Choroidal neovascularization (CNV) causes acute vision loss in neovascular age-related macular degeneration (AMD). Genetic variations of the nuclear receptor RAR-related orphan receptor alpha (RORα) have been linked with neovascular AMD, yet its specific role in pathological CNV development is not entirely clear. In this study, we showed that Rora was highly expressed in the mouse choroid compared with the retina, and genetic loss of RORα in Staggerer mice (Rorasg/sg) led to increased expression levels of Vegfr2 and Tnfa in the choroid and retinal pigment epithelium (RPE) complex. In a mouse model of laser-induced CNV, RORα expression was highly increased in the choroidal/RPE complex post-laser, and loss of RORα in Rorasg/sg eyes significantly worsened CNV with increased lesion size and vascular leakage, associated with increased levels of VEGFR2 and TNFα proteins. Pharmacological inhibition of RORα also worsened CNV. In addition, both genetic deficiency and inhibition of RORα substantially increased vascular growth in isolated mouse choroidal explants ex vivo. RORα inhibition also promoted angiogenic function of human choroidal endothelial cell culture. Together, our results suggest that RORα negatively regulates pathological CNV development in part by modulating angiogenic response of the choroidal endothelium and inflammatory environment in the choroid/RPE complex.

PURPOSE: To describe the association of smoking status with surgical intervention for TED at the population-level. DESIGN: Retrospective cohort study. METHODS: SETTING: : US clinical data registry STUDY POPULATION: : All adults (age ≥18 years) with Graves disease in the Intelligent Research in Sight (IRIS®) Registry (1/1/2013-12/31/2020). OBSERVATION: Surgical intervention for TED, stratified into orbital decompression, strabismus surgery, and eyelid recession surgery. OUTCOME MEASURES: The Kaplan-Meier estimated five-year cumulative probability for each surgical intervention. Multivariable Cox regression was used to evaluate the association between smoking status and each surgical intervention, adjusting for age, sex, race, ethnicity, and geographic region. RESULTS: This study included 87,923 patients. Median age was 59 years (IQR, 48-68 years); 81% were female patients. Current smokers had a greater five-year cumulative probability of orbital decompression (3.7% vs.1.9%; p<0.001), strabismus surgery (4.6% vs.2.2%; p<0.001) and eyelid recession (4.1% vs.2.6%; p<0.001) compared to never smokers. After adjusting for demographic factors, current smokers were at greater risk of orbital decompression (HR, 2.1; 95% CI 1.8-2.4; p<0.001), strabismus surgery (HR, 2.0; 95% CI 1.8-2.3; p<0.001), and eyelid recession (HR, 1.7; 95% CI 1.5-1.9; p<0.001) than never smokers. Former smokers were at higher risk of each type of surgery for TED, though at lower levels than current smokers. CONCLUSIONS: Smoking was associated with increased risk of surgical intervention for TED in the IRIS Registry. Former smokers were at a lower risk than current smokers, supporting the role of smoking cessation on lowering the burden of surgical disease at the population-level.

Artificial intelligence (AI) applications in healthcare will have a potentially far-reaching impact on patient care, however issues regarding algorithmic bias and fairness have recently surfaced. There is a recognized lack of diversity in the available ophthalmic datasets, with 45% of the global population having no readily accessible representative images, leading to potential misrepresentations of their unique anatomic features and ocular pathology. AI applications in retinal disease may show less accuracy with underrepresented populations that may further widen the gap of health inequality if left unaddressed. Beyond disease symptomatology, social determinants of health must be integrated into our current paradigms of disease understanding, with the goal of more personalized care. AI has the potential to decrease global healthcare inequality, but it will need to be based on a more diverse, transparent and responsible use of healthcare data.

