Ophthalmology Science

Background/Objectives: Previous OCTA studies across MacTel severity levels have primarily characterised perfusion- and density-based vascular changes. Whether graph-derived network architecture provides complementary information on severity remains unclear. We therefore tested whether lower Chew grades already show architectural abnormalities despite comparatively preserved global vessel density. Subjects/Methods: This cross-sectional study included 62 MacTel and 64 healthy control eyes. Fovea-centred 3x3-mm high-resolution swept-source OCTA acquired with the DREAM platform was analysed with OCTAVA. Whole-image vessel length density (VLD), regional vessel area density (VAD), peri-FAZ perfusion, foveal avascular zone (FAZ) geometry and network topology were assessed using mixed-effects models adjusted for age, sex and axial length. Results: Grades 0-2 already showed greater FAZ acircularity than controls in the superficial (SCP; +0.132; q<0.001) and deep capillary plexus (DCP; +0.073; q=0.034), with lower SCP branchpoint density (q=0.022). Across MacTel grades, DCP VLD decreased by 0.352 mm-1 per grade (95% CI -0.583 to -0.121; Holm P=0.007), whereas the SCP slope was not significant (Holm P=0.071; plexus interaction P=0.160). DCP parafoveal VAD declined by 0.593 percentage points per grade (95% CI, -0.943 to -0.242; q=0.007), with no comparable decline in foveal VAD. Visual acuity worsened by 0.071 logMAR per grade (P<0.001). Conclusions: OCTA suggests two complementary components of the MacTel vascular phenotype: geometric and topologic remodelling in lower grades, with additional regional and global capillary rarefaction in higher grades. Vascular geometry and network topology, therefore, provide complementary information not captured by vessel density alone.

Diabetic retinopathy (DR) screening commonly relies on fixed follow-up intervals, although progression risk differs across patients. We developed a preliminary image-clinical framework to support personalized follow-up recommendations from retinal fundus images and systemic risk factors. Public DR datasets were harmonized into a binary task distinguishing absence of DR from DR of any grade. An ImageNet-pretrained ResNet50 and a foundation model-based feature extraction pipeline were compared. The selected image model was integrated with literature-derived severe retinopathy progression curves and clinical risk modifiers to estimate personalized cumulative risk and assign follow-up intervals using a predefined acceptable risk threshold. The ResNet50-based model was selected for subsequent analyses. In the target cohort, the integrated model assigned 90.0\% of patients to follow-up within 12 months. Clinical adjustment substantially modified image-only recommendations, generally shifting patients toward shorter intervals. These preliminary findings support the feasibility of combining image-derived estimates of baseline DR status with clinical modifiers to inform personalized screening intervals. Larger longitudinal studies are needed to validate calibration, clinical utility, and safety before real-world implementation.

Purpose: To evaluate the safety, procedural performance, sample recovery, and surgeon preference of an ophthalmic needle designed specifically for anterior chamber (AC) paracentesis. Methods: In this multicenter study, AC paracentesis was performed in clinic and operating-room settings using a 32-gauge x 4-mm needle with low dead space. The procedure was evaluated using a standardized physician survey. Prespecified outcomes included procedure-related adverse events (primary outcome), needle entry and handling, aspiration and sample recovery, comparative performance versus a 30-gauge needle, and physician preference for future use. Results: A total of 110 needle uses by eight surgeons were included. No ocular complications occurred, including lens or iris injury, hyphema, AC collapse, wound leak, hypotony, infection, or retinal complication, and no procedure required needle exchange or conversion to another device. Two technical events without ocular sequelae were noted, in which needle entry was partial thickness and did not reach the AC (1.8%; exact 95% CI, 0.2%-6.4%). Physicians rated needle entry, handling and sample recovery as good or excellent. Compared with a 30-gauge needle, the study needle was rated as at least comparable across all assessed domains. All surgeons rated it better or much better for intra-procedural safety and preferred it for future AC taps. Conclusions and Relevance: This short, 32-gauge low-dead-space ophthalmic needle demonstrated a favorable safety profile and was preferred over a 30-gauge needle by all surgeons. As aqueous humor liquid biopsy expands in clinical diagnostics and trials, an ophthalmic-specific needle design may help improve the consistency and safety of aqueous humor collection for molecular analysis and broader clinical use. Keywords: Anterior chamber paracentesis; Aqueous humor; Liquid biopsy; Low dead space; Ophthalmic needle

