Melatonin Attenuates Diabetic Retinopathy by Regulating EndMT of Retinal Vascular Endothelial Cells via Inhibiting the HDAC7/FOXO1/ZEB1 Axis.

Diabetic retinopathy (DR) is characterized as a microvascular disease. Nonproliferative diabetic retinopathy (NPDR) presents with alterations in retinal blood flow and vascular permeability, thickening of the basement membrane, loss of pericytes, and formation of acellular capillaries. Endothelial-mesenchymal transition (EndMT) of retinal microvessels may play a critical role in advancing NPDR. Melatonin, a hormone primarily secreted by the pineal gland, is a promising therapeutic for DR. This study explored the EndMT in retinal microvessels of NPDR and its related mechanisms. The effect of melatonin on the retina of diabetic rats was evaluated by electroretinogram (ERG) and histopathologic slide staining. Furthermore, the effect of melatonin on human retinal microvascular endothelial cells (HRMECs) was detected by EdU incorporation assay, scratch assay, transwell assay, and tube formation test. Techniques such as RNA-sequencing, overexpression or knockdown of target genes, extraction of cytoplasmic and nuclear protein, co-immunoprecipitation (co-IP), and multiplex immunofluorescence facilitated the exploration of the mechanisms involved. Our findings reveal, for the first time, that melatonin attenuates diabetic retinopathy by regulating EndMT of retinal vascular endothelial cells via inhibiting the HDAC7/FOXO1/ZEB1 axis. Collectively, these results suggest that melatonin holds potential as a therapeutic strategy to reduce retinal vascular damage and protect vision in NPDR.

A Nonrandomized Phase 2 Trial of EG-Mirotin, a Novel, First-in-Class, Subcutaneously Deliverable Peptide Drug for Nonproliferative Diabetic Retinopathy.

Background and objectives: EG-Mirotin (active ingredient EGT022) targets nonproliferative diabetic retinopathy (NPDR), the early stage of retinopathy. EG-Mirotin reverses capillary damage before NPDR progresses to an irreversible stage. EG-Mirotin safety and efficacy were investigated in patients with type 1 or type 2 diabetes mellitus and moderate to severe NPDR. Methods: In this open-label, single-arm, single-center, exploratory phase II study, 10 patients (20 eyes) received EG-Mirotin once a day (3 mg/1.5 mL sterile saline) for 5 days and were evaluated for ischemic index changes and safety. End of study was approximately 8 ± 1 weeks (57 ± 7 days) after the first drug administration. Results: EG-Mirotin injections were well tolerated, with no dose-limiting adverse events, serious adverse events, or deaths. Four treatment-emergent adverse events (TEAEs) unrelated to the investigational drug were observed in 2 out of 10 participants (20%) who had received the investigational drug. The overall average percent change in ischemic index at each evaluation point compared with baseline was statistically significant (Greenhouse-Geisser F = 9.456, p = 0.004 for the main effect of time), and a larger change was observed when the baseline ischemic index value was high (Greenhouse-Geisser F = 10.946, p = 0.002 for time × group interaction). Conclusions: The EG-Mirotin regimen established in this study was shown to be feasible and safe and was associated with a trend toward potential improvement in diabetes-induced ischemia and retinal capillary leakage.

Ocular Blood Flow Measurements in Diabetic Retinopathy Using 3D Pseudocontinuous Arterial Spin Labeling.

BACKGROUND: Distinguishing between the two broad categories of diabetic retinopathy (DR), nonproliferative DR (NPDR) and proliferative DR (PDR), is significant, as the therapeutic strategies for each are completely different. PURPOSE: To characterize the ocular blood flow (OBF) of DR patients and evaluate the potential utility of OBF values in categorizing DR. STUDY TYPE: Prospective. SUBJECTS: A total of 41 DR patients (82 eyes) were recruited in our study. Group 1 comprised 48 eyes with NPDR, and Group 2 comprised 34 eyes with PDR. FIELD STRENGTH/SEQUENCE: 3D pseudocontinuous arterial spin labeling (3D-pcASL) with two postlabeling delays (PLDs) was acquired at 3.0T MR. ASSESSMENT: OBF values were independently obtained by two doctors from the OBF map. STATISTICAL TESTS: OBF values and clinical characteristics were compared between the groups using two-sample t-tests and chi-square tests. Receiver operating characteristic (ROC) curves were obtained, and the area under the curve (AUC) was calculated. The consistency of OBF values reported by the two doctors was evaluated using the intraclass correlation coefficient (ICC). RESULTS: OBF values at PLDs of 1.5 seconds and 2.5 seconds were significantly lower in Group 2 than in Group 1 (P < 0.05 for both PLDs). The OBF values of Group 2 showed a greater increase than those of Group 1 from PLD 1.5 to 2.5 seconds. The AUC of OBF at the 1.5 seconds PLD was 0.90, with a cutoff of 7.73 mL/min/100 g, and the AUC of the OBF at the 2.5 seconds PLD was 0.75, with a cutoff of 8.44 mL/min/100 g. The ICC between the two observers was 0.844 for the OBF at 1.5 seconds PLD and 0.872 for the OBF at 2.5 seconds PLD. DATA CONCLUSION: PDR can be differentiated from NPDR by the value of OBF as measured by 3D-pcASL. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1.

