Investigative Ophthalmology & Visual Science

Cone photoreceptors are essential for daylight vision, and their degeneration has more profound visual consequences than rod loss in retinal degenerative diseases. Metabolic dysfunction is closely associated with cone degeneration, however the relatively small population of cones in mice and humans have limited our understanding of cone-specific metabolism. Here, we leveraged cone-dominant and cone-degeneration mouse models including Nrl-/-, Cnga3-/-, and high-dose Triiodothyronine (T3) treatment to investigate cone-specific metabolism and their metabolic impacts on the retinal pigment epithelium (RPE). Across models, cone-dominant retinas consistently showed lower pyruvate abundance alongside increases in glutathione, purines, pentose phosphate pathway intermediates, and one-carbon metabolites. Increases in several key amino acids were also associated with higher cone abundance, such as proline, arginine, alanine, valine, leucine, and hypotaurine. Strikingly, aminoadipate, an intermediate in lysine catabolism, was the most robustly changed metabolite in the retina, showing highly consistent increases across models. Relative cone increases were also associated with metabolic changes in the RPE/choroid. Like the retina, RPE/choroids showed consistent increases in aminoadipate, proline, and hypotaurine, as well as xanthosine and betaine, alongside decreases in uracil. Moreover, proteomic analysis of Nrl-/- mice showed decreases in many key metabolite transporters in the RPE/choroid, including carriers for glucose, lactate, aspartate, glutamate, serine, lysine, taurine, and proline. Collectively, these findings further our understanding of cone-specific metabolism and highlight potential cone-specific metabolic vulnerabilities in retinal degeneration.

PurposeFuchs endothelial corneal dystrophy (FECD) is a progressive disease, causing premature death of corneal endothelial cells (CECs). Iron-dependent lipid peroxidation and ferroptosis mediate cell death in FECD. We aimed to determine whether FECD progression is mediated by derangements in ferritinophagy - a form of autophagy that degrades ferritin to release labile ferrous iron - and whether ultraviolet A (UVA) exposure drives FECD progression by activating ferritinophagy. MethodsEndothelium-Descemet membrane (EDM) tissues were collected from patients with end-stage FECD undergoing endothelial keratoplasty and from healthy age-matched donor corneas. Separately, immortalized FECD and healthy control CEC lines were cultured. Cellular levels of NCOA4 production and LC3 activation, both markers of ferritinophagy, were quantified using western blotting and PCR. UVA-exposed immortalized cells were plated on coverslips, stained for immunohistochemistry (IHC), and analyzed using confocal microscopy. Corneal endothelial peels were stained and analyzed using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). ResultsSurgically explanted FECD CECs showed significantly increased levels of NCOA4 compared to healthy controls. LC3 activation was increased in FECD immortalized CECs; UV exposure further increased LC3 activation. Additionally, UVA exposure showed trends of increased expression of NCOA4 in immortalized FECD and healthy CECs. On IHC of FECD surgical explant tissue, ferritin was decreased markedly, NCOA4 localized in a dramatic punctate pattern, and both ferritin and LC3 localized within cell nuclei. Spectrometry images showed higher iron levels correlating with areas of higher FECD disease burden. ConclusionsOur results demonstrate ferritinophagy in FECD indicated by the increase of NCOA4 and LC3 ferritinophagy markers in FECD patient and cell culture models. Our finding that UVA activates ferritinophagy implicates this mechanism in UVA-mediated FECD progression. Altogether, aberrant iron dysregulation associated with FECD and ferroptosis may be mediated by ferritinophagy, providing a biomarker to assess disease severity as well as a potential target for future medical therapeutics.

