Safety and efficacy of CRISPR-mediated genome ablation of VEGFA as a treatment for choroidal neovascularization in nonhuman primate eyes.

CRISPR-based genome editing enables permanent suppression of angiogenic factors such as vascular endothelial growth factor (VEGF) as a potential treatment for choroidal neovascularization (CNV)-a major cause of blindness in age-related macular degeneration. We previously designed adeno-associated viral (AAV) vectors with S. pyogenes Cas 9 (SpCas9) and guide RNAs (gRNAs) to target conserved sequences in VEGFA across mouse, rhesus macaque, and human, with successful suppression of VEGF and laser-induced CNV in mice. Here, we advanced the platform to nonhuman primates and found that subretinal AAV8-SpCas9 with gRNAs targeting VEGFA may reduce VEGF and CNV severity as compared with SpCas9 without gRNAs. However, all eyes that received AAV8-SpCas9 regardless of gRNA presence developed subfoveal deposits, concentric macular rings, and outer retinal disruption that worsened at higher dose. Immunohistochemistry showed subfoveal accumulation of retinal pigment epithelial cells, collagen, and vimentin, disrupted photoreceptor structure, and retinal glial and microglial activation. Subretinal AAV8-SpCas9 triggered aqueous elevations in CCL2, but minimal systemic humoral or cellular responses against AAV8, SpCas9, or GFP reporter. Our findings suggest that CRISPR-mediated VEGFA ablation in nonhuman primate eyes may suppress VEGF and CNV, but can also lead to unexpected subretinal fibrosis, photoreceptor damage, and retinal inflammation despite minimal systemic immune responses.

Retinal Microstructural Changes Reflecting Treatment-Associated Cognitive Dysfunction in Patients with Lower-Grade Gliomas.

Purpose: To determine whether microstructural retinal changes, tumor features, and apolipoprotein E (APOE) ε4 polymorphism are correlated with clinically detectable treatment-associated cognitive dysfunction (TACD) in patients with lower-grade gliomas. Design: Cohort study. Participants and Controls: Sixteen patients with lower-grade glioma at a United States academic ophthalmology department between January 2021 and November 2023. Normal controls were recruited from convenient sampling. Methods: Montreal Cognitive Assessment (MoCA) scores and retinal changes were assessed in 6-month intervals. Apolipoprotein E genotyping was performed, and tumor details were recorded. Partial least-squares discriminant (PLSD) model was established to evaluate the association between TACD with APOE genotype, ophthalmic, and tumor features. Main Outcome Measures: The main outcome measure was cognitive status as measured by the MoCA score and analyzed in relation to ophthalmic measurements, tumor features, and APOE genotype. Results: Median time to first eye examination was 34 months (2-266) from tumor diagnosis and 23 months (0-246) from radiation. Nine patients (56%) had abnormal cognition (MoCA <26/30). Montreal Cognitive Assessment scores were significantly worse in patients with temporal (22 ± 7.2) than frontal lobe tumors (26 ± 3.1, P = 0.02) and those with oligodendrogliomas (22 ± 4.1) than astrocytomas (26 ± 3.6, = 0.02). Patients with TACD had significant radial peripapillary capillary density loss (45% ± 4.6) compared with those with normal cognition (49% ± 2.6, P = 0.02). A PLSD model correlated MoCA scores with retinal nerve fiber thickness, intraocular pressure, foveal avascular zone, best-corrected visual acuity, months since first diagnosis, and tumor pathology (oligodendroglioma or not). Using these features, the model identified patients with TACD with 77% accuracy. Apolipoprotein E genotyping showed: 2 ε2/ε3 (13%), 10 ε3/ε3 (63%), and 1 ε3/ε4 (6%). Conclusions: Retinal microstructural changes may serve as biomarkers for TACD in patients with lower-grade gliomas. Temporal lobe tumors and oligodendrogliomas may increase susceptibility to TACD. Utilization of retinal markers may enhance TACD diagnosis, progression monitoring, and inform management of lower-grade patients with glioma. A larger study with serial eye examinations is warranted to evaluate the role of APOE ε4 and develop a predictive model. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Surgical Drainage of Large Macular Cystoid Spaces in Coats Disease.