Purpose: To validate an automated pipeline to detect and quantify focal retinal and choroidal pulsation areas that are synchronous with the cardiac cycle in video indocyanine green angiography (ICGA). Design: Retrospective, observational, hypothesis-generating validation study Subjects, Participants: Consecutive patients with a diagnosis of central serous chorioretinopathy (CSCR) in one or both eyes. Methods: Videos were acquired on Heidelberg HRA+OCT. The pipeline consisted of three steps: signal extraction, foci detection, and quantification. After registration of the constituent frames, each pixel's intensity signal was analyzed at the presumed cardiac frequency (tested from a sample of three detectable frequencies). A synchrony score combining local phase coherence with oscillation amplitude was then derived and computed using a standard deviation ({sigma}) above each video's background oscillation value. Two masked graders marked the retinal and choroidal pulsation areas twice. We compared detection of the pulsation areas against grader consensus using a receiver operating characteristic curve (using multiple grid sizes to divide the scan area) and, separately, using a signal-based area-reduction method to obtain an optimum {sigma} value. Main Outcome Measures: Agreement between the automated algorithm and human graders in detection of pulsation foci, and the optimum threshold multiplier ({sigma}). Results: We studied 20 ICGA videos from 20 eyes. At the 16-pixel grid size, the pipeline achieved a mean area under the curve (AUC) of 0.914, sensitivity of 0.86, and specificity of 0.80. Grader agreement improved with larger grid size, reaching substantial-to-strong levels for choroidal annotations. The two independent validation methods demonstrated similar {sigma} values that differed by 0.62{sigma}, supporting {sigma}=4.0 as the optimum value. Conclusions: We report the first automated method to quantify retinal and choroidal vascular pulsation on video ICGA. It measures pixels that oscillate over time with the presumed cardiac cycle and works reliably at the spatial scale (grid level) where experts agree. Pulsatile hemodynamics may add a new vascular biomarker for glaucoma, diabetes, hypertension, and pachychoroid diseases.

Purpose: Post-marketing reports have associated faricimab, the first intravitreal bispecific antibody, with intraocular inflammation (IOI). Its inflammatory phenotype, temporal pattern and systemic safety relative to established anti-VEGF agents remain unclear. We compared faricimab, aflibercept and ranibizumab across three independent pharmacovigilance databases. Methods: We analysed FAERS reports from Q1 2022 to Q2 2026, with external validation in JADER (PMDA, Japan) and EudraVigilance. Reports were de-duplicated, restricted to primary-suspect reports, and a pre-specified list of 36 non-adverse-event preferred terms (PTs) was excluded. We computed reporting odds ratios (ROR), proportional reporting ratios and Bayesian information components, with Benjamini-Hochberg false discovery rate control. Head-to-head RORs were adjusted for demographic confounders by logistic regression. Time to onset (TTO) was modelled with Weibull distributions. Sensitivity analyses addressed masking and differential market duration. Signals were graded with a pre-specified bidirectional cross-database evidence framework (Confirmed, Consistent, Unconfirmed, Discordant). Results: Faricimab was reported more often for anterior-chamber and vitreal inflammation. Adjusted RORs (comparator versus faricimab, values <1 indicating faricimab excess) were 0.27 (95% CI 0.18-0.40) for iridocyclitis and 0.45 (0.35-0.58) for uveitis versus aflibercept, and 0.13 (0.06-0.24) and 0.12 (0.06-0.20) versus ranibizumab. All four PTs were Confirmed in JADER against both comparators; for iridocyclitis, RORs were 0.048 versus aflibercept and 0.109 versus ranibizumab. Faricimab IOI arose late (median TTO 100 days, IQR 31-182, versus 7 days for both comparators; P = 2.6E-14) and its Weibull onset distribution was markedly flatter (shape 0.81 versus {approx}0.42). In contrast, aflibercept predominated for endophthalmitis-spectrum events and intraocular pressure elevation, and ranibizumab for vitreous haemorrhage, the latter confirmed in JADER. Faricimab showed lower reporting across cardiac, nervous system, vascular and renal system organ classes, confirmed in EudraVigilance. An unadjusted FAERS death signal (ROR 3.16, aflibercept versus faricimab) attenuated after adjustment (aROR {approx}1.8) and was absent in outcome-based JADER analyses. Conclusions: Faricimab exhibits a reproducible, delayed-onset, anterior-predominant IOI phenotype alongside a comparatively favourable systemic safety profile. Clinicians should be aware that faricimab-associated IOI may arise weeks to months after injection. Prospective studies with exposure denominators are needed to quantify absolute risk.

