Search Results (1,680)

Age-related macular degeneration (AMD) is a major cause of irreversible visual impairment, yet identifying effector proteins and tissue-specific mechanisms underlying genome-wide association study (GWAS) loci remains challenging. This study aimed to systematically prioritize candidate causal circulating proteins and delineate their cellular and transcriptional dynamics in AMD. We integrated plasma protein quantitative trait loci (pQTL) summary statistics from the UK Biobank Pharma Proteomics Project (UKB-PPP; $N=\mathrm{53,022}$) with FinnGen AMD GWAS data using proteome-wide association studies (PWAS), summary-data-based Mendelian randomization (SMR) with the HEIDI test, and Bayesian colocalization analysis. Prioritized candidates were mapped across human and murine retinal single-cell/single-nucleus RNA sequencing atlases. Transcriptional responsiveness was validated in an independent clinical microarray dataset (GSE103060) and in human retinal pigment epithelial cells (ARPE-19) via in vitro inflammatory stimulation and RT-qPCR. Target tractability was assessed using pharmacological databases. Multi-stage genetic screening prioritized five candidate proteins stratified into two confidence tiers: three Tier 1 causal drivers supported by colocalization (PP4 > 0.80)—including risk factors CSF2, IL20RB, and WARS1 (also known as WARS)—alongside two Tier 2 candidates supported by SMR and HEIDI, comprising risk factor PILRA and inversely associated metabolic factor ACADSB. Retinal transcriptomic mapping localized PILRA specifically to microglia, ACADSB to inner retinal neurons, and WARS1 to photoreceptors, RPE, and vascular compartments, while IL20RB and CSF2 exhibited low baseline expression. In independent validation cohorts, IL20RB and WARS1 were significantly up-regulated in choroidal neovascularization (CNV) membrane-derived RPE from patients with AMD ($p<0.01$). Exposure of ARPE-19 cells to TNF-$\alpha$ markedly induced mRNA levels of IL20RB ($P=0.0025$) and WARS1 ($p<0.0001$). Dual normalization against ACTB as a secondary internal reference yielded consistent significant induction. Pathway enrichment highlighted cytokine-driven receptor cascades (JAK-STAT signaling) and mitochondrial substrate catabolism (branched-chain amino acid and fatty acid metabolism). Drug–target profiling identified small molecules and nutraceuticals interacting with ACADSB, CSF2, and WARS1. By combining large-scale plasma proteomic genetics with single-cell mapping and experimental validation, this study identifies a prioritized set of candidate causal proteins linking neuroimmune activation, vascular remodeling, and mitochondrial bioenergetics in AMD, providing candidate entry points for mechanistic and therapeutic exploration. Full article

Background/Objectives: The purpose of this study was to evaluate associations between quantitative ellipsoid zone (EZ) integrity metrics derived from spectral-domain OCT (SD-OCT) and visual outcomes, including clinically meaningful visual acuity (VA) loss, in dry age-related macular degeneration (AMD). Methods: This single-center retrospective image-analysis cohort included 351 eyes from 351 patients with intermediate AMD or atrophic changes. Macular SD-OCT scans were analyzed using a certified-reader-validated machine learning-based segmentation platform to delineate the EZ, retinal pigment epithelium (RPE), and Bruch’s membrane (BM). EZ metrics included EZ-RPE thickness (i.e., outer segment thickness) and EZ attenuation, defined as partial attenuation (EZ-RPE thickness of ≤20 µm, abnormal outer segment thinning)) or total attenuation/loss (0 µm). Drusen volume was quantified from the RPE-BM compartment. VA was converted to ETDRS letters. Associations between baseline OCT metrics and baseline VA, Year 2 VA, and ≥15-letter VA loss were assessed using nonparametric testing, linear regression, and ANCOVA. Results: Greater EZ-RPE thickness and lower EZ attenuation were associated with better baseline VA (all p < 0.001), and EZ metrics remained significant in cross-sectional regression models. Among 188 eyes with Year 2 follow-up, 38 (20%) experienced ≥15-letter VA loss. These eyes had significantly lower baseline EZ-RPE thickness (i.e., abnormal outer segment thinning) and greater EZ attenuation than eyes without such loss (all p < 0.001). In ANCOVA models, EZ metrics remained associated with Year 2 VA (all p < 0.001), whereas drusen volume was not. Conclusions: Quantitative EZ integrity metrics were associated with cross-sectional and longitudinal visual outcomes in dry AMD. EZ-RPE thickness and EZ attenuation may serve as clinically relevant OCT biomarkers reflecting photoreceptor integrity and risk of meaningful VA loss. Full article

