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Laurel B Tanke,1 Kevin D Chodnicki,1 Timothy W Olsen,1 M Tariq Bhatti,1,2 John J Chen1,2 1Department of Ophthalmology, Mayo Clinic, Rochester, MN, USA; 2Department of Neurology, Mayo Clinic, Rochester, MN, USACorrespondence: John J ChenDepartment of Ophthalmology, Mayo Clinic, Rochester, MN, USAEmail chen.john@mayo.eduPurpose: To determine the population-based incidence of ocular neovascularization (NV) following central retinal artery occlusion (CRAO) and systemic risk factors associated with its development.Methods: Diagnosis of CRAO between January 1, 1976, and September 9, 2016, was identified using the Rochester Epidemiology Project, a medical records linkage system for all medical care provided to residents of Olmsted County, Minnesota. Records were reviewed to confirm the diagnosis of CRAO, and data were collected on ocular NV and associated systemic diseases.Results: There were 89 patients with CRAO. Subsequent ocular neovascularization developed in 14 (16%) patients. Neovascularization of the iris (NVI) was present in 9/14 (64%) of these patients, neovascularization of the angle (NVA) in 10/14 (71%), neovascularization of the disc (NVD) in 2/14 (14%), and neovascularization elsewhere (NVE) in 1/14 (7%). Of these 14 patients with NV, 9 (64%) developed neovascular glaucoma (NVG). The mean time from CRAO diagnosis to NV was 82 days (range 22 to 268 days). Excluding the patients with proliferative diabetic retinopathy or CRAO caused by CRVO, the mean time to NV diagnosis was 80 days and the shortest time to NV diagnosis was 22 days. Diabetes mellitus was present in 64% of those with NV compared to 23% of those without NV (P = 0.003).Conclusion: The population-based incidence of ocular neovascularization following CRAO is 16% and developed within 2 months in half the cohort. Patients with diabetes mellitus are at increased risk for NV complications.Keywords: central retinal artery occlusion, neovascular glaucoma

Objective: To investigate the frequency and clinical features of intraocular paraneoplastic sarcoid-like reaction (SLR) in patients with chronic lymphocytic leukemia (CLL)., Methods: Retrospective review of patients with CLL from January 1, 1980, to December 31, 2020. Eye examinations were searched for 22 keywords suggestive of SLR, and charts were manually reviewed., Results: Of 4209 unique patients with CLL, 1021 (24%) had at least 1 eye examination on record, and 324 (8%) had 1 or more keyword eye examination findings. After manual review, 12 patients (<1%) were identified as having probable SLR with characteristic features (n = 7), possible but not classic (n = 1), or suspect but less likely (n = 4). All patients (n = 8) with probable or possible SLR were White, and half (n = 4) were male. Intraocular SLR was diagnosed a mean of 49.7 months after the CLL diagnosis (n = 7) or preceded the CLL diagnosis by 1 month (n = 1). Involvement was bilateral in 5 patients, with 13 total affected eyes and mean presenting Snellen visual acuity of 20/50. Common characteristic features on initial examination included vitreous cell (n = 13), anterior-chamber cell (n = 10), keratic precipitates (n = 9), posterior synechiae (n = 6), chorioretinal lesions (n = 5), and vitreous haze (n = 5). Treatment included topical corticosteroids alone (n = 5), with sub-Tenon corticosteroids (n = 1), or with steroid-sparing immunosuppressive agents (n = 1) or oral corticosteroids alone (n = 1). After a mean follow-up of 19.8 months, final mean visual acuity was 20/30., Conclusion: Intraocular SLRs affect fewer than 1% of patients with CLL. SLR should be on the differential diagnosis list for any CLL patient with ocular complaints, and most patients can be managed successfully with corticosteroids., (Copyright © 2023 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To describe ocular involvement in subjects with Whipple's disease (WD)., Methods: Retrospective review of documented WD cases seen at Mayo Clinic between 1980 and 2021 with ocular involvement., Results: Of 217 patients with WD, 30 had eye exams and four (two female, median age 58.5 years) had ocular involvement. Findings included anterior/intermediate uveitis ( n  = 2), intermediate uveitis and phlebitis ( n  = 1), and chorioretinitis with vitritis ( n  = 1). The diagnosis was confirmed by vitreous biopsy in three of four cases. In two cases, WD diagnosis was unconfirmed prior to the ocular diagnosis. Systemic manifestations included gastrointestinal symptoms in all patients, synovitis ( n  = 3), weight loss ( n  = 2), and pericarditis ( n  = 1). Mean time from onset of ocular symptoms to ocular diagnosis was 11 months (range 2-28 months). Prior systemic symptoms were present as long as 3 years., Conclusions: WD is uncommon and ocular involvement is even more rare. However, WD should be considered in the differential for all patients with chronic recalcitrant uveitis, especially in the setting of polyarthralgias and/or gastrointestinal symptoms. Vitreous biopsy is a reliable method to diagnose ocular WD. Abbreviations and Acronyms: Whipple's disease (WD), intestinal lipodystrophy (IL), polymerase-chain reaction (PCR), periodic acid-Schiff (PAS), trimethoprim/sulfamethoxazole (TMP/SMX).

Purpose: To report a rare case of a subretinal Phialophora richardsiae abscess in a patient with chronic granulomatous disease., Methods: A 21-year-old man with chronic granulomatous disease and a history of invasive pulmonary aspergillosis presented with progressive loss of vision and pain in his left eye. He was found to have a subretinal abscess with a macula involving serous retinal detachment. A diagnostic and therapeutic pars plana vitrectomy, subretinal biopsy with debridement, inferior retinectomy, and silicone oil tamponade were performed. Intraoperative cultures grew Pleurostoma (Phialophora) richardsiae. He was treated with systemic liposomal amphotericin B and high-dose posaconazole. However, his eye eventually required enucleation., Results: Preoperative visual acuity was light perception on the left eye and improved to count fingers at 4 weeks postoperative. However, VA rapidly declined to light perception, and he developed an opaque white cataract, iris neovascularization, posterior synechiae, and corectopia. The retina remained attached under silicone oil. Histopathology revealed granuloma formation and active fungal elements., Discussion/conclusion: The case supports the importance of vitreoretinal surgery to determine a definitive systemic diagnosis. Treatment of Phialophora infection is surgically challenging to manage and has a poor visual prognosis in patients with chronic granulomatous disease.

The choroid is a thin layer of highly vascular uveal tissue enclosed externally by sclera and internally by neurosensory retinal tissue. The choroid is a "middle layer" ocular tissue with anatomically challenging surgical access. The primary functional role of the choroid is to provide rapid, oxygenated, and nutrient-rich blood flow to both the highly metabolic retinal pigment epithelium and outer retina (i.e. photoreceptors) while simultaneously removing waste products. Historically, incisional choroidal surgery (ICS) has involved tumor biopsy or excision, removal of choroidal neovascular complex or autologous choroidal translocations; however, ICS also holds unique potential for novel and innovative approaches to address macular pathology. Using large-animal surgical studies, researchers have explored ICS with the objective of finding safer and more effective techniques to reduce surgical risks such as bleeding, tissue contraction, and scar tissue formation. We explore the relevant anatomy and embryology, existing surgical techniques, discuss the implications for retinal drug delivery, define ICS guiding principles, and offer a rationale for implementation of ICS into a vitreoretinal surgical practice. We also identify other future challenges and anticipate future innovations that will advance ICS., Competing Interests: Declaration of Competing Interest NA, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To develop and validate machine learning (ML) models to predict choroidal nevus transformation to melanoma based on multimodal imaging at initial presentation., Design: Retrospective multicenter study., Participants: Patients diagnosed with choroidal nevus on the Ocular Oncology Service at Wills Eye Hospital (2007-2017) or Mayo Clinic Rochester (2015-2023)., Methods: Multimodal imaging was obtained, including fundus photography, fundus autofluorescence, spectral domain OCT, and B-scan ultrasonography. Machine learning models were created (XGBoost, LGBM, Random Forest, Extra Tree) and optimized for area under receiver operating characteristic curve (AUROC). The Wills Eye Hospital cohort was used for training and testing (80% training-20% testing) with fivefold cross validation. The Mayo Clinic cohort provided external validation. Model performance was characterized by AUROC and area under precision-recall curve (AUPRC). Models were interrogated using SHapley Additive exPlanations (SHAP) to identify the features most predictive of conversion from nevus to melanoma. Differences in AUROC and AUPRC between models were tested using 10 000 bootstrap samples with replacement and results., Main Outcome Measures: Area under receiver operating curve and AUPRC for each ML model., Results: There were 2870 nevi included in the study, with conversion to melanoma confirmed in 128 cases. Simple AI Nevus Transformation System (SAINTS; XGBoost) was the top-performing model in the test cohort [pooled AUROC 0.864 (95% confidence interval (CI): 0.864-0.865), pooled AUPRC 0.244 (95% CI: 0.243-0.246)] and in the external validation cohort [pooled AUROC 0.931 (95% CI: 0.930-0.931), pooled AUPRC 0.533 (95% CI: 0.531-0.535)]. Other models also had good discriminative performance: LGBM (test set pooled AUROC 0.831, validation set pooled AUROC 0.815), Random Forest (test set pooled AUROC 0.812, validation set pooled AUROC 0.866), and Extra Tree (test set pooled AUROC 0.826, validation set pooled AUROC 0.915). A model including only nevi with at least 5 years of follow-up demonstrated the best performance in AUPRC (test: pooled 0.592 (95% CI: 0.590-0.594); validation: pooled 0.656 [95% CI: 0.655-0.657]). The top 5 features in SAINTS by SHAP values were: tumor thickness, largest tumor basal diameter, tumor shape, distance to optic nerve, and subretinal fluid extent., Conclusions: We demonstrate accuracy and generalizability of a ML model for predicting choroidal nevus transformation to melanoma based on multimodal imaging., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmology.)

