Investigative Opthalmology & Visual Science

PurposeSubretinal drusenoid deposits (SDDs) are a distinct entity in age-related macular degeneration (AMD) and associated with photoreceptor impairment during progression. Their early impact on photoreceptors remains incompletely understood. This study examined photoreceptor reflectivity during the phase when SDDs were not clinically detectable on optical coherence tomography (OCT) using adaptive optics scanning laser ophthalmoscopy (AOSLO). DesignLongitudinal observational study. ParticipantsPatients with intermediate AMD. MethodsSix eyes of four patients with intermediate AMD and predominantly SDDs underwent multimodal imaging 3-4 times over 3.5 years. Individual SDDs were graded using an OCT-based 3-stage system at each time point. Cross-sectional retinal structure and photoreceptor reflectivity at the location where the new SDDs developed during follow-up were evaluated using OCT and AOSLO. Main Outcome MeasuresPhotoreceptor reflectivity change prior to and during SDD development. ResultsForty-eight retinal locations where new dot-type SDDs developed during follow-up were identified. AOSLO revealed reduced photoreceptor reflectivity in these regions before OCT demonstrated clinically evident deposits (stage [≥] 1) between the ellipsoid zone and the retinal pigment epithelium at the corresponding sites. The mean time to development of stage 1, stage 2, and stage 3 SDDs was 11.78 {+/-} 5.01, 17.40 {+/-} 6.08, and 18.72 {+/-} 4.08 months, respectively. ConclusionsHigh-resolution adaptive optics confocal imaging enables detection of photoreceptor optical property alterations at a stage when SDDs are not yet evident on OCT. This finding underscores the exceptional sensitivity of photoreceptors to minimal structural or functional perturbations during SDD formation and defines an early window for potential intervention.

PurposeTo characterize microscopic alteration of photoreceptors and RPE surrounding cuticular drusen in age-related macular degeneration (AMD) using multimodal imaging, including high resolution adaptive optics scanning laser ophthalmoscopy (AOSLO). MethodsEyes with early to intermediate AMD and predominantly cuticular drusen underwent color fundus photography, infrared reflectance, fundus autofluorescence, optical coherence tomography (OCT), and AOSLO. Cuticular drusen were identified using multimodal imaging and classified into three OCT-defined phenotypes. Cone photoreceptor reflectivity was assessed on AOSLO. A subset of eyes underwent longitudinal AOSLO and OCT imaging. ResultNineteen eyes from 12 subjects aged 70.3 {+/-} 5.8 years were studied. Six eyes had longitudinal follow-up imaging. A total of 3177 cuticular drusen were evaluated and classified into 3 types based on cross sectional OCT imaging. AOSLO revealed corresponding phenotype-dependent cone reflectivity alterations associated with the 3 types of cuticular drusen. Type 1: Maintained cone reflectivity overlying the drusen on a hyporeflective background. Type 2: Cone reflectivity loss overlying the cuticular drusen. Type 3: Cones are predominantly not visible over the cuticular drusen. Lesion diameters were 52.62 {+/-} 9.38 {micro}m (Type 1), 71.88 {+/-} 12.39 {micro}m (Type 2), and 124.72 {+/-} 20.94 {micro}m (Type 3). All lesions were accompanied by hypertransmission in the choroid on OCT. Longitudinal imaging showed that localized outer retinal reflectivity reduction on AOSLO preceded the detection of new cuticular drusen on OCT. ConclusionsCellular-resolution multimodal imaging demonstrates progressive, phenotype-specific disruption of the photoreceptor-RPE complex associated with cuticular drusen in AMD. Early AOSLO-detected reflectivity changes preceding OCT-visible lesions highlight the sensitivity of adaptive optics imaging for identifying early outer retinal alterations and for advancing understanding of the biogenesis of cuticular drusen.