Increasing epidemiological and experimental evidence suggests that age-related macular degeneration (AMD) and cardiovascular disease (CVD) share multiple pathogenic mechanisms. Among these, oxidative stress has emerged as one of the most plausible links connecting retinal degeneration and cardiovascular pathology. Excessive production of reactive oxygen and nitrogen species, combined with declining antioxidant defenses, contributes to lipid peroxidation, mitochondrial dysfunction, chronic inflammation, complement activation, cellular senescence, and impaired cellular stress responses in both the retina and the vascular system. Notably, drusen (AMD) and atherosclerotic plaques (CVD) share several molecular constituents. Therefore, AMD and CVD may represent tissue-specific manifestations of broader age-related disturbances in redox homeostasis and inflammatory regulation. Nevertheless, the coexistence of AMD and CVD is incomplete, suggesting that genetic susceptibility, tissue-specific responses to oxidative stress, biological aging, and mechanisms of cellular resilience influence disease expression. In this review, we summarize current evidence linking AMD and CVD, examine oxidative stress-driven molecular pathways common to both disorders, discuss emerging biomarkers and therapeutic targets, and highlight important unresolved questions regarding disease heterogeneity and causal relationships. A better understanding of the shared mechanisms underlying AMD and CVD may facilitate the development of integrated preventive strategies, improved risk stratification, and more personalized therapeutic approaches for age-related diseases. Full article

Neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) are leading causes of visual impairment and require long-term intravitreal anti-vascular endothelial growth factor (VEGF) therapy. However, treatment burden and suboptimal real-world outcomes remain major challenges. Faricimab is a bispecific monoclonal antibody that simultaneously inhibits VEGF-A and angiopoietin-2 (Ang-2), a key mediator of vascular destabilization, leakage and inflammation, offering a novel dual-pathway approach aimed at improving efficacy and durability. This narrative review summarizes evidence from pivotal clinical trials and recent real-world studies evaluating the efficacy, durability, and safety of faricimab in patients with nAMD and DME. Real-world evidence from international cohorts and emerging data from Spanish routine clinical practice largely corroborate previous findings, showing anatomical improvements, stable or improved visual outcomes, and reduced treatment burden in treatment-naïve and previously treated eyes. Overall, the evidence reviewed indicates that faricimab is an effective and well-tolerated therapeutic option that may help address unmet needs in the long-term management of nAMD and DME. Importantly, data from real-world clinical practice are consistent with findings from pivotal trials, supporting the translation of faricimab’s outcomes into routine care. Full article

Background/Objectives: The timing of exudative recurrence after complete fluid resolution following anti-vascular endothelial growth factor (anti-VEGF) loading in neovascular age-related macular degeneration (nAMD) is unpredictable. We prespecified two questions: whether the speed of fluid resolution during loading, or the baseline pigment epithelial detachment (PED) type, predict recurrence timing. Methods: We retrospectively analyzed 72 treatment-naïve nAMD eyes that achieved complete resolution of subretinal fluid (SRF) and intraretinal fluid (IRF) after three monthly loading injections, then observed them under a pro re nata strategy. Time from the post-loading dry-confirmation visit to first detected recurrence was analyzed with Kaplan–Meier and Cox models; baseline variables with univariable p < 0.10 were entered into a multivariable model. Results: Recurrence was detected in 58 eyes (80.6%); median recurrence-free survival was 139 days (95% CI, 118–158). Resolution of SRF or IRF by one month was not significantly associated with recurrence timing (p = 0.586 and 0.054). Fibrovascular PED was associated with earlier detected recurrence compared with non-fibrovascular PED (adjusted hazard ratio 2.40, 95% CI, 1.17–4.92; p = 0.017; median 130 vs. 602 days). Eyes with fibrovascular PED were monitored more frequently, but the association persisted in an interval-censored sensitivity analysis (adjusted HR 2.71, 95% CI, 1.32–5.60). Conclusions: The speed of fluid resolution was not significantly associated with recurrence timing, whereas fibrovascular PED was associated with earlier detected recurrence and may represent a candidate prognostic marker requiring prospective validation. Full article

