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The American Diabetes Association (ADA) “Standards of Care in Diabetes” includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

In eyes with diabetic macular edema, the relative efficacy of administering aflibercept monotherapy as compared with bevacizumab first with a switch to aflibercept if the eye condition does not improve sufficiently (a form of step therapy) is unclear.At 54 clinical sites, we randomly assigned eyes in adults who had diabetic macular edema involving the macular center and a visual-acuity letter score of 24 to 69 (on a scale from 0 to 100, with higher scores indicating better visual acuity; Snellen equivalent, 20/320 to 20/50) to receive either 2.0 mg of intravitreous aflibercept or 1.25 mg of intravitreous bevacizumab. The drug was administered at randomization and thereafter according to the prespecified retreatment protocol. Beginning at 12 weeks, eyes in the bevacizumab-first group were switched to aflibercept therapy if protocol-specified criteria were met. The primary outcome was the mean change in visual acuity over the 2-year trial period. Retinal central subfield thickness and visual acuity at 2 years and safety were also assessed.A total of 312 eyes (in 270 adults) underwent randomization; 158 eyes were assigned to receive aflibercept monotherapy and 154 to receive bevacizumab first. Over the 2-year period, 70% of the eyes in the bevacizumab-first group were switched to aflibercept therapy. The mean improvement in visual acuity was 15.0 letters in the aflibercept-monotherapy group and 14.0 letters in the bevacizumab-first group (adjusted difference, 0.8 letters; 95% confidence interval, -0.9 to 2.5; P = 0.37). At 2 years, the mean changes in visual acuity and retinal central subfield thickness were similar in the two groups. Serious adverse events (in 52% of the patients in the aflibercept-monotherapy group and in 36% of those in the bevacizumab-first group) and hospitalizations for adverse events (in 48% and 32%, respectively) were more common in the aflibercept-monotherapy group.In this trial of treatment of moderate vision loss due to diabetic macular edema involving the center of the macula, we found no evidence of a significant difference in visual outcomes over a 2-year period between aflibercept monotherapy and treatment with bevacizumab first with a switch to aflibercept in the case of suboptimal response. (Funded by the National Institutes of Health; Protocol AC ClinicalTrials.gov number, NCT03321513.).

OBJECTIVE To correlate inflammatory cytokines and vascular endothelial growth factor (VEGF) in vitreous and plasma with vitreous retinol binding protein 3 (RBP3), diabetic retinopathy (DR) severity, and DR worsening in a population with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS RBP3, VEGF, and inflammatory cytokines were measured in plasma and vitreous samples (n = 205) from subjects of the Joslin Medalist Study and Beetham Eye Institute. RESULTS Higher vitreous RBP3 concentrations were associated with less severe DR (P < 0.0001) and a reduced risk of developing proliferative DR (PDR) (P < 0.0001). Higher RBP3 correlated with increased photoreceptor segment thickness and lower vitreous interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α), and TNF-β (P < 0.05). PDR was associated with lower vitreous interferon-γ and IL-10 and higher VEGF, IL-6, and IL-15 (P < 0.05), but was not associated with their plasma concentrations. CONCLUSIONS Higher vitreous RBP3 concentrations are associated with less severe DR and slower rates of progression to PDR, supporting its potential as a biomarker and therapeutic agent for preventing DR worsening, possibly by lowering retinal VEGF and inflammatory cytokines.

Purpose To determine if treatment with a photobiomodulation (PBM) device results in greater improvement in central subfield thickness as compared with placebo in eyes with center-involved diabetic macular edema (CI-DME) and good vision Design Phase 2 randomized clinical trial Participants Participants had CI-DME and visual acuity (VA) 20/25 or better in the study eye and were recruited from 23 clinical sites in the US. Methods One eye of each participant was randomly assigned 1:1 to a 670-nm light-emitting PBM eye patch or an identical device emitting broad-spectrum white light at low power. Treatment was applied for 90 seconds twice daily for 4 months. Main Outcome Measure Change in central subfield thickness (CST) on spectral-domain optical coherence tomography (OCT) at 4 months. Results From April 2019 to February 2020, 135 adults were randomly assigned to either PBM (N = 69) or placebo (N = 66); median age was 62, 37% were female and 82% were white. Median device compliance was 92% with PBM and 95% with placebo. OCT CST increased from baseline to 4 months by a mean (SD) of 13 (53) μm in PBM eyes and 15 (57) μm in placebo eyes (mean difference (95% CI) = -2 (-20 to 16) μm; p = .84). CI-DME, based on DRCR Retina Network sex and machine-based thresholds, was present in 61 (90%) of PBM eyes and 57 (86%) of placebo eyes at 4 months (adjusted odds ratio (95% CI) = 1.30 (0.44 to 3.83); p = .63). Visual acuity decreased by a mean (SD) of -0.2 (5.5) letters and -0.6 (4.6) letters in the PBM and placebo groups, respectively (difference (95% CI) = 0.4 (-1.3 to 2.0) letters; p = .64). There were eight adverse events possibly related to the PBM device, and two adverse events possibly related to the placebo device. None were serious. Conclusions PBM as given in this study, while safe and well tolerated, was not found to be effective for the treatment of CI-DME in eyes with good vision.

To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody.YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593).3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]).Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema.F Hoffmann-La Roche.