Background: Vitreoretinal lymphoma (VRL) is a rare intraocular malignancy that poses a diagnostic challenge due to the non-specific clinical presentation that resembles uveitis. The use of spectral domain optical coherence tomography (SD-OCT) has emerged as a valuable imaging tool to characterize VRL. Therefore, we sought to determine the specific OCT features in VRL compared to the uveitides., Methods: Retrospective chart review of patients who were seen at Mayo Clinic from January 1, 2010 through December 31, 2022. The medical records and SD-OCT images at time of initial presentation were reviewed in patients with biopsy-proven VRL, intermediate uveitis, or biopsy-confirmed sarcoid posterior uveitis. Patients with VRL or similar uveitides including intermediate uveitis or sarcoid posterior uveitis were included., Results: There were 95 eyes of 56 patients in the VRL group and 86 eyes of 45 patients in the uveitis group, of whom 15 (33.3%) were diagnosed with intermediate uveitis and 30 (66.7%) with sarcoid chorioretinitis. The SD-OCT features more commonly seen at initial presentation in VRL patients (vs. uveitis) included preretinal deposits (31.6% vs. 9.3%, p = 0.002), intraretinal infiltrates (34% vs. 3.5%, p < 0.001), inner retinal hyperreflective spots (15.8% vs. 0%, p < 0.001), outer retinal atrophy (22.1% vs. 2.3%, p < 0.001), subretinal focal deposits (21.1% vs. 4.7%, p = 0.001), retinal pigmented epithelium (RPE) changes (49.5% vs. 3.5%, p < 0.001), and sub-RPE deposits (34.7% vs. 0%, p < 0.001). Features more frequently seen in uveitis included epiretinal membrane (ERM) (82.6% vs. 44.2%, p < 0.001), central macular thickening (95.3% vs. 51.6%, p < 0.001), cystoid macular edema (36% vs. 11.7%, p < 0.001), subretinal fluid (16.3% vs 6.4%, p = 0.04), and subfoveal fluid (16.3% vs. 3.2%, p = 0.003). Multivariate regression analysis controlling for age and sex showed absence of ERM (OR 0.14 [0.04,0.41], p < 0.001) and absence of central macular thickening (OR 0.03 [0,0.15], p = 0.02) were associated with VRL as opposed to uveitis., Conclusion: OCT features most predictive of VRL (vs. uveitis) included absence of ERM and central macular thickening., (© 2024. The Author(s).)

Objective: To determine the association between pre-operative central subfield thickness (CST) and post-radiotherapy visual acuity (VA), cystoid macular edema (CME), and intravitreal anti-vascular endothelial growth factor (VEGF) requirement., Design: Single-center retrospective study., Participants: Patients with plaque-irradiated extramacular choroidal melanoma treated between 11/11/2011 and 4/30/2021. Pre-operative CST difference between the affected and unaffected eye was used. Kaplan-Meier analysis and hazard ratios were calculated., Results: Of 85 patients, pre-operative CST was greater in the melanoma-affected eye (vs. fellow eye) by mean of 20.4 μm (median 14.0, range - 60.0-182.0). Greater CST at presentation (vs. fellow eye) was associated with larger tumor diameter (p = 0.02), greater tumor thickness (p < 0.001), and more frequent tumor-related Bruch's membrane rupture (p = 0.006). On univariate analysis of outcome data, greater CST at presentation (vs. fellow eye) was associated with higher 5-year risk (1.09 [1.02-1.17], p = 0.02) of VA 20/200 or worse and increased (1.10 [1.01-1.20], p = 0.03) likelihood for anti-VEGF injections after plaque irradiation. There was no significant association with CME. The association between CST and VA outcome remained significant on multivariate analysis accounting for impact of tumor thickness and radiation dose to optic disc, while tumor distance to fovea was the only significant factor on multivariate analysis for anti-VEGF injections., Conclusion: Greater CST at presentation (vs. fellow eye) was associated with worse VA outcome following plaque radiotherapy for choroidal melanoma. Large-sized tumors may contribute to a higher intraocular VEGF burden, potentially leading to greater preoperative CST, which correlates with poor VA outcome post-plaque radiotherapy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To determine the appropriateness of ophthalmology recommendations from an online chat-based artificial intelligence model to ophthalmology questions., Patients and Methods: Cross-sectional qualitative study from April 1, 2023, to April 30, 2023. A total of 192 questions were generated spanning all ophthalmic subspecialties. Each question was posed to a large language model (LLM) 3 times. The responses were graded by appropriate subspecialists as appropriate, inappropriate, or unreliable in 2 grading contexts. The first grading context was if the information was presented on a patient information site. The second was an LLM-generated draft response to patient queries sent by the electronic medical record (EMR). Appropriate was defined as accurate and specific enough to serve as a surrogate for physician-approved information. Main outcome measure was percentage of appropriate responses per subspecialty., Results: For patient information site-related questions, the LLM provided an overall average of 79% appropriate responses. Variable rates of average appropriateness were observed across ophthalmic subspecialties for patient information site information ranging from 56% to 100%: cataract or refractive (92%), cornea (56%), glaucoma (72%), neuro-ophthalmology (67%), oculoplastic or orbital surgery (80%), ocular oncology (100%), pediatrics (89%), vitreoretinal diseases (86%), and uveitis (65%). For draft responses to patient questions via EMR, the LLM provided an overall average of 74% appropriate responses and varied by subspecialty: cataract or refractive (85%), cornea (54%), glaucoma (77%), neuro-ophthalmology (63%), oculoplastic or orbital surgery (62%), ocular oncology (90%), pediatrics (94%), vitreoretinal diseases (88%), and uveitis (55%). Stratifying grades across health information categories (disease and condition, risk and prevention, surgery-related, and treatment and management) showed notable but insignificant variations, with disease and condition often rated highest (72% and 69%) for appropriateness and surgery-related (55% and 51%) lowest, in both contexts., Conclusion: This LLM reported mostly appropriate responses across multiple ophthalmology subspecialties in the context of both patient information sites and EMR-related responses to patient questions. Current LLM offerings require optimization and improvement before widespread clinical use., Competing Interests: POTENTIAL COMPETING INTERESTS The authors report no competing interests.