PurposeMuller cell (MC) morphology and markers were investigated using histology and immunohistochemistry in an eye with clinically documented multifocal geographic atrophy (GA) and correlated with clinical images. MethodsThe donor was followed clinically for five years and last examined six years before death. The superior posterior pole retina was dissected and immunolabeled with antibodies against glial fibrillary acidic protein (GFAP; activated MCs and astrocytes) and glutamine synthetase (GS, MC) and Ulex Europaeus Agglutinin-1 lectin (blood vessels) before embedding for JB-4 cross section analysis. The inferior macula was cryopreserved. Cryosections were immunolabeled with MC homeostatic and activation markers. Transmission electron microscopy (TEM) of the fellow eye was used to study ultrastructure changes. ResultsGross examination demonstrated mottled retinal pigment epithelium (RPE) over presumably calcified drusen. In the submacular retina, MC processes surrounding both drusen and outer retinal pigmented lesions created a large subretinal membrane. Cryosection analysis demonstrated persistence of aquaporin 4 and GS in MCs with both proteins prominently expressed in the subretinal membrane. Increased MC S100B and GFAP expression were also observed in the atrophic area as well as the OJZ. Cryosection labeling and TEM confirmed the MC encasing calcified drusen and RPE debris as well as invading basal laminar deposits. ConclusionsThis multifocal GA case demonstrates how MC activation and structural changes surrounding individual drusen could coalesce, contributing to photoreceptor loss. MCs penetrating basal laminar deposits and encasing calcified drusen suggests that they are attempting to clear these and/or protect the retina from harmful contents.

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in ageing populations, with oxidative stress recognised as a key pathogenic driver. The dietary antioxidant and cytoprotectant, L-ergothioneine (ET), is avidly accumulated in many tissues, especially the eye. However its relationship to AMD has not been investigated. Here, we examined ETs distribution in ocular tissue and assessed circulating and intraocular ET levels in patients with neovascular AMD. Compared with ocularly-normal age-matched individuals, AMD patients exhibited significantly lower serum ET; elevated levels of ET metabolites, hercynine and ETSO, which may be generated by oxidative stress; and elevated levels of serum allantoin, a product of oxidative damage to urate in humans. Levels of ET in aqueous humour in AMD patients were marginally lower than cataractous patients who are already known to have significantly lower ET levels than healthy eyes. High ET levels were seen in human ocular tissues concentrating in regions vulnerable to oxidative injury, including the lens, retina, retinal pigment epithelium, and choroid, supporting a physiological protective role of ET in the eye. These findings identify the strong association between low ET levels and AMD, warranting further studies to determine whether ET supplementation can modify AMD risk or progression.

Fluorescence lifetime imaging ophthalmoscopy permits in vivo assessment of retinal metabolism but has remained limited by insufficient cellular resolution in the human eye. Here we present adaptive optics-enhanced fluorescence lifetime imaging ophthalmoscopy (AOFLIO), a method for single-cell-resolved, in vivo structural and metabolic imaging of the human retinal pigment epithelium (RPE). Through real-time correction of ocular wavefront aberrations, precisely synchronized adaptive optics reflectance and lifetime image acquisition via a phase-locked loop-based timing architecture, and sub-pixel photon registration that localizes individual autofluorescence photons with high spatial precision, AOFLIO directly resolves the RPE cell mosaic and measures autofluorescence decay using the same photons, enabling direct structural-functional correlation at the single-cell level. We demonstrate single-cell RPE lifetime mapping in healthy subjects and reveal altered metabolic signatures and fine characterization of RPE metabolic in age-related macular degeneration. AOFLIO establishes a platform for cellular-scale metabolic imaging in the living human eye.

Purpose: To determine the test-retest reliability of visual function parameters in patients with genetically confirmed Pseudoxanthoma elasticum (PXE), as a necessary step toward evaluating their suitability as outcome measures in future therapeutic trials. Methods: In this prospective natural history study (PROPXE, ClinicalTrials.gov ID: NCT05662085), patients with PXE underwent comprehensive visual function evaluation in one study eye at baseline and at a month 2 retest visit. Functional testing included light- and dark-adapted steady state microperimetry and dark-adaptometry at 8{degrees}, 15{degrees} 30{degrees}, and 46{degrees} eccentricity. Test-retest reliability was evaluated using Bland-Altman statistics. Results: Twenty-six patients (14 female, 12 male; median [IQR] age 55 years [43; 59]) with genetically confirmed PXE were included in the study. Overall, the steady-state microperimetry limits of agreement (LoA) were {+/-}2 dB for mean sensitivity and {+/-}6.8 dB for pointwise sensitivity in both scotopic (cyan and red) and mesopic conditions. The LoAs of rod intercept time as a measure of dark adaptometry were {+/-} 12 min at the inner measurement points (8{degrees} and 15{degrees}) and {+/-} 18 min at the outer measurement points (30{degrees} and 46{degrees}). Conclusions: Scotopic and mesopic microperimetry LoAs are similar to earlier published test-retest analyses in other retinal diseases. Dark-adaptometry curve parameters were markedly more variable compared to previous data in healthy volunteers. This is likely attributable to the severe dark adaptation abnormalities in PXE, leading to long test durations. Translational Relevance: The evaluation of functional biomarkers is critical for designing future clinical trials aimed at slowing PXE progression.

