Ophthalmology Science

BackgroundShock involves microcirculatory dysfunction that is not suitably captured well by measurements of large vessels, such as systemic blood pressure. The outer retinal microcirculation (the choroid) can be measured non-invasively and may reflect dysfunction in other organs. We tested the feasibility of measuring the retinal choroid in an intensive care setting and explored associations between choroidal measurements and severity of disease. MethodsWe performed optical coherence tomography on patients admitted to the intensive treatment unit, and repeated imaging once 12-72 hours later. We measured choroidal anatomy using automated image segmentation, compared this to routine clinical data, and described change over time. ResultsOf fifteen patients recruited, 80% (12) had successful baseline imaging and 40% (6) of these had follow-up imaging within intensive care. At baseline, patients with thicker choroids and larger vascularity had larger cumulative fluid balance, and lower disease severity (Acute Physiology and Chronic Health Evaluation II) score, haematocrit, and albumin. A measurable suprachoroidal space was seen in 75% (9) patients and the size of this space tended to be larger in patients with lower heart rates. There was substantial intraindividual variation in choroidal measurements over time. CommentMeasuring the retinal choroid is feasible in patients with critical illness. Exploratory associations with systemic variables suggest that the choroid may provide information about the microvascular function of other major organs. Size and change of choroidal measurements may reflect perfusion pressure or vascular leak in response to inflammation.

PurposeTo develop and demonstrate the anatomical feasibility of a human whole-eye transplantation (WET) protocol that eliminates warm ischemia time (WIT) through continuous retrograde arterial perfusion, enabling uninterrupted ocular oxygenation throughout the transplantation process. DesignExperimental cadaveric feasibility study. SubjectsTwo fresh human cadaveric specimens used to simulate a complete donor-to-recipient WET sequence. MethodsA modified fronto-temporo-orbito-zygomatic craniotomy with anterior clinoidectomy was performed on each donor to expose the anterior cerebral artery (ACA), middle cerebral artery (MCA), and ophthalmic artery (OA). The ACA was cannulated to permit continuous retrograde perfusion of the ophthalmic circulation while the globe, with preserved optic nerve and extraocular muscles, was harvested en bloc. Recipient preparation involved mobilization of the internal maxillary artery (IMAX) in the infratemporal fossa and removal of the native globe. Orthotopic transplantation was achieved with MCA-IMAX and superior ophthalmic vein (SOV- SOV) microvascular anastomoses and optic nerve coaptation under microscopy, maintaining continuous simulated perfusion through the ACA cannula. Main Outcome MeasuresAnatomical feasibility of achieving zero warm ischemia time during the entire transplantation sequence, confirmed by optical coherence tomography (OCT), intraoperative microscopy, and photographic documentation of vascular and neural integration. ResultsContinuous retrograde perfusion was maintained throughout donor harvest and transplantation, achieving zero WIT across both specimens. OCT verified luminal patency and vessel continuity after ACA cannulation and MCA-IMAX anastomosis. The IMAX provided a robust, tension-free arterial recipient site with consistent caliber and orientation. Optic nerve coaptation and extraocular muscle reattachment were anatomically aligned, with sequential imaging confirming vascular and neural integration. The technique proved reproducible across both dissections, supporting its feasibility for perfused, anatomically integrated ocular allotransplantation. ConclusionsThis study establishes a reproducible human WET protocol achieving zero WIT via continuous retrograde extracorporeal perfusion. The approach provides a foundational anatomical framework for future functional and preclinical studies aiming to preserve retinal viability and enable neurovascularly integrated whole-eye transplantation.

Background and ObjectiveAmongst ophthalmologists, familial exudative vitreoretinopathy (FEVR) is agreed to be a rare disease. However, its incidence is currently unknown. The goal of this study is to identify the incidence of FEVR in Michigan. Study Design/Materials and MethodsThis retrospective chart review evaluated new patient encounters from the largest retinal specialty practice within the State of Michigan from over a 6 year period. These identified encounters were queried for the international classification of disease 10 (ICD-10) code (H35.023): exudative retinopathy, not diabetes. Review of both the individual patient encounters and the appropriate clinical imaging resulted in the identification of our FEVR cohort which was subsequently compared with the live birthrate in the State of Michigan over the same 6 years to determine an incidence rate. ResultsThis study revealed 44 new FEVR diagnosis and 666, 102 livebirths over the 6 year period of interest. Thus, the incidence of FEVR in the state of Michigan was estimated to be 0.007%. (95% CI[0.005%- 0.009%) ConclusionFamilial Exudative Vitreoretinopathy is indeed a rare diagnosis with an incidence rate of 0.007% within the State of Michigan.