Purpose Device-specific field-of-view (FOV) may affect quantitative optical coherence tomography angiography (OCTA) metrics. This study quantifies inter-device FOV scale differences across four commonly used clinical OCTA devices. Methods Four devices were evaluated under a nominal 6 by 6 mm (or 20 degrees by 20 degrees) scanning protocol: Zeiss Cirrus, Heidelberg Spectralis, Topcon Triton, and Topcon Maestro2. Device-specific spatial scale was assessed by (1) phantom calibration using a model eye with a 1 by 1 mm checkerboard, computing scale factors relative to Zeiss Cirrus; and (2) in vivo validation, registering same-eye, same-visit retinal images from the three devices to those of Zeiss Cirrus and extracting scale factors from the transformation matrices. Correlation between DICOM-implied FOV and spherical equivalent (SE) was assessed, where DICOM-implied FOV equals pixel-spacing mutiply by image-dimension. Results Phantom measurements showed that Spectralis, Triton, and Maestro2 each captured a systematically smaller FOV than Cirrus, with geometric mean scale factors of 0.933, 0.954, and 0.967. The same pattern was observed across 801 eyes from 556 participants, giving geometric mean scale factors of 0.939, 0.943, and 0.960, agreeing with phantom estimates within 1.2%. DICOM-implied FOV was fixed at 6.000 by 6.000 mm for three devices but varied from 5.212 by 5.209 to 6.743 by 6.739 mm for Spectralis, correlating with SE (P < 0.001). Conclusion Systematic FOV discrepancies exist across clinical OCTA devices despite nominally identical protocols, and DICOM pixel-spacing should be interpreted with caution as a spatial measure. Translational Relevance The reported device-specific scale factors could serve as magnification corrections for quantitative OCTA metrics, addressing the systematic spatial inter-device discrepancies.

Published artificial intelligence for keratoconus is unproven in fellow eyes that topography and tomography call normal, the eyes where surgical decisions are made, although it reports near-perfect accuracy for early disease. In a registered systematic review of 573 studies (PROSPERO CRD420261441197), none of 2,035 claim-by-stratum units from 212 adjudicated studies established discrimination in these eyes. Most units (90.0%) answered a different question, never constructed the target population or certified its normality; external validation did not test label generation, and five systematic reviews did not assess it. In a public cohort, a frozen score yielded an area under the receiver operating characteristic curve of 0.996 against a same-eye index label and 0.549 against a contralateral proxy; its inputs reconstructed the label-generating index (r = 0.991), so accuracy there measured agreement with the index. Anchor-gap evaluation measures accuracy in these eyes against the contralateral clinical diagnosis.

Glaucoma is a leading cause of irreversible blindness worldwide. Ophthalmologists diagnose glaucoma through a structured reasoning process by sequentially evaluating optic nerve head characteristics before reaching a final diagnosis, whereas existing AI systems typically perform direct image classification without providing clinically meaningful reasoning. We present the first clinically annotated fundus reasoning dataset, comprising 1,077 fundus photographs paired with expert-authored six-step diagnostic reports. Building on this dataset, we develop a reasoning-driven vision-language framework that explicitly models the ophthalmologist's diagnostic workflow by generating structured clinical reasoning prior to diagnosis. The generated reports are clinically validated, achieving the best performance across all evaluated clinical findings, including a cup-to-disc ratio mean absolute error of 0.070, an ISNT Kendall distance of 1.73, and the highest semantic agreement with expert reports (BERTScore-F1 = 0.874). The resulting framework also improves glaucoma diagnosis, achieving a balanced accuracy of $94.7\%$ and precision of $94.8\%$, demonstrating that explicitly modeling expert clinical reasoning simultaneously improves interpretability and diagnostic performance. Code and data are available at \url{https://glaucoma-cot.github.io/}.

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.

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.