Mustard keratopathy, caused by exposure of the cornea to sulfur or nitrogen mustard vesicants, chemical warfare agents, can lead to severe and often irreversible vision loss. Despite considerable efforts to develop medical countermeasures, including anti-inflammatory, antioxidant, anti-fibrotic, and anti-angiogenic therapies, no treatment effectively targets the underlying mechanisms responsible for mustard-induced tissue injury or prevents long-term disease progression. In the present study, we comprehensively define mitochondrial mechanisms underlying nitrogen mustard-induced corneal injury in both our cell culture model in vitro and a mouse model in vivo. DNM1L (aka Drp1) is a mitochondria-localized dynamin-related GTPase that executes mitochondrial fission and facilitates the autophagic elimination of damaged mitochondrial components. Using complementary in vitro and in vivo models, we demonstrate that nitrogen mustard rapidly induces excessive mitochondrial fragmentation, bioenergetic collapse, membrane depolarization, oxidative stress, intracellular acidification, mitophagy, and apoptotic cell death. Pharmacological inhibition of DNM1L with Mdivi-1 preserves mitochondrial structure and function, restores cellular metabolism, reduces oxidative damage, and markedly improves corneal epithelial integrity, and tissue repair following nitrogen mustard exposure. Collectively, these findings establish mitochondrial dysfunction as a central pathological mechanism in mustard keratopathy and identify DNM1L-mediated mitochondrial remodeling as a therapeutically actionable target. Our work provides strong preclinical evidence supporting mitochondrial-directed therapy as a promising strategy for treating mustard keratopathy.

PurposeTo evaluate associations between green autofluorescence (GAF) and structural and functional measures relevant to retinal and optic neuropathies, and to establish normative GAF values across the optic nerve head (ONH), macula, and papillofoveal bundle (PFB) in rhesus macaques. MethodsEighty-two macaques with normal ONH morphology by spectral-domain optical coherence tomography (SD-OCT) were included with a mean {+/-} SD age of 12.76 {+/-} 7.18 (range 0.11-29.39) years. The GAF images were acquired in the ONH, macula and PFB with the OcuMet Beacon. In a subset of macaques (n=19), pattern electroretinogram (PERG) and photopic full-field ERG including the photopic negative response (PhNR) were recorded. ResultsThe GAF significantly increased with age in the ONH, macula and PFB. After adjusting by age, there were no sex differences, but IOP showed a positive association with macular GAF. At the ONH, higher GAF correlated with thinner retinal nerve fiber layer, inner and outer segment complex, and total retinal thickness. In the macula, inner nuclear layer thickness was positively associated with GAF, whereas outer plexiform layer and inner and outer segment complex were inversely associated. The PERG amplitudes inversely tracked ONH GAF. ConclusionsGAF rises with age and IOP, couples to retinal structure, and at the ONH, aligns with inner-retinal functional indices. This study provides a regional reference for GAF in rhesus macaques. Translational RelevanceNormative GAF data in healthy rhesus macaques provide a framework for interpreting this noninvasive signal in translational studies of retinal and optic nerve disease.

Purpose: Oxidative stress is thought to contribute to the development of age-related cataracts (ARCs), but the mechanisms by which oxidative damage leads to the opacification of the lens remain unclear. Previous studies suggest that oxidative stress can disrupt lens proteostasis. Therefore, it was hypothesized that ARCs arise from proteomic changes driven by an age-associated decline in oxidative stress defenses that interact with the lens proteostatic state. To test this hypothesis, proteomic analyses of lenses exposed to oxidative stress were performed to examine oxidative and proteostatic stress responses in vivo. Methods: Cataract formation was induced by injecting hydrogen peroxide into the aqueous humor of adult zebrafish. nrf2fh318/fh318 zebrafish were used to model the reduced oxidative stress protection observed in aged human lenses, while cryaba-/- zebrafish were used to model impaired lens proteostasis. Resulting opacities in WT, cryaba-/-, nrf2fh318/fh318, and cryaba-/-; nrf2fh318/fh318 lenses were quantified and proteomic changes in the cortex were analyzed using data independent acquisition Parallel Accumulation Serial Fragmentation mass spectrometry. Results: Hydrogen peroxide treatment induced the formation of cortical cataracts. Proteomic results showed that, dependent on genotype and day, oxidative stress activates the unfolded and mitochondrial unfolded protein responses. Additional changes were also observed in energy metabolism, Ca2+ homeostasis, protein degradation, and cytoskeletal and extracellular matrix remodeling pathways. Conclusions: Treated zebrafish lenses successfully model ARC and mass spectrometry proteomics identified the unfolded and mitochondrial unfolded protein responses as potential therapeutic targets for ARC.

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.

