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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Optical coherence tomography angiography quantitative analysis of the effect of modified Buyang Huanwu Decoction on blood flow to the optic disc in patients with non-proliferative diabetic retinopathy / 国际眼科杂志(Guoji Yanke Zazhi)

AIM:To observe the clinical efficacy of modified Buyang Huanwu Decoction in treating non-proliferative diabetic retinopathy(NPDR)of qi and yin deficiency and stagnation of collaterals, and to quantitatively analyze the changes in peripapillary vessel density before and after treatment using optical coherence tomography angiography(OCTA).METHODS:A randomized controlled trial was used to collect a total of 58 patients(99 eyes)with qi and yin deficiency and stagnation of collaterals NPDR who visited our hospital from June 2022 to November 2022, and patients were randomly divided into an observation group(n=29, 51 eyes)and a control group(n=29, 48 eyes). The control group received basic treatment according to the recommendations for DR published by the American Academy of Ophthalmology in 2019(blood glucose control, diabetes health education, and regular follow-up for patients with mild NPDR; and add local/grid-like laser photocoagulation if necessary for patients with moderate NPDR), while the observation group received modified Buyang Huanwu Decoction in addition to the basic treatment for 1mo. The best-corrected visual acuity(BCVA), traditional Chinese medicine(TCM)efficacy, peripapillary telangiectasia vessel density(ppVD), and changes in peripapillary retinal nerve fiber layer(pRNFL)thickness were compared between the two groups before and after treatment.RESULTS:The BCVA(LogMAR)of the observation group was 0.20(0.10, 0.30)after 1mo of treatment, which was significantly improved compared with that of the control group of 0.30(0.20, 0.40; P&#x003C;0.05). The TCM efficacy in the observation group after 1mo of treatment was better than that in the control group(P&#x003C;0.05). The ppVD in all quadrants of the observation group showed a significant improvement at 1mo after treatment, and the ppVD in all quadrants of the observation group was higher than that of the control group(P&#x003C;0.05). The pRNFL thickness in the superior, temporal, and average peripapillary areas of the observation group increased after 1mo of treatment, and the pRNFL thickness in the superior, temporal, inferior quadrants, and average peripapillary area of the observation group was higher than that of the control group(P&#x003C;0.05).CONCLUSION:Modified Buyang Huanwu Decoction can improve visual acuity and enhance TCM efficacy in patients with NPDR of qi and yin deficiency and stagnation of collaterals. It may be related to its ability to improve ppVD and reduce damage to the pRNFL.

Correlation between blood biochemical parameters and choroidal thickness in patients with nonproliferative diabetic retinopathy / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To investigate the relationship between blood biochemical parameters and choroidal thickness(CT)in na&#x0026;#xEF;ve-treatment of patients with nonproliferative diabetic retinopathy(NPDR).METHODS: Prospective cross-sectional study. A total of 92 patients(92 eyes)with na&#x0026;#xEF;ve-treated NPDR were selected in the Affiliated Eye Hospital of Nanchang University from July 2021 to July 2022. All of the patients included in this study were subjected to ophthalmologic examination including enhanced depth imaging optical coherence tomography(EDI-OCT), best corrected visual acuity(BCVA), fundus fluorescence angiography, intraocular pressure, slit lamp and fundus examination. At the same time, they were also underwent hematological examination including blood glucose, glycosylated hemoglobin(HbA1c), serum creatinine, uric acid, urea, β2 microglobulin, high density lipoprotein(HDL), low density lipoprotein(LDL), serum calcium, serum potassium and other tests. According to the glomerular filtration rate(eGFR)and CT, the patients were divided into normal, mild and moderate to severe renal function group, pachychoroid group and the leptochoroid group. The blood biochemical indexes, CT differences and theirs correlation were analyzed in na&#x0026;#xEF;ve-treated NPDR patients.RESULTS: A total of 92 cases(92 eyes)were included in this study, with 51 males(51 eyes), 41 females(41 eyes), 45 right eyes and 47 left eyes. There was no significant difference in age, axial length and disease duration among the three groups(all P&#x003E;0.05). There were significant differences in nasal 0.5, 1.5mm, subfoveal and temporal 0.5, 1.5mm CT among three groups(all P&#x003C;0.05). There was no statistical significance in age, axial length and the course of disease between the pachychoroid and leptochoroid groups(all P&#x003E;0.05). There were significant differences in creatinine, eGFR, uric acid, urea, potassium and β2-microglobulin between the pachychoroid group and the leptochoroid group(all P&#x003C;0.05). There were no significant differences in total cholesterol, triglyceride, HDL, LDL, HbA1c, serum calcium and glucose between the two groups(all P&#x003E;0.05). CT was negatively correlated with creatinine, urea, uric acid and β2-microglobulin, and positively correlated with eGFR. Multiple regression analysis showed that the thicker the nasal 0.5mm CT, the higher the eGFR(B=0.292, P&#x003C;0.001). CT affected creatinine, eGFR, urea, uric acid and β2-microglobulin(B=16.5, 64.6, 24.1, 18.1, 20.3; P=0.008, &#x003C;0.001, &#x003C;0.001, 0.004, 0.001), while there were no significant effects on total cholesterol, triglyceride, glucose, serum calcium, HDL and LDL(all P&#x003E;0.05).CONCLUSION: In patients with na&#x0026;#xEF;ve-treated NPDR, the thicker the CT, the better the renal function. The decrease of CT in newly diagnosed NPDR patients is an important hint to pay attention to the renal function.