Purpose To evaluate the safety, tolerability, and preliminary bioactivity of a single suprachoroidal injection of AXT107 (Gersizangitide), a multimodal integrin-disrupting peptide that acts on both the VEGFA pathway and angiopoietin-Tie2 pathway, in eyes with neovascular age-related macular degeneration (nAMD). Design Phase 1/2a, open-label, dose-escalation clinical trial. Participants Fifteen subjects with active nAMD, including 11 treatment-experienced partial responders to intravitreal anti-vascular endothelial growth factor (VEGF) therapy and 4 treatment-naive subjects; 14 eyes met the protocol-specified baseline imaging criterion and were included in efficacy analyses. Methods Study eyes received a single suprachoroidal injection of AXT107 microparticles at doses of 0.125, 0.25, or 0.5 mg and were followed for 40 weeks. Protocol-specified rescue intravitreal anti-VEGF treatment was permitted from week 12 based on protocol-specified best-corrected visual acuity (BCVA) or central subfield thickness (CST) criteria; anti-VEGF treatment before Week 12 was investigator-initiated. Primary outcomes were ocular and systemic safety through week 40; secondary outcomes included change in CST, change in BCVA, and time to first protocol-specified rescue injection. Main Outcome Measures Incidence of ocular and systemic adverse events, intraocular pressure (IOP), CST, BCVA, and time to first protocol-specified rescue injection. Results Twenty subjects were screened and 15 enrolled across 4 U.S. sites; 3 eyes received 0.125 mg, 3 received 0.25 mg, and 9 received 0.5 mg of AXT107. No serious adverse events related to AXT107 occurred, and no cases of endophthalmitis, retinal detachment, suprachoroidal hemorrhage, or clinically significant intraocular inflammation were observed through week 40. No clinically meaningful intraocular pressure (IOP) elevations occurred at any dose, and no subject required chronic IOP-lowering therapy. Among the 14 eligible eyes included in efficacy analyses, 2 eyes (01-04 and 01-05) completed 40 weeks without protocol-specified anti-VEGF rescue, and 1 eye (02-04) first received protocol-specified rescue at week 36. At the last on-treatment visit, BCVA changes ranged from +15 to -31 ETDRS letters; 3 eyes gained[&ge;]5 letters, 3 gained[&ge;]10 letters, and 1 gained[&ge;]15 letters. Among the 14 eligible eyes, anatomical improvements in CST were observed in at least 1 eye in each dose cohort. The most durable responses were seen in treatment-experienced eyes receiving 0.5 mg (median durability of 36 weeks), whereas treatment-naive 0.5-mg eyes showed more variable courses and generally earlier protocol-specified rescue in this small cohort. Conclusions In this first-in-human study, a single suprachoroidal injection of AXT107 up to 0.5 mg was well tolerated through Week 40, with no drug-related serious adverse events, no clinically significant intraocular inflammation, and no sustained IOP elevations. After a single suprachoroidal AXT107 injection, 2 eyes completed 40 weeks without protocol-specified rescue anti-VEGF treatment, and 1 additional eye received its first protocol-specified rescue treatment at Week 36. The exploratory observation that durability appeared greatest in treatment-experienced eyes supports further controlled study of AXT107, particularly in treatment-experienced nAMD populations.

Purpose: To understand the functional impact of macular atrophy (MA) and fibrosis in eyes with treated neovascular age-related macular degeneration (nAMD) based on deep visual sensitivity losses. Design: Cross-sectional study. Participants: One-hundred and nine eyes from 97 individuals with nAMD that had been treated for >=12 months without significant retinal fluid. Methods: All participants underwent defect-mapping microperimetry (DMP) testing - a strategy optimized to quantify the spatial extent of deep visual sensitivity losses through single 10 decibel stimuli presentations - where 208 locations were sampled in the central 8 degrees radius region. Participants also underwent color fundus photography, fundus autofluorescence and OCT imaging, which were co-registered and manually annotated for MA and fibrosis to determine their two-dimensional pointwise extent at individual test locations, and global extent in the corresponding region where DMP was performed. Main Outcome Measures: Pointwise association between the presence of MA and fibrosis with missing a stimulus on DMP and global association between the extent of MA and fibrosis with the proportion of locations missed (PLM) on DMP. Results: At a pointwise level, the presence of MA and fibrosis were independently associated with an increased likelihood of missing a stimulus on DMP (odds ratio = 42.5 and 2.5 respectively; P < 0.001 for both). However, at a global level, only an increasing extent of MA was associated with a significantly higher PLM on DMP (P < 0.001), but not fibrosis (P <= 0.227). MA extent explained a substantial proportion of the variance in the PLM (R2 = 0.97) and there was a very strong correlation between the two parameters ({rho} = 0.93). Conclusions: This study confirmed the expected functional impact of MA and fibrosis on DMP testing at a pointwise level. However, it showed at the global level that only the extent of MA, and not fibrosis, was independently associated with functional loss on DMP, and that there was a very strong structure-function correlation based on MA. These findings thus suggest that evaluating MA alone may be sufficient for capturing structural changes strongly associated with the global extent of deep visual sensitivity losses in those with treated nAMD.