IMPORTANCE: Methods that increase visible retinal area (VRA; measured in millimeters squared) may improve identification of diabetic retinopathy (DR) lesions. OBJECTIVE: To evaluate the association of dilation and manual eyelid lifting (MLL) with VRA on ultra-widefield imaging (UWFI) and the association of VRA with grading of DR severity and detection of predominantly peripheral lesions (PPLs). DESIGN, SETTING, AND PARTICIPANTS: Retrospective, comparative case-control study at the Joslin Diabetes Center, Boston, Massachusetts. Nonmydriatic UWFI with MLL was acquired from a DR teleophthalmology program (Joslin Vision Network [JVN]). A second cohort of mydriatic UWFI was acquired at an academic retina practice (Beetham Eye Institute [BEI]) from November 6, 2017, to November 6, 2018, and with MLL thereafter until November 6, 2019. Fully automated algorithms determined VRA and hemorrhage and/or microaneurysm (HMA) counts. Predominantly peripheral lesions and HMAs were defined as present when at least 1 field had greater HMA number in the peripheral retina than within the corresponding Early Treatment Diabetic Retinopathy Study field. Participants included 3014 consecutive patients (5919 eyes) undergoing retinal imaging at JVN and BEI. EXPOSURES: Dilation and MLL performed at the time of UWFI. MAIN OUTCOMES AND MEASURES: Visible retinal area, DR severity, and presence of PPLs. RESULTS: Of the 3014 participants, mean (SD) age was 56.1 (14.5) years, 1302 (43.2%) were female, 2450 (81.3%) were White, and mean (SD) diabetes duration was 15.9 (11.4) years. All images from 5919 eyes with UWFI were analyzed. Mean (SD) VRA was 665.1 (167.6) mm(2) for all eyes (theoretical maximal VRA, 923.9 mm(2)), 550.8 (240.7) mm(2) for nonmydriatic JVN with MLL (1418 eyes [24.0%]), 688.1 (119.9) mm(2) for mydriatic BEI images (3650 eyes [61.7%]), and 757.0 (69.7) mm(2) for mydriatic and MLL BEI images (851 eyes [14.4%]). Dilation increased VRA by 25% (P

Purpose To evaluate pneumatic vitreolysis (PVL) in eyes with vitreomacular traction (VMT) with and without full-thickness macular hole (FTMH). Design Two multicenter (28 sites) studies: a randomized clinical trial comparing PVL with observation (sham injection) for VMT without FTMH (Protocol AG) and a single-arm study assessing PVL for FTMH (Protocol AH). Participants Participants were adults with central VMT (vitreomacular adhesion was ≤3000 μm). In Protocol AG, visual acuity (VA) was 20/32 to 20/400. In Protocol AH, eyes had a FTMH (≤250 μm at the narrowest point) and VA of 20/25 to 20/400. Methods Pneumatic vitreolysis using perfluoropropane (C3F8) gas. Main Outcome Measures Central VMT release at 24 weeks (Protocol AG) and FTMH closure at 8 weeks (Protocol AH). Results From October 2018 through February 2020, 46 participants were enrolled in Protocol AG, and 35 were enrolled in Protocol AH. Higher than expected rates of retinal detachment and tear resulted in early termination of both protocols. Combining studies, 7 of 59 eyes (12% [95% CI, 6%–23%]; 2 eyes in Protocol AG, 5 eyes in Protocol AH) that received PVL developed rhegmatogenous retinal detachment (n = 6) or retinal tear (n = 1). At 24 weeks in Protocol AG, 18 of 23 eyes in the PVL group (78%) versus 2 of 22 eyes in the sham group (9%) achieved central VMT release without rescue vitrectomy (adjusted risk difference, 66% [95% CI, 44%–88%]; P Conclusions In most eyes with VMT, PVL induced hyaloid release. In eyes with FTMH, PVL resulted in hole closure in approximately one third of eyes. These studies were terminated early because of safety concerns related to retinal detachments and retinal tears.

PURPOSE: Since eyes with center-involved diabetic macular edema (CI-DME) and good baseline visual acuity (VA) showed no difference in VA loss when managed initially with observation, laser, or aflibercept, understanding the estimated costs of these strategies to the US population is relevant for health care planning. METHODS, SETTING, AND PARTICIPANTS: Total costs for managing participants with CI-DME and good baseline VA assigned to aflibercept (n= 236), laser (n=240), or observation (n = 236) during the 2-year trial were calculated. Using epidemiological data and extrapolating costs, 10-year costs for caring for persons with CI-DME and good baseline VA throughout the US was estimated. INTERVENTIONS: Observation or laser groups initiated aflibercept if VA decreased. Aflibercept group received injections up to every 4 weeks. MAIN OUTCOMES AND MEASURES: Estimated 10-year U.S. population costs to manage CI-DME with good VA. RESULTS: Assuming all patients in the US with CI-DME and good baseline VA received aflibercept initially, 10-year costs were projected to be $28.80 billion compared with $14.42 billion if initially receiving laser treatment or $15.70 billion if initially observed, with aflibercept added if VA worsened in the laser or observation arms. CONCLUSIONS AND RELEVANCE: Similar VA outcomes on average are obtained by initially managing CI-DME and good baseline VA with laser or observation strategies instead of immediately using aflibercept. While any one of these three strategies might be warranted depending on an individual’s specific circumstances, on a societal level, cost savings might be achieved with these first two approaches. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01909791

Purpose To evaluate the association of retinal nonperfusion and diabetic retinopathy (DR) severity with location of vascular caliber measurement using ultrawide field (UWF) imaging. Design Retrospective image review. Participants Adults with diabetes mellitus. Methods All images from subjects with same-day UWF fluorescein angiography (FA) and color imaging were evaluated. Predominantly peripheral lesions (PPL) and DR severity were graded from UWF color images. Nonperfusion was quantified using UWF-FA in defined retinal regions [posterior pole (PP), mid-periphery (MP), far-periphery (FP)]. Retinal vessel calibers were measured at an optic disc centered inner and outer zone. Main Outcome Measures Nonperfusion index (NPI) in the PP, MP and FP. Mean arteriole and venule diameter in the inner and outer zones. Results Two hundred eighty-five eyes of 193 patients (24.9% mild nonproliferative DR [NPDR], 22.8% moderate NPDR, 37.5% severe NPDR and 14.7% proliferative DR [PDR]) were reviewed. No significant associations between inner zone arteriolar diameter and retinal NPI overall or in any retinal region. In the outer zone, eyes with thinnest arteriolar calibers (quartile 1) were associated with a 1.7- to 2.4-fold nonperfusion increase across all retinal regions compared to the remaining eyes (P = 0.002 [PP] to 0.048 [FP]). In the outer zone, the percentage of eyes in the thinnest quartile of retinal arteriolar diameter increased with worsening DR severity (mild NPDR: 10% vs PDR: 31%, P = 0.007). This association was not observed when measured within the inner zone (P = 0.129). All venular caliber associations were not statistically significant when corrected for potentially confounding factors. Thinner outer zone retinal arteriolar caliber (quartile 1) was more common in eyes with PPL compared to eyes without PPL (34.1% vs 20.8%, P = 0.017) as were thicker outer venular calibers (quartile 4) (33% vs 21.3%, P = 0.036). Presence of PPL was associated with thinner outer zone arteriolar caliber (109.7 ± 26.5μm vs 123.0 ± 29.5μm, P = 0.001). Conclusions The association of vascular caliber with nonperfusion and DR severity differs based upon the retinal location at which vascular caliber is measured. Peripheral arterial narrowing is associated with increasing nonperfusion, worsening DR severity and presence of PPL. In contrast, inner zone retinal arteriolar caliber is not associated with these findings.