Subthreshold Pan-Retinal Photocoagulation Using Endpoint Management Algorithm for Severe Nonproliferative Diabetic Retinopathy: A Paired Controlled Pilot Prospective Study.

PURPOSE: The aim of this study was to report the efficacy and safety profile of subthreshold pan-retinal photocoagulation (PRP) using endpoint management (EPM) algorithm compared with conventional threshold PASCAL PRP for the treatment of severe nonproliferative diabetic retinopathy (NPDR). METHODS: This was a prospective, single-center, paired randomized controlled trial of 56 eyes of 28 participants with bilateral symmetric severe NPDR. One eye of the participant was randomly assigned to receive the subthreshold EPM PRP, while the other eye of the same participant received the threshold PASCAL PRP. The primary outcome measures included the difference in the 1-year risk of progression to PDR between 2 groups, and mean changes of the logarithm of the minimal angle of resolution (logMAR) visual acuity (VA). The second outcome measures included central foveal thickness (CFT), 1-year risk of progression to PDR, and visual field (VF) parameters. RESULTS: The subthreshold EPM PRP group and the threshold PASCAL PRP group had similar 1-year risk of progression to PDR during the 12-month follow-up visits (17.86 vs. 14.29%, p > 0.05). Slightly decreased VA was found in both groups (0.08 vs. 0.09 logMAR VA); however, no statistical difference was found for neither group (p > 0.05). Similar results were found for thickened CFT for both groups (23.59 vs. 28.34 µm, p > 0.05). Specifically, although substantial loss of VF was found in the threshold PASCAL PRP group (p < 0.05), no obvious damage to VF was seen in the subthreshold EPM PRP group (p > 0.05). CONCLUSION: The subthreshold EPM PRP is noninferior to the conventional threshold PASCAL PRP in the treatment of severe NPDR during 12-month follow-up and could be an alternative treatment option for patients with severe NPDR.

Venous beading in two or more quadrants might not be a sensitive grading criterion for severe nonproliferative diabetic retinopathy.

PURPOSE: To determine whether venous beading (VB) in two or more quadrants is an appropriate grading criterion for severe nonproliferative diabetic retinopathy (NPDR). METHODS: A hospital-based, retrospective, cross-sectional study. A total of 806 patients admitted with diabetic retinopathy (DR) from January 2014 to April 2017 were included in this study. DR severity was graded by the international grading criterion. The status of VB, intraretinal microvascular abnormalities (IRMA), capillary nonperfusion, arteriovenous nicking, and diabetic macular edema was evaluated based on fundus fluorescein angiography. RESULTS: The prevalence of VB in eyes with proliferative diabetic retinopathy (PDR), severe NPDR, and moderate NPDR was 41.3% (327/791), 5.9% (31/526), and 0% (0/295), respectively (p < 0.001). Moreover, the proportion of VB in two or more quadrants was even lower (27.1% for PDR and 2.1% for severe NPDR, p < 0.001), and among the total of 225 eyes with VB in two or more quadrants, 214 eyes (95.1%) were graded as PDR. Furthermore, VB formation was significantly correlated with capillary nonperfusion, duration of diabetes (both p < 0.001), and smoking (p < 0.05). After adjusting for age, sex, and other possible factors, VB (OR = 7.479, p < 0.001) and IRMA (OR = 2.433, p < 0.001) were determined as independent risk factors for developing PDR. CONCLUSIONS: Our study suggested that VB in two or more quadrants might not be a sensitive grading criterion for severe NPDR among a Chinese population with type 2 diabetes. Nevertheless, VB has a great specificity to define an advanced form of DR.

Subclinical Macular Edema as a Predictor of Progression to Central-Involved Macular Edema in Type 2 Diabetes.