Purpose: To investigate the prevalence of myopia and high myopia in Olmsted County, Minnesota, from 1966 to 2019., Design: Retrospective, cross-sectional, trend study., Methods: Manifest refractions or lens prescription were converted to spherical equivalent (SE) to estimate the prevalence of adult myopia and high myopia. Age, sex, race, and visual acuity were recorded. Subjects with an SE of -0.5 diopters (D) or less were considered to have myopia; those with an SE of -6.0 D or less were considered to have high myopia. Exclusion criteria included visually significant cataract, pseudophakia, prior refractive surgery, or age less than 18 years., Results: Among 81,706 sampled subjects, the myopia prevalence increased from 33.9% (95% CI, 31.1-36.8) in the 1960s to 57.1% (95% CI, 56.6-57.6) in the 2010s (P < .001). The high myopia prevalence increased from 2.8% (95% CI, 1.95-3.98) in the 1960s to 8.3% (95% CI, 8.08-8.62) in the 2010s (P < .001). Both male (32.0%-55.1%, P < .001) and female (40.6%-58.5%, P < .001) subjects experienced increasing myopia prevalence from the 1960s to the 2010s; both male (2.6%-7.4%, P < .001) and female (3.4%-9.1%, P < .001) subjects also had higher high myopia prevalence rates from the 1960s through the 2010s. Increasing myopia and high myopia prevalence was detected by decade in nearly all age groups (excluding 18- to 24-year-old high myopia subjects). White and Asian subjects had the highest myopia prevalence, whereas Black subjects had the lowest. From the 2000s to the 2010s, White (53.3%-57.0%, P < .001) and Black (41.0%-47.0%, P = .001) subjects had significant increases in myopia prevalence. The mean SE decreased from the 1960s (-0.42 D; 95% CI, -0.59 to +2.49) to the 2010s (-1.85 D; 95% CI, -1.88 to +2.96) (P < .001)., Conclusions: From 1966 to 2019 in Olmsted County, Minnesota, there was a 68% and 199% increase in myopia and high myopia prevalence, respectively., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To review the published literature evaluating the visual and refractive outcomes and rotational stability of eyes implanted with toric monofocal intraocular lenses (IOLs) for the correction of keratometric astigmatism during cataract surgery and to compare those outcomes with outcomes of eyes implanted with nontoric monofocal IOLs and other astigmatism management methods performed during cataract surgery. This assessment was restricted to the toric IOLs available in the United States., Methods: A literature search of English-language publications in the PubMed database was last conducted in July 2022. The search identified 906 potentially relevant citations, and after review of the abstracts, 63 were selected for full-text review. Twenty-one studies ultimately were determined to be relevant to the assessment criteria and were selected for inclusion. The panel methodologist assigned each a level of evidence rating; 12 studies were rated level I and 9 studies were rated level II., Results: Eyes implanted with toric IOLs showed excellent postoperative uncorrected distance visual acuity (UCDVA), reduction of postoperative refractive astigmatism, and good rotational stability. Uncorrected distance visual acuity was better and postoperative cylinder was lower with toric IOLs, regardless of manufacturer, when compared with nontoric monofocal IOLs. Correcting pre-existing astigmatism with toric IOLs was more effective and predictable than using corneal relaxing incisions (CRIs), especially in the presence of higher magnitudes of astigmatism., Conclusions: Toric monofocal IOLs are effective in neutralizing pre-existing corneal astigmatism at the time of cataract surgery and result in better UCDVA and significant reductions in postoperative refractive astigmatism compared with nontoric monofocal IOLs. Toric IOLs result in better astigmatic correction than CRIs, particularly at high magnitudes of astigmatism., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the quality, empathy, and safety of expert edited large language model (LLM), human expert created, and LLM responses to common retina patient questions., Design: Randomized, masked multicenter study., Participants: Twenty-one common retina patient questions were randomly assigned among 13 retina specialists., Methods: Each expert created a response (Expert) and then edited a LLM (ChatGPT-4)-generated response to that question (Expert + artificial intelligence [AI]), timing themselves for both tasks. Five LLMs (ChatGPT-3.5, ChatGPT-4, Claude 2, Bing, and Bard) also generated responses to each question. The original question along with anonymized and randomized Expert + AI, Expert, and LLM responses were evaluated by the other experts who did not write an expert response to the question. Evaluators judged quality and empathy (very poor, poor, acceptable, good, or very good) along with safety metrics (incorrect information, likelihood to cause harm, extent of harm, and missing content)., Main Outcome: Mean quality and empathy score, proportion of responses with incorrect information, likelihood to cause harm, extent of harm, and missing content for each response type., Results: There were 4008 total grades collected (2608 for quality and empathy; 1400 for safety metrics), with significant differences in both quality and empathy ( P  < 0.001, P  < 0.001) between LLM, Expert and Expert + AI groups. For quality, Expert + AI (3.86 ± 0.85) performed the best overall while GPT-3.5 (3.75 ± 0.79) was the top performing LLM. For empathy, GPT-3.5 (3.75 ± 0.69) had the highest mean score followed by Expert + AI (3.73 ± 0.63). By mean score, Expert placed 4 out of 7 for quality and 6 out of 7 for empathy. For both quality ( P  < 0.001) and empathy ( P  < 0.001), expert-edited LLM responses performed better than expert-created responses. There were time savings for an expert-edited LLM response versus expert-created response ( P  = 0.02). ChatGPT-4 performed similar to Expert for inappropriate content ( P  = 0.35), missing content ( P  = 0.001), extent of possible harm ( P  = 0.356), and likelihood of possible harm ( P  = 0.129)., Conclusions: In this randomized, masked, multicenter study, LLM responses were comparable with experts in terms of quality, empathy, and safety metrics, warranting further exploration of their potential benefits in clinical settings., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of the article., (© 2024 by the American Academy of Ophthalmology.)

Purpose: To investigate the in vivo effect of scleral buckle surgery on ocular biomechanics and aqueous humor dynamics., Design: Prospective observational cross-sectional study., Participants: Nine patients with unilateral 360 degree encircling scleral buckles without vitrectomy for rhegmatogenous retinal detachments, between 3 and 39 months postoperative., Methods: All measurements were performed in both eyes of all participants. Intraocular pressure (IOP) was measured in the seated and supine positions using pneumatonometry. Outflow facility was measured using 2-minute weighted pneumatonography. Ocular rigidity coefficient was determined from the Friedenwald equations based on the difference in IOP with and without a weighted tonometer tip. The percentage change in IOP upon transitioning from seated to supine was calculated. Measurements for buckled and nonbuckled eyes were compared using paired Student t test of means., Main Outcome Measures: Sitting and supine IOP and percentage difference between the 2 positions; outflow facility; ocular rigidity coefficient., Results: Seated IOP was similar between buckled and nonbuckled eyes (16.1 ± 2.5 vs. 16.7 ± 2.7 mmHg; P = 0.5) whereas supine IOP was lower in buckled eyes compared with nonbuckled eyes (18.7 ± 2.6 vs. 21.3 ± 2.5 mmHg; P = 0.008). The percentage increase in IOP upon change in body position from seated to supine was greater in nonbuckled eyes (17.4 ± 9.4% vs. 27.6 ± 9.5%; P = 0.005). Ocular rigidity coefficient was lower in buckled (9.9 × 10 -3 ± 1.4 × 10 -3 μL -1 ) vs. nonbuckled eyes (14.4 × 10 -3 ± 3.1 × 10 -3 μL -1 ; P = 0.006). Outflow facility was not significantly different in buckled and nonbuckled eyes., Conclusions: Scleral buckling decreases ocular rigidity but does not affect outflow facility. This change in ocular biomechanics likely results in the attenuated IOP change from seated to supine position. Decreased ocular rigidity may also reduce IOP fluctuations and potentially reduce the risk for glaucoma progression., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Decades of studies on age-related macular degeneration (AMD), cardiovascular disease and stroke have not found consistent associations between AMD and systemic vascular disease. This study suggests that there is in fact no general relationship, but instead a strong, specific association between only the subretinal drusenoid deposit (SDD) phenotype of AMD on retinal imaging and certain co-existent vascular diseases that are high risk for compromised cardiac output or internal carotid artery stenosis. Future screening initiatives for these high -risk vascular diseases (HRVDs) with fast, inexpensive retinal imaging could make a significant contribution to public health and save lives. Likewise, screening patients with known HRVDs for unrecognized AMD of the SDD form could enable needed treatment and save vision., Competing Interests: Declaration of Competing Interest T.W. Olsen is owner of iMacular Regeneration, LLC [P] with medical device technology to address end-stage AMD as well as unrelated drug-delivery technology. We have received NIH/NEI funding for developing these technologies (R41EY028803, R41EY030819, and R43EY023504). No devices or technology from iMacular Regeneration is discussed or mentioned in this manuscript. The Minnesota Grading System (MGS), mentioned in this study, generates income for iMacular Regeneration as a service to Lions Vision World Institute (LVWI), Tampa FL. Dr. Olsen serves on the data safety and monitoring committee for Aura Biosciences, Inc. No technology from Aura Biosciences is discussed in this manuscript; V Chong is an employee of Janssen R&D LLC; this paper was written outside of Janssen's employment and is not endorsed by Janssen; R Rosen is a consultant to OptoVue, Boehringer-Ingelheim, Astellas, Genentech-Roche, NanoRetina, OD-OS, Regeneron, Bayer, Diopsys and Teva. He has personal financial interests in Opticology, Guardion and CellView; S. Sivaprasad received financial support from advisory boards from AbbVie, Apellis, Bayer, Biogen, Boehringer Ingelheim, Novartis, Eyebiotech, Janssen Pharmaceuticals, Optos, Ocular Therapeutix, OcuTerra, Roche. Sivaprasad reported receiving research grant support from AbbVie, Bayer, Boehringer Ingelheim, Novartis, Optos. Sivaprasad is a DMC/TSC member for studies sponsored by Nova Nordisk and Bayer., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To identify choroidal nevus features associated with referral to a retina or ocular oncology subspecialist., Design: Population-based retrospective cohort study., Subjects: Patients diagnosed with choroidal nevus., Methods: Population-based retrospective cohort study of residents of Olmsted County, Minnesota, with an incident diagnosis of choroidal nevus from January 1, 2006, to December 31, 2015 using the Rochester Epidemiology Project, a medical record linkage system. Tumor features and patient demographics associated with referral to a retina or ocular oncology subspecialist were assessed. Wilcoxon rank sum test, chi-square test, and Fisher exact test were used for statistical analysis., Main Outcome Measures: Tumor features and patient demographics associated with referral to subspecialty care., Results: There were 826 incident diagnoses of choroidal nevus, of which 88 cases (11%) were referred, with highest level of referral being retina in 29 cases (33%) and ocular oncology in 59 cases (67%). None of the analyzed demographic features were associated with choroidal nevus referral to subspecialty care. Tumor features associated with referral (vs. not referred) included greater mean basal diameter (4.6 mm vs. 2.4 mm, P < 0.001), greater mean tumor thickness (0.7 mm vs. 0.1 mm, P < 0.001), greater distance to optic disc (6.9 mm vs. 3.4 mm, P = 0.02), halo around nevus (5.7% vs. 0.4%, P < 0.001), and drusen on OCT (51% vs. 25%, P = 0.002). Presence of orange pigment (8% vs. 0%, P = 0.14), subretinal fluid (9% vs. 2.5%, P = 0.09), and low internal reflectivity on A-scan (7.7% vs. 0%, P = 1.00) were not found more frequently in the subspecialty referral group., Conclusions: Greater basal diameter and mean tumor thickness of choroidal nevus were associated with referral to retina or ocular oncology. However, several features associated with increased risk of malignant transformation were not associated with subspecialty referral. These findings highlight the importance of educating eye care providers about high-risk tumor features associated with choroidal nevus transformation to melanoma. In the primary eye care setting where not all multimodal imaging may be available, we encourage color photography and OCT with referral for any features of basal diameter > 5 mm, presence of subretinal fluid, or thickness too large for capture by enhanced-depth imaging OCT., Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to describe an exceedingly rare presentation of secondary vitreoretinal involvement by the uncommon entity "indolent T-cell lymphoproliferative disorder of the gastrointestinal tract" and illustrate the utility of fluorescence in situ hybridization for diagnosis., Methods: This is a case report., Results: A 57-year-old woman with presumed iritis on chronic topical prednisolone acetate presented with increased vitreous opacities in the right eye. She had a history of biopsy-confirmed indolent T-cell lymphoproliferative disorder of the gastrointestinal tract involving the stomach and duodenum, JAK2 -rearrangement positive, controlled on maintenance oral methotrexate. Vitreous biopsy was unremarkable with small CD3-positive and CD4-positive and CD20-negative lymphocytes, along with histiocytes and fibroblasts. Immunostains showed CD4 positivity, and fluorescence in situ hybridization revealed a JAK2 gene rearrangement, consistent with the patient's previously diagnosed indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. Intravitreal methotrexate injections were started in the right eye. MRI of the brain and lumbar puncture with cytology, MYD88 , IL10, and flow cytometry performed at the time of right eye vitreoretinal lymphoma diagnosis revealed no evidence of central nervous system lymphoma, but subsequent bone marrow biopsy demonstrated 5% involvement by indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, JAK2 -rearrangement positive, with a lung nodule on PET computed tomography. She returned 4 months later with fatigue, night sweats, and blurry vision in the left eye with vitreous and anterior chamber cellular infiltration and retinal vasculitis., Conclusion: T-cell vitreoretinal lymphoma is rare, and diagnosis can be challenging. Despite inconclusive cytology in this case, interphase fluorescence in situ hybridization detected a JAK2 gene rearrangement, which confirmed the involvement by indolent T-cell lymphoproliferative disorder of the gastrointestinal tract and prompted appropriate treatment and workup for recurrent systemic or central nervous system lymphoma.