Evaluate the differences between clinical visual acuity (VA) as recorded in medical records and electronic ETDRS (eETDRS) protocol VA measurements and factors affecting the size of the differences.Retrospective chart review.Study and fellow eyes of participants enrolled in DRCR Retina Network Protocols AC and AE (diabetic macular edema), and W (non-proliferative diabetic retinopathy) with clinical VA recorded within 3 months before the protocol visit.Linear mixed models evaluated the differences and their association with patient and ocular factors in univariable and multivariable models, with random effects for correlations within sites and participants.Difference between VA letter scores measured by eETDRS during a study protocol visit versus measured by Snellen during a regular clinical visit (Snellen fraction converted to eETDRS).Data from 1016 eyes (511 participants) across 74 sites were analyzed. The mean VA measurements were 68.6 letters (Snellen equivalent 20/50) at the clinical visit and 76.3 letters (Snellen equivalent 20/32) at the protocol visit, with a mean (standard deviation, SD) of 26 (21) days between visits. Mean (SD) protocol VA was better than clinical VA by 7.6 (9.6) letters overall, 10.7 (12.6) letters in eyes with clinical VA ≤20/50 (n = 376) and 5.8 (6.6) letters in eyes with clinical VA ≥20/40 (n = 640). On average, the difference between clinical and protocol VA was 1.3 letters smaller for every 1-line (5 letters) increase in clinical VA (p0.001). Mean (SD) differences by clinical correction of refractive error were 3.9 (9.0) letters with refraction, 6.9 (9.2) letters with glasses/contact lenses, 7.9 (11.5) letters with pinhole and 9.8 (9.3) letters without correction (p=0.06).On average, clinical Snellen VA is likely to be 1-2 lines worse than eETDRS protocol refraction and VA testing, which may partly explain why clinical practice does not always replicate clinical trial results. Eyes with lower clinical measurements and eyes tested without clinical refraction tended to have larger differences. Considering the potential discrepancies between clinical and protocol VA measurements, refracting eyes in the clinic may benefit patients when determining treatment plans and study referrals based on vision.

To compare nonmydriatic (NM) and mydriatic (MD) handheld retinal imaging with standard ETDRS 7-field color fundus photography (ETDRS photographs) for the assessment of diabetic retinopathy (DR) and diabetic macular edema (DME).Prospective, comparative, instrument validation study.A total of 225 eyes from 116 patients with diabetes mellitus.Following a standardized protocol, NM and MD images were acquired using handheld retinal cameras (NM images: Aurora, Smartscope, and RetinaVue-700; MD images: Aurora, Smartscope, RetinaVue-700, and iNview) and dilated ETDRS photographs. Grading was performed at a centralized reading center using the International Clinical Classification for DR and DME. Kappa statistics (simple [K], weighted [Kw]) assessed the level of agreement for DR and DME. Sensitivity and specificity were calculated for any DR, referable DR (refDR), and vision-threatening DR (vtDR).Agreement for DR and DME; sensitivity and specificity for any DR, refDR, and vtDR; ungradable rates.Severity by ETDRS photographs: no DR, 33.3%; mild nonproliferative DR, 20.4%; moderate DR, 14.2%; severe DR, 11.6%; proliferative DR, 20.4%; no DME, 68.0%; DME, 9.3%; non-center involving clinically significant DME, 4.9%; center-involving clinically significant DME, 12.4%; and ungradable, 5.3%. For NM handheld retinal imaging, Kw was 0.70 to 0.73 for DR and 0.76 to 0.83 for DME. For MD handheld retinal imaging, Kw was 0.68 to 0.75 for DR and 0.77 to 0.91 for DME. Thresholds for sensitivity (0.80) and specificity (0.95) were met by NM images acquired using Smartscope and MD images acquired using Aurora and RetinaVue-700 cameras for any DR and by MD images acquired using Aurora and RetinaVue-700 cameras for refDR. Thresholds for sensitivity and specificity were met by MD images acquired using Aurora and RetinaVue-700 for DME. Nonmydriatic and MD ungradable rates for DR were 15.1% to 38.3% and 0% to 33.8%, respectively.Following standardized protocols, NM and MD handheld retinal imaging devices have substantial agreement levels for DR and DME. With mydriasis, not all handheld retinal imaging devices meet standards for sensitivity and specificity in identifying any DR and refDR. None of the handheld devices met the established 95% specificity for vtDR, suggesting that lower referral thresholds should be used if handheld devices must be utilized. When using handheld devices, the ungradable rate is significantly reduced with mydriasis and DME sensitivity thresholds are only achieved following dilation.