PURPOSE: The aim of this study was to examine the relationship between subclinical diabetic macular edema (SCME) and the development of central-involved macular edema (CIME) in patients with diabetes mellitus type-2 and mild nonproliferative diabetic retinopathy (NPDR), from 2 populations of different ethnicities. METHODS: Two hundred and five patients with diabetes mellitus type-2 and mild NPDR with no prior laser or intravitreal treatment were followed for 2 years or until the development of CIME. Ophthalmological examinations, including BCVA, fundus photography with RetmarkerDR analysis, and optical coherence tomography were performed at baseline and months 6, 12, and 24. RESULTS: One hundred and fifty eight eyes/patients reached either the study endpoint, CIME (n = 24), or performed the 24-month visit without developing CIME (n = 134). Fifty eyes/patients had SCME at baseline (31.6%). Of these 50 eyes, 16 (32.0%) developed CIME, whereas of the 108 eyes with normal retinal thickness (RT) at baseline, only 8 (7.4%) developed CIME (p < 0.001). Patients with increased RT in the central subfield at baseline showed a 12-fold risk of progression to CIME compared with patients without SCME. CONCLUSIONS: In patients with mild NPDR, the presence of SCME is a good predictor of progression to CIME.

Different Phenotypes of Mild Nonproliferative Diabetic Retinopathy with Different Risks for Development of Macular Edema (C-TRACER Study).

PURPOSE: To evaluate diabetic retinopathy (DR) progression in patients with diabetes mellitus type 2 in 2 populations of different ethnicity. METHODS: A prospective observational study was designed to follow eyes/patients with mild nonproliferative DR, for 2 years or until the development of central-involved macular edema (CIME), in 2 centers from different regions of the world. A total of 205 eyes/patients fulfilled the inclusion/exclusion criteria and were included in this study. Ophthalmological examinations, fundus photography with RetmarkerDR analysis, and optical coherence tomography were performed at baseline and at 6, 12 and 24 months. RESULTS: Of the 158 eyes/patients that completed this study, 24 eyes developed CIME and 134 eyes were present at the last study visit. Eighty-eight eyes (56.4%) were classified as phenotype A, 49 (31.4%) as phenotype B, and 19 (12.2%) as phenotype C. Phenotype A is associated with a very low risk for development of CIME in comparison with phenotypes B and C. The OR for development of CIME was 19.0 for phenotype B and 25.1 for phenotype C. CONCLUSION: Eyes in the initial stages of DR show different phenotypes with different risks of progression to ME. The phenotypes associated with increased risks of progression show different distributions in patients of different ethnicities.

Transplantation of IL-10-transfected endothelial progenitor cells improves retinal vascular repair via suppressing inflammation in diabetic rats.

PURPOSE: We aimed to evaluate the effect of IL-10 gene transfection on endothelial progenitor cells (EPCs) under inflammatory conditions, and explore the therapeutic potential of IL-10-transfected EPC transplantation on nonproliferative diabetic retinopathy (NPDR). METHODS: Lentivirus vectors encoding IL-10 were constructed and introduced into EPCs isolated from rat bone marrow. After exposure to recombinant rat TNF-α, abilities of nontransfected EPCs (non-EPCs) and EPCs transfected with normal control lentivirus (EPCs-GFP) or IL-10 expressing lentivirus (EPCs-IL-10-GFP) were assessed, including migration, adhesion, and tube formation. IL-10 production by EPCs-IL-10-GFP was determined by ELISA. Following 12 weeks after establishment of diabetes, diabetic rats were randomly injected with non-EPCs, EPCs-GFP, or EPCs-IL-10-GFP via tail vein. Expression of inflammatory factors and factors associated with nuclear factor-kappa B (NF-kB) signal pathway, retinal histological analysis, and retinal vascular permeability were assessed 2 weeks after transplantation. RESULTS: The detrimental effects of TNF-ɑ on the abilities of EPCs were significantly attenuated in EPCs-IL-10-GFP compared with non-EPCs and EPCs-GFP. The concentration of IL-10 in the EPCs-IL-10-GFP group was significantly higher than the non-EPCs and EPCs-GFP groups. Additionally, transplantation of EPCs-IL-10-GFP significantly inhibited inflammatory factors expression and activation of NF-kB signal pathway, improved retinal histological changes, and attenuated retinal vascular permeability. CONCLUSION: In conclusion, transplantation of IL-10-transfected EPCs significantly improved EPCs-mediated retinal vascular repair and subsequently suppressed NPDR progression. This was associated with inflammation suppression, at least partly via inhibiting the NF-kB signal pathway. Transplantation of IL-10-transfected EPCs may be a new strategy for treatment of NPDR.

Characterization and Automatic Discrimination between Predominant Hypoperfusion and Hyperperfusion Stages of NPDR.