Purpose: To determine the effectiveness of aerosol-delivered methotrexate (AD-MTx) in a large-animal (porcine) model of proliferative vitreoretinopathy (PVR)., Design: Prospective, randomized, interventional, double-masked, controlled, large-animal study with predetermined clinical and histopathologic outcome criteria., Controls: Half of the pigs were randomly assigned to receive an identical volume of aerosol-delivered normal saline (AD-NS) using identical delivery systems and treatment intervals., Methods: Proliferative vitreoretinopathy was surgically induced in 16 pigs (8 males and 8 females), randomly assigned to receive 2 doses (group A) or 3 doses (group B) of either AD-MTx (1.6 mg/0.4 ml) or normal saline (AD-NS). Group A pigs were euthanized at week 2 (n = 8), and group B pigs were euthanized at week 3 (n = 8). Masked clinical PVR scores (0-6) by a vitreoretinal surgeon and histopathology PVR scores (0-8) by a masked ophthalmic pathologist were used to determine outcomes., Main Outcome Measures: The mean, combined clinical and histopathology scores (both anterior and posterior) were used to determine the overall treatment effect between the groups., Results: The mean masked score (± standard deviation) when all grading end points (clinical + histopathology) were combined was a mean of 8.0 ± 2.3 in the AD-MTx group versus a higher 9.9 ± 2.0 in the AD-NS control group ( P  = 0.05). The clinical score was 3.88 ± 1.2 in the AD-MTx group versus 4.63 ± 1.6 in the AD-NS group ( P  = 0.16). The histopathology score for anterior PVR was 2.5 ± 0.8 in the AD-MTx group versus 2.5 ± 0.5 in the AD-NS group ( P  = 0.50), and the posterior PVR was 1.63 ± 1.6 in the AD-MTx group versus 2.75 ± 1.3 in the AD-NS group ( P  = 0.07). When the frequency of methotrexate dosing in group A (2 doses) was compared with that in group B (3 doses), the mean score was 8.75 versus 9.13 ( P  = 0.38), respectively, suggesting an insignificant difference., Conclusions: After surgical induction of PVR in an aggressive, high-risk, large-animal model, AD-MTx reduced posterior PVR formation compared with AD-NS. Additional dosing at week 3 did not improve the outcomes. No difference in anterior PVR formation was noted with intervention. This novel drug delivery system has implications for PVR reduction and warrants further investigation., Financial Disclosures: Proprietary or commercial disclosure may be found after the references., (© 2023 Published by Elsevier Inc. on behalf of American Academy of Ophthalmology.)

Age-related macular degeneration (AMD), the leading cause of blindness in elderly populations, involves the loss of central vision due to progressive dysfunction of the retinal pigment epithelium (RPE) and subsequent loss of light-sensing photoreceptors. While age is a key risk factor, not every aged individual develops AMD. Thus, the critical question is what specific cellular changes tip the balance from healthy aging to disease. To distinguish between changes associated with aging and AMD, we compared the RPE proteome in human eye bank tissue from nondiseased donors during aging ( n = 50, 29-91 years) and in donors with AMD ( n = 36) compared to age-matched donors without disease ( n = 28). Proteins from RPE cells were separated on two-dimensional gels, analyzed for content, and identified using mass spectrometry. A total of 58 proteins displayed significantly altered content with either aging or AMD. Proteins involved in metabolism, protein turnover, stress response, and cell death were altered with both aging and AMD. However, the direction of change was predominantly opposite. With aging, we detected an overall decrease in metabolism and reductions in stress-associated proteins, proteases, and chaperones. With AMD, we observed upregulation of metabolic proteins involved in glycolysis, TCA, and fatty acid metabolism, with a concurrent decline in oxidative phosphorylation, suggesting a reprogramming of energy utilization. Additionally, we detected upregulation of proteins involved in the stress response and protein turnover. Predicted upstream regulators also showed divergent results, with inhibition of inflammation and immune response with aging and activation of these processes with AMD. Our results support the idea that AMD is not simply advanced aging but rather the culmination of perturbed protein homeostasis, defective bioenergetics, and increased oxidative stress within the aging RPE, exacerbated by environmental factors and the genetic background of an individual., Competing Interests: The authors declare no conflict of interest for information presented in this study., (Copyright © 2022 Pabalu P. Karunadharma et al.)

Purpose: To report optical coherence tomography findings of choroidal melanoma with subretinal fluid (SRF)., Methods: Single-center, retrospective review of spectral-domain optical coherence tomography in treatment-naive choroidal melanoma with associated SRF presenting between July 2009 and August 2021., Results: Of 236 included patients, choroidal melanoma was small (n = 98, 41.5%), medium (n = 99, 41.9%), or large (n = 39, 16.5%). The most common optical coherence tomography feature was ellipsoid zone loss/disruption (n = 174, 73.7%), with unique features of bacillary layer detachment (n = 67, 28.4%), and heterogenous (n = 72, 30.5%) or homogenous (n = 48, 20.3%) subretinal hyperreflective material. Comparison (small vs. medium vs. large) revealed greater SRF extent with increasing tumor size (SRF ≥2 quadrants: 6.1% vs. 27.2% vs. 67.7%, P < 0.001). Ellipsoid zone disruption was less common in small tumors (52.0% vs. 86.9% vs. 94.9%, P < 0.001). Bacillary layer detachment was more common in medium tumors (16.3% vs. 40.4% vs. 28.2%, P < 0.001) and, compared with eyes without bacillary layer detachment, was associated with more SRF (minimal SRF vs. SRF ≥1 quadrant: likelihood ratio 18.8, P < 0.001) and more frequent heterogenous subretinal hyperreflective material (58.2% vs. 19.5%, P < 0.001)., Conclusion: Optical coherence tomography features of choroidal melanoma-associated SRF vary by tumor size, with greater SRF extent in larger tumors, less ellipsoid zone disruption in small tumors, and more bacillary layer detachment in medium tumors.