Purpose: To describe an option of surgically draining large macular cystoid spaces in a patient with Coats disease. Methods: A case and its findings were analyzed. Results: A standard pars plana vitrectomy was performed to aspirate large macular cystoid spaces using a subretinal cannula with intraoperative optical coherence tomography guidance. Because of the viscous nature of the chronic fluid and lipid exudates, the contents of the large cystoid spaces were drained through a retinotomy using a soft-tipped aspiration cannula. Postoperative follow-up after surgical drainage showed immediate resolution of the macular cystoid spaces and gradual resolution of the dense subfoveal exudates over 1 year. Although surgical intervention led to the eventual resolution of the macular edema and exudates, visual recovery was limited by the chronicity of the condition. Conclusions: Surgical drainage of large macular cystoid spaces in Coats disease can be achieved in eyes that are refractory to medical management. Earlier surgical intervention in select cases may allow for visual rehabilitation.

A Novel Predictive Model Utilizing Retinal Microstructural Features for Estimating Survival Outcome in Patients with Glioblastoma.

Glioblastoma is a highly aggressive brain tumor with poor prognosis despite surgery and chemoradiation. The visual sequelae of glioblastoma have not been well characterized. This study assessed visual outcomes in glioblastoma patients through neuro-ophthalmic exams, imaging of the retinal microstructures/microvasculature, and perimetry. A total of 19 patients (9 male, 10 female, average age at diagnosis 69 years) were enrolled. Best-corrected visual acuity ranged from 20/20-20/50. Occipital tumors showed worse visual fields than frontal tumors (mean deviation - 14.9 and - 0.23, respectively, p < 0.0001). Those with overall survival (OS) < 15 months demonstrated thinner retinal nerve fiber layer and ganglion cell complex (p < 0.0001) and enlarged foveal avascular zone starting from 4 months post-diagnosis (p = 0.006). There was no significant difference between eyes ipsilateral and contralateral to radiation fields (average doses were 1370 cGy and 1180 cGy, respectively, p = 0.42). A machine learning algorithm using retinal microstructure and visual fields predicted patients with long (≥ 15 months) progression free and overall survival with 78% accuracy. Glioblastoma patients frequently present with visual field defects despite normal visual acuity. Patients with poor survival duration demonstrated significant retinal thinning and decreased microvascular density. A machine learning algorithm predicted survival; further validation is warranted.

Impact of Prophylactic Ranibizumab to Prevent Neovascular Age-Related Macular Degeneration on Eyes With Intermediate Age-Related Macular Degeneration.

Purpose: The purpose of this study was to determine the impact of prophylactic ranibizumab (PR) injections given every 3 months in eyes with intermediate nonexudative age-related macular degeneration (AMD) on drusen volume, macular layer thicknesses, and progression of geographic atrophy (GA) area over 24 months in the PREVENT trial. Methods: This post hoc analysis of the prospective PREVENT trial compared eyes with intermediate AMD randomized to PR versus sham injections to determine rates of conversion to neovascular AMD over 24 months. Drusen area and volume, macular thickness and volume, and retinal layer thicknesses were measured on spectral-domain optical coherence tomography images and analyzed. Masked grading of GA area and subretinal drusenoid deposits (SDDs) using fundus autofluorescence images was performed. Results: There were no statistical differences in drusen area and volumes between groups, and similar reductions in central subfield thickness, mean cube thickness, cube volume, and retinal sublayer thickness from baseline to 24 months (P = 0.018 to < 0.001), with no statistical differences between groups in any of these anatomic parameters. These findings were not impacted by the presence or absence of SDD. Among the 9 eyes with GA in this study, mean GA growth rate from baseline to 24 months was 1.34 +/- 0.79 mm2/year after PR and 1.95 +/- 1.73 mm2/year in sham-treated eyes (P = 0.49), and similarly showed no statistical difference with square root transformation (P = 0.61). Conclusions: Prophylactic ranibizumab given every 3 months did not appear to affect drusen volume, macular thinning, or GA progression in eyes with intermediate AMD. Translational Relevance: This work investigates the impact of PR on progressive retinal degeneration in a clinical trial.

Barriers to Implementation of Teleretinal Diabetic Retinopathy Screening Programs Across the University of California.