BACKGROUND/OBJECTIVES: Diabetic retinopathy (DR) is a common diabetes complication that can lead to blindness through vision-threatening complications like clinically significant macular edema and proliferative retinopathy. Identifying eyes at risk of progression using non-invasive methods could help develop targeted therapies to halt diabetic retinal disease progression. METHODS: A set of 82 imaging and systemic features was used to characterize the progression of nonproliferative diabetic retinopathy (NPDR). These features include baseline measurements (static features) and those capturing the temporal dynamic behavior of these static features within one year (dynamic features). Interpretable models were trained to distinguish between eyes with Early Treatment Diabetic Retinopathy Study (ETDRS) level 35 and eyes with ETDRS levels 43-47. The data used in this research were collected from 109 diabetic type 2 patients (67.26 ± 2.70 years; diabetes duration 19.6 ± 7.26 years) and acquired over 2 years. RESULTS: The characterization of the data indicates that NPDR progresses from an initial stage of hypoperfusion to a hyperperfusion response. The performance of the classification model using static features achieved an area under the curve (AUC) of the receiver operating characteristics equal to 0.84 ± 0.07, while the model using both static and dynamic features achieved an AUC of 0.91 ± 0.05. CONCLUSION: NPDR progresses through an initial hypoperfusion stage followed by a hyperperfusion response. Characterizing and automatically identifying this disease progression stage is valuable and necessary. The results indicate that achieving this goal is feasible, paving the way for the improved evaluation of progression risk and the development of better-targeted therapies to prevent vision-threatening complications.

Correlation between vessel density and thickness in the retina and choroid of severe non-proliferative diabetic retinopathy patients.

Objectives: To explore the correlation between the vessel density (VD) of the retina and choroid vascular plexuses and the thicknesses of their respective retinal layers and choroid membranes in participants with severe non-proliferative diabetic retinopathy (NPDR). Methods: We retrospectively analyzed the data of 42 eyes of 42 participants with diabetes mellitus (DM) and severe NPDR. In addition, 41 eyes of 41 healthy controls were evaluated. Measurements were taken for both groups using optical coherence tomography angiography (OCTA), including the area and perimeter of the foveal vascular zone (FAZ) and the vascular density (VD) in the superficial capillary plexus (SCP), deep capillary plexus (DCP), and choroid capillary (CC). These measurements were compared with the retinal thickness (RT) of the inner/intermediate retinal layers and choroidal thickness (CT). The study evaluated the correlation between RT or CT and VD in the respective vascular networks, namely superficial capillary plexus (SCP), deep capillary plexus (DCP), or CC. Results: The inner RT and VD in all plexuses were significantly lower in the severe NPDR group than in the healthy controls. Furthermore, the FAZ area and perimeter were larger in the severe NPDR group. Inner RT was correlated with VD in the SCP group (r=0.67 and r=0.71 in the healthy control and severe NPDR groups, respectively; p<0.05). CT negatively correlated with VD in the CC (r=-0.697 and r=-0.759 in the healthy control and severe NPDR groups, respectively; p<0.05). Intermediate RT significantly correlated with VD in the DCP of the severe NPDR group (r=-0.55, p<0.05), but not in the healthy control group. Conclusions: Retinal or choroidal thickness strongly correlated with VD. Therefore, patients with severe NPDR must consider the distinct anatomical and functional entities of the various retinal layers and the choroid.

Impact of Bariatric Surgery on Treatment Burden and Progression of Diabetic Retinopathy.

Purpose: To assess the severity, progression, and treatment burden of diabetic retinopathy (DR) in patients after bariatric surgery compared with controls. Methods: A retrospective cohort study was performed of patients with type 2 diabetes and DR seen at the Duke Eye Center between 2014 and 2023. Clinical data included hemoglobin A1c (HbA1c), diagnostic stage of DR, diabetic macular edema (DME) or vitreous hemorrhage (VH), visual acuity (VA), and treatment burden at baseline and follow-up. Generalized estimating equation analysis was used to account for the correlation between 2 eyes of the same patient. Results: Sixteen patients who had bariatric surgery were matched by age, sex, and duration of diabetes with 60 control patients managed medically during the same time period. The HbA1c level, severity of DR, presence of DME or VH, VA, and treatment burden were not significantly different (all P > .05) at the baseline examination. On average, patients were followed for 6 years. The HbA1c level at the follow-up was significantly lower in the bariatric surgery group (6.4% vs 8.5%; P < .001). At the follow-up, the treatment burden was reduced in the bariatric surgery group compared with the control group (P = .04). There was a clear trend toward reduced progression of DR and treatment burden in the bariatric surgery group over the follow-up. Conclusions: Bariatric surgery may improve glycemic control, stabilize DR progression, and reduce the treatment burden, which may have a significant impact on quality of life for patients with DR.

