeutic benefits in SZ and MDD. Substantial heterogeneity likely reflects protocol differences, highlighting the need for well-powered future trials.

Single photon emission computed tomography (SPECT) is a highly specialized imaging modality that enables measurement of regional cerebral perfusion and, in particular, resting cerebral blood flow (rCBF). Recent technological advances have improved SPECT quantification and reliability, making it increasingly useful for studying rCBF abnormalities and perfusion network alterations in psychiatric and neurological disorders. To characterize large scale functional organization in SPECT data, data driven decomposition methods such as independent component analysis (ICA) have been used to extract covarying perfusion patterns that map onto interpretable brain networks. Blind ICA provides a data driven approach to estimate these networks without strong prior assumptions. More recently, a hybrid approach that leverages spatial priors to guide a spatially constrained ICA (sc ICA) have been used to fully automate the ICA analysis while also providing participant-specific network estimates. While this has been reliably demonstrated in fMRI with the NeuroMark template, there is currently no comparable SPECT template. A SPECT template would enable automatic estimation of functional SPECT networks with participant-specific expressions that correspond across participants and studies. The current study introduces a new replicable NeuroMark SPECT template for estimating canonical perfusion covariance patterns (networks). We first identify replicable SPECT networks using blind ICA applied to two large sample SPECT datasets. We then demonstrate the use of the resulting template by applying sc-ICA to an independent schizophrenia dataset. In sum, this work presents and shares the first NeuroMark SPECT template and demonstrating its utility in an independent cohort, providing a scalable and robust framework for network-based analyses.

ImportanceBlood neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are entering clinical use in neurology as markers of neuroaxonal and astrocytic injury, but their utility in psychiatry is unclear. ObjectiveTo determine whether psychiatric diagnoses are associated with altered plasma NfL and GFAP levels. Design, Setting, and ParticipantsThis population-based study examined plasma NfL and GFAP among 47,495 participants from the UK Biobank (54.0% female; 93.5% White; mean [SD] age 56.8 [8.2] years) who provided blood samples and sociodemographic and clinical data between 2006 and 2010. Normative modeling was applied to assess associations between 7 lifetime psychiatric diagnostic categories and deviations from expected NfL and GFAP levels, while accounting for neurological diagnoses, cardiometabolic burden, and substance use. Data were analyzed between July 2025 and March 2026. Main Outcomes and MeasuresDeviations in plasma NfL and GFAP levels from normative predictions. ResultsRelative to the reference population, plasma NfL levels were higher among individuals with bipolar disorder (d=0.20; 95% CI, 0.03-0.37; p=0.03), recurrent depressive disorder (d=0.23; 95% CI, 0.07-0.38; p=0.009), and depressive episodes (d=0.06; 95% CI, 0.02-0.10; p=0.01), lower among individuals with anxiety disorders (d=-0.07; 95% CI, -0.12 to -0.02; p=0.008), but did not differ in schizophrenia spectrum, stress-related, or other psychiatric disorders. Plasma GFAP levels were not elevated in any psychiatric disorders. Variability in NfL levels was greater among individuals with schizophrenia spectrum disorders (variance ratio [VR]=1.30; p=0.005), depressive episodes (VR=1.06; p=0.006), and anxiety disorders (VR=1.08; p=0.005). Variability in GFAP levels was increased only in anxiety disorders (VR=1.08; p=0.01). Plasma NfL levels exceeding percentile-based normative thresholds were more common among individuals with schizophrenia spectrum disorders, bipolar disorder, recurrent depressive disorder, and depressive episodes. Neurological diagnoses, cardiometabolic burden, and substance use were associated with plasma NfL and GFAP levels. Conclusions and RelevanceThis study provides population-level evidence of plasma NfL elevation in bipolar and depressive disorders and increased variability in schizophrenia spectrum, bipolar and depressive disorders, supporting its potential as a biomarker in psychiatry and informing its ongoing neurological applications. Plasma GFAP levels, in contrast, were largely unaltered across psychiatric disorders. Key PointsO_ST_ABSQuestionC_ST_ABSAre plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) levels altered in psychiatric disorders? FindingsIn this cohort study including 47,495 individuals, normative modeling revealed that plasma NfL levels were elevated in bipolar and depressive disorders, whereas plasma GFAP levels were not elevated in any psychiatric disorder. Plasma NfL levels also showed higher variability in schizophrenia spectrum, bipolar, and depressive disorders. MeaningPlasma NfL shows distinct alterations in schizophrenia spectrum and affective disorders, supporting its further investigation as a biomarker in clinical psychiatry and highlighting the need to consider psychiatric comorbidity in neurological applications.