Heritability of common eye diseases and ocular traits are relatively high. Here, we develop an automated algorithm to detect genetic relatedness from color fundus photographs (FPs). We estimated the degree of shared ancestry amongst individuals in the UK Biobank using KING software. A convolutional Siamese neural network-based algorithm was trained to output a measure of genetic relatedness using 7224 pairs (3612 related and 3612 unrelated) of FPs. The model achieved high performance for prediction of genetic relatedness; when computed Euclidean distances were used to determine probability of relatedness, the area under the receiver operating characteristic curve (AUROC) for identifying related FPs reached 0.926. We performed external validation of our model using FPs from the LIFE-Adult study and achieved an AUROC of 0.69. An occlusion map indicates that the optic nerve and its surrounding area may be the most predictive of genetic relatedness. We demonstrate that genetic relatedness can be captured from FP features. This approach may be used to uncover novel biomarkers for common ocular diseases.

PurposeThe purpose of this study is to report the genetic findings of a large heterogeneous patient population (n=551) with the clinical diagnosis of Familial Exudative Vitreoretinopathy (FEVR). MethodsPatients (n=486) were clinically diagnosed with FEVR by exam, birth history, family history, and wide-field fluorescein angiography (WFA). Patients were excluded if WFA was not performed to confirm a proper diagnosis. DNA samples were prospectively collected and analyzed for gene mutations associated with FEVR. The patients represent a heterogenous population: 40% Michigan residents; 48% U.S. residents (non-Michigan); 12% non-U.S. residents. Specifically, alterations in NDP, FZD4, LRP5, TSPAN12, ZNF408, CTNNB1, KIF11 were evaluated. ResultsThe majority of FEVR patients (69%) had an identifiable gene mutation, with 55% of mutations affecting traditional Wnt-signaling genes: NDP 13%; FZD4 11%; LRP5 25%; TSPAN12 6%. Other affected genes represented 14% of mutations, with ZNF408 accounting for 9%. ConclusionsFEVR remains a clinical diagnosis with WFA necessary for making the diagnosis of FEVR. This database demonstrated that, with proper diagnosis, the majority of patients have a definable genetic alteration.

PurposeTo determine whether AI significantly affects the performance of diabetic retinopathy (DR) grading by ophthalmology residents. Secondary objectives included evaluation of AIs effects on intergrader variability, self-reported confidence, and decision making. MethodsFour ophthalmology residents at a single academic medical center across all years of training (PGY-2 to PGY-4) analyzed 265 retinal fundus photographs for diabetic retinopathy from a publicly available dataset without and with the assistance of an AI algorithm, separated by a 3-week washout period ResultsOverall, there was no significant difference without versus with AI in five-class grading, as measured by QWK, with differences ranging from +0.010-0.017, p=0.09-0.32. No significant difference without and with AI was observed for binary classification of referable DR, except for the specificity of the PGY-3 resident (71.8% to 80%, p=0.019). Intergrader agreement among residents significantly increased with AI (FK +0.072, p=0.0003). Self-reported confidence also significantly increased for 3 out of 4 residents. ConclusionThe use of an AI algorithm did not significantly affect the DR grading performance of ophthalmology residents but did increase intergrader agreement and self-reported confidence. Introducing AI into the ophthalmology residency curriculum may be beneficial as the technology becomes more prevalent. Summary StatementA cross-sectional study that evaluated the performance of ophthalmology residents grading diabetic retinopathy fundus photographs with and without the assistance of an artificial intelligence algorithm.