To investigate whether anti-vascular endothelial growth factor (anti-VEGF) for diabetic macular edema or proliferative diabetic retinopathy (PDR) increases the risk of traction retinal detachment (TRD) among eyes with PDR.Pooled analysis of PDR eyes from Protocols I, J, N, S, or T with Early Treatment Diabetic Retinopathy Study level ≥61 (prompt vitrectomy was not planned) randomly assigned to the control group (laser photocoagulation, sham, or intravitreal saline; 396 eyes) or anti-VEGF (487 eyes). The primary outcome was investigator-identified TRD within 1 year of randomization.The 1-year cumulative probability of TRD was 6.8% (95% confidence interval: 4.6%-9.9%, 25 events) in control-group eyes and 4.8% (95% confidence interval: 3.2%-7.3%, 22 events) in anti-VEGF group eyes (hazard ratio = 0.95 [95% confidence interval: 0.54-1.66, P = 0.86]). The cumulative probability of vitrectomy for TRD was 4.4% (16 events) in control-group eyes and 2.2% (9 events) in anti-VEGF group eyes (P = 0.19). Percentage with TRD and vitrectomy for TRD were similar within strata of diabetic retinopathy severity.These findings do not support the hypothesis that anti-VEGF therapy for diabetic macular edema or PDR increases the risk of TRD among eyes with PDR similar to those enrolled in five DRCR Retina Network protocols for which prompt vitrectomy was not planned.

Care of Patients with Diabetic Retinopathy Diabetic retinopathy is a leading cause of both moderate and severe vision loss worldwide. Over the past decade, advances in technology have dramatically ...

Importance The follow-up schedule for individuals with eyes treated with anti–vascular endothelial growth factor agents for proliferative diabetic retinopathy (PDR) requires that patients return frequently for monitoring and repeated treatment. The likelihood that a patient will comply should be a consideration in choosing a treatment approach. Objective To describe completion of scheduled examinations among participants assigned to intravitreous injections of ranibizumab for PDR in a multicenter randomized clinical trial. Design, Setting, and Participants This post hoc analysis evaluates data from a randomized clinical trial conducted at 55 US sites among 305 adults with proliferative diabetic retinopathy enrolled between February and December 2012. Both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. The final 2-year visit was completed in January 2015. Data were analyzed from April 2019 to July 2021. Interventions Ranibizumab injections for PDR or macular edema. Main Outcomes and Measures A long lapse in care of 8 or more weeks past a scheduled examination, dropout from follow-up, visual acuity at 5 years. Results Among 170 participants, the median age was 51 years, and 44.7% were female. Through 5 years of follow-up, 94 of 170 participants (55.3%) had 1 or more long lapse in care. Median time to the first long lapse was 210 weeks, and 69 of 94 participants (73.4%) returned for examination after the first long lapse. Fifty of 170 participants (29.4%) dropped out of follow-up by 5 years. Among the 120 participants who completed the 5-year examination, median change from baseline in visual acuity was −2 letters for participants who had 1 or more long lapse compared with +5 letters for those without a long lapse (P = .02). After multivariable adjustment, the odds ratio (95% CI) for baseline associations with 1 or more long lapse was 1.21 (1.03-1.43) for each 5-letter decrement in visual acuity score, 2.19 (1.09-4.38) for neovascularization of the disc and elsewhere, and 3.48 (1.38-8.78) for no prior laser treatment for diabetic macular edema. Conclusions and Relevance Over 5 years, approximately half of the participants assigned to ranibizumab for PDR had a long lapse in care despite substantial effort by the DRCR Retina Network to facilitate timely completion of examinations. The likelihood of a long lapse in care during long-term follow-up needs to be considered when choosing treatment for PDR. Trial Registration ClinicalTrials.gov Identifier:NCT01489189

Diabetic retinal disease (DRD), the most common complication of diabetes and a leading cause of blindness in working age individuals, is now understood to be a form of sensory neuropathy or neurovascular degeneration. Current treatments are focused on advanced vision-threatening disease and a single molecular target, vascular endothelial growth factor, has an approved therapy. We trace the evolution of understanding of DRD pathogenesis, identify new approaches to clinical assessment, trials infrastructure and design, and target identification to accelerate selection and evaluation of new therapeutics that will speed development of potentially curative interventions. Critically, the "Restoring Vision Moonshot" framework will address gaps in knowledge to be filled to achieve the goal of restoring sight and preventing vision loss in persons with diabetes.

Retinal imaging is a fundamental tool for clinical and research efforts in the evaluation and management of diabetic retinopathy. Adaptive optics (AO) is an imaging technique that enables correction of over 90% of the optical aberrations of an individual eye induced primarily by the tear film, cornea and lens. The two major tasks of any AO system are to measure the optical imperfections of the eye and to then compensate for these aberrations to generate a corrected wavefront of reflected light from the eye. AO scanning laser ophthalmoscopy (AOSLO) provides a theoretical lateral resolution limit of 1.4 μm, allowing the study of microscopic features of the retinal vascular and neural tissue. AOSLO studies have revealed irregularities of the photoreceptor mosaic, vascular loss, and details of vascular lesions in diabetic eyes that may provide new insight into development, regression, and response to therapy of diabetic eye disease.

Purpose To evaluate the durability of diabetic retinopathy (DR) improvements after a change in ranibizumab dosing from monthly to individualized pro re nata (PRN) therapy. Design Pooled analysis of the open-label extension (OLE) of RIDE and RISE ( clinicaltrials.gov identifiers, NCT00473382 and NCT00473330 ) patients with DR and diabetic macular edema (DME). Participants Patients who completed 36-month participation in RIDE and RISE and entered the OLE. Methods In RIDE and RISE, patients (n = 759) were randomized 1:1:1 to ranibizumab 0.3 mg monthly, 0.5 mg monthly, or monthly sham injections with rescue macular laser available after 6 months, per protocol-specified criteria. After 24 months, sham patients crossed over to ranibizumab 0.5 mg monthly. After 36 months in the core studies, patients in the OLE (n = 500) could receive ranibizumab 0.5 mg PRN based on predefined DME re-treatment criteria. Diabetic retinopathy severity was evaluated photographically using the Early Treatment Diabetic Retinopathy Study DR severity scale. Main Outcome Measures Change in DR severity from months 36 to 48 by re-treatment status. Results Among patients who entered the OLE, 121 of 500 (24%) did not require additional ranibizumab injections. Overall, 367 patients had evaluable DR at months 36 and 48. Among patients not requiring ranibizumab re-treatment from months 36 to 48 (88/367), 57% to 78%, 0% to 7%, and 22% to 36% experienced DR severity stability, 2-step or more improvement, and 2-step or more worsening, respectively. Among patients requiring ranibizumab re-treatment (279/367), 84% to 94%, 2%, and 3% to 14% experienced DR severity stability, 2-step or more improvement, and 2-step or more worsening, respectively. On average, vision improvements were maintained during the OLE regardless of change in DR severity. Conclusions Diabetic retinopathy severity improvements with ranibizumab were maintained in over 70% of OLE patients after switching from ranibizumab monthly to an individualized ranibizumab 0.5 mg PRN dosing regimen. Because approximately one third of OLE patients experienced DR worsening, careful monitoring should be part of the long-term management of patients with DR.