Comparison of Widefield Laser Ophthalmoscopy and ETDRS Retinal Area for Diabetic Retinopathy.

Purpose: To evaluate agreement of nonmydriatic confocal scanning laser ophthalmoscopy (SLO; EIDON [CenterVue]) and the 7-standard field ETDRS area on ultrawide-field (UWF) SLO imaging for identification of diabetic retinopathy (DR) severity. Design: Single-site, prospective, comparative, instrument validation study. Participants: One hundred ten eyes of 55 patients with diabetes mellitus were evaluated. Methods: Each patient underwent nonmydriatic, nonsimultaneous stereoscopic imaging using the EIDON camera and 4 fields of 60° × 55° were acquired (macula centered, disc centered, temporal macula, superotemporal). Mydriatic UWF retinal images were acquired using a nonsimultaneous stereographic protocol with UWF imaging (California; Optos plc). Before grading, a standardized ETDRS 7-field image mask was applied to all UWF retinal images. Images from each device were graded independently by 2 masked graders using the ETDRS clinical DR classification. Any discrepancy in DR grading between the devices was adjudicated by a third grader. Main Outcome Measures: κ Levels of agreement, sensitivity, and specificity for DR thresholds. Results: Severity by ETDRS grading was as follows: no DR, 10.9%; mild nonproliferative DR (NPDR), 45.5%; moderate NPDR, 16.5%; severe NPDR, 11.8%; proliferative DR, 12.7%; high-risk proliferative DR, 2.7%; and ungradable, 0%. After adjudication, the level of DR identified on EIDON images agreed exactly with that of UWF ETDRS imaging in 87% of eyes (n = 96) and was within 1 step in 99.1% of eyes (n = 109) with a simple κ value of 0.8244 ± 0.0439 (95% confidence interval [CI], 0.7385-0.9104) and weighted (linear) κ value of 0.9041 ± 0.0257 (95% CI, 0.8537-0.9545). Sensitivity and specificity compared with ETDRS field grading for any DR were 0.96 and 0.75, for moderate NPDR or worse were 0.96 and 0.97, and for severe NPDR or worse were 0.91 and 1.00, respectively. Conclusions: Nonmydriatic 4-field stereoscopic widefield imaging using the EIDON device was comparable with the DR severity identified within the ETDRS 7-standard field area of UWF images. Future studies will need to evaluate the applicability of this device as a clinical and research tool and the impact of different widefield coverage areas.

Alterations in the Choroidal Sublayers in Relationship to Severity and Progression of Diabetic Retinopathy: A Swept-Source OCT Study.

Purpose: To examine the association of baseline choroidal sublayers metrics with the risk of diabetic retinopathy (DR) progression over 2 years, with adjustment for confounding factors that affect choroidal measurements. Design: Prospective, observational cohort study. Participants: One hundred three eyes from 62 patients with diabetes mellitus (DM). Methods: Patients were followed up at 6-month intervals for at least 2 years. Choroidal metrics including choroidal area, choroidal thickness (CT), and choroidal vascularity index were measured for both (1) the choriocapillaris plus Sattler's layer and (2) the Haller's layer within the subfoveal and parafoveal region. Cox proportional models were constructed to estimate the relationship between baseline choroidal metrics and DR progression, adjusted for intereye correlation, established risk factors (i.e., duration of DM, glycated hemoglobin [HbA1c] level, body mass index [BMI], use of insulin, and mean arterial blood pressure [MABP]) and confounding factors of choroidal measurements (i.e., age and axial length). Additional predictive value of choroidal metrics was assessed using the C-statistic. Main Outcome Measures: Hazard ratios (HRs) calculated by Cox proportional hazards model to demonstrate the associations between baseline choroidal metrics and DR progression. Results: After adjusting for age, axial length, and intereye correlation, choroidal metrics in Haller's layer at baseline that were associated with a higher risk of DR progression included increases in subfoveal choroidal area (HR, 2.033; 95% confidence interval [CI], 1.179-3.505; P = 0.011), subfoveal plus parafoveal choroidal area (HR, 1.909; 95% CI, 1.096-3.326; P = 0.022), subfoveal CT (HR, 2.032; 95% CI, 1.181-3.498; P = 0.010), and subfoveal plus parafoveal CT (HR, 1.908; 95% CI, 1.097-3.319; P = 0.022). These associations remained statistically significant after additionally adjusting for duration of DM, HbA1c level, BMI, use of insulin, and MABP. Addition of these choroidal metrics significantly improved the discrimination for DR progression when compared with established risk factors alone (e.g., duration of DM and HbA1c; increase in C-statistic ranged from 8.08% to 9.67% [P < 0.05]). Conclusions: Eyes with a larger choroidal area and CT in Haller's layer at baseline were associated with a higher risk of DR progression over 2 years.

