Many patients with diabetic eye disease respond inadequately to anti-VEGF therapies, implicating additional vasoactive mediators in its pathogenesis. We demonstrate that levels of angiogenic proteins regulated by HIF-1 and -2 remain elevated in the eyes of people with diabetes despite treatment with anti-VEGF therapy. Conversely, by inhibiting HIFs, we normalized the expression of multiple vasoactive mediators in mouse models of diabetic eye disease. Accumulation of HIFs and HIF-regulated vasoactive mediators in hyperglycemic animals was observed in the absence of tissue hypoxia, suggesting that targeting HIFs may be an effective early treatment for diabetic retinopathy. However, while the HIF inhibitor acriflavine prevented retinal vascular hyperpermeability in diabetic mice for several months following a single intraocular injection, accumulation of acriflavine in the retina resulted in retinal toxicity over time, raising concerns for its use in patients. Conversely, 32-134D, a recently developed HIF inhibitor structurally unrelated to acriflavine, was not toxic to the retina, yet effectively inhibited HIF accumulation and normalized HIF-regulated gene expression in mice and in human retinal organoids. Intraocular administration of 32-134D prevented retinal neovascularization and vascular hyperpermeability in mice. These results provide the foundation for clinical studies assessing 32-134D for the treatment of patients with diabetic eye disease.

Background. To reduce the treatment burden for patients with neovascular age-related macular degeneration (nvAMD), emerging therapies targeting vascular endothelial growth factor (VEGF) are being designed to extend the interval between treatments, thereby minimizing the number of intraocular injections. However, which patients will benefit from longer-acting agents is not clear. Methods. Eyes with nvAMD (n = 122) underwent 3 consecutive monthly injections with currently available anti-VEGF therapies, followed by a treat-and-extend protocol. Patients who remained quiescent 12 weeks from their prior treatment entered a treatment pause and were switched to pro re nata (PRN) treatment (based on vision, clinical exam, and/or imaging studies). Proteomic analysis was performed on aqueous fluid to identify proteins that correlate with patients’ response to treatment. Results. At the end of 1 year, 38 of 122 eyes (31%) entered a treatment pause (≥30 weeks). Conversely, 21 of 122 eyes (17%) failed extension and required monthly treatment at the end of year 1. Proteomic analysis of aqueous fluid identified proteins that correlated with patients’ response to treatment, including proteins previously implicated in AMD pathogenesis. Interestingly, apolipoprotein-B100 (ApoB100), a principal component of drusen implicated in the progression of nonneovascular AMD, was increased in treated patients who required less frequent injections. ApoB100 expression was higher in AMD eyes compared with controls but was lower in eyes that develop choroidal neovascularization (CNV), consistent with a protective role. Accordingly, mice overexpressing ApoB100 were partially protected from laser-induced CNV. Funding. This work was supported by the National Eye Institute, National Institutes of Health grants R01EY029750, R01EY025705, and R01 EY27961; the Research to Prevent Blindness, Inc.; the Alcon Research Institute; and Johns Hopkins University through the Robert Bond Welch and Branna and Irving Sisenwein professorships in ophthalmology. Conclusion. Aqueous biomarkers could help identify patients with nvAMD who may not require or benefit from long-term treatment with anti-VEGF therapy.

BACKGROUND. Studies assessing the efficacy of therapies for neovascular age-related macular degeneration (nvAMD) have demonstrated that aflibercept may have a longer treatment interval than its less-expensive alternative, bevacizumab. However, whether this benefit justifies the additional cost of aflibercept remains under debate. We have recently reported that a treat-and-extend-pause/monitor approach can be used to successfully wean 31% of patients with nvAMD off anti-VEGF therapy. Here, we examined whether the choice of therapy influences the outcomes of this approach. METHODS. In this retrospective analysis, 122 eyes of 106 patients with nvAMD underwent 3 consecutive monthly injections with either aflibercept (n = 70) or bevacizumab (n = 52), followed by a treat-and-extend protocol, in which the decision to extend the interval between treatments was based on visual acuity, clinical exam, and the presence or absence of fluid on optical coherence tomography. Eyes that remained stable 12 weeks from their prior treatment were given a 6-week trial of holding further treatment, followed by quarterly monitoring. Treatment was resumed for worsening vision, clinical exam, or optical coherence tomography findings. RESULTS. At the end of 1 year, eyes receiving bevacizumab had similar vision but required more injections (8.7 ± 0.3 treatments vs. 7.2 ± 0.3 treatments) compared with eyes receiving aflibercept. However, eyes treated with aflibercept were almost 3 times more likely to be weaned off treatment (43% vs. 15%) compared with eyes treated with bevacizumab at the end of 1 year. CONCLUSION. These observations expose an advantage of aflibercept over bevacizumab and have important clinical implications for the selection of therapy for patients with nvAMD. FUNDING. This work was supported by the National Eye Institute, NIH grants R01EY029750 and R01EY025705, Research to Prevent Blindness, the Alcon Young Investigator Award from the Alcon Research Institute, and the Branna and Irving Sisenwein Professorship in Ophthalmology.