It is clear that the human retina and its underlying retinal pigment epithelium and choroid (RPE/choroid) form an interdependent metabolic ecosystem, but how metabolism differs between the cone-rich macula and rod-rich periphery remains unclear. Using targeted metabolomics, we quantified 133 metabolites in paired macular and peripheral neural retina and RPE/choroid explants from human donor eyes following short-term culture to restore metabolic activity. Distinct metabolic differences were identified between retinal regions and between tissues. Compared with the peripheral retina, the macula showed metabolic features consistent with greater glycolytic activity, increased NADH availability and higher levels of the neurotransmitter-associated metabolites N-acetyl-aspartate (NAA) and N-acetyl-aspartyl-glutamate (NAAG), consistent with increased energetic and neuronal activity. Compared with peripheral RPE/choroid, the macular RPE/choroid had higher levels of the flavin cofactor FAD together with NAD-related metabolites, including NAD, NADP and NAAD. Comparisons between the neural retina and RPE/choroid further showed that the neural retina was primarily associated with energy production and neurotransmission, whereas the RPE/choroid was associated with cofactor metabolism, nucleotide salvage and lipid metabolism. These findings are consistent with metabolic coupling between the neural retina and RPE/choroid. The macula has metabolic features consistent with high energetic demand, providing a potential metabolic basis for its selective vulnerability in macular disease.

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

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.

Meibomian gland dysfunction (MGD), a disorder of the eyelid's modified sebaceous glands, is the leading cause of dry eye disease and ocular surface morbidity, yet the immune mechanisms driving gland obstruction remain poorly defined. In a cross-sectional study of 66 patients with ocular surface inflammation, we used meibography and spectral flow cytometry of tear washes to identify a disease-associated, remodeled neutrophil state whose abundance is associated with gland atrophy. Using single-cell transcriptomics in a murine model of immune-mediated MGD, we revealed a disease-associated neutrophil state that exhibited ocular surface-enrichment, CD14 and ICAM-1 expression, and elevated IFN-{gamma} response and inflammatory signatures. Spatial transcriptomics localized IFN-{gamma} signaling and neutrophil migration signatures to the periglandular compartment. The remodeled neutrophils exhibited PAD4-dependent histone citrullination, with Padi4 deletion reducing NET-associated obstructive plugging, thus identifying PAD4-dependent NETotic activity as their disease-producing output. Inhibition of IFN-{gamma} signaling phenocopied Padi4 deficiency, yet combined disruption of these pathways provided no additive protection, indicating that IFN-{gamma} and PAD4 function as separable required inputs. Remodeled neutrophils accumulated under both conditions, uncoupling disease severity from cell abundance alone. Our findings support immune-mediated obstructive MGD as a mechanistic endotype driven by the IFN-{gamma}- and PAD4-dependent effector output of a remodeled neutrophil state.

Under homeostatic conditions, the cornea is avascular and contains few immune cells, but this changes rapidly following injury. Although the long-term consequences of corneal damage are well characterized, the earliest vascular and immune responses remain poorly understood. Here, we used a murine corneal alkali-burn model to examine limbal vascular activation and leukocyte recruitment immediately and at 2, 6, and 24 hours after injury. Limbal blood vessels underwent immediate dilation; however, vascular leakage into the corneal stroma occurred only in males. Lymphatic capillaries rapidly formed directed extensions toward the injury without significantly increasing their total vascular area, with males exhibiting longer extensions than females. Fluorescent dextran uptake provided evidence that these lymphatic vessels were functionally engaged in early tracer drainage. Despite pronounced vascular activation, early recruitment of neutrophils, monocytes, dendritic cells, macrophages, T cells, B cells, and natural killer cells remained limited. Thus, limbal blood and lymphatic vessels initiate the earliest response to corneal alkali injury before substantial leukocyte infiltration. These findings reveal sex-dependent differences in vascular permeability and lymphatic remodeling and identify the limbal vasculature as an early regulator of corneal inflammation and tissue repair.