Primary open-angle glaucoma (POAG) disproportionately affects individuals of African ancestry, yet rare coding variation in this population remains understudied. To address this gap, we performed a multi-cohort exome-wide meta-analysis across POAAGG, PMBB, All of Us, and UK Biobank, including 4,815 POAG cases and 22,922 controls of genetically inferred African ancestry. Although no gene reached exome-wide significance, we identified several suggestive gene-level associations driven by rare variants (minor allele frequency [≤]0.1% or singletons),including signals in SRF, BLTP3A, METTL2A, and KRT10. Among these, SRF demonstrated the strongest association and was driven by rare missense variants with moderate effect sizes. Given its role in cytoskeletal organization and actin dynamics; processes central to trabecular meshwork function and intraocular pressure regulation SRF represents a biologically plausible candidate gene. Notably, these genes have not been previously highlighted in predominantly European ancestry POAG association studies, suggesting potential ancestry-specific rare variant contributions. Overall, our findings highlight the critical importance of investigating rare coding variation in POAG, in disproportionately affected populations to deepen understanding of POAG etiology and genetic risk.

PurposeTo identify genetic variants associated with glucocorticoid (GC)-induced intraocular pressure (IOP) change using genome-wide association study (GWAS) and whole exome sequencing (WES) analyses. Methods530 participants from the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) trials were analyzed, with replication performed in an independent cohort of 588 participants from the Mass Eye and Ear/Retina Health Center (MEE/RHC). All participants were exposed to GC, primarily via intravitreal injection. IOP was measured at baseline and serially within 6 months following GC exposure. GWAS and rare variant gene burden analyses were applied, adjusting for covariates. ResultsGenetic associations for maximal IOP change within 6 months after GC exposure were evaluated. For the primary outcome across all ancestries in FAME, one variant, rs13425173 within the UBE2E3 locus reached genome-wide significance (P=2.88 X 10-8). In the FAME and MEE/RHC meta-analysis, variant rs1040227, also in the UBE2E3 locus, was significantly associated at the genome-wide level (P=2.88 X 10-8) and showed nominal significance in the MEE/RHC cohort (P=0.02). In the colocalization analyses, the significant FAME GWAS UBE2E3 locus was linked to expression regulation of this gene in six tissues including artery aorta. In gene-level analysis, UBE2E3 also demonstrated subthreshold significance (P=6 X 10-6). 532 FAME and 586 MEE/RHC participants were included in the WES gene burden analysis. One gene, MSTO1, passed false discovery rate correction for the primary outcome in FAME. ConclusionWe have identified genome-wide significant common variants associated with GC-IOP change, as well as genes and rare variants that may influence GC-induced IOP change.