Purpose The purpose of this study was to determine factors affecting predominantly peripheral lesion (PPL) grading, such as qualitative versus quantitative assessment, device type, and severity of diabetic retinopathy (DR) in ultrawide field color images (UWF-CIs). Methods Patients with DR had UWF-CI qualitatively graded for PPL using standardized techniques and had hemorrhages/microaneurysms (H/Mas) individually annotated for quantitative PPL grading on two different ultrawide field devices. Results Among 791 eyes of 481 patients, 38.2% had mild nonproliferative DR (NPDR), 34.7% had moderate NPDR, and 27.1% had severe NPDR to proliferative DR (PDR). The overall agreement between qualitative and quantitative PPL grading was moderate (ĸ = 0.423, P < 0.001). Agreement rates were fair in eyes with mild NPDR (ĸ = 0.336, P < 0.001) but moderate in eyes with moderate NPDR (ĸ = 0.525, P < 0.001) and severe NPDR-PDR (ĸ = 0.409, P < 0.001). Increasing thresholds for quantitative PPL determination improved agreement rates, with peak agreements at H/Ma count differences of six for mild NPDR, five for moderate NPDR, and nine for severe NPDR-PDR. Based on ultrawide field device type (California = 412 eyes vs. 200Tx = 379 eyes), agreement between qualitative and quantitative PPL grading was moderate for all DR severities in both devices (ĸ = 0.369-0.526, P < 0.001) except for mild NPDR on the 200Tx, which had poor agreement (ĸ = 0.055, P = 0.478). Conclusions Determination of PPL varies between standard qualitative and quantitative grading and is dependent on NPDR severity, device type, and magnitude of lesion differences used for quantitative assessment. Translational Relevance Prior UWF studies have not accounted for imaging and grading factors that affect PPL, such factors need to be reviewed when assessing thresholds for DR progression rates.

Vision-threatening DR (vtDR) is commonly defined as moderate nonproliferative or more severe DR, or the presence of diabetic macular edema (DME). Modifiable risk factors of DR and vtDR are well-established in adults. This study identified risk factors associated with DR and vtDR in a large pediatric cohort with T1D. Medical chart review was performed of baseline visits of pediatric (≤21 yrs old) patients at an academic eye center from 2005-2020 to collect demographic characteristics, medical history and DR severity. Analyses were adjusted for correlation between eyes of the same person. In total, 1735 subjects (3454 eyes) were included with mean±SD age 15.4±4.6 years, T1D duration 7.1±5.3 years, T1D onset 8.3±5.4 years, and A1c 8.4±1.3; 50.7% were female, 30.7% were overweight/obese and 4.1% had elevated/high BP. Any DR was present in 8.5% and vtDR in 2.4% of eyes. Unadjusted analyses found DR presence associated with higher A1c (p Disclosure C. Jacoba: None. K. Sampani: None. C. Gilbert: None. P. S. Silva: Research Support; Self; Hillrom, Optomed, Optos plc. J. Keady: None. L. M. Laffel: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompe, Insulogic LLC, Janssen Pharmaceuticals, Inc., Laxmi Therapeutic Devices, LifeScan, Lilly Diabetes, Medtronic, Provention Bio, Inc. L. P. Aiello: Consultant; Self; KalVista Pharmaceuticals, Novo Nordisk, Regeneron Pharmaceuticals Inc., Stock/Shareholder; Self; KalVista Pharmaceuticals. J. Sun: Other Relationship; Self; Novo Nordisk, Roche Pharma, Research Support; Self; Adaptive Sensory Technology, Boehringer Ingelheim Pharmaceuticals, Inc., KalVista Pharmaceuticals, Optovue, Roche Pharma.

Patient cancellations of scheduled visits may result in missed opportunities for timely treatment and counseling and adversely impact quality of patient care. Identification of risk factors for cancellations might allow clinicians to define subgroups more likely to miss visits and interventions that prevent lapses in care. The purpose of this study was to identify patient factors associated with visit cancellations in patients followed at a tertiary care referral center for diabetes eye care. A retrospective review of the Joslin Diabetes Center’s Beetham Eye Institute electronic medical record was performed for patients with a first visit in 2016 and subsequent follow-up data. Analyses adjusted for repeated measures from the same patient. A total of 1,785 patients with diabetes (46.5% type 1, 53.5% type 2) were evaluated with baseline mean ± SD diabetes duration 24.5 ± 0.6 yrs, A1c 8.0 ± 0.1; 44.0% were female, 64.7% White, 10.3% Black and 4.0% Asian. Baseline diabetic retinopathy (DR) severity in the eye with more advanced disease was no DR in 40.3%, nonproliferative DR in 40.8% and proliferative DR (PDR) in 19.0%. Over the study time period, 333/13,085 (2.5%) visits were cancelled by patients. Bivariate analyses revealed increased cancellations were associated with older age (OR:1.00, p = 0.02), Asian versus White race (OR:3.77, p = 0.003), longer DM duration (OR:1.01, p < 0.05), the presence of DM complications (OR:1.43, p = 0.02), not being insured by Medicare (OR:1.29, p = 0.01), and the presence of PDR (OR:2.28, p = 0.004). After backwards elimination analysis, only PDR remained significantly associated with cancellations. These findings suggest that patient cancellations may be associated with DR severity. Future studies should explore this relationship in expanded patient datasets and the relationship of cancelled to missed visits in order to better understand potential barriers to follow up for patients undergoing diabetes eye care. Disclosure C. Gilbert: None. W. Fickweiler: None. A. Adam: None. J. Sun: Other Relationship; Self; Novo Nordisk, Roche Pharma, Research Support; Self; Adaptive Sensory Technology, Boehringer Ingelheim Pharmaceuticals, Inc., KalVista Pharmaceuticals, Optovue, Roche Pharma. Funding Massachusetts Lions Eye Research Fund