Introduction Anatomical endoscopic enucleation of the prostate (AEEP) techniques, including bipolar enucleation (B-TUEP), holmium laser enucleation (HoLEP), thulium laser enucleation (ThuLEP), and thulium fibre laser enucleation (ThuFLEP), demonstrate comparable clinical outcomes for benign prostatic hyperplasia. As clinical equivalence is increasingly established, cost becomes a key determinant of modality selection. We performed a cost minimisation analysis comparing index procedural costs across AEEP modalities from an institutional perspective. Methods A cost minimisation model was developed from the institutional perspective, incorporating amortised capital costs, maintenance, and consumables. In addition to the base-case scenario of 180 cases per year, we modelled two additional case volume scenarios: low (50 cases/year) and high (500 cases/year) volume. Thu:YAG laser fibres were modelled on two scenarios: disposable single-use, and reusable fibres (up to 10 cases per fibre). Breakeven analysis determined the threshold volume at which each laser modality achieves cost parity with B-TUEP, and one-way sensitivity analysis was performed on key cost parameters. Analysis was limited to index procedural costs calculated in Singapore dollars. Results At the base case of 180 cases per year, B-TUEP had the lowest index procedure cost (SGD 1,018), followed by ThuFLEP (SGD 1,584), ThuLEP (1,599), and HoLEP (SGD 1,655). Breakeven analysis demonstrated that HoLEP, ThuLEP, and ThuFLEP can never achieve cost parity with B-TUEP when laser fibres are single-use, as laser modalities carry higher costs on both capital and per-case dimensions. ThuLEP with reusable fibres (10 uses per fibre) was the only modality to cross below B-TUEP, at a breakeven volume of 198 cases per year. At 500 cases per year with reusable fibres, ThuLEP achieved the lowest cost (SGD 847), representing a 15.4% saving over B-TUEP. Sensitivity analysis identified annual case volume and B-TUEP loop cost as the most influential parameters. Conclusion Index procedural costs in AEEP are strongly influenced by case volume and consumable strategy. While B-TUEP remains cost-efficient at low volume, high-volume practice combined with reusable Thu:YAG fibre technology enables cost parity and potential cost advantage for laser enucleation. These findings highlight the importance of economies of scale and device utilisation in technology adoption.

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in older adults. It is characterised by early retinal pigment epithelium (RPE) dysfunction followed by progressive photoreceptor degeneration. Cigarette smoking is a major environmental risk factor for AMD, and hydroquinone (HQ), a redox-active cigarette smoke component, induces oxidative stress and apoptosis in RPE cells. To analyse how RPE stress contributes to photoreceptor degeneration, we employed a retinal co-culture model composed of human induced pluripotent stem cell-derived RPE (iPSC-RPE) cells in conjunction with porcine neuroretina explants. Exposure to HQ induced oxidative stress in iPSC-RPE cells as well as retinal photoreceptors (RPR), resulting in apoptosis, executed at least in part by caspase activation. Concomitantly, HQ caused endoplasmic reticulum (ER) stress (ERAD) in RPR followed by their degeneration, evidenced by reduced outer nuclear layer (ONL) rows and shortened RPR outer segments (OS). Based on earlier results, which suggest a perturbation of proteostasis due to HQ, we tested whether ML240, a bona fide inhibitor of valosin-containing protein (VCP), would influence the degree of degenerative activities. ML240 did not prevent HQ-induced apoptosis in iPSC-RPE cells. However, it significantly preserved photoreceptor integrity, retaining OS length and cone density in HQ-stressed co-cultures. Proteomic analysis suggested that ML240 reshapes stress response patterns of the HQ-exposed neuroretina, as evidenced by a reduction in ERAD-associated markers, increased levels of antioxidant response proteins, and the preservation of cytochrome c enrichment in photoreceptor inner segments, which indicates improved mitochondrial integrity consistent with the observed preservation of photoreceptor structure. Together, these findings establish the iPSC-RPE/neuroretina co-culture as a platform to analyse pathophysiological features of AMD, dissect cell type-specific retinal responses to environmental stress and test neuroprotective pharmacological approaches to protect photoreceptors in oxidative stress-associated retinal degeneration.