ImportanceGenome-wide association studies have identified hundreds of common single nucleotide polymorphisms (SNPs) and small insertions/deletions (indels) associated with primary open-angle glaucoma (POAG) risk, though these variants have modest effect sizes and individually may have minor contributions to disease development. As whole-genome sequencing data is becoming more readily available, structural variants and other complex genomic features can be interrogated for contribution to disease risk. ObjectiveTest the association of structural variants in known glaucoma loci with disease risk. DesignCross-sectional study. SettingA multicenter cohort of individuals from the United States who contributed genomic and electronic health record data to the All of Us Research Program. ParticipantsPOAG case/control cohorts were generated in the All of Us Researcher Workbench using age (>40 for cases, >65 for controls) and ICD 9/10 diagnosis codes. Main Outcomes and MeasuresLogistic regression analyses adjusted for age, sex, and the top 10 principal components of ancestry were used to test association of structural variants within 500 kilobases of 309 known open-angle glaucoma risk loci. The significance threshold after Bonferroni correction was set at p<1.6x10-4. Results516 POAG cases and 18,716 controls of European ancestry from the All of Us v8 data release were included in the analysis. Mean age was 77.0 years among cases and 74.7 years among controls. Females comprised 45.7% of cases and 56.5% of controls. An 8,732 base pair deletion upstream of PITX2 (chr4:110680827-110689558) was associated with 7.3-fold higher odds of POAG (95% confidence interval: 2.9-18.5, p= 2.4x10-5, variant carrier frequency= 1.6% in cases and 0.25% in controls). Functional annotation identified multiple enhancers overlapping the deletion, suggesting that this structural variant likely impacts gene regulation and expression. Conclusion and RelevanceWhole genome sequencing data captures rare structural variants with large effect sizes that are missed by conventional SNP and indel genotyping approaches, enabling improved POAG risk stratification. These data also expand the phenotypic spectrum of structural variation in the PITX2 locus from childhood glaucoma to adult-onset disease, where age at diagnosis and clinical severity may be influenced by the extent of disrupted regulatory elements.

PurposeTo investigate whether the geometric shape of the globe, sagittal length (SL) and Posterior Radius of curvature (rPC), differ between patients with rhegmatogenous retinal detachment (RD) and macular hole (MH), and to determine if these parameters offer better diagnostic differentiation than axial length (AL) alone. MethodsThis retrospective study included 20 MH and 20 RD patients. Groups were axial-length matched. Ocular biometry was performed with ultrasound to measure AL and SL. The PR was calculated. Due to the non-normal distribution of the data, the Mann-Whitney U test was used for continuous variables and Fishers Exact Test for gender distribution. ResultsThere was no significant difference between the MH and RD groups in terms of age (median: 33.8 vs 32.6 years; p=1.00), gender (p=0.341), or AL (27.65 mm vs 28.58 mm; p=0.39). However, RD eyes showed significantly higher SL (median: 25.70 mm vs 22.90 mm; p=0.001) and a significantly flatter rPC (median: 28.25 mm vs 24.30 mm; p < 0.001). ConclusionRD eyes exhibit a distinct vertical equatorial expansion and posterior flattening that is not present in MH eyes, despite similar axial lengths. These geometric differences suggest that SL and PR are structural risk factors in vitreoretinal disease.

AimTo assess the relationship between pointwise visual field (VF) sensitivity fluctuation and localised glaucoma progression. MethodsRetrospective observational analysis of prospective cohort data from 399 participants (641 eyes) in the African Descent and Glaucoma Evaluation Study (ADAGES). Glaucoma, glaucoma suspect, and control participants underwent annual examinations including VF testing. VF fluctuation was evaluated using the pointwise standard deviation (SD) of total deviation (TD) residuals during the early 30-month period. Pointwise progression was defined independently at each location as a confirmed sensitivity loss >7 dB. The primary outcome was the association between early fluctuation and subsequent pointwise progression. We additionally evaluated whether the early pointwise rate of change (slope) strengthened this association. ResultsOf 33,332 VF points, 5.8% showed progression over 12.2 {+/-} 3.1 years. Progression occurred more frequently in glaucoma (15.6%) than in suspects (1.6%) or controls (0.4%) (p<0.0001). In glaucomatous eyes, progressive points demonstrated greater early fluctuation (median 1.75 dB; IQR 1.52-2.00) than non-progressive points (1.14 dB; IQR 0.97-1.34; p<0.0001) and faster early slopes (-0.65 vs 0.08 dB/year; p<0.0001). In multivariable mixed-effects models, higher early fluctuation ({beta} = 0.40 {+/-} 0.02; p<0.0001) and faster early slopes ({beta} = - 0.40 {+/-} 0.02; p<0.0001), but not baseline TD (p=0.92), were associated with progression. Conclusions: Greater early pointwise VF fluctuation independently predicted future localised progression. The slope analysis mirrored these findings, indicating that early functional variability reflects underlying local instability. These results support early pointwise fluctuation as a predictor of glaucoma progression and a potential endpoint for clinical trials.