Aim: To describe barriers to implementation of diabetic retinopathy (DR) teleretinal screening programs and artificial intelligence (AI) integration at the University of California (UC). Methods: Institutional representatives from UC Los Angeles, San Diego, San Francisco, Irvine, and Davis were surveyed for the year of their program's initiation, active status at the time of survey (December 2021), number of primary care clinics involved, screening image quality, types of eye providers, image interpretation turnaround time, and billing codes used. Representatives were asked to rate perceptions toward barriers to teleretinal DR screening and AI implementation using a 5-point Likert scale. Results: Four UC campuses had active DR teleretinal screening programs at the time of survey and screened between 246 and 2,123 patients at 1-6 clinics per campus. Sites reported variation between poor-quality photos (<5% to 15%) and average image interpretation time (1-5 days). Patient education, resource availability, and infrastructural support were identified as barriers to DR teleretinal screening. Cost and integration into existing technology infrastructures were identified as barriers to AI integration in DR screening. Conclusions: Despite the potential to increase access to care, there remain several barriers to widespread implementation of DR teleretinal screening. More research is needed to develop best practices to overcome these barriers.

Predictors of As-Needed Ranibizumab Injection Frequency in Patients With Macular Edema Following Retinal Vein Occlusion.

PURPOSE: To evaluate spectral-domain optical coherence tomography (SD-OCT) biomarkers associated with ranibizumab injection frequency after 7 monthly doses in the prospective, multicenter SHORE study for macular edema due to retinal vein occlusion (RVO). DESIGN: Prospective phase IV clinical trial data. METHODS: Post hoc analysis of 95 patients who received 7 monthly doses of ranibizumab followed by either pro re nata (PRN) or nonrandomized monthly injections from months 7-15 in eyes with macular edema secondary to RVO. Baseline SD-OCT biomarkers assessed include central subfield thickness (CST), epiretinal membrane presence, intraretinal and subretinal fluid, hyperreflective foci, disorganization of retinal inner layers (DRIL), and disruption of the external limiting membrane, ellipsoid zone, or interdigitation zone. Univariate and multivariable regression analyses evaluated the association between SD-OCT biomarkers and ranibizumab injection frequency. RESULTS: Mean age of patients was 65.3 (SD, 12.7) years. Overall, 57.9% had BRVO/HRVO and 42.1% of eyes had CRVO. Mean BCVA improved (+17.5 [SD, 1.2] Early Treatment of Diabetic Retinopathy Study [ETDRS] letters) during the 7-month fixed dosing period, remaining stable from baseline (+20.1 [SD, 1.5] ETDRS letters) during the PRN phase from months 7-15. The mean number of PRN injections was 4.32 (SD, 2.35). On multivariate regression, greater baseline DRIL (ß = 0.021, P = .0275) and higher CST at month 3 (ß = 0.01, P < .001) were associated with a higher total number of PRN injections. CONCLUSION: Greater baseline DRIL and higher CST at 3 months after starting ranibizumab treatment are associated with more frequent ranibizumab injections in PRN-treated patients with macular edema due to RVO.

Teleophthalmology Using Remote Retinal Imaging During the COVID-19 Pandemic.

Introduction: Lower insurance reimbursements have limited the financial sustainability of remote eye screening programs. Greater utilization and insurance coverage for teleophthalmology screening during the coronavirus disease 2019 (COVID-19) pandemic in 2020 may enhance awareness and expand remote retinal imaging services. This retrospective cross-sectional study evaluates utilization and insurance coverage for remote retinal imaging in the United States in 2020. Methods: We analyzed teleretinal imaging utilization and insurance payments from January 1 to December 31, 2020, using the Optum Labs Data Warehouse, a comprehensive national database of deidentified administrative claims for commercial and Medicare Advantage enrollees in the United States. We evaluated frequency of claims and insurance payment for services using the Current Procedural Terminology codes 92227 and 92228 for remote eye imaging by any provider, and 92250 for fundus photography by non-eye care providers. Results: The use of remote retinal imaging in the United States declined rapidly during the initial COVID-19 lockdown from 3,627 claims in February 2020 to 1,414 claims in April 2020, but returned to 3,133 claims by December 2020, similar to mean prepandemic levels in 2019 (2,841 ± 174.8 claims). The proportion of insurance payments for remote imaging increased temporarily from 47.4% in February to 56.7% in April, and then returned to 45.9% in December of 2020. Discussion: Utilization of remote retinal imaging declined steeply, while the insurance coverage increased during the initial COVID-19 lockdown in 2020, but returned to prepandemic levels by end of the year. Changes in utilization and relaxed restrictions on insurance reimbursements for teleophthalmology during the COVID-19 pandemic were not sustained.