Virtual reality (VR) and augmented reality (AR) are three-dimensional (3D) environments designed to mimic the real world. They have shown significant applications in science, especially in medicine. Their use spans various areas, including education, surgical training, patient education, and medical instruction. In ophthalmology, which is considered a field of microsurgery, VR and AR provide a 3D environment for practicing precise procedures. The ability to repeat exercises, independence from real patients, and tactile feedback allow residents to practice numerous times in a risk-free setting. Learning in a 3D environment is not limited to surgical techniques but it also supports learning theoretical concepts and practicing patient history-taking, reducing dependence on traditional professional training. This approach allows students in low socioeconomic countries to access high-quality training platforms. Beyond medical education, VR and AR can also be used to educate patients in a simple and accessible way, helping them understand their pathophysiology. Raising awareness about signs and symptoms is an effective method to prevent the progression of eye conditions. In this narrative review, we discuss the applications of VR and AR in ophthalmology, their benefits, and future directions.

Cataract surgery is one of the most common and effective surgeries performed worldwide, yet patient education remains a challenge due to limitations in health literacy among the general population. Our study evaluated the reliability of different large language models (LLMs) in providing accurate, complete, and clear responses to frequently asked questions (FAQs) related to cataract surgery. A comprehensive list of 20 FAQs about cataract surgery were submitted sequentially as a prompt to nine different LLMs. All 180 answers were recorded and scored by two expert ophthalmologists, blinded to the model type, on a 5-point scale measuring the degree of accuracy, completeness, and clarity. Interrater agreement was measured using a weighted kappa coefficient and model performances were compared using the Friedman test and post-hoc analysis. Our results showed all models performed well responding to FAQs (79% of responses scored “excellent”), serving as effective tools in answering patient FAQs. LLaMA 4 and Copilot scored lower on average relative to other models ( p < .05), however, they remained effective at FAQ responses overall. Potential expansion of LLMs as patient education tools into clinical settings should be considered, as they exhibit effectiveness in providing clear, accurate, and complete responses to cataract surgery FAQs.

Background: Cytomegalovirus retinitis (CMVR) is a vision-threatening retinal infection that primarily affects severely immunocompromised individuals. Objectives: This study aimed to compare the clinical presentations, long-term visual outcomes, and predictors of visual prognosis in CMVR patients across different immunodeficiency subtypes. Design: Retrospective cohort study. Methods: This study analyzed 117 eyes from 91 patients with CMVR who were treated at a tertiary eye center between 2009 and 2024. Eyes were stratified by the underlying cause of immunosuppression into a human immunodeficiency virus (HIV)-positive group (71 eyes of 58 patients) and an HIV-negative group (46 eyes of 33 patients). The HIV-negative group included patients with hematologic malignancies, drug-induced immunosuppression (e.g., posttransplant or autoimmune therapy), solid organ transplantation, autoimmune disease, congenital immunodeficiency, and poorly controlled diabetes mellitus type 2 (DM2). Patient demographics and comprehensive ophthalmologic examination findings were recorded and compared across these subgroups. Results: The study included 91 patients (117 eyes) with a mean age of 40.1 ± 14.7 years; 62.6% were male. Of these, 58 patients (71 eyes) were HIV-positive (mean age 39.7 ± 10.9 years; 65.5% male) and 33 patients (46 eyes) were HIV-negative. Among HIV-negative patients, 19 eyes were in patients with hematologic malignancies (mean age 35.3 ± 21.1 years; 75% male), 20 eyes were in patients with drug-induced immunosuppression (mean age 38.6 ± 17.9 years; 40% male), and the remainder eyes were associated with solid organ transplant, autoimmune disease, congenital immunodeficiency, or poorly controlled DM (7 eyes). Eyes in HIV-negative patients exhibited more severe vitritis than those in HIV-positive patients (34.8% vs 19.7% with vitritis grade +2; p = 0.009). Conversely, HIV-positive patients presented with worse baseline visual acuity (mean 1.85 ± 1.14 logMAR vs 1.31 ± 1.17 logMAR; p = 0.045). Comparing the two main HIV-negative subgroups, the drug-induced immunosuppression group showed a significantly higher incidence of retinal vascular sheathing (30% vs 0% of eyes; p = 0.009), whereas the hematologic malignancy group demonstrated more cotton-wool spots (21.1% vs 0% of eyes; p = 0.030). Despite these phenotypic differences, long-term visual outcomes were similar across all groups. On multivariable regression, baseline best-corrected visual acuity (BCVA) (β = 0.527, p < 0.001) and retinal detachment (β = 0.254, p = 0.017) were independent predictors of poorer final visual acuity. Conclusion: CMV retinitis demonstrates distinct clinical phenotypes in different immunosuppressed populations. HIV-negative patients tend to show more pronounced vitritis and vasculopathic retinal features, whereas HIV-positive patients have worse baseline visual acuity. However, the long-term visual prognosis was not significantly influenced by the underlying cause of immunosuppression.