Purpose: To examine the impact of physician face mask use on the rates and outcomes of postinjection endophthalmitis., Methods: A multicenter retrospective, comparative cohort study comparing endophthalmitis rate and visual acuity of eyes that developed endophthalmitis after antivascular endothelial growth factor injections at Mayo Clinic Rochester (MCR) and at Mayo Clinic Health System sites depending on physician masking., Results: A total of 164,824 injections were performed at MCR and Mayo Clinic Health System sites. Of these, 66,098 injections were in the no mask group and 98,726 injections were in the mask group. Overall, there were no differences in the rates of infectious endophthalmitis in the no mask versus mask cohorts (overall: no mask: 20 cases [0.0303%] vs. mask: 41 cases (0.0415%); P = 0.24; infectious: no mask: 12 cases [0.018%] versus mask: 13 cases [0.0132%]; P = 0.42). At MCR alone, there was a significant reduction in infectious endophthalmitis between the no mask versus mask groups (no mask: 9 cases [0.0297%] versus mask: 2 cases [0.003%]; P < 0.001). Only 2 cases of infectious endophthalmitis occurred at MCR after the face mask policy was implemented (1 in 30,000 injections). At presentation and at 6 months, the average visual acuity was similar for patients who developed endophthalmitis between the no mask versus mask groups., Conclusion: Physician face mask use did not affect the rate or outcome of postinjection endophthalmitis. However, there was a significant reduction at MCR after masking along with other quality improvement measures, including performance of injections in a dedicated procedure room and preparation of patients by nurses, that led to a low rate of endophthalmitis.

Objective: To determine the root causes of patient safety events in a high-volume intravitreal injection clinic and to assess the effect of interventions to reduce the rate of events., Design: Quality improvement study., Subjects: All cases of intravitreal injection in a designated injection clinic between January 1, 2016, and December 31, 2019., Methods: The injection clinic model involved an injecting physician, who usually differed from a prescribing physician. The procedural injection area was also physically separate from the retina outpatient clinic. A root cause analysis was used to determine the factors that contributed to possible patient safety events in an institutional quality improvement project. Specific interventions were implemented to address each specific root cause. The rates of patient safety events (never events and near misses), whether associated with patient harm or not, were compared before and after the intervention., Main Outcome Measures: Frequency (%) of patient-safety-related intravitreal injection events before (January 1, 2016, to December 31, 2018) and after (January 1, 2019, to December 31, 2019) intervention., Results: The root cause analysis included complex treatment plans that could be difficult to interpret, insufficient time to adequately review the designated treatment plans, and the risk of human error given the pace and volume of scheduled injections. Quality improvement strategies included revising the standardized treatment plan documentation template, scheduling block time for injecting physicians to review treatment plans within 24 hours of the injection clinic, and requiring agreement between dual, independent, site, and medication verifications of the treatment plan by the injecting physician and an allied health coordinator before site marking. The rate of events was 0.1% (28 in 27 400, or 9.3 events per year) before intervention and decreased to 0.01% (1 in 9375, or 1 event per year) after intervention (P = 0.01). Most events were classified as near misses, and there were no instances of patient harm., Conclusions: A high level of patient safety can be achieved in a complex, high-volume intravitreal injection practice by recognizing potential safety issues and root causes and implementing relevant quality improvements. Although most events were near misses and no patients were harmed, reducing near misses can reduce the likelihood of harm associated with never events., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Myeloproliferative neoplasms (MPNs) have been associated with increased systemic levels of vascular endothelial growth factor (VEGF). This study investigated an association between systemic busulfan for treatment of MPN and the requirement for intravitreal anti-VEGF injections for treatment of retinal pathology., Methods: Retrospective chart review of patients receiving systemic busulfan for myeloproliferative neoplasm and intravitreal anti-VEGF injections for macular and retinal vascular diseases from 2007 to 2021., Results: Of seven patients receiving oral busulfan for a hematological neoplasm and having concomitant retinal pathology requiring intravitreal anti-VEGF, all were white females >60 years old with MPN and exudative age-related macular degeneration. Of these, two patients had a reduced anti-VEGF requirement while on systemic busulfan, two took busulfan for fewer than 5 months, one developed retinal pathology over one year after stopping busulfan, one developed new retinal pathology while taking busulfan, and one had limited follow-up. Of the two patients with reduced anti-VEGF requirement while taking systemic busulfan, both had JAK2 V617F mutated MPN, and subsequent busulfan discontinuation was associated with an increased requirement for intravitreal anti-VEGF injections., Conclusions and Importance: Systemic busulfan for treatment of MPN was associated with a reduced requirement for intravitreal anti-VEGF injections for retinal vascular disease in two patients. This association could be a result of inhibition of proliferative angiogenesis or reduced systemic VEGF levels with effective systemic treatment for MPN. Further study is required to confirm this association and determine whether this relationship is specific to busulfan or extends to other systemic medications used to treat MPN., (© 2022 The Authors.)

Background: To determine risk factors for postradiation optic atrophy (PROA) after plaque radiotherapy for uveal melanoma., Methods: A single center, retrospective cohort study of patients diagnosed with uveal melanoma involving choroid and/or ciliary body treated with plaque between January 1, 2008, and December 31, 2016. Outcomes included development of PROA with pallor alone or with concomitant neuroretinal rim thinning (NRT). Cox regression analysis was performed to identify risk factors for PROA., Results: Of 78 plaque-irradiated patients, PROA developed in 41 (53%), with concomitant NRT in 15 (19%). Risk factors for PROA of any type included presentation with worse visual acuity (odds ratio [95% confidence interval] 5.6 [2.3-14.1], P < 0.001), higher baseline intraocular pressure (IOP; 14 vs 16 mm Hg) (1.1 [1.0-1.2], P = 0.03), shorter tumor distance to optic disc (1.3 [1.2-1.5], P < 0.001) and foveola (1.2 [1.1-1.3], P < 0.001), subfoveal subretinal fluid (3.8 [2.0-7.1], P < 0.001), greater radiation prescription depth (1.3 [1.1-1.6], P = 0.002), dose to fovea (point dose) (1.01 [1.01-1.02], P < 0.001), and mean (1.02 [1.02-1.03], P < 0.001) and maximum dose to optic disc per 1 Gy increase (1.02 [1.01-1.03], P < 0.001). On multivariate modeling, dose to disc, baseline IOP, and subfoveal fluid remained significant. Subanalysis revealed risk factors for pallor with NRT of greater mean radiation dose to disc (1.03 [1.01-1.05], P = 0.003), higher maximum IOP (17 vs 20 mm Hg) (1.4 [1.2-1.7], P < 0.001), and subfoveal fluid (12 [2-63], P = 0.004)., Conclusion: PROA may result in NRT in addition to optic disc pallor. Risk factors for PROA included higher radiation dose to optic disc, higher baseline IOP, and subfoveal fluid. Higher maximum IOP contributed to concomitant NRT., Competing Interests: T. W. Olsen is a board member of the American Academy of Ophthalmology, holds an unrelated grant NIH/NEI R41EY028803 Novartis, and holds unrelated patents #08083751, #1986581, #9539082, and #10278808. The remaining authors report no conflicts of interest., (Copyright © 2021 by North American Neuro-Ophthalmology Society.)