Efficacy and safety of intravitreal injection of conbercept for moderate to severe nonproliferative diabetic retinopathy.

Purpose: This study aimed to assess the effectiveness and safety of intravitreal injection of conbercept (IVC) in treating moderate to severe nonproliferative diabetic retinopathy (NPDR), with or without accompanying diabetic macular edema. Methods: In this longitudinal retrospective study, 35 patients (50 eyes) with moderate to severe NPDR and Diabetic Retinopathy Severity Scale (DRSS) scores between 43 and 53 were treated at the Department of Ophthalmology, First Affiliated Hospital of Kunming Medical University, from October 2018 to January 2023. Treatment protocol included three monthly IVC injections followed by a pro re nata (PRN) regimen over a two-year follow-up period. Outcome measures were best-corrected visual acuity (BCVA), intraocular pressure, central macular thickness (CMT), extent of hard exudate (HE), and changes in DRSS scores. DRSS scores before and after treatment were analyzed using the Wilcoxon rank-sum test. Both systemic and ocular adverse events were meticulously documented to ascertain safety. Results: From baseline to the final follow-up, the mean BCVA improved from 0.41 ± 0.39 to 0.23 ± 0.20 logMAR (p<0.05). The mean CMT decreased from 306.22 ± 77.40 to 297.97 ± 88.15 µm (p = 0.385). At 24 months, DRSS scores improved by ≥1 stage in 40 eyes (80%), ≥ 2 stages in 28 eyes (56%), ≥3 stages in 10 eyes (20%), and remained stable in 6 eyes (12%). The DRSS scores at each follow-up interval demonstrated statistically significant improvement from baseline (p<0.05). In 15 of 27 eyes (55.56%) with diabetic macular edema (DME), there was a significant reduction in the mean area of HE from baseline (p<0.05). No serious systemic adverse events were observed. Conclusion: IVC is an effective and safe treatment for moderate to severe NPDR, demonstrating significant improvements in DRSS scores.

Deep Capillary Nonperfusion on OCT Angiography Predicts Complications in Eyes with Referable Nonproliferative Diabetic Retinopathy.

OBJECTIVE: To evaluate the ability of capillary nonperfusion parameters on OCT angiography (OCTA) to predict the development of clinically significant outcomes in eyes with referable nonproliferative diabetic retinopathy (NPDR). DESIGN: Prospective longitudinal observational study. SUBJECTS: In total, 59 patients (74 eyes) with treatment-naive moderate and severe (referable) NPDR. METHODS: Patients were imaged with OCTA at baseline and then followed-up for 1 year. We evaluated 2 OCTA capillary nonperfusion metrics, vessel density (VD) and geometric perfusion deficits (GPDs), in the superficial capillary plexus, middle capillary plexus (MCP), and deep capillary plexus (DCP). We compared the predictive accuracy of baseline OCTA metrics for clinically significant diabetic retinopathy (DR) outcomes at 1 year. MAIN OUTCOME MEASURES: Significant clinical outcomes at 1 year, defined as 1 or more of the following-vitreous hemorrhage, center-involving diabetic macular edema, and initiation of treatment with pan-retinal photocoagulation or anti-VEGF injections. RESULTS: Overall, 49 patients (61 eyes) returned for the 1-year follow-up. Geometric perfusion deficits and VD in the MCP and DCP correlated with clinically significant outcomes at 1 year (P < 0.001). Eyes with these outcomes had lower VD and higher GPD, indicating worse nonperfusion of the deeper retinal layers than those that remained free from complication. These differences remained significant (P = 0.046 to < 0.001) when OCTA parameters were incorporated into models that also considered sex, baseline corrected visual acuity, and baseline DR severity. Adjusted receiver operating characteristic curve for DCP GPD achieved an area under the curve (AUC) of 0.929, with sensitivity of 89% and specificity of 98%. In a separate analysis focusing on high-risk proliferative diabetic retinopathy outcomes, MCP and DCP GPD and VD remained significantly predictive with comparable AUC and sensitivities to the pooled analysis. CONCLUSIONS: Evidence of deep capillary nonperfusion at baseline in eyes with clinically referable NPDR can predict short-term DR complications with high accuracy, suggesting that deep retinal ischemia has an important pathophysiologic role in DR progression. Our results suggest that OCTA may provide additional prognostic benefit to clinical DR staging in eyes with high risk.

Novel risk score model for non-proliferative diabetic retinopathy based on untargeted metabolomics of venous blood.