ObjectiveTo assess the performance of a deep learning system (DLS) to discriminate between optic disc drusen (ODD) and papilledema caused by intracranial hypertension, using standard color ocular fundus photographs collected in a large international multi-ethnic population. DesignRetrospective study. ParticipantsThe study included 4,508 color fundus images in 2,180 patients from 30 neuro-ophthalmology centers (19 countries) participating in the Brain and Optic Nerve Study with Artificial Intelligence (BONSAI) Group. MethodsWe trained, validated, and tested a dedicated DLS for binary classification of ODD vs. papilledema (including various subgroups within each category), on conventional mydriatic digital ocular fundus photographs. For training and internal validation, we used 857 ODD images and 3,230 papilledema images, in 1,959 patients. External-testing was subsequently performed on an independent dataset (221 patients) including 207 images with ODD (96 visible and 111 buried), provided by 3 centers of the Optic Disc Drusen Studies Consortium, and 214 images of papilledema (92 mild-to-moderate and 122 severe) from a previously validated study. Main outcome measuresArea under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity were used to discriminate between ODD and papilledema. ResultsOverall, the DLS could accurately distinguish between all ODD and papilledema (all severities included): AUC 0.97 (95% confidence interval [CI], 0.96 to 0.98), accuracy 90.5% (95% CI, 88.0% to 92.9%), sensitivity 86.0% (95% CI, 82.1% to 90.1%), and specificity 94.9% (95% CI, 92.3% to 97.6%). The performance of the DLS remained high for discrimination of buried ODD from mild-to-moderate papilledema: AUC 0.93 (95% CI, 0.90 to 0.96), accuracy 84.2% (95% CI, 80.2%-88.6%), sensitivity 78.4% (95% CI, 72.2% to 84.7%), and specificity 91.3% (95% CI, 87.0% to 96.4%). ConclusionsA dedicated DLS can accurately distinguish between ODD and papilledema caused by elevated intracranial pressure, even when considering buried ODD vs mild-to-moderate papilledema. Future studies are required to validate the utility of this DLS in clinical practice.

PurposeQuantitative metrics obtained from retinal fundus images (such as vessel length, tortuosity and other scale-dependent measures) are increasingly used as potential biomarkers for systemic diseases, including cardio- and neurovascular conditions. However, with the increasing prevalence of myopia and related axial growth, this study aims to evaluate if axial length scaling significantly alters the overall distributions of the inferred biomarkers when compared to biomarker data obtained without axial length scaling and if these effects can be corrected. Methods2,309 clinic visits from patients aged [≤]21 years were analysed and extracted for axial-length scaling analysis (range) 20 to 28 mm). The retinal fundus photographs were automatically segmented using Automorph to extract biometric data, including vascular metrics. The parameters were further corrected for axial length using correction factors based on the Bennett-Littmann formula and true axial length. ResultsAxial length significantly influenced biometric parameters (vessel metrics) derived from fundus photography. The magnitude of error in diameter and length of blood vessels was approximately 4-5% for each 1 mm deviation from the reference axial length of 24 mm, whereas the error in vessel area was approximately 9-10% per 1 mm, consistent with the geometric expectation that area scales with the square of linear dimensions. The scaling corrections for different axial lengths are presented. ConclusionsAxial-length-related magnification introduces systematic bias into retinal vascular metrics from fundus photographs. Bennett-Littmann correction using true axial length reduces these errors and should be adopted in quantitative fundus imaging and Al biomarker development.

PurposeTo characterize retinal tears (RTs) and calculate the economic burden of RTs that present to the emergency department (ED) in the US. MethodsWe used a large national ED database to retrospectively analyze RTs that presented to the ED from 2006 to 2019. Using extrapolation methods, national estimates of RT incidence, demographics, comorbidities, disposition, inpatient (IP) costs, and ED costs were calculated. ResultsDuring the time period between 2006 and 2019, 15,841 patients presented to the ED with RT as the primary diagnosis. RT incidence was stable at 8.2 per million US population (95% Confidence Interval (CI): 5.3 - 21.0) in this time period. Most patients were males, Caucasian, paid with private insurance, and admitted to EDs in the Northeast. The most common comorbidities were hypertension (19%), a history of cataracts (15%), and diabetes (7.2%). During this time period, RTs costs added up to more than $79 million and $33 million in the ED and IP settings, respectively. Mean per-patient ED and IP costs increased by 145% (p=0.0008) and 86% (p=0.0047), respectively. ConclusionDespite the stable incidence of RTs, RTs place a significant economic burden to the healthcare system, which increases yearly. We recommend physicians and policy makers to work together to pass laws that could prevent the increasing healthcare costs.

Fundus angiography, including fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA), are essential examination tools for visualizing lesions and changes in retinal and choroidal vasculature. However, the interpretation of angiography images is labor-intensive and time-consuming. In response to this, we are organizing the third APTOS competition for automated and interpretable angiographic report generation. For this purpose, we have released the first angiographic dataset, which includes over 50,000 images labeled by retinal specialists. This dataset covers 24 conditions and provides detailed descriptions of the type, location, shape, size and pattern of abnormal fluorescence to enhance interpretability and accessibility. Additionally, we have implemented two baseline methods that achieve an overall score of 7.966 and 7.947 using the classification method and language generation method in the test set, respectively. We anticipate that this initiative will expedite the application of artificial intelligence in automatic report generation, thereby reducing the workload of clinicians and benefiting patients on a broader scale.