PURPOSEBEST1-associated inherited retinal disease constitutes one of the largest inherited retinal disease patient populations across the world. Innovative therapies are currently in development to address this significant unmet need. To better understand the scale of unmet need, and the distribution of phenotypes and genotypes, we conducted a meta-analysis of BEST1 patients reported in the literature to provide up-to-date patient number estimates. METHODSWe utilized the GeneScape(R) IRD Patient Atlas, an expertly curated database of [~]73K retinal disease patients undergoing extensive genetic testing, in combination with a dedicated literature search to estimate the proportion of IRD patients attributed to BEST1 using fixed effects weighting. This was also translated to patient number estimates for each country. Further extrapolation of patient subtypes was estimated based on cohorts of BEST1 patients reporting phenotypes and genotypes. In addition, a summary of contributing variants is reported by region. RESULTSAcross regions BEST1 retinopathy patients are estimated to occur from 1 in 38K (in Germany) to 1 in 363K in Japan. In the western countries, bi-allelic patients are expected to contribute nearly 20% of the total BEST1 population, whereas one third of patients in East Asia are anticipated to be bi-allelic. CONCLUSIONSWhile patients are reported across the world, their prevalence and composition vary across geographies. In the literature bi-allelic patients are less often reported explicitly as ARB patients in the United States as compared to Europe. Variant diversity is reflected in regional reports and drives phenotypic distribution.

PurposeTo investigate the effects of morning and evening narrowband blue light exposure on axial length, and to examine the short-term effect of morning blue light combined with myopic defocus on axial length. MethodsFor objective 1, 18 individuals underwent 60 minutes of narrowband blue light exposure (460nm) in the morning (9:00-11:00AM) and evening (5:00-7:00PM) of the same day. The axial length values were normalized to the average of the morning and evening axial length values. For objective 2, 27 young adults were exposed to 60 minutes of narrowband blue light and broadband white light while wearing a +3.00 D lens over the right eye. Axial length was measured using Lenstar LS900. ResultsA significant reduction in axial length was observed after exposure to morning blue light compared to evening blue light (-10.0{+/-}3.96{micro}m vs.-0.67{+/-}3.30{micro}m; p=0.02), whereas no such effect was observed with broadband white light exposure (0.0{+/-}3.53 {micro}m vs. -2.50{+/-}4.23{micro}m, p=0.70). While the broadband white light exposure did not alter the normal diurnal variation in axial length (+2.35{+/-}1.82{micro}m vs.-6.25{+/-}2.21{micro}m, p=0.04), blue light diminished such a pattern (-4.12{+/-}1.72{micro}m vs. - 2.00{+/-}2.00{micro}m, p=0.48). The myopic defocus did not influence axial length under either narrowband blue or broadband white light conditions. ConclusionThe short-term narrowband blue light exposure led to a significant decrease in axial length in the morning than evening exposure, with a likely influence on the diurnal rhythm of axial length. Morning blue light exposure with lens-induced myopic defocus did not provide additional short-term modulation of axial length.

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 [&le;]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 evaluate the efficacy and safety of Gene III L-ergothioneine (EGT) Eye Care Solution for alleviating ocular discomfort in patients with dry eye syndrome (DES). MethodsIn this single-center, randomized, open-label, self-controlled trial, 40 DES patients were randomly assigned in a 1:1 ratio to one of two treatment groups: Group 1 received the Gene III EGT Eye Care Wash Solution via an eye wash cup (5 mL/vial), and Group 2 received the same formulation as Gene III EGT Eye Care Drops Solution (0.5 mL/vial). Outcomes were assessed at baseline and after 14 days using validated scales, including the Chinese Dry Eye Questionnaire, the Ocular Surface Disease Index (OSDI), and the Comprehensive Assessment of Visual Fatigue (CAVF), along with fluorescein tear film break-up time (TBUT). ResultsCombined analysis (N = 40) demonstrated significant improvements in dry eye symptoms with mean scores decreasing from 12.50 to 10.65 (P = 0.0353). Ocular Surface Disease Index (OSDI) scores improved from 12.25 to 9.2 (P = 0.0309), and visual fatigue, assessed by the CAVF scale, decreased from 11.18 to 6.60 (P = 0.0008). Significant increases in TBUT were observed in both groups, with left eye first TBUT rising in Group 1 (P = 0.0199) and Group 2 (P < 0.0001). No treatment-related adverse events were reported. ConclusionGene III EGT Eye Care Solution effectively alleviated DES symptoms and demonstrated a favorable safety profile. Larger placebo-controlled trials are warranted to confirm these findings.