Introduction: Loss of BAP1 protein expression emerged as a negative prognostic marker in uveal melanoma (UM) and has primarily been studied in enucleations. Intraocular biopsy is frequently performed prior to UM globe-conserving therapy., Methods: We retrospectively evaluated BAP1 immunostaining of UM in 16 biopsies and 8 subsequent enucleations, and results were correlated with the UM-specific gene expression profile (GEP; n = 11), chromosome 3 status by FISH and/or chromosomal microarray ( n = 12; 9 also had GEP), and clinical outcomes., Results: UM involved the choroid in 15 (of 16) cases. Biopsy was performed for prognostication ( n = 12) or diagnosis ( n = 4). Treatment included brachytherapy ( n = 13; 5 followed by enucleation) or enucleation only ( n = 3). BAP1 nuclear immunostaining was positive in 9, negative in 4, and equivocal in 3 biopsies. For the 3 equivocal biopsies, BAP1 immunostaining was positive in 2 (of 3) subsequent enucleations. BAP1 immunostaining was concordant between all 5 remaining biopsies and enucleations. BAP1-positive biopsies had disomy 3 ( n = 6) or 3p loss ( n = 1) and class 1 GEP ( n = 6). BAP1-negative biopsies had monosomy 3 ( n = 3) and class 2 GEP ( n = 2). Median follow-up was 62.5 months (range, 17-150). For BAP1-positive UM patients, 8 were alive (7 without metastatic disease) and 3 had died (1 melanoma-related death). Among BAP1-negative UM patients, 2 were alive (1 with metastatic disease) and 3 had melanoma-related deaths., Conclusion: BAP1 immunostaining in biopsies highly correlates with results in subsequent enucleations and with well-established UM prognostic markers, representing a potential additional prognostic tool for UM biopsies., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 by S. Karger AG, Basel.)

Purpose: To determine the risk of stroke, transient ischemic attack (TIA), and transient monocular vision loss (TMVL) before and after a central retinal artery occlusion (CRAO)., Design: Population-based, retrospective case series., Participants: Patients diagnosed with a CRAO in Olmsted County, Minnesota, from 1976 to 2016., Methods: Patients living in Olmsted County with a diagnosis code of CRAO from 1976 to 2016 were reviewed. New CRAOs were confirmed, and stroke, TIA, and TMVL events in the 15 days before and after CRAO were recorded., Main Outcome Measures: Incidence of stroke, TIA, and TMVL events in the 15 days before and after CRAO., Results: Eighty-nine patients with a CRAO were identified, providing an annual incidence of 2.58/100 000 (95% confidence interval [CI], 2.04-3.11). Median age at the time of CRAO was 76 years (range, 46-100 years); 56.2% were male, and 89.9% of the cohort was White. In the 15 days before and after CRAO, there were 2 ischemic strokes (2.2%), 1 hemorrhagic stroke (1.1%), 2 TIAs (2.2%), and 9 TMVL events (10.1%). Starting in 1999, 15 of 45 patients underwent magnetic resonance imaging within 2 months of CRAO. One patient (6.7%) had evidence of asymptomatic diffusion restriction, and 9 patients (60%) had a remote infarct., Conclusions: This population-based study demonstrated that the risk of symptomatic ischemic stroke is 2.2% in the 15 days before and after a CRAO, which is slightly lower than most studies from tertiary centers. These data should be considered as practice recommendations are developed regarding the urgency of neurovascular workup in patients with acute CRAO., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

The American Academy of Ophthalmology evaluated the practice of routine screening for intraocular infection from Candida septicemia. In the United States, ophthalmologists are consulted in the hospital to screen for intraocular infection routinely for patients with Candida bloodstream infections. This practice was established in the era before the use of systemic antifungal medication and the establishment of definitions of ocular disease with candidemia. A recent systematic review found a rate of less than 1% of routinely screened patients with endophthalmitis from Candida septicemia. Other studies found higher rates of endophthalmitis but had limitations in terms of inaccuracies in ocular disease classification, lack of vitreous biopsies, selection biases, and lack of longer-term visual outcomes. Some studies attributed ocular findings to Candida infections, rather than other comorbidities. Studies also have not demonstrated differences in medical management that are modified for eye disease treatment; therefore, therapy should be dictated by the underlying Candida infection, rather than be tailored on the basis of ocular findings. In summary, the Academy does not recommend a routine ophthalmologic consultation after laboratory findings of systemic Candida septicemia, which appears to be a low-value practice. An ophthalmologic consultation is a reasonable practice for a patient with signs or symptoms suggestive of ocular infection regardless of Candida septicemia., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine whether age-related macular degeneration (AMD) severity or the frequency of retinal pigment epithelium mitochondrial DNA lesions differ in human donor eyes that have undergone cataract surgery compared to phakic eyes., Methods: Eyes from human donors aged ≥ 55 years were obtained from the Minnesota Lions Eye Bank. Cataract surgery status was obtained from history provided to Eye Bank personnel by family members at the time of tissue procurement. Donor eyes were graded for AMD severity using the Minnesota Grading System. Quantitative PCR was performed on DNA isolated from macular punches of retinal pigment epithelium to quantitate the frequency of mitochondrial DNA lesions in the donor tissue. Univariable and multivariable analyses were performed to evaluate for associations between (1) cataract surgery and AMD severity and (2) cataract surgery and mitochondrial DNA lesion frequency., Results: A total of 157 subjects qualified for study inclusion. Multivariable analysis with age, sex, smoking status, and cataract surgery status showed that only age was associated with AMD grade. Multivariable analysis with age, sex, smoking status, and cataract surgery status showed that none of these factors were associated with retinal pigment epithelium mitochondrial DNA lesion frequency., Conclusions: In this study of human donor eyes, neither retinal pigment epithelium mitochondrial DNA damage nor the stage of AMD severity are independently associated with cataract surgery after adjusting for other AMD risk factors. These new pathologic and molecular findings provide evidence against a relationship between cataract surgery and AMD progression and support the idea that cataract surgery is safe in the setting of AMD., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: TWO: Equity owner – iMacular Regeneration LLC. DAF: Scientific advisory board member – Vinci Pharmaceuticals. The authors have no proprietary or commercial interest in any materials discussed in this article. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose: To review the published literature assessing the efficacy and safety of presbyopia-correcting intraocular lenses (IOLs) for the treatment of presbyopia after cataract removal., Methods: Literature searches were undertaken in January 2018 and September 2020 in the PubMed, Medline, and Cochrane Library databases. This yielded 761 articles, of which 34 met the criteria for inclusion in this assessment and were assigned a level of evidence rating by the panel methodologist. Thirteen studies were rated level I and 21 studies were rated level II., Results: Presbyopia-correcting lenses were effective at improving distance and near visual acuity after cataract surgery. Near acuity at different focal lengths was related directly to the effective add power of multifocal and extended depth-of-focus (EDOF) IOLs. Most multifocal and EDOF lenses that were compared with a control monofocal lens demonstrated that patient-reported spectacle independence was superior to the monofocal lens. All patients who had multifocal and EDOF lenses implanted showed decreased contrast sensitivity and reported more visual phenomena as compared with control participants who received monofocal lenses., Conclusions: Presbyopia-correcting lenses improve uncorrected near and distance visual acuity and decrease spectacle dependence after cataract surgery. Mesopic contrast sensitivity is decreased compared with monofocal lenses, and patient-reported visual phenomena are more likely in patients receiving multifocal or EDOF lenses., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to demonstrate the role of carbon fiducial markers (fiducials) for guiding radiotherapy in the management of uveal melanoma (UM)., Methods: This is a retrospective interventional case series at a single-center ocular oncology practice. The medical records were reviewed retrospectively for all patients with UM treated with stereotactic radiosurgery using episcleral fiducials. We report our short-term experience with surgical placement of fiducials, UM localization, treatment outcomes, and optimization approaches., Results: We evaluated 11 cases of UM (mean age: 65 years; 64% female). The placed fiducials were numbered from 2 to 4, each secured to the sclera with a surgical microscope or surgical loupes and either 5-0 or 8-0 nylon sutures at 50% scleral depth and 3 mm beyond the tumor margin. Over a median follow-up of 11 months (range: 4.2-43.2 months), no recurrences of intraocular UM were observed. One case of enucleation after stereotactic radiosurgery developed because of radiation-related surface irritation, ocular dryness, and secondary keratopathy. Two patients (18%) with 5-0 nylon sutures required fiducial removal because of suture exposure, successfully accomplished in an outpatient setting., Conclusions: Fiducials represent a viable alternative to tantalum rings for guiding stereotactic radiotherapy to manage UM and provide additional definition of the tumor border with linear orientation that helps optimize targeted radiation delivery. Fiducial placement with a 3-mm margin from the visible tumor border should not result in clinically important radiation dose attenuation at the tumor margins. Anteriorly placed fiducials may cause discomfort, yet they are easily removed in the outpatient setting., Competing Interests: No conflicting relationships exist for any author. Dr. Olsen holds equity in iMacular Regeneration LLC. None of the technology discussed in this article is related to technology held or distributed by iMacular Regeneration LLC., (Copyright © 2021 by S. Karger AG, Basel.)