BackgroundNeurotrophic keratopathy (NK) is a rare degenerative corneal disease caused by impaired trigeminal innervation, resulting in reduced corneal sensation, impaired epithelial healing, ulceration, and risk of perforation or vision loss. Corneal innervation is essential for protective reflexes, epithelial maintenance, and ocular surface homeostasis. Conventional medical therapies may promote epithelial healing but do not directly restore corneal innervation. Corneal neurotization (CN) has emerged as a surgical strategy in which healthy donor sensory axons are transferred to denervated corneas to provide innervation. Multiple procedural variations now exist, including differences in donor nerve selection, graft use, and methods of limbal nerve insertion. A broad variety of NK etiologies is also being treated, including congenital, infectious, tumor, or other causes. However, published evidence remains limited by small case series, heterogeneous surgical methods, short follow-up periods, and inconsistent outcome reporting. ObjectiveTo address the need for standardized long-term outcome data in CN, we established the Corneal Neurotization Assessment (CorNeA) Registry, an international multicenter observational registry designed to evaluate patients undergoing CN. MethodsThe CorNeA Registry captures demographic characteristics, disease etiology, surgical technique, and longitudinal ocular outcomes in patients with NK treated with CN. Data are recorded in REDCap and include both retrospective and prospective patient enrollment across participating centers. Patients are followed longitudinally after surgery without a predefined endpoint to permit long-term assessment of corneal sensation recovery, ulcer recurrence, and visual outcomes. At the time of reporting, the registry includes 58 patients from multiple international centers, with active expansion ongoing. ConclusionBecause NK is rare and CN remains an evolving surgical field, long-term comparative data are lacking. The CorNeA Registry provides the first international platform to characterize patient selection, procedural variation, and long-term outcomes after CN, with the goal of informing future surgical decision-making and outcome standardization.

PurposeTo investigate the epidemiology of post-injection endophthalmitis (PIE) and evaluate the association of sociodemographic and clinical factors with incidence, timing of onset, and presenting visual acuity (VA) using the IRIS(R) Registry (Intelligent Research in Sight). DesignRetrospective cohort study. ParticipantsPatients with endophthalmitis after an intravitreal anti-VEGF injection in the IRIS(R) Registry from 2016-2023. MethodsOnly the first anti-VEGF injection per eye was included. Exclusion criteria were cataract surgery during the study, intravitreal corticosteroids within 30 days prior to PIE, uveitis, or cystoid macular edema. Mean best VA was recorded within 100 days prior to anti-VEGF treatment and at the time of PIE. Regression modeling evaluated associations between endophthalmitis and sociodemographic and clinical factors, and time to PIE. Linear regression assessed predictors of VA at the time of PIE, and descriptive statistics were used to analyze time to onset. Main Outcome MeasuresIncidence of post-injection endophthalmitis, time to symptom onset, and best VA at diagnosis. ResultsAmong 1,025,788 eyes treated, 600 (0.059%) developed endophthalmitis. Key risk factors included residence in U.S. territories (OR = 2.62; P = 0.038 vs. Northeast) and history of intravitreal corticosteroid injection (OR = 2.35; P = 0.004 vs. no history). The strongest protective factor was non-smoking (OR = 0.71; P = 0.023 vs. smokers). The median time from injection to onset of PIE was 5 days (interquartile range [IQR]: 3-8). The salient predictors of time to PIE included patient age (4.3 days sooner per decade older; P = 0.04), prior corticosteroid treatment (11.7 days sooner; P = 0.02), and a diagnosis of diabetic retinopathy (2.3 days sooner; P=0.03). Baseline VA before PIE was the only significant predictor of VA at the time of PIE diagnosis (0.67, P < 0.001). ConclusionPost-injection endophthalmitis was significantly associated with residence in U.S. territories and prior intravitreal corticosteroid exposure, while non-smoking status was protective. Most cases presented 3-8 days following anti-VEGF injection. Older age, history of prior corticosteroid treatment, and diabetic retinopathy were associated with earlier PIE. Baseline VA predicted VA at the time of PIE.

