INTRODUCTION: We evaluated the associations of clinical and demographic characteristics with visual acuity (VA) with over 5 years in a subspecialty noninfectious uveitis population. METHODS: Retrospective data from 5,530 noninfectious uveitis patients were abstracted by expert reviewers, and contemporaneous associations of VA with demographic and clinical factors were modeled. RESULTS: Patients were a median of 41 years old, 65% female, and 73% white. Eyes diagnosed ≥5 years prior to cohort entry had worse VA (-1.2 lines) than those diagnosed <6 months prior, and eyes with cataract surgery performed prior to entry had worse VA (-5.9 lines) than those performed during follow-up. Vitreous haze (-4.2 lines for 3+ vs quiet), hypotony (-2.5 lines for ≤5 mm Hg vs 6-23 mm Hg), and CNV (-1.8 lines) all were strongly associated with reduced VA. CONCLUSION: Factors associated with reduced VA included well-known structural complications, and lack of subspecialty care during cataract surgery.

BACKGROUND: The Delphi process has been widely used to delineate guidelines for the treatment of disorders for which there is little or no evidence in the published literature. The purpose of this study was to use the Delphi process to identify areas of consensus and disagreement on the definition of success after surgery for each type of strabismus. METHODS: Two rounds of electronic questionnaires were sent to 28 members of the Strabismus Success Definition Delphi Study Group. For the first round, responses to 70 questions were captured as agree (= 1) and disagree (= 2). For round 2, a total of 89 questions were captured on a Likert scale ranging from 1 (strongly disagree) to 7 (strongly agree). Consensus was determined a priori at 85%. RESULTS: In both the first and second rounds, inter-rater agreement of 85% consensus was reached for only 20% of questions. Intra-rater agreement per question was low, with κ values ranging from -0.11 to 0.62. Intra-rater agreement was also low among themes, ranging from poor to fair agreement: κ = 0.25 for motor, κ = 0.28 for sensory, and κ = 0.35 for follow-up. CONCLUSIONS: This study highlights consensus areas that could be considered by researchers in designing studies and identifies areas where lack of consensus indicates that further research is needed.

Purpose: To review preclinical and clinical advances in gene therapy, with a focus on gene editing technologies, and application to inherited retinal disease.Methods: A narrative overview of the literature, summarizing the state-of-the-art in clinical gene therapy for inherited retinal disease, as well as the science and application of new gene editing technology.Results: The last three years has seen the first FDA approval of an in vivo gene replacement therapy for a hereditary blinding eye disease and, recently, the first clinical application of an in vivo gene editing technique. Limitations and challenges in this evolving field are highlighted, as well as new technologies developed to address the multitude of molecular mechanisms of disease.Conclusion: Genetic therapy for the treatment of inherited retinal disease is a rapidly expanding area of ophthalmology. New technologies have revolutionized the field of genome engineering and rekindled an interest in precision medicines for these conditions.

Understanding the molecular composition of pathogenic tissues is a critical step in understanding the pathophysiology of disease and designing therapeutics. First described in 2009, single cell RNA sequencing (scRNAseq) is a methodology whereby thousands of cells are simultaneously isolated into individual micro-environments that can be altered experimentally and the genome-wide RNA expression of each cell is captured. It has undergone significant technological improvement over the last decade and gained tremendous popularity. scRNAseq is an improvement over prior pooled RNA analyses which cannot identify the cellular composition and heterogeneity of a tissue of interest. This new approach offers new opportunity for new discovery, as tissue samples can now be sub-categorized into groups of cell types based on genome-wide gene expression in an unbiased fashion. As ophthalmologists, we are uniquely positioned to obtain pathologic samples from the eye for further study. ScRNAseq has already been applied in ophthalmology to characterize retinal tissue, and it may offer the key to understanding various pathological processes in the future.

Age-related macular degeneration (AMD) affects nearly 200 million people and is the third leading cause of irreversible vision loss worldwide. Deep learning, a branch of artificial intelligence that can learn image recognition based on pre-existing datasets, creates an opportunity for more accurate and efficient diagnosis, classification, and treatment of AMD on both individual and population levels. Current algorithms based on fundus photography and optical coherence tomography imaging have already achieved diagnostic accuracy levels comparable to human graders. This accuracy can be further increased when deep learning algorithms are simultaneously applied to multiple diagnostic imaging modalities. Combined with advances in telemedicine and imaging technology, deep learning can enable large populations of patients to be screened than would otherwise be possible and allow ophthalmologists to focus on seeing those patients who are in need of treatment, thus reducing the number of patients with significant visual impairment from AMD.

PURPOSE: To assess the relationship between baseline age-related macular degeneration (AMD) and disease stage, as well as optical coherence tomography features seen in AMD, with 3-year changes in dark adaptation (DA). METHODS: Prospective longitudinal study including patients with AMD and a comparison group (n = 42 eyes, 27 patients). At baseline and 3 years, we obtained color fundus photographs, spectral-domain optical coherence tomography, and rod-mediated DA (20 minutes protocol). Multilevel mixed-effect models were used for analyses, with changes in rod intercept time at 3 years as the primary outcome. As some eyes (n = 11) reached the DA testing ceiling value at baseline, we used 3-year changes in area under the DA curve as an additional outcome. RESULTS: Baseline AMD, AMD stage, and hyperreflective foci on optical coherence tomography were associated with larger changes in rod intercept time at 3 years. When change in area under the DA curve was used as an outcome, in addition to these features, the presence of retinal atrophy and drusenoid pigment epithelial detachment had significant associations. New subretinal drusenoid deposits at 3 years were also associated with more pronounced changes in rod intercept time and area under the DA curve. CONCLUSION: Specific optical coherence tomography features are associated with DA impairments over time, which supports that structural changes predict functional loss over 3 years.