Background/Aims: Neovascular glaucoma (NVG) is a severe, secondary glaucoma. This study aimed to identify factors associated with vision, intraocular pressure (IOP), and ocular pain outcomes. Methods: The cohort included all patients diagnosed with NVG during 2008-2024 at Helsinki University Hospital, Finland. Linear mixed-effects models used pre-specified covariates, whereas machine learning was given the full longitudinal data with biomicroscopic findings as an exploratory approach. Results: 626 patients were analysed. Worse baseline vision and a closed angle were associated with worse follow-up vision. Treatments were associated with lower IOP and less pain rather than better vision. Age, sex and comorbidity were largely not associated with the outcomes. Glaucoma drainage devices showed the greatest initial IOP reduction (-10.2 mmHg, 95% confidence interval, CI -11.9 to -8.6 mmHg), followed by transscleral cyclophotocoagulation (TSCPC, -4.7 mmHg, 95% CI -5.8 to -3.7 mmHg) and peripheral retinal cryotherapy (-2.2 mmHg, 95% CI -3.1 to -1.4 mmHg). TSCPC and cryotherapy were also associated with reduced pain (odds ratio 0.51 and 0.46). Pan-retinal photocoagulation and anti-VEGF showed smaller IOP reductions, with a pain reduction for pan-retinal photocoagulation only. Both methods agreed, and machine learning added no novel clinical findings. Conclusions: Vision in this cohort was largely set by the state of the eye at diagnosis. IOP control and pain relief therefore remain realistic goals even when sight cannot be saved. Peripheral retinal cryotherapy stood out, linked to both lower IOP and less pain, seldom reported in NVG. These associations from a large, unselected cohort identify treatments worth comparing prospectively.

Ophthalmic decisions require probabilities tied to a clinical question, a candidate set and an operating policy. We present OphJev, an endpoint-aware System One framework that combines frozen image and text representations, candidate scoring, schema-specific calibration and selective generalist queries for fundus and OCT imaging. Across eight external resources, multiple representation families, three generalist sizes and three seeds, controlled interventions separate the effects of wording, supervision and computation. Schema-aware affine calibration lowers mean held-out Brier loss and selective risk in all eight primary image--text configurations. On HYGD, matched-supervision fusion raises AUROC from 0.772 to 0.798, while a separate gain-routing policy lowers Brier from 0.618 to 0.599 using at most 20\% logical generalist image calls. These effects demonstrate complementary decision-level capabilities rather than universal gains: external transfer and larger specialist banks remain cohort dependent. A retrospective text extension evaluates 1,996 clinical notes and 91 ophthalmic questions; validation-based calibration improves note probability scores, while a lexical control remains strong. OphJev provides an auditable decision framework; prospective clinical benefit remains unvalidated.

Purpose: To develop an interpretable automated pipeline for dome-shaped macula (DSM) detection and measurement from optical coherence tomography (OCT) B-scans. Methods: We analyzed one eye from each of 300 children aged 4-18 years in the Shanghai Child and Adolescent Large-scale Eye Study High Myopia (SCALE-HM) cohort (50 DSM-positive; 100 test eyes). A U-Net pretrained on OCTA-500 and fine-tuned on the development set segmented the retinal pigment epithelium (RPE) boundary. A geometric module located the apex, fitted a tangent-line baseline, and computed perpendicular height in physical coordinates. An eye was DSM-positive if any gradable B-scan had height >= 50 um. Two masked graders evaluated the test set; a third adjudicated disagreements. Results: The area under the receiver operating characteristic curve was 0.927 (95% confidence interval [CI], 0.850-0.986), sensitivity was 82.1% (95% CI, 64.4%-92.1%), and specificity was 100% (95% CI, 94.9%-100%) against the adjudicated reference. In concordant-positive eyes, automated height agreed with manual measurements (intraclass correlation coefficient, 0.949; mean absolute error, 6.9 um; bias, -5.7 um, versus Doctor A). Mean RPE-boundary error on pediatric test scans was 1.54 um. Conclusions: The pipeline may be considered a reliable and reproducible tool for automated DSM detection and height measurement on radial OCT, with each value traceable to landmarks on the source B-scan. External validation across populations, devices, and acquisition protocols is needed. Translational Relevance: The pipeline provides an objective and reproducible method to detect DSM and quantify dome height, width, and orientation across OCT meridians. Because each measurement can be verified on the source B-scan, it enables standardized DSM assessment.