Purpose: To characterize ophthalmology research output relative to disease burden and national economic capacity after accounting for population size. Methods: We analyzed Scopus publications, Global Burden of Disease disability-adjusted life years (DALYs), and World Bank economic and population data from 2011 to 2021. Negative binomial and Gamma models evaluated publication volume and positive citation-weighted impact, adjusting for DALYs, gross domestic product (GDP) per capita, population, disease category, and publication year. Results: Refractive disorders accounted for 45.4% of DALYs and 23.2% of publication volume; cataract, 44.7% and 29.8%; glaucoma, 5.2% and 30.6%; and age-related macular degeneration, 3.8% and 15.2%. High-income countries accounted for 11.8% of burden, 67.2% of publication volume, and 74.2% of citation-weighted impact; lower-middle-income countries accounted for 49.1%, 7.9%, and 6.8%, respectively. DALYs were not independently associated with publication volume (adjusted count ratio [aCR], 0.99; 95% confidence interval [CI], 0.98–1.01; p = 0.278), whereas GDP per capita (aCR, 4.47) and population (aCR, 13.99) were strongly associated (both p < 0.001). For positive citation-weighted impact, DALYs had a small association (adjusted ratio of means [aRM], 1.05), whereas GDP per capita (aRM, 2.86) and population (aRM, 4.96) were strongly associated (all p < 0.001). Conclusions: After accounting for population size, absolute disease burden was not independently associated with publication volume, whereas national economic capacity remained strongly associated with both outcomes. These patterns should inform research and service-delivery priorities. Full article

Intravitreal inhibition of vascular endothelial growth factor (VEGF) has transformed the management of neovascular age-related macular degeneration, diabetic macular oedema and macular oedema secondary to retinal vein occlusion, but frequent monitoring and retreatment remain major burdens. Ocular half-life is often used as shorthand for durability, although the clinical interval is produced by a wider molecular and biological system. This narrative review examines how dose, molecular format, hydrodynamic size, binding affinity, valency, ligand spectrum, target turnover, tissue distribution and delivery architecture determine the time for which an eye remains controlled. Human ocular pharmacokinetic and pharmacodynamic evidence is interpreted according to compartment, assay and model provenance, with particular attention to the distinction between drug elimination, free-ligand suppression, anatomical control and protocol-assigned treatment interval. Trial evidence for ranibizumab, aflibercept, conbercept, brolucizumab and faricimab shows that extended dosing can arise from greater starting exposure, altered binding architecture or pathway expansion without a proportionate change in intrinsic ocular half-life. Patient phenotype and retreatment rules further modify the observed interval. Refillable reservoirs, biodegradable depots and ocular gene therapy change the governing kinetics from bolus elimination to controlled release or sustained local production, thereby increasing the importance of reversibility and cumulative safety. We propose that durability be defined as a time-to-threshold phenotype integrating active target-site exposure, biological demand, anatomical recurrence, all treatment-related procedures and safety. Standardised estimands, longitudinal human ocular sampling, spatial exposure methods and externally validated mechanism-informed models are needed to make molecular durability comparable and clinically actionable. Full article