Abnormal angiogenesis is associated with myriad human diseases, including proliferative diabetic retinopathy (PDR). Signaling transduction through phosphoinositide 3-kinases (PI3Ks) plays a critical role in angiogenesis. Herein, we showed that p110δ, the catalytic subunit of PI3Kδ, was highly expressed in pathological retinal vascular endothelial cells (ECs) in a mouse model of oxygen-induced retinopathy (OIR) and in fibrovascular membranes from patients with PDR. To explore novel intervention with PI3Kδ expression, we developed a recombinant dual adeno-associated viral (rAAV) system for delivering CRISPR/Cas9 in which Streptococcus pyogenes (Sp) Cas9 expression was driven by an endothelial specific promoter of the intercellular adhesion molecule 2 (pICAM2) to edit genomic Pik3cd, the gene encoding p110δ. We then demonstrated that infection of cultured mouse vascular ECs with the dual rAAV1s of rAAV1-pICAM2-SpCas9 and rAAV1-SpGuide targeting genomic Pik3cd resulted in 80% DNA insertion/deletion in the locus of genomic Pik3cd and 70% depletion of p110δ expression. Furthermore, we showed that in the mouse model of OIR editing retinal Pik3cd with the dual rAAV1s resulted in not only a significant decrease in p110δ expression, and Akt activation, but also a dramatic reduction in pathological retinal angiogenesis. These findings reveal that Pik3cd editing is a novel approach to treating abnormal retinal angiogenesis.

PURPOSE: To assess the effect of corneal scarring location on corneal nerve regeneration in patients with herpes simplex virus (HSV) keratitis in their affected and contralateral eyes over a 1-year period by in vivo confocal microscopy (IVCM), and to correlate these findings to corneal sensation measured by Cochet-Bonnet Esthesiometer. METHODS: Prospective, longitudinal, case-control study. Bilateral corneal nerve density and corneal sensation was analyzed centrally and peripherally in 24 healthy controls and 23 patients with unilateral HSV-related corneal scars using IVCM. RESULTS: In the central scar (CS) group, total nerve density in the central cornea remained significantly lower compared to controls at follow-up (11.05 ± 1.97mm/mm2, p < 0.001), and no significant nerve regeneration was observed (p = 0.090). At follow-up, total nerve density was not significantly different from controls in the central and peripheral cornea of peripheral scar (PS) group (all p > 0.05), and significant nerve regeneration was observed in central corneas (16.39 ± 2.39mm/mm2, p = 0.007) compared to baseline. In contralateral eyes, no significant corneal nerve regeneration was observed in central or peripheral cornea of patients with central scars or peripheral scars at 1-year follow-up, compared to baseline (p > 0.05). There was a positive correlation between corneal nerve density and sensation in both central (R = 0.53, p < 0.0001) and peripheral corneas (R = 0.27, p = 0.0004). In the CS group, the corneal sensitivity was <4 cm in 4 (30.8%) and 7 (53.8%) patients in the central and peripheral corneas at baseline, and in 5 (38.5%) and 2 subjects (15.4%) at follow-up, whereas in the PS group only 1 patient (10%) showed a corneal sensation < 4cm in the central cornea at baseline, and only 1 (10.0%), 3 (30.0%) and 1 (10.0%) patients at follow-up in the central, affected and opposite area of the cornea, respectively. CONCLUSION: The location of HSV scarring in the cornea affects the level of corneal nerve regeneration. Eyes with central corneal scar have a diminished capacity to regenerate nerves in central cornea, they show a more severe reduction in corneal sensation in the central and peripheral cornea that persist at follow-up, and they have a reduced capability to restore the corneal sensitivity above the cut-off of 4 cm. Thus, clinicians should be aware that CS patients would benefit from closer monitoring for potential complications associated with neurotrophic keratopathy, as they have a lower likelihood for nerve regeneration.

Salt stress is of the most detrimental abiotic stress factors on either crop or non-crop species. Of the strategies employed to boost the performance of the plants against harmful impacts of salt stress; application of novel nano-engineered particles have recently gained great attention as a promising tool. Octa-aminopropyl polyhedral oligomeric silsesquioxanes nanoparticles (OA-POSS NPs) were synthesized and then a foliar-application of OA-POSS NPs were carried out on sweet basil plants subjected to the salt stress. In that context, interactive effects of OA-POSS NPs (25, 50 and 100 mg L-1) and salinity stress (50 and 100 mM NaCl) were assayed by estimating a series of agronomic, physiological, biochemical and analytical parameters. OA-POSS NPs decreased the harmful effects of salinity by increasing photosynthetic pigment content, adjusting chlorophyll fluorescence, and triggering non-enzymatic (phenolic content) and enzymatic antioxidant components. The findings suggested that 25 mg L-1 OA-POSS NPs is the optimum concentration for sweet basil grown under salt stress. Considering the essential oil profile, estragole was the predominant compound with a percentage higher than 50% depending on the treatment. In comparison to the control group, 50 mM NaCl did not significantly affect estragole content, whilst 100 mM NaCl caused a substantial increase in estragole content. Regarding OA-POSS NPs treatments, increments by 16.8%, 11.8% and 17.5% were observed following application with 25, 50 and 100 mg L-1, respectively. Taken together, the current study provides evidence that POSS NPs can be employed as novel, 'green' growth promoting agents in combating salt stress in sweet basil.