Purpose: To stage maculopathy, assess and quantify drusen, determine drusen subtype frequency, and compare subtypes with age-related macular degeneration (AMD) stage and cause of death using an eye-bank model of AMD., Design: Cross-sectional study., Participants: Two thousand ninety-two human eyes from 1067 eye-bank donors, selected from a population at risk for AMD., Methods: We analyzed donor eye tissue images (2005-2020) using both the 4- and 9-step Minnesota Grading System (MGS), an AMD grading system for eye-bank eyes corresponding to the Age-Related Eye Disease Study classification. The 9-step MGS quantifies total drusen area, hyperpigmentation, and depigmentation. We analyzed reticular pseudodrusen (RPD), basal laminar drusen (BLD), and calcified drusen (CaD) frequency within this population and explored associations with AMD stage, donor age, gender, and cause of death. Statistical analyses were performed using Wilcoxon rank-sum and chi-square tests. Testing encompassed staging eye-bank eyes using MGS analysis., Main Outcome Measures: Drusen subtype frequency associations with AMD stage and cause of death., Results: We detected RPD in 228 (13%), BLD in 131 (7%), and CaD in 84 (5%) of the examined eyes (n = 1777). All subtypes were associated with advanced AMD (RPD: odds ratio [OR], 3.4 [95% confidence interval (CI), 2.5-4.5; P < 0.0001]; BLD: OR, 2.2 [95% CI, 1.5-3.2; P < 0.0001]; and CaD: OR, 39.1 [95% CI, 16.8-91.0; P < 0.0001]). Only the RPD subtype was associated statistically with cardiovascular death when compared with those without cardiovascular death (48% vs. 32%; OR, 2.0 [95% CI, 1.4-2.9]; P = 0.0002)., Conclusions: In a large group of eye-bank eyes selected from a population at risk for AMD and graded using the 4-step and 9-step MGS, RPD, BLD, and especially CaD were associated strongly with advanced AMD. The RPD subtype was associated with a cardiovascular cause of death and may represent an ophthalmologic biomarker for cardiovascular disease., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors report no conflicts of interest.

Prolactin (PRL) hormone functions as a pleiotropic cytokine with a protective role in the retina. We recently identified by transcriptome profiling that PRL is one of the most highly upregulated mRNAs in the retinas of mutant rcd1 (PDE6B) and xlpra2 (RPGR) dogs at advanced stages of photoreceptor disease. In the present study, we have identified the expression of a short PRL isoform that lacks exon 1 in canine retinas and analyzed the time-course of expression and localization of this isoform in the retinas of these two models. Using laser capture microdissection to isolate RNA from each of the retinal cellular layers, we found by qPCR that this short PRL isoform is expressed in photoreceptors of degenerating retinas. We confirmed by in situ hybridization that its expression is localized to the outer nuclear layer and begins shortly after the onset of disease at the time of peak photoreceptor cell death in both models. PRL protein was also detected only in mutant dog retinas. Our results call for further investigations into the role of this novel PRL isoform in retinal degeneration.

Purpose: To describe modern multimodal imaging of the choroidal and optic disk vessels in optic disk pits., Methods: Case reports of four patients with optic disk pit who underwent multimodal imaging of the optic pit and surrounding structures. Patients included in this article were found to have optic disk pits and subsequently underwent multimodal imaging., Results: Cilioretinal arteries were present in two of the four cases (50%). SPECTRALIS optical coherence tomography showed intraretinal and subretinal fluid in all cases. Small vessels in the choroid and in the disk around the pit were also present in all cases through optical coherence tomographic angiography. Confocal fluorescein angiographic imaging in the first case showed leakage from the vessels adjacent to the optic disk pit., Conclusion: Modern multimodal imaging shows that there are anomalous vessels in and around an optic pit. Whether these vessels affect the development of optic pit, maculopathy needs to be further evaluated.

Purpose: To determine local ocular tissue levels of the bile acid, tauroursodeoxycholic acid (TUDCA), in the pig model using oral, intravenous (IV), intravitreal injection (IVitI) and low- and high-dose suprachoroidal, sustained-release implants (SCI-L or SCI-H)., Methods: Forty-six pigs (92 globes) were included in the study. TUDCA was delivered orally in 5 pigs, IV in 4, IVitI in 6, SCI-L in 17, and SCI-H in 14. Testing timeframes varied from the same day (within minutes) for IV; 1 to 6 days, oral; and 1 to 4 weeks, IVitI and SCI. Enucleated globes were dissected, specimens from specific tissues were separated, and TUDCA was extracted and quantified using mass spectrometry., Results: The highest TUDCA tissue levels occurred after IV delivery in the macula (252 ± 238 nM) and peripheral retina (196 ± 171 nM). Macular choroid and peripheral choroid levels were also high (1032 ± 1269 and 1219 ± 1486 nM, respectively). For IVitI delivery, macular levels at day 6 were low (0.5 ± 0.5 nM), whereas peripheral choroid was higher (15.3 ± 16.7 nM). Neither the SCI-L nor SCI-H implants delivered meaningful macular doses (≤1 nM); however, peripheral retina and choroid levels were significantly higher. Bile acid isoforms were found in the serum specimens., Conclusions: The highest TUDCA tissue levels in the pig model were obtained using IV delivery. Oral delivery was associated with reasonable tissue levels. Local delivery (IVitI and SCI) was able to achieve measurable local ocular tissue levels., Translational Relevance: Diffusional kinetics from the suprachoroidal space follow the choroidal blood flow, away from the macula and toward the periphery., Competing Interests: Disclosure: T.W. Olsen, Emory University (P), iMacular Regeneration, LLC (I); R.B. Dyer, None; F. Mano, None; J.H. Boatright, Emory University (P); M.A. Chrenek, None; D. Paley, None; K. Wabner, None; J. Schmit, None; J.B. Chae, None; J.T. Sellers, None; R.J. Singh, None; T.S. Wiedmann, None, (Copyright 2020 The Authors.)

Aims: To investigate the association of peripheral retinal non-perfusion with retinal haemangioblastoma., Methods: Medical and widefield fluorescein angiography records of patients diagnosed with retinal haemangioblastoma from 1990 to 2018 were reviewed for patient demographics, tumour features, fluorescein angiography features and characteristics of peripheral retinal non-perfusion., Results: There were 41 eyes of 40 patients with retinal haemangioblastoma imaged by widefield fluorescein angiography during this time period. Of 41 eyes, 14 (34%) had haemangioblastoma-associated peripheral retinal non-perfusion on fluorescein angiography. A comparison of eyes with versus without non-perfusion revealed younger mean age at presentation (28 vs 43 years old, p=0.05), increased prevalence of von Hippel-Lindau (VHL) disease (62% vs 22%, p=0.01), greater mean largest tumour basal diameter (3.7 vs 2.5 mm, p=0.04), greater tumour distance from optic nerve (8.4 vs 1.9 mm, p<0.01) and increased prevalence of vascular leakage from the tumour (86% vs 52%, p=0.03). After mean follow-up of 97 versus 71 months (p=0.52), eyes with non-perfusion were significantly more likely to develop neovascularisation (40% vs 0%, p<0.01) and experience a three-line or greater decrease in visual acuity (60% vs 11%, p<0.01)., Conclusion: Peripheral retinal non-perfusion can be associated with retinal haemangioblastoma, and could be more common with larger, more peripheral tumours in younger patients with VHL disease. Eyes with haemangioblastoma-associated peripheral non-perfusion could be more likely to develop neovascularisation and lose visual acuity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Retinal pigment epithelium (RPE) transplantation for the treatment of macular degeneration has been studied for over 30 years. Human clinical trials have demonstrated that RPE monolayers exhibit improved cellular engraftment and survival compared to single cell suspensions. The use of a scaffold facilitates implantation of a flat, wrinkle-free, precisely placed monolayer. Scaffolds currently being investigated in human clinical trials are non-degradable which results in the introduction of a chronic foreign body. To improve RPE transplant technology, a degradable scaffold would be desirable. Using human fibrin, we have generated scaffolds that support the growth of an RPE monolayer in vitro. To determine whether these scaffolds are degraded in vivo, we developed a surgical approach that delivers a fibrin hydrogel implant to the sub-retinal space of the pig eye and determined whether and how fast they degraded. Using standard ophthalmic imaging techniques, the fibrin scaffolds were completely degraded by postoperative week 8 in 5 of 6 animals. Postmortem histologic analysis confirmed the absence of the scaffold from the subretinal space at 8 weeks, and demonstrated the reattachment of the neurosensory retina and a normal RPE-photoreceptor interface. When mechanical debridement of a region of native RPE was performed during implantation surgery degradation was accelerated and scaffolds were undetectable by 4 weeks. These data represent the first in situ demonstration of a fully biodegradable scaffold for use in the implantation of RPE and other cell types for treatment of macular degeneration and other retinal degenerative diseases., Competing Interests: JSP and ADM have ownership interests in LAgen Laboratories LLC. ADM serves as CEO of LAgen Laboratories LLC. TWO has ownership of iMacular Regeneration LLC, none of the technology used in this study is relevant. However, none of the disclosures pertain directly to this paper and none of the companies provided financial support for this paper.