Retinol Binding Protein 3 (RBP3), a retinol transport protein secreted mainly by photoreceptors, may inhibit progression of diabetic retinopathy (DR) by decreasing glucose uptake and inflammation in the retina. In people with type 1 diabetes with duration of ≥50yrs (Joslin Medalist Study), >40% of Medalists exhibited no to mild non-proliferative diabetic retinopathy (NPDR) and increased expression of RBP3 compared to those with severe DR. We examined 213 vitreous samples from a larger population of Medalists and patients with type 1 and type 2 diabetes with shorter diabetes duration (mean±SD 26.5±12.7 years) from the Joslin Beetham Eye Institute to determine whether vitreous RBP3 levels are correlated with DR severity and progression in a broad population with diabetes. RBP3 was increased in vitreous from people with no diabetes compared to subjects with type 1 and type 2 diabetes (p Disclosure W. Fickweiler: None. G. L. King: Consultant; Self; Agios, Inc., Medtronic, Other Relationship; Self; Janssen Pharmaceuticals, Inc. H. Park: None. K. Park: None. T. Boumenna: None. J. Gauthier: None. I. Wu: None. J. D. Cavallerano: None. L. P. Aiello: Consultant; Self; KalVista Pharmaceuticals, Novo Nordisk, Regeneron Pharmaceuticals Inc., Stock/Shareholder; Self; KalVista Pharmaceuticals. J. Sun: Other Relationship; Self; Novo Nordisk, Roche Pharma, Research Support; Self; Adaptive Sensory Technology, Boehringer Ingelheim Pharmaceuticals, Inc., KalVista Pharmaceuticals, Optovue, Roche Pharma. Funding National Eye Institute (R01EY026080-01); National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK094333-01); JDRF (17-2013-310); Beatson Foundation; Dianne Nunnally Hoppes Fund

Drinking water concentrations of per- and polyfluoroalkyl substances (PFAS) exceed provisional guidelines for millions of Americans. Data on private well PFAS concentrations are limited in many regions and monitoring initiatives are costly and time-consuming. Here we examine modeling approaches for predicting private wells likely to have detectable PFAS concentrations that could be used to prioritize monitoring initiatives. We used nationally available data on PFAS sources, and geologic, hydrologic and soil properties that affect PFAS transport as predictors and trained and evaluated models using PFAS data (n~2300 wells) collected by the state of New Hampshire between 2014 and 2017. Models were developed for the five most frequently detected PFAS: perfluoropentanoate, perfluorohexanoate, perfluoroheptanoate, perfluorooctanoate, and perfluorooctane sulfonate. Classification random forest models that allow non-linearity in interactions among predictors performed the best (area under the receiver operating characteristics curve: 0.74 – 0.86). Point sources such as the plastics/rubber and textile industries accounted for the highest contribution to accuracy. Groundwater recharge, precipitation, soil sand content, and hydraulic conductivity were secondary predictors. Our study demonstrates the utility of machine learning models for predicting PFAS in private wells and the classification random forest model based on nationally available predictors is readily extendable to other regions.

IMPORTANCE: Although there were no differences in mean visual acuity (VA) over 24 weeks after vitrectomy with panretinal photocoagulation (PRP) vs aflibercept in a randomized clinical trial among eyes with vitreous hemorrhage due to proliferative diabetic retinopathy (PDR), post hoc analyses may influence treatment choices. OBJECTIVE: To compare exploratory outcomes between treatment groups that may affect treatment choices for patients with vitreous hemorrhage due to PDR. DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis of a randomized clinical trial conducted at 39 DRCR Retina Network sites included adults with vision loss due to PDR-related vitreous hemorrhage for whom vitrectomy was considered. Data were collected from November 2016 to January 2020. INTERVENTIONS: Random assignment to 4 monthly injections of aflibercept vs vitrectomy with PRP. Both groups could receive aflibercept or vitrectomy during follow-up based on protocol-specific criteria. MAIN OUTCOMES AND MEASURES: Visual acuity area under the curve (adjusted for baseline VA) and clearance of vitreous hemorrhage. RESULTS: A total of 205 eyes were included in the analysis (115 male [56%] and 90 [44%] female participants; mean [SD] age, 57 [11] years). Among 89 eyes with a baseline VA of 20/32 to 20/160 (47 receiving aflibercept, including 4 [9%] that had undergone vitrectomy; 42 undergoing vitrectomy, including 3 [7%] that had received aflibercept), the adjusted mean difference in VA letter score over 24 weeks between the aflibercept and vitrectomy groups was −4.3 (95% CI, −10.6 to 1.9) compared with −16.7 (95% CI, −24.4 to −9.1) among 59 eyes with baseline VA worse than 20/800 (P = .02 for interaction; 26 in the aflibercept group, including 6 [23%] that had undergone vitrectomy; 33 in the vitrectomy group, including 8 [24%] that had received aflibercept). In the full cohort, the median time to clearance of the initial vitreous hemorrhage was 36 (interquartile range [IQR], 24-52) weeks in the aflibercept group vs 4 (IQR, 4-4) weeks in the vitrectomy group (difference, 32 [95% CI, 20-32] weeks; P