Objectives: Longer lifespans lead to longer time on retirement, despite the efforts to raise the retirement age. Therefore, it is important to study how the retirement years can be spent without diseases. This study examined socioeconomic and sociodemographic differences in healthy years spent on retirement. Methods: We followed a cohort of retired Finnish municipal employees (N=4231, average follow-up 15.4 years) on national administrative registers for major chronic diseases: cancer, coronary heart disease, cerebrovascular disease, diabetes, asthma or chronic obstructive pulmonary disease, dementia, mental disorders, and alcohol-related disorders. Median healthy years on retirement and age at first occurrence of illness (ICD-10 and ATC-based) in each combination of sex, occupational class, and age of retirement were predicted using Royston-Parmar models. Prevalence rates for each diagnostic group were calculated. Results: Most healthy years on retirement were spent by women having worked in semi-professional jobs who retired at age 60-62 (median predicted healthy years 11.6, 95% CI 10.4-12.7). The least healthy years on retirement were spent by men having worked in routine non-manual jobs who retired after age 62 (median predicted healthy years 6.5, 95% CI 4.4-9.5). Diabetes was slightly more common among lower occupational class women, and dementia among manual working women having retired at age 60-62. Discussion: Healthy years on retirement are not enjoyed equally by women and men and those who retire early or later. Policies aiming to increase the retirement age should consider the effects of these gaps on retirees and the equitability of those effects.

Human papillomavirus (HPV) testing is the primary method for cervical cancer screening, and a negative HPV test is associated with a very low subsequent risk of invasive cancer. Nevertheless, a small number of cervical cancers are diagnosed following an HPV-negative testing result, posing challenges within HPV-based screening pathways. Using nationwide Swedish registry data of HPV testing, we identified women diagnosed with invasive cervical cancer between 2019 and 2024 and reconstructed HPV testing histories from the National Cervical Screening Registry (NKCx). The most recent HPV test prior to diagnosis was defined as the index test, and longitudinal HPV testing trajectories were classified among women with an HPV-negative index test. Of 3,000 women diagnosed with invasive cancer, 243 (8.1%) had an HPV-negative index test. These women were older at diagnosis and more frequently diagnosed at advanced stages compared with women with an HPV-positive index test. Most HPV-negative index tests (66.3%) were performed in the peri-diagnostic period (+/- 30 days). Among women with an HPV-negative index test, 52.7% (128/243) had no prior HPV testing recorded, while the remainder had consistently HPV-negative histories (33.3%, 83/243) or evidence of prior HPV positivity before the index negative test (14%, 32/243). Possible recurrent HPV positivity following an intervening negative test was rare (0.4%, 1/243). HPV-negative screening results preceding invasive cancer reflect heterogeneous screening histories and cannot be explained solely by test failure. Findings highlighting the importance of reaching women earlier in screening programs and show that fluctuating HPV detectability is rare.