Background and Purpose: Nonproliferative diabetic retinopathy (NPDR) occurs in the early stages of Diabetic retinopathy (DR), and the study of its metabolic markers will help to prevent DR. Hence, we aimed to establish a risk score based on multiple metabolites through untargeted metabolomic analysis of venous blood from NPDR patients and diabetic non-DR patients. Experimental Approach: Untargeted metabolomics of venous blood samples from patients with NPDR, diabetes melitus without DR were performed using high-performance liquid chromatography-mass spectrometry. Results: Detailed metabolomic evaluation showed distinct clusters of metabolites in plasma samples from patients with NPDR and diabetic non-DR patients. NPDR patients had significantly higher levels of phenylacetylglycine, L-aspartic acid, tiglylglycine, and 3-sulfinato-L-alaninate, and lower level of indolelactic acid, threonic acid, L-arginine (Arg), and 4-dodecylbenzenesulfonic acid compared to control. The expression profiles of these eight NPDR risk-related characteristic metabolites were analyzed using Cox regression to establish a risk score model. Subsequently, univariate and multivariate Cox regression analyses were used to determine that this risk score model was a predictor of independent prognosis for NPDR. Conclusions: Untargeted metabolome analysis of blood metabolites revealed unreported metabolic alterations in NPDR patients compared with those in diabetic non-DR patients or MH. In the venous blood, we identified depleted metabolites thA and Arg, indicating that they might play a role in NPDR development.

The effect of calcium dobesilate combined with hypoglycemic drugs in the treatment of cataract NPDR and its effect on fundus microcirculation and blood ICAM-1, MCP-1 and MIF levels.

Background: To explore the effect of calcium dobesilate combined with hypoglycemic drugs in the treatment of cataract complicated with non-proliferative diabetic retinopathy (NPDR) and its effects on fundus microcirculation, intercellular adhesion molecule 1 (ICAM-1), mono - cyte chemoattractant protein 1 (MCP-1), and macrophage migration inhibitory factor (MIF). Methods: From March 2019 to January 2021, a total of 114 patients with cataract and NPDR were included, and the patients were assigned into the control and the observation groups by random number table method, with 57 cases/group. The control was given hypoglycemic drugs, and the observation was given calcium dobesilate combined therapy. The therapeutic efficacy, blood glucose and blood lipid levels, fluorescein fundus angiography results, fundus microcirculation indexes, retinal neovascularizationrelated factors, and ICAM-1, MCP-1, and MIF levels before and after treatment were compared between the two groups. Results: The total effective rate of treatment in the observation was higher vs. the control (P < 0.05); Fasting blood glucose (FBG), 2 h postprandial blood glucose (2hPG), glycosylated hemoglobin (HbA1c), triglyceride (TG), total cholesterol (TC) and low density lipoprotein (LDL) in the observation after treatment were reduced vs. the control (P < 0.05); The number of micro-hemangiomas in the observation after treatment was less vs. the control, and the area of hemorrhage, the area of exudation and the thickness of the yellow plate were smaller vs. the control (P < 0.05); The resistance index (RI) value of the observation after treatment was lower than the control, and the end-diastolic blood flow velocity (EDV) and the peak systolic blood flow velocity (PSV) of the observation were higher vs. the control (P < 0.05). ICAM-1, MCP-1, MIF, vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF1) in the observation after treatment were reduced vs. the control, but pigment epithelium-derived factor (PEDF) were higher vs. the control (P < 0.05); one case of gastrointestinal reaction took place in the observation, but no adverse reaction occurred in the control, and no clear difference exhibited in the incidence of adverse reactions between the two groups (P > 0.05). Conclusions: Calcium dobesilate combined with hypoglycemic drugs has good clinical efficacy in the treatment of cataract complicated with NPDR, which can effectively reduce the level of blood glucose and blood lipids, reduce inflammation, and mitigate the microcirculation of branch retinal vein occlusion lesions.

Developing and Validating Models to Predict Progression to Proliferative Diabetic Retinopathy.