IMPORTANCE: The role of anti–vascular endothelial growth factor injections for the management of nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) has not been clearly established. OBJECTIVE: To determine the efficacy of intravitreous aflibercept injections compared with sham treatment in preventing potentially vision-threatening complications in eyes with moderate to severe NPDR. DESIGN, SETTING, AND PARTICIPANTS: Data for this study were collected between January 15, 2016, and May 28, 2020, from the ongoing DRCR Retina Network Protocol W randomized clinical trial, conducted at 64 US and Canadian sites among 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study severity level, 43-53), without CI-DME. Analyses followed the intent-to-treat principle. INTERVENTIONS: Eyes were randomly assigned to 2.0 mg of aflibercept injections (n = 200) or sham (n = 199) given at baseline; 1, 2, and 4 months; and every 4 months through 2 years. Between 2 and 4 years, treatment was deferred if the eye had mild NPDR or better. Aflibercept was administered in both groups if CI-DME with vision loss (≥10 letters at 1 visit or 5-9 letters at 2 consecutive visits) or high-risk proliferative diabetic retinopathy (PDR) developed. MAIN OUTCOMES AND MEASURES: Development of CI-DME with vision loss or PDR through May 2020, when the last 2-year visit was completed. RESULTS: Among the 328 participants (57.6% men [230 of 399 eyes]; mean [SD] age, 56 [11] years), the 2-year cumulative probability of developing CI-DME with vision loss or PDR was 16.3% with aflibercept vs 43.5% with sham. The overall hazard ratio for either outcome was 0.32 (97.5% CI, 0.21-0.50; P

OBJECTIVE: To evaluate pneumatic vitreolysis (PVL) in eyes with vitreomacular traction (VMT) with and without full-thickness macular hole (FTMH). DESIGN: Two multi-center (28 sites) studies: one randomized clinical trial comparing PVL with observation (sham injection) for VMT without FTMH (Protocol AG), and a single-arm study assessing PVL for closure of FTMH (Protocol AH). PARTICIPANTS: Participants were adults with central VMT in which the vitreomacular adhesion was 3000 μm or less. In AG, visual acuity (VA) was 20/32 to 20/400. In AH, eyes had FTMH (≤250 μm at the narrowest point) and VA of 20/25 to 20/400. INTERVENTION: PVL using C(3)F(8) gas. MAIN OUTCOME MEASURES: Central VMT release without rescue treatment at 24 weeks (AG). FTMH closure without rescue treatment at 8 weeks (AH). RESULTS: From October 2018 to February 2020, 46 participants were enrolled in AG and 35 eligible participants were enrolled in AH. Higher than expected rates of retinal detachments and tears resulted in early termination of both protocols. Combining studies, 7 of 59 (12% [95% CI, 6%–23%]; 2 in AG, 5 in AH) eyes that received PVL developed rhegmatogenous retinal detachment (6) or retinal tear (1). At 24 weeks in AG, 18 of 23 eyes in the PVL group (78%) versus 2 of 22 eyes in the sham group (9%) had central VMT release without rescue vitrectomy (adjusted risk difference = 66% [95% CI, 44%–88%], P < .001). The mean change in VA letter score from baseline at 24 weeks in AG was 6.7 in the PVL group and 6.1 in the sham group (adjusted difference = −0.8 [95% CI, −6.1 to 4.5], P=.77; negative values indicate greater improvement in sham group). In AH,10 of 35 eyes (29% [95% CI, 16%–45%]) had FTMH closure without rescue vitrectomy at 8 weeks. The mean change in VA from baseline at 8 weeks in AH was −1.5 letters (95% CI, −10.3 to 7.3). CONCLUSIONS: In most eyes with VMT, PVL induced hyaloid release. In eyes with FTMH, PVL resulted in hole closure in approximately one third of eyes. These studies were terminated early because of safety concerns related to retinal detachments and retinal tears. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT03677869, NCT03647267

Purpose To explore optical coherence tomography angiography (OCTA) quality and associated factors in multicenter clinical studies. Methods OCTA scans were obtained from participants with diabetic retinopathy from three DRCR Retina Network clinical studies using the Optovue AngioVue and ZEISS AngioPlex. Macular (3 × 3 mm and 6 × 6 mm) and optic nerve scans were captured. Quality was assessed by the Casey Reading Center. Scans were considered “poor” if the signal strength index (SSI) was less than 55 (AngioVue) or 7 (AngioPlex) or if excess motion, media opacities, beam defocus, incorrect axial position, or other artifacts were present. Results Included were 7539 scans from 787 eyes (461 participants). Sixty-one percent of scans were considered “good” (n = 4630). Of the 3 × 3-mm (n = 2294), 6 × 6-mm (n = 2705), and optic nerve scans (n = 2540), 62%, 63%, and 59%, respectively, were good. Differences in percentage of good scans by machine were not identified (61% of 6216 for the AngioVue and 63% of 1323 for the AngioPlex). The primary reason for poor scans was low SSI for the AngioVue (67%) and excess motion for the AngioPlex (47%). Good scans were associated with younger age (60 ± 12 years vs. 65 ± 11 years; P < 0.001), male gender (64% of males had good scans vs. 57% female; P = 0.007), and better visual acuity (ETDRS letter score 86.5 ± 6.4 [approximate Snellen equivalent 20/20] vs. 81.6 ± 9.7 [approximate Snellen equivalent 20/25]; P < 0.001). Conclusions Scan quality or analysis must be improved for OCTA metrics to be used as outcomes in future research. Translational Relevance Clinicians and researchers should be aware that poor SSI and artifacts are common issues for OCTA images.

Background: Over the next 25 years, the global prevalence of diabetes is expected to grow to affect 700 million individuals. Consequently, an unprecedented number of patients will be at risk for vision loss from diabetic eye disease. This demand will almost certainly exceed the supply of eye care professionals to individually evaluate each patient on an annual basis, signaling the need for 21st century tools to assist our profession in meeting this challenge. Methods: Review of available literature on artificial intelligence (AI) as applied to diabetic retinopathy (DR) detection and predictionResults: The field of AI has seen exponential growth in evaluating fundus photographs for DR. AI systems employ machine learning and artificial neural networks to teach themselves how to grade DR from libraries of tens of thousands of images and may be able to predict future DR progression based on baseline fundus photographs. Conclusions: AI algorithms are highly promising for the purposes of DR detection and will likely be able to reliably predict DR worsening in the future. A deeper understanding of these systems and how they interpret images is critical as they transition from the bench into the clinic.