PurposeAntibiotic use (ABU) is a major driver of antimicrobial resistance (AMR), but ABU patterns are poorly understood in low-income countries where the burden of AMR is great and ABU is insufficiently regulated. Here, we report ABU from ten sites ranging from rural villages to small cities in Madagascar, a country with high AMR levels, and present results from modeling to identify factors that may be associated with ABU in this setting. MethodsWe conducted surveys of 290 individuals from ten sites in the SAVA Region of northeast Madagascar to gather data on sociodemographic characteristics, agricultural and animal husbandry practices, recent antibiotic use, the antibiotics that participants recalled using in their lifetimes, and the sources of their antibiotics. Using these data, we conducted statistical analyses with a mixed-effects logistic model to determine which characteristics were associated with recent antibiotic use. ResultsNearly all respondents (N=283, 97.6%) reported ABU in their lifetimes, with amoxicillin being the most widely reported antibiotic (N=255, 90.1% of those reporting ABU). All recalled antibiotics were classified as frontline drugs except for ciprofloxacin. Most respondents who reported antibiotic use also reported obtaining antibiotics without prescriptions from local stores (N=273, 96.5%), while only 52.3% (N=148) reported obtaining antibiotics through a prescriptive route, such as from a health clinic or private doctor. Of the 127 individuals (44.9%) who reported recent ABU, men were found to be significantly less likely to have recently taken antibiotics than women. ConclusionsOur findings provide new insights into ABU in agricultural settings in low-income countries, which have historically been understudied in AMR and pharmacoepidemiologic research. Knowledge of ABU patterns supports understanding of AMR dynamics and AMR control efforts in these contexts, such as interventions on inappropriate antibiotic dispensing. Key pointsO_LIAntibiotic use (ABU) in Madagascar is largely unstudied despite its role in antimicrobial resistance (AMR), which Madagascar faces a high burden of. C_LIO_LIABU was widespread among livestock owners in northeast Madagascar, with the majority of study participants reporting ABU in their lifetimes and most people reporting ABU also having taken antibiotics in the previous three months. C_LIO_LIMost respondents reported obtaining their antibiotics from non-pharmaceutical stores, indicating high levels of unregulated ABU, though more than half also reported sourcing their antibiotics through prescriptive means (like doctors and health clinics). C_LIO_LIMen were less likely than women to have taken antibiotics in the previous three months. C_LIO_LIThese findings support the development of interventions to mitigate the burden of AMR in Madagascar and similar contexts while underscoring the need for more comprehensive research on the drivers and patterns of ABU. C_LI Plain language summaryIn this study, we provide basic information on antibiotic use (ABU) patterns in Madagascar, a country that experiences high levels of resistance but has been particularly understudied in AMR and pharmacological research. We surveyed 290 farmers with livestock from ten sites across northeast Madagascar about their ABU and found that nearly all study participants (N=283, 97.6%) have used antibiotics in their lifetimes, while a little under half of those who reported ABU also reported using antibiotics in the previous three months (N=127, 44.9%). The most used antibiotic was amoxicillin (N=255, 90.1%). Most people obtained their antibiotics from sources that do not require prescriptions, like general stores, indicating that most ABU is unregulated. Through modeling, we also found that men were less likely than women to have taken antibiotics in the previous three months (OR=0.50, CI 0.30-0.82). These findings help us better understand the dynamics of ABU in low-income countries, which have historically been understudied in AMR and pharmacological research. They also support efforts to mitigate the burden of AMR by revealing ABU dynamics that may contribute to the emergence and spread of AMR, as well as identifying targets for intervention to curb inappropriate ABU.

PurposeNavigational ability develops throughout childhood alongside the maturation of brain regions supporting egocentric and allocentric processing. In Autism Spectrum Disorder (ASD), atypical hippocampal development may impact flexible spatial memory; however, findings on navigational ability in autistic children remain inconsistent. This study aimed to compare both objective and perceived navigation ability in children with ASD and typically developing (TD) peers. MethodTwenty-six children with high-functioning ASD and twenty-five age- and gender-matched TD children (M_age = 12.04 years, SD = 1.64) completed a battery of navigational tasks from the Spatial Performance Assessment for Cognitive Evaluation (SPACE), including Path Integration, Egocentric Pointing, Mapping, Associative Memory, and Perspective Taking. Perceived navigation ability was assessed using the Santa Barbara Sense of Direction (SBSOD) scale. ResultsNo significant group differences were observed across any objective navigation tasks. However, children with ASD reported significantly lower perceived navigation ability compared to TD peers. ConclusionThese findings suggest a dissociation between perceived and actual navigational ability in ASD. By early adolescence, objective navigation performance appears intact, potentially reflecting sufficient maturation of underlying neural systems or the presence of compensatory mechanisms. The results underscore the importance of incorporating objective, task-based measures when assessing cognitive abilities in autistic populations.