Purpose: To develop models for progression of nonproliferative diabetic retinopathy (NPDR) to proliferative diabetic retinopathy (PDR) and determine if incorporating updated information improves model performance. Design: Retrospective cohort study. Participants: Electronic health record (EHR) data from a tertiary academic center, University of California San Francisco (UCSF), and a safety-net hospital, Zuckerberg San Francisco General (ZSFG) Hospital were used to identify patients with a diagnosis of NPDR, age ≥ 18 years, a diagnosis of type 1 or 2 diabetes mellitus, ≥ 6 months of ophthalmology follow-up, and no prior diagnosis of PDR before the index date (date of first NPDR diagnosis in the EHR). Methods: Four survival models were developed: Cox proportional hazards, Cox with backward selection, Cox with LASSO regression and Random Survival Forest. For each model, three variable sets were compared to determine the impact of including updated clinical information: Static0 (data up to the index date), Static6m (data updated 6 months after the index date), and Dynamic (data in Static0 plus data change during the 6-month period). The UCSF data were split into 80% training and 20% testing (internal validation). The ZSFG data were used for external validation. Model performance was evaluated by the Harrell's concordance index (C-Index). Main Outcome Measures: Time to PDR. Results: The UCSF cohort included 1130 patients and 92 (8.1%) patients progressed to PDR. The ZSFG cohort included 687 patients and 30 (4.4%) patients progressed to PDR. All models performed similarly (C-indices ∼ 0.70) in internal validation. The random survival forest with Static6m set performed best in external validation (C-index 0.76). Insurance and age were selected or ranked as highly important by all models. Other key predictors were NPDR severity, diabetic neuropathy, number of strokes, mean Hemoglobin A1c, and number of hospital admissions. Conclusions: Our models for progression of NPDR to PDR achieved acceptable predictive performance and validated well in an external setting. Updating the baseline variables with new clinical information did not consistently improve the predictive performance. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Artificial Intelligence Detection of Diabetic Retinopathy: Subgroup Comparison of the EyeArt System with Ophthalmologists' Dilated Examinations.

Objective: To compare general ophthalmologists, retina specialists, and the EyeArt Artificial Intelligence (AI) system to the clinical reference standard for detecting more than mild diabetic retinopathy (mtmDR). Design: Prospective, pivotal, multicenter trial conducted from April 2017 to May 2018. Participants: Participants were aged ≥ 18 years who had diabetes mellitus and underwent dilated ophthalmoscopy. A total of 521 of 893 participants met these criteria and completed the study protocol. Testing: Participants underwent 2-field fundus photography (macula centered, disc centered) for the EyeArt system, dilated ophthalmoscopy, and 4-widefield stereoscopic dilated fundus photography for reference standard grading. Main Outcome Measures: For mtmDR detection, sensitivity and specificity of EyeArt gradings of 2-field, fundus photographs and ophthalmoscopy grading versus a rigorous clinical reference standard comprising Reading Center grading of 4-widefield stereoscopic dilated fundus photographs using the ETDRS severity scale. The AI system provided automatic eye-level results regarding mtmDR. Results: Overall, 521 participants (999 eyes) at 10 centers underwent dilated ophthalmoscopy: 406 by nonretina and 115 by retina specialists. Reading Center graded 207 positive and 792 eyes negative for mtmDR. Of these 999 eyes, 26 eyes were ungradable by the EyeArt system, leaving 973 eyes with both EyeArt and Reading Center gradings. Retina specialists correctly identified 22 of 37 eyes as positive (sensitivity 59.5%) and 182 of 184 eyes as negative (specificity 98.9%) for mtmDR versus the EyeArt AI system that identified 36 of 37 as positive (sensitivity 97%) and 162 of 184 eyes as negative (specificity of 88%) for mtmDR. General ophthalmologists correctly identified 35 of 170 eyes as positive (sensitivity 20.6%) and 607 of 608 eyes as negative (specificity 99.8%) for mtmDR compared with the EyeArt AI system that identified 164 of 170 as positive (sensitivity 96.5%) and 525 of 608 eyes as negative (specificity 86%) for mtmDR. Conclusions: The AI system had a higher sensitivity for detecting mtmDR than either general ophthalmologists or retina specialists compared with the clinical reference standard. It can potentially serve as a low-cost point-of-care diabetic retinopathy detection tool and help address the diabetic eye screening burden.

Clinically Significant Nonperfusion Areas on Widefield OCT Angiography in Diabetic Retinopathy.