Several reports have suggested that genetic susceptibility contributes to the development and progression of diabetic retinopathy. We aimed to identify genetic loci that confer susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes. We analysed 5 790 508 single nucleotide polymorphisms (SNPs) in 8880 Japanese patients with type 2 diabetes, 4839 retinopathy cases and 4041 controls, as well as 2217 independent Japanese patients with type 2 diabetes, 693 retinopathy cases and 1524 controls. The results of these two genome-wide association studies (GWAS) were combined with an inverse variance meta-analysis (Stage-1), followed by de novo genotyping for the candidate SNP loci (P < 1.0 × 10-4) in an independent case-control study (Stage-2, 2260 cases and 723 controls). After combining the association data (Stages 1 and 2) using meta-analysis, the associations of two loci reached a genome-wide significance level: rs12630354 near STT3B on chromosome 3, P = 1.62 × 10-9, odds ratio (OR) = 1.17, 95% confidence interval (CI) 1.11-1.23, and rs140508424 within PALM2 on chromosome 9, P = 4.19 × 10-8, OR = 1.61, 95% CI 1.36-1.91. However, the association of these two loci was not replicated in Korean, European or African American populations. Gene-based analysis using Stage-1 GWAS data identified a gene-level association of EHD3 with susceptibility to diabetic retinopathy (P = 2.17 × 10-6). In conclusion, we identified two novel SNP loci, STT3B and PALM2, and a novel gene, EHD3, that confers susceptibility to diabetic retinopathy; however, further replication studies are required to validate these associations.

Nucleic acids are used in many therapeutic modalities, including gene therapy, but their ability to trigger host immune responses in vivo can lead to decreased safety and efficacy. In the case of adeno-associated viral (AAV) vectors, studies have shown that the genome of the vector activates Toll-like receptor 9 (TLR9), a pattern recognition receptor that senses foreign DNA. Here, we engineered AAV vectors to be intrinsically less immunogenic by incorporating short DNA oligonucleotides that antagonize TLR9 activation directly into the vector genome. The engineered vectors elicited markedly reduced innate immune and T cell responses and enhanced gene expression in clinically relevant mouse and pig models across different tissues, including liver, muscle, and retina. Subretinal administration of higher-dose AAV in pigs resulted in photoreceptor pathology with microglia and T cell infiltration. These adverse findings were avoided in the contralateral eyes of the same animals that were injected with the engineered vectors. However, intravitreal injection of higher-dose AAV in macaques, a more immunogenic route of administration, showed that the engineered vector delayed but did not prevent clinical uveitis, suggesting that other immune factors in addition to TLR9 may contribute to intraocular inflammation in this model. Our results demonstrate that linking specific immunomodulatory noncoding sequences to much longer therapeutic nucleic acids can "cloak" the vector from inducing unwanted immune responses in multiple, but not all, models. This "coupled immunomodulation" strategy may widen the therapeutic window for AAV therapies as well as other DNA-based gene transfer methods.

PURPOSE: Flanged intrascleral haptic fixation (FISHF) is a useful method for securing intraocular lenses (IOLs) in eyes without capsular support. Biomechanical studies were conducted to support the use of this technique. DESIGN: Laboratory investigation. METHODS: Haptics of 3-piece IOLs were passed through cadaveric human sclera using 30- and 27-gauge needles. Flanges were created by melting 1.0 mm from the haptic ends using cautery. The forces required to remove the flanged haptic from the sclera and disinsert the haptic from the optic were measured using a mechanical tester and a custom-fabricated mount. RESULTS: The mean FISHF dislocation force using 30-gauge needles was greatest with the CT Lucia 602 (2.04 ± 0.24 newtons [N]) compared to the LI61AO (0.93 ± 0.41 N; P = .001), ZA9003 (0.70 ± 0.34 N; P = <.001), and MA60AC (0.27 ± 0.19 N; P <.001). Using 27-gauge needles with the CT Lucia resulted in a lower dislocation force (0.56 ± 0.36 N; P <.001). The FISHF dislocation force was correlated with the flange-to-needle diameter ratio (r = 0.975). The FISHF dislocation forces of the CT Lucia and LI61AO using 30-gauge needles were not significantly different from their haptic-optic disinsertion forces (P = .79 and .27, respectively). There were no differences in flange diameters between 1.0 mm and 2.0 mm haptic melt lengths across the IOLs (P = .15-.85). CONCLUSIONS: These data strongly support the biomechanical stability of FISHF with the polyvinylidene fluoride haptics of the CT Lucia using small diameter instruments for the creation of an intrascleral tunnel. 1.0 mm of haptic may be the optimal melt length.