Importance Vitreous hemorrhage from proliferative diabetic retinopathy can cause loss of vision. The best management approach is unknown. Objective To compare initial treatment with intravitreous aflibercept vs vitrectomy with panretinal photocoagulation for vitreous hemorrhage from proliferative diabetic retinopathy. Design, Setting, and Participants Randomized clinical trial at 39 DRCR Retina Network sites in the US and Canada including 205 adults with vison loss due to vitreous hemorrhage from proliferative diabetic retinopathy who were enrolled from November 2016 to December 2017. The final follow-up visit was completed in January 2020. Interventions Random assignment of eyes (1 per participant) to aflibercept (100 participants) or vitrectomy with panretinal photocoagulation (105 participants). Participants whose eyes were assigned to aflibercept initially received 4 monthly injections. Both groups could receive aflibercept or vitrectomy during follow-up based on protocol criteria. Main Outcomes and Measures The primary outcome was mean visual acuity letter score (range, 0-100; higher scores indicate better vision) over 24 weeks (area under the curve); the study was powered to detect a difference of 8 letters. Secondary outcomes included mean visual acuity at 4 weeks and 2 years. Results Among 205 participants (205 eyes) who were randomized (mean [SD] age, 57 [11] years; 115 [56%] men; mean visual acuity letter score, 34.5 [Snellen equivalent, 20/200]), 95% (195 of 205) completed the 24-week visit and 90% (177 of 196, excluding 9 deaths) completed the 2-year visit. The mean visual acuity letter score over 24 weeks was 59.3 (Snellen equivalent, 20/63) (95% CI, 54.9 to 63.7) in the aflibercept group vs 63.0 (Snellen equivalent, 20/63) (95% CI, 58.6 to 67.3) in the vitrectomy group (adjusted difference, −5.0 [95% CI, −10.2 to 0.3],P = .06). Among 23 secondary outcomes, 15 showed no significant difference. The mean visual acuity letter score was 52.6 (Snellen equivalent, 20/100) in the aflibercept group vs 62.3 (Snellen equivalent, 20/63) in the vitrectomy group at 4 weeks (adjusted difference, −11.2 [95% CI, −18.5 to −3.9],P = .003) and 73.7 (Snellen equivalent, 20/40) vs 71.0 (Snellen equivalent, 20/40) at 2 years (adjusted difference, 2.7 [95% CI, −3.1 to 8.4],P = .36). Over 2 years, 33 eyes (33%) assigned to aflibercept received vitrectomy and 34 eyes (32%) assigned to vitrectomy received subsequent aflibercept. Conclusions and Relevance Among participants whose eyes had vitreous hemorrhage from proliferative diabetic retinopathy, there was no statistically significant difference in the primary outcome of mean visual acuity letter score over 24 weeks following initial treatment with intravitreous aflibercept vs vitrectomy with panretinal photocoagulation. However, the study may have been underpowered, considering the range of the 95% CI, to detect a clinically important benefit in favor of initial vitrectomy with panretinal photocoagulation. Trial Registration ClinicalTrials.gov Identifier:NCT02858076

IMPORTANCE: Studies have not yet determined whether the distribution of lesions in the retinal periphery alters the association between the severity of diabetic retinopathy (DR) and macular vessel density. OBJECTIVE: To evaluate the association of DR lesion distribution with optical coherence tomography angiography (OCTA) metrics and DR severity. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional observational study was conducted at a tertiary care center for diabetic eye disease among 225 patients with type 1 or 2 diabetes who had undergone imaging between February 15, 2016, and December 31, 2019. EXPOSURES: Optical coherence tomography angiography 3 × 3-mm macular scans and ultra-widefield color imaging. MAIN OUTCOMES AND MEASURES: Optical coherence tomography angiography vessel density in the superficial capillary plexus, intermediate capillary plexus, and deep capillary plexus and choriocapillaris flow density. The severity of DR and the predominantly peripheral lesions (PPL) were evaluated from ultra-widefield color imaging. RESULTS: The study evaluated 352 eyes (225 patients; 125 men [55.6%]; mean [SD] age, 52.1 [15.1] years), of which 183 eyes (52.0%) had mild nonproliferative diabetic retinopathy (NPDR), 71 eyes (20.2%) had moderate NPDR, and 98 eyes (27.8%) had severe NPDR or proliferative diabetic retinopathy (PDR). In eyes with no PPL (209 [59.4%]), the mean (SD) vessel density in the superficial capillary plexus (mild NPDR, 38.1% [4.7%]; moderate NPDR, 36.4% [4.6%]; severe NPDR or PDR, 34.1% [4.1%]; P

Context Cognitive dysfunction is a growing and understudied public health issue in the aging type 1 diabetic population and is difficult and time-consuming to diagnose. Studies in long duration type 1 diabetes have reported the presence of proliferative diabetic retinopathy was associated with cognitive dysfunction. Objective This study assessed whether structural and vascular abnormalities of the retina, representing an extension of the central nervous system, are associated with cognitive impairment and other complications of type 1 diabetes. Methods An observational cross-sectional study of individuals with 50 or more years of type 1 diabetes (Joslin Medalist Study) was conducted at a university hospital in the United States. The study included 129 participants with complete cognitive testing. Validated cognitive testing measures included psychomotor speed, and immediate, and delayed memory. Optical coherence tomography (OCT) and OCT angiography (OCTA) were performed to obtain neural retinal layer thicknesses and vascular density for superficial (SCP) and deep retinal capillary plexus (DCP). Multivariable modeling was adjusted for potential confounders associated with outcomes in unadjusted analyses. Results Decreased vessel density of the SCP and DCP was associated with worse delayed memory (DCP: P = .002) and dominant hand psychomotor speed (SCP: P = .01). Thinning of the retinal outer nuclear layer was associated with worse psychomotor speed both in nondominant and dominant hands (P = .01 and P = .05, respectively). Outer plexiform layer thickness was associated with delayed memory (P = .04). Conclusion These findings suggest that noninvasive retinal imaging using OCT and OCTA may assist in estimating the risks for cognitive dysfunction in people with type 1 diabetes.