Epithelial mesenchymal transition (EMT) plays a vital role in a variety of human diseases including proliferative vitreoretinopathy (PVR), in which retinal pigment epithelial (RPE) cells play a key part. Transcriptomic analysis showed that the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway was up-regulated in human RPE cells upon treatment with transforming growth factor (TGF)-β2, a multifunctional cytokine associated with clinical PVR. Stimulation of human RPE cells with TGF-β2 induced expression of p110δ (the catalytic subunit of PI3Kδ) and activation of NFκB/p65. CRISPR-Cas9-mediated depletion of p110δ or NFκB/p65 suppressed TGF-β2-induced fibronectin expression and activation of Akt as well as migration of these cells. Intriguingly, abrogating expression of NFκB/p65 also blocked TGF-β2-induced expression of p110δ, and luciferase reporter assay indicated that TGF-β2 induced NFκB/p65 binding to the promoter of the PIK3CD that encodes p110δ. These data reveal that NFκB/p65-mediated expression of PI3Kδ is essential in human RPE cells for TGF-β2-induced EMT, uncovering hindrance of TGF-β2-induced expression of p110δ as a novel approach to inhibit PVR.

PURPOSE OF REVIEW: There is now a large body of experience with intraoperative aberrometry. This review aims to synthesize available data regarding intraoperative aberrometry applications and outcomes. RECENT FINDINGS: The Optiwave Refractive Analysis (ORA) System utilizes Talbot-moiré interferometry and is the only commercially available intraoperative aberrometry device. There are few studies that include all-comers undergoing intraoperative aberrometry-assisted cataract surgery, as most studies examine routine patients only or atypical eyes only. In non-post-refractive cases, studies have consistently shown a small but statistically significant benefit in spherical equivalent refractive outcome for intraoperative aberrometry versus preoperative calculations. In studies examining axial length extremes, most studies have shown intraoperative aberrometry to perform similarly to preoperative calculations. Amongst post-refractive cases, post-myopic ablation cases appear to benefit the most from intraoperative aberrometry. For toric intraocular lenses (IOLs), intraoperative aberrometry may be used for refining IOL power (toricity and spherical equivalent) and alignment, and most studies show intraoperative aberrometry to achieve low postoperative residual astigmatism. SUMMARY: Intraoperative aberrometry can be utilized as an adjunct to preoperative planning and surgeon's judgment to optimize cataract surgery refractive outcomes. Non-post-refractive cases, post-myopic ablation eyes, and toric intraocular lenses may have the greatest demonstrated benefit in intraoperative aberrometry studies to date, but other eyes may also benefit from intraoperative aberrometry use.

To identify strategies for effective curriculum development and implementation in United States (US) ophthalmology residency training programs. A literature review was conducted for all English-language PubMed/Medline articles relating to ophthalmology residency education or curriculum/curricula. Despite ACGME-defined program requirements outlining curricular goals for US ophthalmology residency training programs, there is no comprehensive, national curriculum with detailed plans for instruction of necessary topics within the 36-month residency training period. Several articles identify a need for detailed curricula on various topics, propose ideas on how residency programs could create curricula, and explore ways of assessing resident competence. There is a paucity of literature evaluating how ophthalmology residents best learn various ophthalmology topics. We need to develop an intentional, comprehensive, and timely national curriculum for ophthalmology residency programs in the US, with detailed plans on how to meet curricular objectives and consideration of the most effective teaching strategies for different ophthalmology concepts.

An underlying diagnosis of keratoconus (KC) can complicate cataract surgery. In this study, the results of a focused review of the literature pertaining to cataract surgery in patients with KC are detailed. Topics essential for the appropriate management of this patient population are discussed. First, the individual and shared epidemiology and pathophysiology of cataract and KC are reviewed. Then, the theory and approach to intraocular lens power calculation are discussed, highlighting particularities and pitfalls of this exercise when performed in patients with KC. Finally, several special-although not uncommon-management scenarios and questions are addressed, such as surgical planning in cases where corneal stabilization or tissue replacement interventions are also necessitated.