PurposeThere is a need for novel therapies for diabetic retinopathy (DR) because existing therapies treat only certain features of DR and do not work optimally for all patients. While proteomic studies provide insight into disease pathobiology, they are often limited to small sample sizes due to high costs, limiting their generalizability and reproducibility. Moreover, they often yield lists of tens to hundreds of proteins with differential expression, making it difficult to prioritize the most biologically relevant biomarkers beyond using arbitrary fold-change and false-detection rate cutoffs. Here, we applied a two-stage multimodal AI approach: first, we integrated EHR and proteomics data to rationally prioritize candidate protein biomarkers and, next, validated these biomarkers in an independent cohort. These protein biomarkers of DR are rooted in the EHR data and thereby more likely to be biological drivers of disease. MethodsWe obtained EHR data from a large number of patients with and without DR (N=319,997) from the STARR-OMOP database and obtained aqueous humor liquid biopsies from a subset of these patients (N=101) for high-resolution proteomic profiling. We developed Clinical and Omics Multi-Modal Analysis Enhanced with Transfer Learning (COMET) to perform integrated analysis of proteomics and all available EHR data to identify protein biomarkers of DR. The model was trained in two phases: first, it was pretrained using patients with EHR data alone (N=319,896), and then, it was fine tuned using patients with both EHR and proteomics data (N=101), allowing it to learn both clinical and molecular features associated with DR. Findings from COMET were then validated with liquid biopsies from an independent, validation cohort (N=164). Resultst-distributed stochastic neighbor embedding (t-SNE) analysis of EHR and proteomics data identified proteins clustering with related EHR features. Levels of STX3 and NOTCH2, proteins involved in retinal function, were correlated with a diagnosis of macular edema, a record of a visual field exam, and a prescription for latanoprost, highlighting protein-EHR alignment. The pretrained, multimodal COMET model was superior (AUROC=0.98, AUPRC=0.91) compared to models generated using either EHR or proteomics data alone or without pretraining (AUROC: 0.76 to 0.92; AUPRC: 0.47 to 0.74). The proteins SERPINE1, QPCT, AKR1C2, IL2RB, and SRSF6 were prioritized by the COMET model compared to the models without pretraining, supporting their potential role in DR pathobiology, and were subsequently validated in an independent cohort. ConclusionWe used multimodal AI to prioritize protein biomarkers of DR that are most strongly linked to EHR elements, as well as identifying other protein biomarkers associated with disease features like diabetic macular edema. These findings serve as a foundation for future mechanistic studies and highlight the synergistic value of using multimodal AI to fuse EHR and proteomics data for enhanced proteomics analysis.

Age related macular degeneration is known to be one of the major causes of irreversible blindness among the older generation. We present a mathematical model of partial differential equations for the therapy of this disease, which is based on the intravitreal injection of a drug into the vitreous body. For the treatment to work, the drug has to travel past the inner-limiting membrane into the retina and reduce the free vascular endothelial growth factor (VEGF) concentration by binding to at least one of the two binding sites of the VEGF molecule. Therefore, our model consists of two compartments, the vitreous and the retina. In the vitreous we employ four coupled convection-diffusion-reaction equations with an additional coupling to the underlying aqueous humor flow and four coupled diffusion-reaction equations in the retina. The resulting PDE system is solved numerically in a realistic 3D eye geometry. Temporal discretization is based on one-step theta schemes and spatial discretization is done using the Finite Element method. The numerical results are used to demonstrate the therapy concept and to analyze the drug efficacy of aflibercept and ranibizumab. The results show, among other things, that only about 20 % of the drug reaches the retina through the inner-limiting membrane and that 50 % of the VEGF concentration has been rebuilt in the retina after 38.19 days for a single ranibizumab injection.