Long-Term Retinal Vascular Changes in Age-Related Macular Degeneration Measured Using Optical Coherence Tomography Angiography.

BACKGROUND AND OBJECTIVE: To determine if age-related macular degeneration (AMD) status affects longitudinal retinal vessel changes. PATIENTS AND METHODS: Retrospective, cohort study of 125 eyes (75 patients) with AMD, following retinal vessel density (VD) and foveal avascular zone (FAZ) measurements using optical coherence tomography angiography (OCT-A) over 24 months. RESULTS: FAZ area (P < .001) and perimeter (P < .001) increased over 2 years, with no difference between nonexudative and exudative AMD (P = .134-.976). Eyes with geographic atrophy (GA) showed greater progressive VD loss (P = .023-.038), and greater increase in FAZ area (P = .044) and perimeter (P = .040) compared to eyes without GA. Neither baseline nor 2-year change in vascular parameters were associated with choroidal neovascularization (CNV) or GA incidence in nonexudative AMD, or anti-VEGF injection frequency in exudative AMD (P = .070-.952). CONCLUSION: AMD eyes with GA undergo more rapid loss of retinal vessel density and FAZ enlargement over 2 years, suggesting a relationship between the retinal vasculature and AMD pathophysiology. [Ophthalmic Surg Lasers Imaging Retina 2022;53:529-536.].

Relationship of Retinal Vessel Caliber with Age-Related Macular Degeneration.

Purpose: Evaluate the relationship between retinal vascular caliber and age-related macular degeneration (AMD) severity or progression. Methods: A retrospective secondary analysis of 1172 fundus photographs and clinical data from the prospective Age-Related Eye Disease Study (AREDS). Central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), and arteriole-to-venule ratio (AVR) were measured using the Parr-Hubbard-Knudtson formula. Univariate and multivariate regressions were used to determine the association of CRAE, CRVE, and AVR with age, sex, smoking status, presence of cilioretinal artery, and AMD severity at baseline and 5 years using the 9-step AMD severity score. Results: Only CRAE and CRVE were higher in men (P < 0.001), current smokers (P < 0.001), and the eyes with a cilioretinal artery (P=0.009 - 0.043). AMD severity was greater in older patients (P=0.001), current smokers (P=0.012), the eyes without a cilioretinal artery (P=0.001), and lower AVR (P=0.034) on multivariate regression but was not influenced by CRAE or CRVE (P=0.240 - 0.500). Choroidal neovascularization (CNV) presence was associated with older age (P=0.003) and absence of a cilioretinal artery (P=0.009), while central geographic atrophy (CGA) was associated with narrower CRAE (P=0.002) and possibly AVR (P=0.046). None of the retinal vessel parameters were predictive of AMD severity score or new onset of CNV or CGA at 5 years. Conclusion: A lower arteriole-to-venule ratio may be associated with AMD severity, with narrower arterioles seen in the eyes with geographic atrophy, suggesting a role of the retinal vasculature in AMD pathophysiology. This trial is registered with ClinicalTrials.gov Identifier: NCT00000145.

Retinal dystrophies: A look beyond the eyes.