Purpose: To estimate the economic effects of implementing a universal screening and treatment program for retinopathy of prematurity (ROP) in the Philippines with the Economic Model for Retinopathy of Prematurity (EcROP)., Methods: The EcROP is a cost-effectiveness, cost-benefit, and cost-utility analysis. Fifty parents of legally blind individuals (aged 3 to 28 years) from three schools for the blind in the Philippines were interviewed to estimate the societal burden of raising a blind child. A decision tree analytic model, with deterministic and probabilistic sensitivity analysis, was used to calculate the incremental cost-effectiveness ratio (primary outcome) and the incremental monetary benefit (secondary outcome) for implementing an optimal national ROP program, compared to estimates of the current policy. Findings were extrapolated to estimate the national economic benefit of an ideal screening and treatment program., Results: The incremental cost-effectiveness ratio for a national program over the current policy was strongly favorable to the ideal program for the Philippines and represents an opportunity for substantial societal cost savings. The per-child incremental, annual monetary benefit of a national program over the current policy was $2,627. Extrapolating to the population of children at risk in 1 year showed that the national annual net benefit estimate would be $64,320,692, which is favorable to the current policy., Conclusions: The EcROP demonstrates that implementing a national ROP screening and treatment program is cost-saving and cost-effective, and would substantially decrease childhood blindness in the Philippines. [J Pediatr Ophthalmol Strabismus. 2019;56(6):388-396.]., (Copyright 2019, SLACK Incorporated.)

Background: Age-related macular degeneration (AMD) is a degenerative disorder of the central retina and the foremost cause of blindness. The retinal pigment epithelium (RPE) is a primary site of disease pathogenesis. The genetic basis of AMD is relatively well understood; however, this knowledge is yet to yield a treatment for the most prevalent non-neovascular disease forms. Therefore, tissue-specific epigenetic mechanisms of gene regulation are of considerable interest in AMD. We aimed to identify differentially methylated genes associated with AMD in the RPE and differentiate local DNA methylation aberrations from global DNA methylation changes, as local DNA methylation changes may be more amenable to therapeutic manipulation., Methods: Epigenome-wide association study and targeted gene expression profiling were carried out in RPE cells from eyes of human donors. We performed genome-wide DNA methylation profiling (Illumina 450k BeadChip array) on RPE cells from 44 human donor eyes (25 AMD and 19 normal controls). We validated the findings using bisulfite pyrosequencing in 55 RPE samples (30 AMD and 25 normal controls) including technical (n = 38) and independent replicate samples (n = 17). Long interspersed nucleotide element 1 (LINE-1) analysis was then applied to assess global DNA methylation changes in the RPE. RT-qPCR on independent donor RPE samples was performed to assess gene expression changes., Results: Genome-wide DNA methylation profiling identified differential methylation of multiple loci including the SKI proto-oncogene (SKI) (p = 1.18 × 10 -9 ), general transcription factor IIH subunit H4 (GTF2H4) (p = 7.03 × 10 -7 ), and Tenascin X (TNXB) (p = 6.30 × 10 -6 ) genes in AMD. Bisulfite pyrosequencing validated the differentially methylated locus cg18934822 in SKI, and cg22508626 within GTF2H4, and excluded global DNA methylation changes in the RPE in AMD. We further demonstrated the differential expression of SKI, GTF2H4, and TNXB in the RPE of independent AMD donors., Conclusions: We report the largest genome-wide methylation analysis of RPE in AMD along with associated gene expression changes to date, for the first-time reaching genome-wide significance, and identified novel targets for functional and future therapeutic intervention studies. The novel differentially methylated genes SKI and GTF2H4 have not been previously associated with AMD, and regulate disease pathways implicated in AMD, including TGF beta signaling (SKI) and transcription-dependent DNA repair mechanisms (GTF2H4).

Purpose: We measure and compare surgical devices using an ex vivo, temperature-controlled, choroidal incision model during thermal energy transfer with a high-resolution infrared camera., Methods: Ex vivo porcine choroidal tissue specimens ( n = 516) were isolated and placed on a temperature-regulated (37°C) perfusion platform. We tested the pulsed electron avalanche knife (PEAK), micropulse laser (MpL), continuous laser (CL), and bipolar cautery (BpC) at three energy settings (11 [low], 45 [medium], and 134 [high] mJ/mm). Each device was clamped to a stationary mechanical arm. Movement of tissue specimens beneath the surgical device was achieved using a stepping motor-driven x-y table. An infrared video camera measured orthogonal temperature variation in the surrounding tissue., Results: Increased power resulted in greater lateral thermal spread using all modalities ( P < 0.001). Mean (standard deviation) lateral thermal spread at low energy was smallest for the MpL at 0.0 (0.01) mm ( P < 0.001), whereas BpC had the least collateral tissue damage at medium and high energies (0.02 [0.08] and 0.34 [0.22] mm, respectively; P < 0.001). Fluidics of the ex vivo system may limit thermal spread. The PEAK had the greatest thermal spread across all energy groups ( P < 0.001), with clinically relevant variation between disposable blades., Conclusions: Our ex vivo model enabled direct comparison of threshold thermal tissue injury across four devices. MpL and BpC showed the least thermal damage. PEAK had a higher variation in energy delivery, but also has the advantage of more effective tissue cutting., Translational Relevance: Our ex vivo surgical device analysis provides thermal tissue injury predictions for choroidal surgery.

Background: To report a 68-year-old female with an autosomal-dominant vitreoretinochoroidopathy (ADVIRC) phenotype associated with a subretinal hemorrhage (SRH) and novel BEST1 pathogenic variation p.Met571Thr., Materials and Methods: The patient was assessed by fundus photography, fluorescence and indocyanine green angiography, spectral-domain optical coherence tomography, photopic and scotopic electroretinogram (ERG), and electrooculogram (EOG). Whole-exome and Sanger sequencing of the patient's and selected family members' DNA was performed. Ophthalmoscopic examinations were also performed on six patient's relatives., Results: The patient presented moderate vitreous and SRH in the left eye. A distinct, annular hyperpigmented band was present in both eyes. Vitrectomy improved visual acuity, and the SRH gradually regressed without recurrence. Preserved macular function was shown by optical coherence tomography (OCT). Genetic analysis identified a novel heterozygous mutation, resulting in p.Met571Thr in BEST1. No mutations were observed in a panel of other eye disease genes, suggesting that this pathogenic variation in BEST1 is associated with an ADVIRC phenotype. No other evaluated family member had the variant or the fundus findings., Conclusions: We present a patient with a novel p.Met571Thr pathogenic variation associated with an ADVIRC phenotype. SRH is a unique finding in ADVIRC patients and may correspond to peripheral exudative hemorrhagic chorioretinopathy. The BEST1 pathogenic variation p.Met571Thr might be the likely cause of ADVIRC in this patient. However, further study is necessary to determine whether this mutation is causative.

Importance: Identifying and prioritizing unanswered clinical questions may help to best allocate limited resources for research associated with the treatment of age-related macular degeneration (AMD)., Objective: To identify and prioritize clinical questions and outcomes for research associated with the treatment of AMD through engagement with professional and patient stakeholders., Design, Setting, and Participants: Multiple cross-sectional survey questions were used in a modified Delphi process for panel members of US and international organizations, the American Academy of Ophthalmology (AAO) Retina/Vitreous Panel (n=7), health care professionals from the American Society of Retinal Specialists (ASRS) (n=90), Atlantic Coast Retina Conference (ACRC) and Macula 2017 meeting (n=34); and patients from MD (Macular Degeneration) Support (n=46). Data were collected from January 20, 2015, to January 9, 2017., Main Outcomes and Measures: The prioritizing of clinical questions and patient-important outcomes for AMD., Results: Seventy clinical questions were derived from the AAO Preferred Practice Patterns for AMD and suggestions by the AAO Retina/Vitreous Panel. The AAO Retina/Vitreous Panel assessed all 70 clinical questions and rated 17 of 70 questions (24%) as highly important. Health care professionals assessed the 17 highly important clinical questions and rated 12 of 17 questions (71%) as high priority for research to answer; 9 of 12 high-priority clinical questions were associated with aspects of anti-vascular endothelial growth factor agents. Patients assessed the 17 highly important clinical questions and rated all as high priority. Additionally, patients identified 6 of 33 outcomes (18%) as most important to them (choroidal neovascularization, development of advanced AMD, retinal hemorrhage, gain of vision, slowing vision loss, and serious ocular events)., Conclusions and Relevance: Input from 4 stakeholder groups suggests good agreement on which 12 priority clinical questions can be used to underpin research related to the treatment of AMD. The 6 most important outcomes identified by patients were balanced between intended effects of AMD treatment (eg, slowing vision loss) and adverse events. Consideration of these patient-important outcomes may help to guide clinical care and future areas of research.