PurposeTo evaluate the three-year efficacy and safety of compound trabeculectomy for uveitic glaucoma (UG). MethodsThis retrospective study enrolled 51 patients (53 eyes) requiring compound trabeculectomy, divided into UG (25 eyes) and non-UG groups (28 eyes). Outcomes including intraocular pressure (IOP), medication use, surgical success rates, and complications were analyzed over 3 years. ResultsBaseline characteristics including age, sex, preoperative IOP and medication use were comparable (all P>0.05). At 36 months, postoperative IOP was showed no significant differences, which was 15.4{+/-}8.4 mmHg and 14.6{+/-}3.3 mmHg (P=0.73) with 54% and 55% reduction (P=0.88) in UG and non-UG groups respectively. The qualified success rate was 76.0% and 85.7% at 36 months in UG and non-UG group, and Kaplan-Meier analysis showed no significant difference. Medication reduction of UG group was significant lower than non-UG group (P=0.0058). Comparable complication rates were observed between groups (all P>0.05), yet bleb scarring and cataract progression showed elevated incidence in both cohort. ConclusionCompound trabeculectomy effectively reduced IOP and medications use in UG and non-UG. There was no significant difference in both qualified and completed success rate between UG and non-UG. Complications of filtering bleb fibrosis and cataract progression should be pay close attention for both groups.

The prevalence of the two types of horizontal strabismus, esotropia and exotropia, varies considerably between studies. This variability has been attributed to factors such as geography/environment, research methodology, age of study subjects, and/or ethnicity. Comprehensive estimates of regional and global prevalences of esotropia and exotropia are lacking, making it difficult to recognize true patterns, trends, and etiologies. Our systematic review compiles prevalences and ratios of esotropia to exotropia from 315 population-based studies and 374 clinic-based studies. We analyze data to assess effects of ethnicity, geography, age, and identify generational changes of horizontal strabismus. Major ethnicities differ in patterns and ratios of esotropia and exotropia prevalence, not only Caucasians and East Asians, but also Latinos/Hispanics, South Asians, Africans, and Native Americans. Compared to population-based studies, clinic-based studies underestimate exotropia frequency. By weighing prevalences according to the population size of ethnicities, we estimate the worldwide prevalence of horizontal strabismus in the current generation at 1.81% (138.5 million), comprising 60.0 million people with esotropia (0.67%) and 87.5 million with exotropia (1.14%). In the previous generation, the worldwide prevalence of horizontal strabismus was 1.64% (86.5 million people), comprising 50.5 million with esotropia (0.96%) and 36.0 million with exotropia (0.68%). Generational trends in esotropia and exotropia prevalences differ between ethnicities, indicating that extrinsic factors can modify the underlying intrinsic (genetic) disposition.

PurposeTo evaluate the diagnostic performance of anterior segment optical coherence tomography (ASOCT) compared to slit lamp examination for identification of corneal perforation in microbial keratitis, and to assess ASOCT grading reproducibility. MethodsWe conducted a diagnostic concordance study of 150 eyes with microbial keratitis at a tertiary eye hospital in India. Two masked graders independently evaluated ASOCT scans for perforation, with disagreements resolved by consensus. We calculated Cohens kappa for inter-grader concordance and intra-grader repeatability. Sensitivity and specificity of slit lamp examination were calculated using ASOCT as the reference standard. Logistic regression identified factors associated with disagreement between modalities. ResultsInter-grader agreement for ASOCT was near-perfect ({kappa}=0.98; 95% CI, 0.92-1.00). ASOCT identified perforation in 24 eyes (16.0%) compared to 12 eyes (8.0%) by slit lamp examination. Using ASOCT as reference, slit lamp examination demonstrated 33.3% sensitivity (95% CI, 14.9-52.2%) and 96.8% specificity (95% CI, 93.4-99.2%). Odds of disagreement were significantly higher for eyes with stromal thinning (OR=8.19; 95% CI, 2.27-29.54), mid-stromal involvement (OR=4.44; 95% CI, 1.08-18.30), and infection within 2mm of the limbus (OR=8.81; 95% CI, 1.77-43.80). ConclusionsASOCT enables highly reproducible perforation grading and detects substantially more perforations than slit lamp examination, particularly in severe disease. These findings support ASOCT as an objective tool for clinical assessment and outcome ascertainment in microbial keratitis.