Purpose: To illustrate the importance of systemic evaluation in retinal dystrophies through examples of Alstrom syndrome, Bardet Biedl syndrome, and Refsum disease. Observations: Detailed eye evaluations, including visual acuity, visual field, slit lamp examination, and indirect ophthalmoscopy were performed. Retinal imaging included fundus photography and spectral domain optical coherence tomography (SD-OCT). Functional testing of the retina was done using full field electroretinography (ffERG). In addition, molecular genetic testing was performed using a ciliopathy panel, a retinal dystrophy panel, and whole genome sequencing (WGS).We report three individuals who presented with vision concerns first to ophthalmology, noted to have retinal dystrophy, and then referred to genomic medicine for genetic testing. Additional evaluation led to suspicion of specific groups of systemic disorders and guided appropriate genetic testing. The first individual presented with retinal dystrophy, obesity, and short stature with no reported neurocognitive deficits. Genetic testing included a ciliopathy panel that was negative followed by WGS that identified biallelic variants in ALMS: a novel frame-shift pathogenic variant c.6525dupT (p.Gln2176Serfs*17) and a rare nonsense pathogenic variant c.2035C > T (p.Arg679Ter) consistent with Alstrom syndrome. The second individual presented with retinal dystrophy, central obesity, and mild neurocognitive deficits. A ciliopathy genetic testing panel identified a homozygous pathogenic variant in BBS7: c.389_390del (p.Asn130Thrfs*4), confirming the diagnosis of Bardet Biedl syndrome. The third individual presented with progressive vision loss due to retinitis pigmentosa, anosmia, hearing loss, and shortened metatarsals and digits. Genetic testing identified two variants in PHYH: c.375_375del (p.Glu126Argfs*2) a pathogenic variant and c.536A > G (p.His179Arg), a variant of uncertain significance (VUS), suggestive of Refsum disease. Additional biochemical testing revealed markedly elevated phytanic acid with a low concentration of pristanic acid and normal concentrations of very long-chain fatty acids (C22:0, C24:0, C26:0), a pattern consistent with a diagnosis of Refsum disease. Conclusions and importance: In individuals who present with retinal dystrophy to ophthalmologists, additional systemic manifestations such as sensorineural hearing loss, anosmia, or polydactyly, should be sought and a positive history or examination finding should prompt an immediate referral to a clinical geneticist for additional evaluation and appropriate genetic testing. This facilitates pre-test genetic counseling and allows for more accurate diagnosis, prognosis, and management of affected individuals along with better recurrence risk estimates for family members. Identification of an underlying etiology also enhances the understanding of the pathophysiology of disease and expands the genotypic and phenotypic spectrum. Ultimately, successful recognition of these diseases facilitates development of targeted therapies and surveillance of affected individuals.

CRISPR-based VEGF suppression using paired guide RNAs for treatment of choroidal neovascularization.

Clustered regularly interspaced short palindromic repeats (CRISPR)-based genomic disruption of vascular endothelial growth factor A (Vegfa) with a single gRNA suppresses choroidal neovascularization (CNV) in preclinical studies, offering the prospect of long-term anti-angiogenesis therapy for neovascular age-related macular degeneration (AMD). Genome editing using CRISPR-CRISPR-associated endonucleases (Cas9) with multiple guide RNAs (gRNAs) can enhance gene-ablation efficacy by augmenting insertion-deletion (indel) mutations with gene truncations but may also increase the risk of off-target effects. In this study, we compare the effectiveness of adeno-associated virus (AAV)-mediated CRISPR-Cas9 systems using single versus paired gRNAs to target two different loci in the Vegfa gene that are conserved in human, rhesus macaque, and mouse. Paired gRNAs increased Vegfa gene-ablation rates in human cells in vitro but did not enhance VEGF suppression in mouse eyes in vivo. Genome editing using paired gRNAs also showed a similar degree of CNV suppression compared with single-gRNA systems. Unbiased genome-wide analysis using genome-wide unbiased identification of double-stranded breaks (DSBs) enabled by sequencing (GUIDE-seq) revealed weak off-target activity arising from the second gRNA. These findings suggest that in vivo CRISPR-Cas9 genome editing using two gRNAs may increase gene ablation but also the potential risk of off-target mutations, while the functional benefit of targeting an additional locus in the Vegfa gene as treatment for neovascular retinal conditions is unclear.

Prophylactic Ranibizumab to Prevent Neovascular Age-Related Macular Degeneration in Vulnerable Fellow Eyes: A Randomized Clinical Trial.