Genetic variants in PROM1 are associated with inherited blindness, but clinical phenotypes vary widely with currently no consensus on disease expectations or predicted patient outcomes. To address this issue, we performed chi-square correlation analysis on 190 published pathogenic and likely pathogenic variants from ClinVar Miner and the Human Gene Mutation Database. We identified a statistically significant increase in observed cases of dominantly inherited missense variants, which were associated with milder forms of macular dystrophy. Recessive inheritance of truncating frameshift variants was associated with more severe forms of inherited retinal degeneration such as rod-cone dystrophy. We also present case studies from 7 patients with phenotypes that are unique, unreported, or do not match the reported phenotype in online databases. We report two patients with VUS that have clinical phenotypes and dominantly inherited missense variants, one patient with a long natural history at our clinic, two patients with the same variant, but a different clinical diagnosis, and two patients with retinal deposits comprising subretinal drusenoid deposits (SDD) and soft drusen.

Purpose: To test whether juvenile open-angle glaucoma (JOAG) and primary congenital glaucoma (PCG) are polygenically continuous with primary open-angle glaucoma (POAG), using a multi-trait POAG polygenic risk score (PRS). Design: Retrospective cohort study. Participants: 3,102 open-angle glaucoma index cases, of whom 2,836 had a recorded age at diagnosis (52 PCG, 226 JOAG, and 2,558 POAG) and 999 European-ancestry controls from a glaucoma disease registry and a population-based cohort. Two replication cohorts comprised 70 JOAG and 31 PCG probands with 230 controls (Mass Eye and Ear, MEE), and 9 PCG and 120 POAG cases (Genetics of Glaucoma Study, GOGS). Methods: One index case per family was analysed. PRS were calculated from weighted SNPs and adjusted for ancestry. Cases were stratified by age at diagnosis (PCG <=3 years, JOAG >=4 and <40 years, POAG >=40 years) and presence of pathogenic/likely pathogenic variants ("Mendelian"). Groups were compared by Kruskal-Wallis test, with logistic regression and area under the curve for per-SD effects. Main Outcome Measures: PRS centile values compared across glaucoma subtypes and Mendelian and non-Mendelian subgroups. Results: Mean PRS was highest in cases diagnosed in the fourth decade of life. Among subgroups, it was highest in non-Mendelian JOAG (84.1%), exceeding controls (53.3%), Mendelian JOAG (68.9%), and non-Mendelian POAG (79.3%) (all P <= 0.003). Non-Mendelian JOAG was also the best discriminated from controls (OR 3.66 per SD increase, 95% CI 3.02-4.49; AUC 0.814, 95% CI 0.782-0.845). Neither PCG subgroup differed from controls. Among Mendelian cases, only MYOC p.Gln368Ter showed significantly elevated PRS (OR 2.49 per SD, 95% CI 1.89-3.34). In the MEE replication cohort, JOAG was associated with higher PRS (OR 2.12 per SD, 95% CI 1.50-3.07) while PCG was not (OR 0.90, P = 0.73). In GOGS, mean PRS was higher in POAG than PCG (84.8 vs 59.7 centile; P = 0.026). Conclusions: A POAG PRS predicts JOAG risk with discrimination comparable to or greater than POAG itself, supporting a shared polygenic architecture across juvenile and adult open-angle glaucoma. PCG showed no PRS elevation regardless of Mendelian status, indicating a distinct architecture for which rare-variant sequencing remains appropriate.