Objectives: To describe intraoperative and postoperative outcomes of the Eight-Chop Technique in elderly patients, with particular attention to nonagenarian patients undergoing cataract surgery. Methods: This retrospective study included consecutive eligible eyes undergoing Eight-Chop phacoemulsification and posterior chamber intraocular lens implantation at a single clinic. Eyes were stratified by age at surgery into 70–79 years, 80–89 years, and ≥90 years groups. Sixty eyes were included in each younger group, and all 49 eligible nonagenarian eyes were included. Eyes were not intentionally excluded from the younger groups because of poor pupillary dilation, zonular weakness, white cataract, pseudoexfoliation, glaucoma, age-related macular degeneration, or advanced nuclear grade. Preoperative characteristics, intraoperative parameters, best-corrected visual acuity (BCVA), intraocular pressure, and corneal endothelial cell density (CECD) were evaluated. Linear mixed-effects models accounted for fellow-eye correlation. Results: A total of 169 eyes were analyzed. The ≥90-year cohort had greater baseline complexity; intraoperative differences were descriptive, with the highest operative time, phacoemulsification time, aspiration time, cumulative dissipated energy, and irrigation fluid volume (all p < 0.001). Postoperative BCVA improved from baseline in all groups. Mean CECD loss at 19 weeks was −1.3 ± 5.7%, −0.7 ± 5.7%, and 3.5 ± 9.2% in the 70–79-, 80–89-, and ≥90-year groups, respectively. No serious intraoperative complications occurred. Conclusions: The Eight-Chop Technique was used across elderly age groups, including nonagenarian patients. Observed age-group differences represent associations in this retrospective dataset and do not establish causal age effects or comparative superiority, safety, or endothelial protection of the technique. Full article

Background/Objectives: Age-related macular degeneration (AMD) is a leading cause of irreversible visual impairment, and AREDS2-based nutritional supplementation is recommended for clinically eligible patients to reduce the risk of disease progression. However, successful implementation depends on regular supplement use and sustained adherence. This study investigated demographic, socioeconomic, clinical, and physician-related factors associated with regular AREDS2 supplement use and evaluated medication adherence, physician counseling, and patient-reported barriers among clinically eligible patients with AMD. Methods: In this single-center cross-sectional study, 389 patients with intermediate AMD or advanced AMD in one eye who fulfilled the indications for AREDS2 supplementation were enrolled. Participants reporting occasional supplement use were excluded. A structured interviewer-administered questionnaire was used to collect demographic, socioeconomic, and clinical data, together with information on physician recommendation, medication adherence, patient knowledge, and perceived barriers to supplementation. Factors associated with regular AREDS2 supplement use were evaluated using univariable and multivariable logistic regression analyses, whereas adherence patterns and patient-reported barriers were analyzed descriptively. Results: Of the 389 participants, 273 (70.2%) reported regular AREDS2 supplement use, whereas 116 (29.8%) were non-users. Multivariable analysis showed that younger age, educational attainment, and physician recommendation were independently associated with regular supplement use (adjusted OR for physician recommendation, 5.38; 95% CI, 2.68–10.81; p < 0.001). Among regular users, 53.5% met the study-defined criteria for good medication adherence. The most frequently reported barriers among non-users were financial burden, limited supplement availability, polypharmacy, and insufficient knowledge regarding AREDS2 supplementation. Conclusions: Regular AREDS2 supplement use among clinically eligible patients with AMD was associated with demographic, educational, and physician-related factors, whereas long-term adherence remained suboptimal despite substantial uptake. These findings emphasize the importance of effective physician counseling, structured patient education, and interventions addressing socioeconomic barriers to improve the real-world implementation of evidence-based nutritional supplementation in AMD. Full article