PURPOSE: To determine whether prophylactic ranibizumab prevents the development of neovascular age-related macular degeneration (nAMD) in eyes with intermediate age-related macular degeneration (AMD) for patients with preexisting nAMD in their contralateral eye. DESIGN: Multicenter randomized clinical trial. PARTICIPANTS: Adults aged 50 years and older with intermediate AMD (multiple intermediate drusen [≥63 µm and <125 µm] or ≥1 large drusen [≥125 µm] and pigmentary changes) in the study eye and nAMD in the contralateral eye. INTERVENTION: Intravitreal ranibizumab injection (0.5 mg) or sham injection every 3 months for 24 months. MAIN OUTCOME MEASURES: Conversion to nAMD over 24 months (primary). Change in best-corrected visual acuity from baseline to 24 months (secondary). RESULTS: Among 108 enrolled participants (54 [50%] in each group), all except 2 were non-Hispanic Whites, 61 participants (56%) were female, and the mean age was 78 years. The mean baseline visual acuity was 77.7 letters (Snellen equivalent 20/32). Conversion to nAMD over 24 months occurred among 7 of 54 eyes (13%) in both groups (ranibizumab vs. sham hazard ratio = 0.91 [95% confidence interval (CI), 0.32-2.59]; P = 0.86). At 24 months, the cumulative incidence of nAMD adjusted for loss to follow-up was 14% (95% CI, 4%-23%) in the ranibizumab group and 15% (95% CI, 4%-25%) in the sham group. At 24 months, the mean change in visual acuity from baseline was -2.1 letters (standard deviation, 5.4 letters) with ranibizumab and -1.4 letters (standard deviation, 7.7 letters) with sham (adjusted difference = -0.8 letters [95% CI, -3.7 to 2.2 letters]; P = 0.62). The proportion of eyes that lost at least 10 letters of visual acuity from baseline at 24 months was 2 of 39 (5%) with ranibizumab and 4 of 40 (10%) with sham. There were no serious ocular adverse events in either group. CONCLUSIONS: Quarterly dosing of 0.5 mg ranibizumab in eyes with intermediate AMD did not reduce the incidence of nAMD compared with sham injections; however, the study was likely underpowered given the 95% CI, and a clinically meaningful effect cannot be excluded. There also was no effect on visual acuity at 24 months. Other strategies to reduce neovascular conversion in these vulnerable eyes are needed.

CONVERSION AND SPONTANEOUS REVERSION OF LAMELLAR HOLE FROM FULL-THICKNESS MACULAR HOLE.

PURPOSE: To report the conversion and spontaneous reversion of a lamellar hole from full-thickness macular hole after vitrectomy surgery for retinal detachment repair. METHODS: Case report of a patient with a preexisting lamellar hole who underwent retinal detachment repair. RESULTS: A patient with a history of a lamellar hole developed a fovea-sparing retinal detachment that was repaired by vitrectomy surgery with gas tamponade. Two months after the surgery, he developed a full-thickness macular hole that spontaneously reverted back to a lamellar hole configuration over several months. CONCLUSION: Although spontaneous closure of full-thickness macular hole after retinal detachment repair has been reported, the conversion and spontaneous reversion of a lamellar hole from full-thickness macular hole after vitrectomy provide insight into the tractional forces involved in the pathophysiology of lamellar and full-thickness macular holes.

Intraoperative Retinal Changes May Predict Surgical Outcomes After Epiretinal Membrane Peeling.

Purpose: To investigate whether intraoperative retinal changes during epiretinal membrane (ERM) peeling affect anatomic or functional outcomes after surgery. Methods: We measured retinal thickness using an intraoperative optical coherence tomography (iOCT) device in patients undergoing pars plana vitrectomy with membrane peeling for idiopathic ERM. Changes in intraoperative central macular thickness (iCMT) were compared with postoperative improvements in CMT and best-corrected visual acuity (VA). Results: Twenty-seven eyes from 27 patients (mean age 68 years) underwent iOCT-assisted ERM peeling surgery. Before surgery, mean VA was logMAR 0.50 ± 0.36 (Snellen 20/63), and mean baseline CMT was 489 ± 82 µm. Mean iCMT before peeling was 477 ± 87 µm, which correlated well with preoperative CMT (P < 0.001). Mean change in iCMT was -39.6 ± 37 µm (range -116 to +77 µm). After surgery, VA improved to logMAR 0.40 ± 0.38 (Snellen 20/50) at month 1 and logMAR 0.27 ± 0.23 (Snellen 20/37) at month 3, whereas CMT decreased to 397 ± 44 µm and 396 ± 51 µm at months 1 and 3. Eyes that underwent greater amount of iCMT change (absolute value of iCMT change) were associated with greater CMT reduction at month 1 (P < 0.001) and month 3 (P = 0.010), whereas those with greater intraoperative thinning (actual iCMT change) showed a trend toward better VA outcomes at months 1 (P = 0.054) and 3 (P = 0.036). Conclusions: Intraoperative changes in retinal thickness may predict anatomic and visual outcomes after idiopathic ERM peeling surgery. Translational Relevance: Our study suggests that intraoperative retinal tissue response to ERM peeling surgery measured by iOCT may be a prognostic indicator for restoration of retinal architecture and for visual acuity outcomes.