PurposeFundus fluorescein angiography (FFA) is essential for diagnosing and managing retinal vascular diseases, while its evaluation is time-consuming and subject to inter-observer variability. We aim to develop a deep-learning-based model for accurate multi-lesion segmentation for these diseases. MethodsA dataset comprising 428 standard 55{degrees} and 53 ultra-wide-field (UWF) FFA images was labeled for various lesions, including non-perfusion areas (NPA), microaneurysms (MA), neovascularization (NV) and laser spots. A U-net-based network was trained and validated (80%) to segment FFA lesions and then tested (20%), with performance assessed via Dice score and Intersection over Union (IoU). ResultsOur model achieved Dice scores for NPA, MA, NV, and Laser on 55{degrees} FFA images at 0.65{+/-}0.24, 0.70{+/-}0.13, 0.73{+/-}0.23 and 0.70{+/-}0.17, respectively. UWF results were slightly lower for NPA (0.48{+/-}0.21, p=0.02), MA (0.58{+/-}0.19, p=0.01), NV (0.50{+/-}0.34, p=0.14), but similar for Laser (0.74{+/-}0.03, p=0.90). Notably, NV segmentation in choroidal neovascularization achieved a high Dice score of 0.90{+/-}0.09, surpassing those in DR (0.68{+/-}0.22) and RVO (0.62{+/-}0.28), p<0.01. In RVO, NPA segmentation outperformed that in DR, scoring 0.77{+/-}0.25 versus 0.59{+/-}0.22, p<0.01, while in DR, MA segmentation was superior to that in RVO, with scores of 0.70{+/-}0.18 compared to 0.53{+/-}0.20, p<0.01. Moreover, NV segmentation was significantly stronger in venous phase (0.77{+/-}0.17) and late phase (0.75{+/-}0.24) compared to arteriovenous phase (0.50{+/-}0.32), p<0.05. ConclusionThis study has established a model for precise multi-lesion segmentation in retinal vascular diseases using 55{degrees} and UWF FFA images. This multi-lesion segmentation model has the potential to expand databases, ease grader burden and standardize FFA image interpretation, thereby improving disease management. Furthermore, it enhances interpretable AI, fostering the development of sophisticated systems and promoting cross-modal image generation for medical applications. SynopsisWe developed deep-learning models for segmenting multiple retinal lesions in both normal and ultra-field FFA images; the satisfactory performances set the foundation for quantifiable clinical biomarker assessment and building interpretable generative artificial intelligence.

BackgroundSpecialized terminology employed by ophthalmologists creates a comprehension barrier for non-ophthalmology providers, compromising interdisciplinary communication and patient care. Current solutions such as manual note simplification are impractical or inadequate. Large language models (LLMs) present a potential low-burden approach to translating ophthalmology documentation into accessible language. MethodsThis prospective, randomized trial evaluated the addition of LLM-generated plain language summaries (PLSs) to standard ophthalmology notes (SONs). Participants included non-ophthalmology providers and ophthalmologists. The study assessed: (1) non-ophthalmology providers comprehension and satisfaction with either the SON (control) or SON+PLS (intervention), (2) ophthalmologists evaluation of PLS accuracy, safety, and time burden, and (3) objective semantic and linguistic quality of PLSs. Results85% of non-ophthalmology providers (n=362, 33% response rate) preferred the PLS to SON. Non-ophthalmology providers reported enhanced diagnostic understanding (p=0.012), increased note detail satisfaction (p<0.001), and improved explanation clarity (p<0.001) for notes containing a PLS. The addition of a PLS narrowed comprehension gaps between providers who were comfortable and uncomfortable with ophthalmology terminology at baseline (intergroup difference p<0.001 to p>0.05). PLS semantic analysis demonstrated high meaning preservation (BERTScore mean F1 score: 0.85) with greater readability (Flesch Reading Ease: 51.8 vs. 43.6, Flesch-Kincaid Grade Level: 10.7 vs. 11.9). Ophthalmologists (n=489, 84% response rate) reported high PLS accuracy (90% "a great deal") with minimal review time burden (94.9% [&le;] 1 minute). PLS error rate on initial ophthalmologist review and editing was 26%, and 15% on independent ophthalmologist over-read of edited PLSs. 84.9% of identified errors were deemed low risk for patient harm and 0% had a risk of severe harm/death. ConclusionsLLM-generated plain language summaries enhance accessibility and utility of ophthalmology notes for non-ophthalmology providers while maintaining high semantic fidelity and improving readability. PLS error rates underscore the need for careful implementation and ongoing safety monitoring in clinical practice.