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

Traumatic optic neuropathy (TON) occurs due to direct or indirect injury to the optic nerve and is a significant cause of visual disability. So far, there is no effective treatment. The lack of understanding of the cellular mechanisms by which trauma induces inflammation and damage in retinal neurons is a critical knowledge gap in developing effective therapies. We have studied the role of the arginase 1 (A1) enzyme in this pathology. We have found previously that treatment with a long-acting form of human recombinant A1, pegylated A1 (PEG-A1) after optic nerve crush limits activation of retinal microglia and macrophages (M{Phi}) and reduces inflammation, thereby decreasing injury and protecting visual function. Here we report on studies designed to demonstrate the therapeutic efficacy of PEG-A1 in mouse models of direct and indirect TON and to elucidate the underlying mechanisms. We used ONC to model direct TON and sonication-induced trauma to the supraorbital rim to model indirect TON (SI-TON). At different times after injury, mice were treated with PEG-A1 which was delivered systemically by i.p. injection or locally by intravitreal injection. In order to assess the role of A1-induced activation of the ornithine/polyamine pathway in the protective effects of PEG-A1, some mice were treated with the ornithine decarboxylase (ODC) inhibitor, difluoromethylornithine (DFMO) immediately after the PEG-A1 treatment. Retinal function was determined by OptoMotry and electroretinography. Retinal injury and microglia/M{Phi} activation were assessed by immunofluorescence imaging. Expression of inflammatory cytokines was determined by Western blotting and quantitative RT PCR. Liquid chromatography mass spectrometry was used to analyze changes in arginase/ODC pathway metabolites. Results showed that PEG-A1 treatment improved neuronal survival and visual function whether delivered systemically or intravitreally. This neuroprotection was associated with decreased microglia/M{Phi} activation, decreased inflammatory cytokine expression, and increased formation of L-ornithine and putrescine. Furthermore, DFMO treatment blocked these effects, indicating that PEG-A1 limits retinal injury and preserves vision after ocular injury by activating ODC. ODC processes the arginase product L-ornithine to form polyamines which are known to promote reparative functions. Thus, PEG-A1 therapy offers a new strategy to limit trauma-induced vision loss and promote repair after TON.

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.

Elevated intraocular pressure (IOP) and aging are major risk factors for primary open-angle glaucoma (POAG), but how aging affects IOP regulation remains poorly understood. IOP remains within a narrow range despite age-associated changes predicted to increase aqueous humor outflow (AHO) resistance at the interface between the trabecular meshwork and Schlemm's canal (SC), suggesting compensatory mechanisms preserve AHO homeostasis during aging. Single-cell RNA sequencing of mouse ocular angle tissues revealed immunomodulatory transcriptional reprogramming of SC endothelial cells in older mice, while mouse and human imaging showed reduced SC size and increased peri-SC macrophage accumulation with aging. Ligand-receptor analysis predicted enhanced macrophage-to-SC VEGFA-VEGFR signaling in aged and Tie2-haploinsufficient mice, an independent model of vascular stress and glaucoma risk. Deletion of Vegfa in CX3CR1+ macrophages increased IOP and reduced AHO facility in 9-month-old wild-type mice, demonstrating that macrophage-derived VEGFA supports AHO homeostasis. Tie2 haploinsufficiency recapitulated key age-associated SC niche changes, including peri-SC macrophage accumulation, whereas gene therapy boosting TIE2 activity protected wild-type mice against age-related changes. Together, these findings identify peri-SC macrophage-derived VEGFA as a compensatory mechanism maintaining AHO homeostasis during aging and vascular stress and support TIE2 activation as a therapeutic strategy to preserve SC function and IOP regulation.

Purpose. To evaluate whether a Geographic Atrophy Morphology-based Mapping Algorithm (GAMMA) grid, informed by geographic atrophy (GA) lesion morphology, can accelerate functional progression detection compared with a conventional 10-2 grid and a dense grid (129 locations). This work is motivated by emerging regulatory expectations requiring at least five locations to worsen by [&ge;]7 dB from baseline. Methods. Binary atrophy masks from six autofluorescence images were used to simulate GA expansion over 3 years at 3-month intervals using a stochastic perimeter-growth model with a fixed preferential expansion direction (Pdir). For each image, 32 independent growth histories and 32 microperimetric test realisations per history were generated. For each grid (10-2, Dense, and GAMMA), 5-point clusters were selected outside the baseline GA lesion along three directions (0{degrees}, 30{degrees}, 120{degrees}) away from Pdir, simulating full, partial, and no prior knowledge of Pdir. Ground-truth sensitivities were <0 dB inside the GA lesion and normal outside, calculated using a published normative equation. Response variability was simulated following Henson et al. with baseline averaging. Detection time was the first visit at which all five selected locations showed [&ge;]7 dB loss from baseline. Survival curves and median detection times (T50) were used to compare grid performance. Results. The GAMMA grid achieved the earliest progression detection across all scenarios. Under full knowledge of the expansion direction, T50 was 1.0 year for GAMMA versus 1.25 and 1.5 years for Dense and 10-2, respectively. With partial knowledge, GAMMA's T50 was 1.25 years versus 1.5 and 2.0 years for Dense and 10-2. Even under no knowledge, GAMMA detected progression earliest (T50 = 1.5 years), while Dense required 6 months longer and 10-2 nearly double the time (2.75 years). Conclusions. The automatic GAMMA grid accelerates detection of localised functional progression compared with conventional and dense grids. Structure-informed grid optimisation may better align testing with likely expansion paths, potentially reducing follow-up duration and sample sizes in perimetry-based interventional trials.