Abstract Purpose To apply a mathematical model integrating vascular permeability, lesion transmural pressure, choroidal excess pressure, and wall stability to incomplete fluid response and massive submacular hemorrhage in neovascular age-related macular degeneration. Methods Permeability was calculated from aqueous vascular endothelial growth factor (VEGF). Windkessel gave usual lesion pressure from choriocapillaris pressure and high inflow from an arterial-level puncture pressure used as a working value. Choroidal excess pressure was calculated from choroidal thickness and a pachy index as increased outflow resistance. Exudative change used a revised Starling equation scaled to early central-retinal-thickness reduction, with 40-m threshold. A relative rupture-hazard index was calculated from Laplace wall stress and wall stability. VEGF, pressures, and that reduction were from the literature. Pressure was isolated from permeability and choroidal excess. Results In the model, raising lesion pressure from choroidal-excess lesion pressure to high inflow increased untreated exudative change from 150 to 760 m. Residual under saturation was 64 m as a lower-end reference (Monte Carlo 69 - 286 m; median, 170) and 90 m with high-hazard choroidal excess; both above 40 m. Reducing choroidal thickness in the thickened choroidal-excess state added 13 - 14 m, smaller than that residual. Lowering lesion pressure from high inflow to usual lesion pressure (21 to 10 mmHg) reduced the index to 0.64 of the high-hazard reference, and to 0.34 with wall stabilization. Conclusion Lesion transmural pressure due to high inflow left residual exudation even after permeability suppression with anti-VEGF. Fluid resolution on optical coherence tomography may not parallel a reduction in the rupture-hazard index, depending on wall stability.

Purpose: To evaluate whether initiation of GLP-1 receptor agonists (GLP-1RAs) is associated with anti-VEGF treatment burden in type 2 diabetes patients with diabetic macular edema (DME) in the IRIS(R) Registry (Intelligent Research in Sight). Methods: Incident GLP-1RA initiators were matched 1:1 with controls via Mahalanobis distance matching (9,896 pairs; N=19,792) on sociodemographics, DME risk factors, and factors influencing GLP-1RA prescription including hypertension, obesity, chronic kidney disease. A longitudinal mixed-effects event-study model evaluated monthly anti-VEGF injection frequency over a 36-month window (12 months before through 24 months after initiation), adjusting for DME duration. Visual acuity (VA) and central subfield thickness (CST) were secondary outcomes. Results: Following GLP-1RA initiation, anti-VEGF injection trajectories did not significantly differ between the matched GLP-1RA and control cohorts (interaction coefficients -0.18 to 1.59, P>0.05). Likewise, no differences in VA were observed between cohorts (-0.05 to 0.04 logMAR, P>0.05) or CST (-14.12 to 33.58 {micro}m, P>0.05). Conclusion: In these matched cohorts, GLP-1RA initiation was not associated with the trajectory of anti-VEGF use or changes in VA or CST. Precis We used the American Academy of Ophthalmology IRIS(R) Registry (Intelligent Research in Sight) to identify patients with DME. In 19,792 matched patients, there was no significant reduction in injection frequency post GLP1-RA initiation and no significant change in VA or CST.

Automated segmentation of Optical Coherence Tomography (OCT) images is a critical component of structural biomarker extraction for retinal diagnostics. Deep learning models achieve state-of-the-art performance on controlled datasets, yet exhibit unpredictable failures on real-world data. Current quality gates rely on device-reported scan quality scores, which have been shown to be unreliable predictors of segmentation performance. We define scan quality in a task-specific sense, that is, whether a given B-scan will yield a reliable segmentation from a particular trained model. Under this definition, we systematically evaluate No-Reference Image Quality Assessment (NR-IQA) metrics, general-purpose pretrained representations, and domain-specific pretrained representations as alternative quality gates. We use choroid segmentation as the prototype task, with a dataset of 6,076 OCT B-scans from 80 subjects. These quality gate candidates are evaluated at three levels: scalar metrics (BRISQUE, NIQE, PIQE, SNR, PSNR), supervised linear probing, and unsupervised partitioning (K-Means) of feature vectors and learned representations. All scalar NR-IQA metrics proved inadequate (|r| < 0.20). General-purpose pretrained representations (EfficientNet-B0, ResNet-50, ViT-B/16) outperform NR-IQA, achieving ROC-AUC up to 0.77, indicating that learned representations are better suited to task-specific quality gating than hand-crafted scalar statistics. Retinal foundation models (FMs) further improve performance: RETFound, an OCT-specific FM, achieves ROC-AUC of approximately 0.81. Unsupervised K-Means partitioning of the embeddings recovers the same hierarchy geometrically: only the two retinal foundation models produce quality-aligned clusters that exceed a patient-level permutation null, while NR-IQA and general-purpose pretrained feature spaces do not, suggesting that domain-specific pretraining provides an additional benefit beyond general-purpose learned representations.