Research Funding, Income, and Career Satisfaction Among Clinician-Scientists in Ophthalmology in the United States.

PURPOSE: The purpose of this study was to characterize clinician-scientists in ophthalmology and identify factors associated with successful research funding, income, and career satisfaction. DESIGN: Cross-sectional study. METHODS: A survey was conducted of clinician-scientists in ophthalmology at US academic institutions between April 17, 2019, and May 19, 2019. Collected information including 1) demographic data; 2) amount, type, and source of startup funding; first extramural grant; and first R01-equivalent independent grant; 3) starting and current salaries; and 4) Likert-scale measurements of career satisfaction were analyzed using multivariate regression. RESULTS: Ninety-eight clinician-scientists in ophthalmology were surveyed across different ages (mean: 48 ± 11 years), research categories, institutional types, geographic regions, and academic ranks. Median startup funding ranged from $50-99k, and median starting salaries ranged from $150-199k. A majority of investigators (67%) received their first extramural award from the National Eye Institute, mainly through K-award mechanisms (82%). The median time to receiving their first independent grant was 8 years, mainly through an R01 award (70%). Greater institutional startup support (P = .027) and earlier extramural grant success (P = .022) were associated with earlier independent funding. Male investigators (P = .001) and MD degreed participants (P = .008) were associated with higher current salaries but not starting salaries. Overall career satisfaction increased with career duration (P = .011) but not with earlier independent funding (P = .746) or higher income (P = .300). CONCLUSIONS: Success in research funding by clinician-scientists in ophthalmology may be linked to institutional support and earlier acquisition of extramural grants but does not impact academic salaries. Nevertheless, career satisfaction among clinician-scientists improves with time, which is not necessarily influenced by research or financial success.

NATURAL HISTORY AND PREDICTORS OF VISION LOSS IN EYES WITH DIABETIC MACULAR EDEMA AND GOOD INITIAL VISUAL ACUITY.

PURPOSE: To identify clinical and anatomic factor-associated vision loss in eyes with treatment-naïve diabetic macular edema and good initial visual acuity. METHODS: Retrospective cohort study after long-term history of eyes with untreated center-involving diabetic macular edema and baseline visual acuity ≥ 20/25 seen at the University of California, Davis Eye Center between March 2007 and March 2018. We collected characteristics including diabetes type, hemoglobin A1c, presence of visual symptoms, visual acuity, and diabetic retinopathy severity; and spectral-domain optical coherence tomography biomarkers including central subfield thickness, intraretinal cyst size, intraretinal hyperreflective foci, disorganization of retinal inner layers, and outer layer disruptions to determine factors associated with vision loss as defined by DRCR Protocol V as threshold for initiating aflibercept therapy. RESULTS: Fifty-six eyes (48 patients) with untreated diabetic macular edema and mean baseline visual acuity of logMAR 0.05 ± 0.05 (Snellen 20/22) were followed for an average of 5.1 ± 3.3 years, with a median time to vision loss of 465 days (15 months). Older age (hazard ratio [HR] 1.04/year, P = 0.0195) and eyes with severe NPDR (HR 3.0, P = 0.0353) or proliferative diabetic retinopathy (HR 7.7, P = 0.0008) had a higher risk of a vision loss event. None of the spectral-domain optical coherence tomography biomarkers were associated with vision loss except central subfield thickness (HR 0.98, P = 0.0470) and cyst diameter (HR 1.0, P = 0.0094). CONCLUSION: In eyes with diabetic macular edema and good initial vision, those with older age and worse diabetic retinopathy severity should be monitored closely for prompt treatment initiation when vision loss occurs.