Purpose: To investigate the distribution of clinically significant nonperfusion areas (NPAs) on widefield OCT angiography (OCTA) images in patients with diabetes. Design: Prospective, cross-sectional, observational study. Participants: One hundred and forty-four eyes of 114 patients with diabetes. Methods: Nominal 20 × 23 mm OCTA images were obtained using a swept-source OCTA device (Xephilio OCT-S1), followed by the creation of en face images 20-mm (1614 pixels) in diameter centering on the fovea. The nonperfusion squares (NPSs) were defined as the 10 × 10 pixel squares without retinal vessels, and the ratio of eyes with the NPSs to all eyes in each square was referred to as the NPS ratio. The areas with probabilistic differences (APD) for proliferative diabetic retinopathy (PDR) and nonproliferative diabetic retinopathy (NPDR) (APD[PDR] and APD[NPDR]) were defined as sets of squares with higher NPS ratios in eyes with PDR and NPDR, respectively. The P ratio (NPSs within APD[PDR] but not APD[NPDR]/all NPSs) was also calculated. Main Outcome Measures: The probabilistic distribution of the NPSs and the association with diabetic retinopathy (DR) severity. Results: The NPSs developed randomly in eyes with mild and moderate NPDR and were more prevalent in the extramacular areas and the temporal quadrant in eyes with severe NPDR and PDR. The APD(PDR) was distributed mainly in the extramacular areas, sparing the areas around the vascular arcades and radially peripapillary capillaries. The APD(PDR) contained retinal neovascularization more frequently than the non-APD(PDR) (P = 0.023). The P ratio was higher in eyes with PDR than in those with NPDR (P < 0.001). The multivariate analysis designated the P ratio (odds ratio, 8.293 × 107; 95% confidence interval, 6.529 × 102-1.053 × 1013; P = 0.002) and the total NPSs (odds ratio, 1.002; 95% confidence interval, 1.001-1.003; P < 0.001) as independent risk factors of PDR. Most eyes with NPDR and 4-2-1 rule findings of DR severity had higher P ratios but not necessarily greater NPS numbers. Conclusions: The APD(PDR) is uniquely distributed on widefield OCTA images, and the NPA location patterns are associated with DR severity, independent of the entire area of NPAs. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Efficacy of intravitreal conbercept combined with panretinal photocoagulation for severe nonproliferative diabetic retinopathy without macular edema.

AIM: To assess efficacy of intravitreal conbercept (IVC) injection in combination with panretinal photocoagulation (PRP) vs PRP alone in patients with severe nonproliferative diabetic retinopathy (SNPDR) without macular edema (ME). METHODS: Forty-eight patients with SNPDR without ME (56 eyes) were divided into the PRP group and IVC+PRP group (the pulse group) in this retrospective clinical study. Conbercept was intravitreally administered to patients in the pulse group 1wk before treatment with PRP and followed up for 1, 3, and 6mo. The best-corrected visual acuity (BCVA, logMAR), center foveal thickness (CFT), visual acuity (VA) improvement, and adverse reactions were compared between groups. RESULTS: In the PRP group, the BCVA reduced at 1 and 3mo before improving at 6mo. In the pulse group, baseline BCVA decreased continuously at 1mo, increased at 3 and 6mo. BCVA in the pulse group was better than that in the PRP group at 1, 3, and 6mo. There was an increase in CFT in the PRP group during follow-up compared with baseline. In the pulse group, CFT was increased at 1mo relative to baseline, steadily decreased to the baseline level at 3 and 6mo. There was a more significant reduction in CFT in the pulse group during follow-up compared with the PRP group. The effective rates of VA in the PRP and the pulse groups were 81.48% and 100%, respectively. CONCLUSION: As PRP pretreatment, a single dose of IVC administration has beneficial effects for preventing PRP-induced foveal thickening and increasing VA in patients with SNPDR without ME.

Update on Management of Non-proliferative Diabetic Retinopathy without Diabetic Macular Edema; Is There a Paradigm Shift?

Diabetic retinopathy (DR) is the major cause of visual impairment and blindness in the working-age population. Conventional management for nonproliferative diabetic retinopathy (NPDR) without diabetic macular edema (DME) is derived from the findings of the Early Treatment Diabetic Retinopathy Study (ETDRS). Although the ETDRS protocol basically includes observation, selected cases of severe NPDR may undergo scatter laser photocoagulation. Post-hoc analysis of recent trials has shown that patients with NPDR receiving intravitreal anti-vascular endothelial growth factor (anti-VEGF) for DME would experience improvement in the DR severity scale (DRSS). In addition, recent randomized trials (PANORAMA and Protocol W) have revealed that early intervention with intravitreal aflibercept in eyes with moderately severe to severe NPDR is associated with significant improvement in DRSS and reduced vision-threatening complications of DR. Based on recent studies, it seems that the therapeutic approach to NPDR may undergo a substantial change and a paradigm shift toward considering early intervention with the administration of intravitreal anti-VEGF injections. However, the long-term results and the duration of adherence to anti-VEGF therapy for eyes with NPDR are not yet defined. It is also not apparent whether improvement in DRSS is a true disease modification. Studies showed that DRSS improvement is not associated with retinal reperfusion. In addition, DRCR.net Protocol W showed no visual acuity benefit with the early intravitreal aflibercept injection in moderate to severe NPDR as compared with performing observation plus intravitreal aflibercept applied only after progression to proliferative DR or vision-impairing DME. The cost-benefit ratio is also a challenge. Herein, we look at different aspects of early anti-VEGF application and discuss its pros and cons in the process of treating NPDR.