ObjectiveTo quantify microvascular lesions in a large Real-World Data (RWD) set, based on single central retinal fundus images from different origins, with the aim of validating its use as a precision tool for classifying Diabetic Retinopathy (DR) severity. DesignRetrospective meta-analysis across multiple fundus image datasets. Sample sizeThe study analyzed 2,340 retinal fundus images from diabetic patients across four diverse RWD international datasets, including populations from Spain, India, China and the US. InterventionThe quantification of specific microvascular lesions: microaneurysms (MAs), hemorrhages (Hmas) and hard exudates (HEs) using advanced automated image analysis techniques on central retinal images to validate reliable metrics for DR severity assessment. The images were pre-classified in the DR severity levels as defined by the International Clinical Diabetic Retinopathy (ICDR) scale. Main Outcome MeasuresThe primary variables measured were the number of MAs, Hmas, red lesions (RLs) and HEs. These counts were related with DR severity levels using statistical methods to validate the relationship between lesion counts and disease severity. ResultsThe analysis revealed a robust and statistically significant increase (p<0.001) in the number of microvascular lesions and the DR severity across all datasets. Tight data distributions were reported for MAs, Hmas and RLs, supporting the reliability of lesion quantification for accurately assessing DR severity. HEs also followed a similar pattern, but with a broader dispersion of data. Data used in this study are consistent with the definition of the DR severity levels established by the ICDR guidelines. ConclusionsThe statistically significant increase in the number of microvascular lesions across DR severity validate the use of lesion quantification in a single central retinal field as a key biomarker for disease classification and assessment. This quantification method demonstrates an improvement over traditional assessment scales, providing a quantitative metric that enhances the precision of disease classification and patient monitoring. The inclusion of a numerical component allows for the detection of subtle variations within the same severity level, offering a deeper understanding of disease progression. The consistency of results across diverse datasets not only confirms the methods reliability but also its applicability in a global healthcare setting.

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.

IntroductionAnti-vascular endothelial growth factor (anti-VEGF) therapies are standards of care for vision-threatening retinal diseases. This retrospective observational study describes demographics, utilization, best recorded visual acuity (BRVA), and safety among eyes with neovascular age-related macular degeneration (nAMD), diabetic retinopathy (DR), diabetic macular edema (DME), or retinal vein occlusion (RVO) treated with the biosimilar aflibercept-ayyh (PAVBLU(R)) in routine clinical practice. MethodsElectronic medical records from the Retina Consultants of America database of patients receiving aflibercept-ayyh (12/1/2024-10/31/2025) were analyzed, focusing on eyes with [&ge;]84 days of follow-up. The index date was the first documented aflibercept-ayyh injection. Postindex data were used to assess treatment patterns, BRVA (Wilcoxon signed rank test), and adverse events of special interest (AESIs). ResultsA total of 1,000 consecutive eyes from 989 patients received 3,730 injections of aflibercept-ayyh; most (91%) switched from prior anti-VEGF therapy and 9% were anti-VEGF treatment-naive. Disease distribution was 58% nAMD, 19% RVO, 16% DME, and 7% DR. Among switchers, median (IQR) number of prior injections was 21 (8-46). Median (IQR) follow-up was 6.0 months (4.6-7.1). Median (IQR) number of aflibercept-ayyh injections per eye was 4 (3-5). Among eyes with [&ge;]84 days of follow-up (n=889), mean BRVA expressed as logarithm of minimum angle of resolution (logMAR) remained stable for switchers (0.4 to 0.4; P=0.96) and improved from baseline in anti-VEGF-naive eyes (0.5 to 0.4; P<0.01). Confirmed AESIs included iritis (n=2; 0.05% of injections), with no events of vitreous cells, endophthalmitis, retinal detachment, retinal vasculitis, or vitreous hemorrhage. ConclusionIn this descriptive real-world analysis, aflibercept-ayyh was associated with stable visual acuity in previously treated eyes and vision improvement in treatment-naive eyes, with no new or unexpected safety findings, consistent with expectations for aflibercept. These findings add real-world experience to preexisting evidence demonstrating no clinically meaningful differences between aflibercept-ayyh (PAVBLU(R)) and reference aflibercept (EYLEA(R)). KEY SUMMARY POINTSO_ST_ABSWhy carry out this study?C_ST_ABSO_LIThe anti-vascular endothelial growth factor (VEGF) drug aflibercept, approved in 2011 and marketed in the United States as EYLEA(R),* has demonstrated efficacy in treating retinal diseases such as neovascular age-related macular degeneration (nAMD), diabetic retinopathy (DR), diabetic macular edema (DME), or retinal vein occlusion (RVO) and is a standard of care for these disorders. C_LIO_LIAflibercept-ayyh is a biosimilar to aflibercept that has demonstrated comparable efficacy and safety in the treatment of nAMD in a randomized controlled clinical trial. C_LIO_LIThis study describes the real-world use patterns, vision outcomes, and safety of aflibercept-ayyh in clinical settings in the United States for the treatment of nAMD, DR, DME, and RVO. C_LI What was learned from the study?O_LIIn this real-world study of 1,000 consecutive eyes treated with the biosimilar aflibercept-ayyh in patients with retinal diseases, we observed no new safety concerns and that aflibercept-ayyh maintained visual acuity in eyes switching anti-VEGF agents and improved vision in anti-VEGF-naive eyes, consistent with expected responses to aflibercept. C_LIO_LIThese findings support aflibercept-ayyh as a suitable treatment option when anti-VEGF therapy is indicated. *EYLEA(R) is a registered trademark of Regeneron Pharmaceuticals, Inc. PAVBLU(R) is a registered trademark of Amgen Inc. C_LI