Background: Age-related macular degeneration (AMD) represents a leading cause of irreversible vision loss worldwide, driven by intricate interactions among oxidative stress, low-degree chronic inflammation, and macular pigment depletion in aging retinas. Lutein, a component of the macular pigment, has attracted significant attention in AMD management for its antioxidant and blue-light filtering properties. Its oral supplementation, however, although showing potential in slowing AMD progression, requires daily intake and results in variable macular absorption. Trans-scleral iontophoresis (TSI) is a non-invasive technique using low-intensity electric currents to deliver charged molecules into biological tissues and represents an innovative method to deliver lutein into the retina. Methods: The present narrative review synthesizes and discusses the results of lutein supplementation in AMD patients; the ocular iontophoresis basal principles, efficacy, safety and limitations in treating different ophthalmic pathologies; and the evolving clinical evidence supporting lutein TSI in the AMD management. Results: Ex-vivo studies have shown that lutein TSI may provide efficient, localized, rapid, and sustained retinal supplementation of macular pigment, overcoming oral intake limitations. Recent preliminary clinical studies have demonstrated that this technique is well-tolerated and effective in enhancing macular pigment optical density and improving some visual functions in AMD patients. Conclusions: Ex-vivo and pilot clinical studies highlight the capacity of TSI to deliver lutein inside the retina, overcoming physiological barriers that may limit the efficacy of lutein oral administration. The demonstration of the efficacy of the procedure in preserving/improving visual functions and delaying disease progression in AMD patients requires further long-term randomized controlled clinical studies. Full article

Vision impairment affects approximately 2.2 billion people worldwide, with glaucoma, age-related macular degeneration, fungal keratitis, and diabetic retinopathy among the leading causes of preventable blindness. Effective pharmacotherapy remains severely constrained by the eye’s multilayered barrier architecture. Tear film, the corneal epithelium, the blood–aqueous barrier, and the blood–retinal barrier collectively restrict conventional topical drug bioavailability to less than 5% of the administered dose. Liposomal drug delivery systems have emerged as a clinically translatable platform capable of overcoming these barriers through targeted surface modification. This review provides a brief introduction to ocular barriers to drug delivery and transport and critically examines numerous surface-modification strategies applied to liposomal carriers to enhance corneal permeation and ocular bioavailability of drugs. It highlights the advantages and disadvantages of each modification strategy, as well as the convergent mechanism of liposomal surface modification in overcoming ocular barriers, and provides a comparative analysis of different surface-modification strategies of liposomes in terms of safety, efficacy and corneal retention. Additionally, it describes challenges associated with liposomal ophthalmic formulations in industrial scaling up. The review also sheds light on some FDA-approved liposomal ophthalmic products, active clinical trials on liposomal formulations, and relevant patents, demonstrating the potential benefits of liposomal drug delivery in the treatment of ocular disorders. Full article

Neovascular age-related macular degeneration is a retinal disease of older adults causing central vision loss associated with macular neovascularization. Treatment response is commonly evaluated using visual acuity and retinal morphology. These measures may not fully reflect patient-perceived benefit. We report two older adults with neovascular age-related macular degeneration treated with faricimab who demonstrated discordance between clinical and patient-reported outcomes. In the first case, best-corrected visual acuity changed from 20/200 to 20/180 and central retinal thickness decreased from 480 to 389 µm, whereas the National Eye Institute Visual Function Questionnaire–25 score increased from 33.87 to 60.99 and the exploratory ordinal colour-vividness rating was 25 at baseline and 100 at follow-up. In the second case, best-corrected visual acuity improved from 20/100 to 20/45 and central retinal thickness decreased from 341 to 186 µm, whereas the National Eye Institute Visual Function Questionnaire–25 score declined from 67.08 to 33.17 and the exploratory ordinal colour-vividness rating was 75 at baseline and 25 at follow-up. Changes in patient-reported visual functioning may not always parallel conventional clinical outcomes, while the contrasting exploratory colour-vividness ratings observed in these two cases warrant further investigation. Full article