Objective: To describe trends in cataract surgical volume, district-level surgical burden, and early postoperative visual outcomes among patients treated through a multi-district outreach programme in Bangladesh. Methods and Analysis: This retrospective study was conducted using data from patients undergoing cataract surgery through the outreach eye-camp programme of Bashundhara Eye Hospital and Research Institute across eight districts of Bangladesh, between 2016 and 2025 (excluding 2021 because of COVID-19). Annual surgical volume trend was assessed using Poisson regression. Postoperative visual outcome on day 1 was categorized as good, borderline, or poor per WHO criteria. Univariable and multivariable ordinal logistic regression identified predictors of worse outcome. Results: 1,929 cataract-surgery records were included. Surgical volume rose from 34 cases in 2016 to a peak of 677 in 2023 (IRR = 1.20; 95% CI: 1.180, 1.220; p-value< 0.001). Small incision cataract surgery (SICS) was used in 99.43% cases. On postoperative day 1, 70.09% of eyes had a good outcome, 19.44% borderline, and 10.47% poor. Increasing age was independently associated with worse outcome, with 2 to 3 times higher odds among patients over 70. District was independently associated with outcome, with Chapainawabganj and Kushtia having lower odds of worse outcome than Brahmanbaria. Sex was significant only in unadjusted analysis. Conclusion: Surgical volume rose substantially over time. About seven in ten eyes achieved a good outcome on day 1, with age and district as the main predictors of worse outcome. Limitations include a single early assessment, exclusion of incomplete records, no standardized refraction, and unmeasured predictors.

Introduction: Community outreach eye camps extend eye care to underserved rural populations across South Asia, but published data mostly describe surgical yield rather than the full range of presenting conditions. This study described the pattern of ocular diagnoses among patients attending community eye camps in Bangladesh and examined how these patterns varied by year, age, and sex. Methodology: This was a retrospective, registry-based study of patients screened through the outreach eye-camp programme of Bashundhara Eye Hospital and Research Institute, Bangladesh, between 2020 and 2024 (2021 excluded due to COVID-19). Age, sex, and provisional diagnosis were recorded for every patient and grouped into five categories: cataract and lens disorders, refractive errors and presbyopia, ocular surface inflammatory disorders, lacrimal system disorders, and miscellaneous disorders. Multivariable logistic regression models estimated the adjusted odds and predicted prevalence of each diagnostic category by calendar year (adjusted for age group and sex) and by age group and sex (adjusted for calendar year). Results: Among 7,267 patients, refractive errors and presbyopia were the most common category (51.31%), followed by cataract and lens disorders (23.54%), miscellaneous disorders (13.86%), ocular surface inflammatory disorders (8.59%), and lacrimal disorders (2.70%). Ocular surface disorders declined significantly over time (adjusted OR: 0.80/year; p-value<0.001). Cataract showed a borderline decline (adjusted OR: 0.94; p-value=0.065). Cataract prevalence rose steeply with age, from 3-6% below 18 years to 49-55% at 60 and older, while refractive errors/presbyopia peaked at 40-59 years (64-68%) before declining thereafter (30-37%). Ocular surface disorders were most frequent among children. Lacrimal disorders remained uncommon (2-5%), with no significant interaction. Conclusion: Refractive errors and presbyopia were the leading reason for presentation, with distinct age patterns across diagnostic categories. Outreach eye camps should be resourced for both comprehensive refraction, primary eye care and cataract-surgical referral, reflecting actual community-level diagnostic needs.