ObjectiveComplement biomarker analysis in ocular fluid samples from subjects with geographic atrophy (GA) in a Phase I/II clinical trial of subretinal AAV2 complement factor I (CFI; FI) gene therapy, PPY988 (formerly GT005), to understand target pharmacokinetics/pharmacodynamics. Clinical findings were subsequently utilized to investigate the therapeutic dose in an in vitro complement activation assay. Design, setting and participantsBiomarker data were evaluated from 28 subjects in FOCUS, a Phase I/II clinical trial evaluating the safety and efficacy of three ascending doses of PPY988. Main outcomes and measuresVitreous humor (VH), and aqueous humor (AH) from subjects before surgery and at serial timepoints (week 5 or 12, 36, 96) were evaluated for changes in levels of intact complement factors I, B and H (FI, FB, FH) components C3, C4, and C1q and breakdown products (Ba, C3a, C3b/iC3b, C4b) using validated assays and OLINK(R) proteomics. A modified in vitro assay of complement activation modelling VH complement concentrations was used to compare PPY988 potency to the approved intravitreal C3 inhibitor pegcetacoplan (Apellis) and complement Factor H (FH). ResultsAn average 2-fold increase in VH FI was observed post-treatment at week 36 and week 96. This correlated with a marked post-treatment reduction in VH concentration of the FB breakdown product Ba and Ba:FB ratio, but minimal changes in C3a and C3b/iC3b levels. Variable concordance in complement biomarker levels in VH versus AH suggest AH is not a reliable proxy for VH for complement activation. During the experimental comparison of doses, a 2-fold increase of FI achieved in the vitreous had only a minor effect on the complement amplification loop in vitro, indicating limited impact [IC50: 1229nM]. Pegcetacoplan completely blocks C3a generation at concentrations much lower than the estimated trough level for monthly intravitreal injections [IC50: 2nM]. Supplementation with FH in the assay revealed similar potency to pegcetacoplan [IC50: 6nM]. Conclusions and relevancePPY988 subretinal gene therapy may not have provided sufficient FI protein to meaningfully modulate complement activation to slow GA growth. Reviewing VH biomarkers is important for understanding target expression, pathway engagement, and determining optimal dose, thereby informing future clinical development.

Handheld optical coherence tomography (OCT) systems have shown promises to provide detailed evaluation of the pediatric retina. It is less stressful for preterm infants compared to binocular indirect ophthalmoscopy and shows promises for screening for retinopathy of prematurity. There are currently only one commercially available non-contact handheld OCT systems, and no commercially available widefield handheld OCT systems. Here we report and evaluate the first use of the Theia Imaging Investigational handheld OCT system with widefield lens (T1-W, Theia Imaging, Durham, NC) in pediatric subjects. We compare the OCT en face view to handheld widefield or tabletop ultra-widefield fundus photographs and evaluate the ability to visualize the vitreoretinal interface, intraretinal, subretinal and choroidal features on cross-sectional OCT scans.

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