Background/Objectives: Double reading with arbitration improves diagnostic reliability in fundus screening but requires repeated human interpretation. Whether artificial intelligence (AI) can serve as a first-pass decision source within this workflow, and whether this applies consistently across retinal diseases with differing inter-reader agreement, remains unclear. Methods: In this retrospective study, 6904 color fundus photographs from 2593 patients at a tertiary screening center were analyzed for age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinal vein occlusion (RVO). Three retina specialists independently labeled each image, and an AI system provided binary classifications at a prespecified operating threshold targeting 0.99-sensitivity. In AI–human double reading, the AI and one reader independently interpreted each image, and a second reader arbitrated discordant cases; this was compared with conventional human–human double reading. Three reader combinations were evaluated per disease. Results: AI–human reading required 1.02–1.11 human reads per image versus 2.00–2.10 for human–human reading. For DR and RVO, human–human reading yielded sensitivities of 0.974 and 0.982 and specificities of 0.999 and 1.000, respectively. Across AI–human combinations, sensitivity and specificity did not differ significantly from human–human reading (all p ≥ 0.05; specificity differences ≤0.001). For AMD (human–human sensitivity 0.845, specificity 1.000), AI–human sensitivity varied: two combinations were higher (0.916 and 0.950; both p < 0.001) and one comparable (0.842; p = 0.742). AMD specificity remained ≥0.978. Conclusions: AI–human reading halved human reading volume without significant loss for DR and RVO; AMD varied by configuration. AI use within double-reading workflows should account for disease-specific inter-reader agreement, reader composition, and operating threshold. This was a single-center, retrospective study, prospective external validation in a multicenter setting is warranted before clinical implementation. Full article

Background: Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss and is strongly driven by oxidative stress and inflammation. This study investigated the protective effects of cynarin against sodium iodate (NaIO₃)-induced retinal pigment epithelium (RPE) injury, focusing on the MAPK and NF-κB signaling pathways. Materials and Methods: Human ARPE-19 cells were exposed to NaIO₃, and cell viability was assessed by the MTT assay. Protein expression of MAPK components (p38, JNK, ERK) and the NF-κB pathway was analyzed by Western blotting, and pro-inflammatory cytokine (IL-1β, IL-6, TNF-α) mRNA expression was measured by RT-qPCR. In vivo, NaIO₃-induced retinal degeneration in C57BL/6 mice was treated with cynarin (3 or 10 mg/kg) for seven days, and retinal changes were evaluated by fundus photography, fluorescein angiography, and OCT. Results: Cynarin preserved ARPE-19 cell viability without cytotoxicity. It significantly attenuated NaIO₃-induced p38 and JNK phosphorylation, IκB degradation, and NF-κB activation while downregulating IL-1β, IL-6, and TNF-α expression. In vivo, cynarin reduced drusen-like lesions, hyperfluorescent abnormalities, and retinal thinning, and dose-dependently suppressed ocular pro-inflammatory cytokines. Conclusions: Cynarin protects against oxidative stress-induced retinal degeneration by suppressing MAPK and NF-κB inflammatory signaling, representing a promising therapeutic candidate for preventing or delaying NaIO₃-induced dry AMD-like retinal injury. Full article

Optical coherence tomography (OCT) is a high-resolution and non-contact optical imaging and sensing modality that provides depth-resolved cross-sectional visualization of retinal microstructures. It plays an important role in the assessment of retinal diseases, including age-related macular degeneration (AMD) and diabetic macular edema (DME). However, automated OCT image classification commonly relies on fully supervised models that require large-scale expert annotations, which are costly and time-consuming because of the complex layered anatomy and subtle pathological patterns present in retinal OCT images. To reduce annotation dependence, this study proposes a self-supervised representation learning framework with local dimensionality regularization for retinal OCT image classification. The proposed method estimates the local intrinsic dimensionality of learned representations and incorporates it into an asymptotic Fisher-Rao regularization objective to mitigate local dimensional degeneration and preserve fine-grained structural information. Logarithmic scaling and geometric averaging are further introduced to reduce sensitivity to outliers and improve optimization stability. Experiments on three independent OCT datasets achieved classification accuracies of 94.35%, 92.48%, and 92.56%, respectively, demonstrating competitive performance compared with mainstream self-supervised methods. These results demonstrate that explicitly modeling local feature geometry can improve the discrimination of sensor-acquired OCT images while reducing reliance on manual annotations, providing an effective approach for intelligent analysis of biomedical optical imaging data. Full article