Proteomic profiling and correlations with clinical features reveal biomarkers indicative of diabetic retinopathy with diabetic kidney disease.

Diabetic retinopathy (DR) and diabetic kidney disease (DKD) are complications of diabetes and place serious health and economic burdens on society. However, the identification and characterization of early biomarkers for DKD, especially for nonproliferative DR (NPDR) patients with DKD, are still needed. This study aimed to demonstrate the plasma proteomic profiles of NPDR+DKD and NPDR patients and identify potential biomarkers for early diagnosis of DKD. Fifteen plasma samples from the NPDR group and nine from the NPDR+DKD group were analyzed by LC-MS/MS to identify the differentially expressed proteins between the two groups. Functional enrichment, protein-protein interaction and clinical feature correlation analyses revealed the target protein candidates, which were verified using ELISA and receiver operating characteristic (ROC) analysis. In total, 410 proteins were detected in plasma; 15 were significantly upregulated and 7 were downregulated in the NPDR+DKD group. Bioinformatics analysis suggested that DKD is closely related to cell adhesion and immunity pathways. ß-2-Microglobulin (B2M) and vimentin (VIM) were upregulated in NPDR+DKD, enriched as hub proteins and strongly correlated with clinical features. ELISA showed that B2M (p<0.001) and VIM (p<0.0001) were significantly upregulated in NPDR+DKD compared with NPDR. In ROC analysis, B2M and VIM could distinguish DKD from NPDR with area under the curve values of 0.9000 (p < 0.0001) and 0.9950. Our proteomic study revealed alterations in the proteomic profile and identified VIM and B2M as early biomarkers of DKD, laying the foundation for the prevention, diagnosis and treatment of DKD.

A Deep Learning Network for Classifying Arteries and Veins in Montaged Widefield OCT Angiograms.

Purpose: To propose a deep-learning-based method to differentiate arteries from veins in montaged widefield OCT angiography (OCTA). Design: Cross-sectional study. Participants: A total of 232 participants, including 109 participants with diabetic retinopathy (DR), 64 participants with branch retinal vein occlusion (BRVO), 27 participants with diabetes but without DR, and 32 healthy participants. Methods: We propose a convolutional neural network (CAVnet) to classify retinal blood vessels on montaged widefield OCTA en face images as arteries and veins. A total of 240 retinal angiograms from 88 eyes were used to train CAVnet, and 302 retinal angiograms from 144 eyes were used for testing. This method takes the OCTA images as input and outputs the segmentation results with arteries and veins down to the level of precapillary arterioles and postcapillary venules. The network also identifies their intersections. We evaluated the agreement (in pixels) between segmentation results and the manually graded ground truth using sensitivity, specificity, F1-score, and Intersection over Union (IoU). Measurements of arterial and venous caliber or tortuosity are made on our algorithm's output of healthy and diseased eyes. Main Outcome Measures: Classification of arteries and veins, arterial and venous caliber, and arterial and venous tortuosity. Results: For classification and identification of arteries, the algorithm achieved average sensitivity of 95.3%, specificity of 99.6%, F1 score of 94.2%, and IoU of 89.3%. For veins, the algorithm achieved average sensitivity of 94.4%, specificity of 99.7%, F1 score of 94.1%, and IoU of 89.2%. We also achieved an average sensitivity of 76.3% in identifying intersection points. The results show CAVnet has high accuracy on differentiating arteries and veins in DR and BRVO cases. These classification results are robust across 2 instruments and multiple scan volume sizes. Outputs of CAVnet were used to measure arterial and venous caliber or tortuosity, and pixel-wise caliber and tortuosity maps were generated. Differences between healthy and diseased eyes were demonstrated, indicating potential clinical utility. Conclusions: The CAVnet can classify arteries and veins and their branches with high accuracy and is potentially useful in the analysis of vessel type-specific features on diseases such as branch retinal artery occlusion and BRVO.

Oct biomarkers of treatment-naive diabetic macular edema in patients with non-proliferative and proliferative diabetic retinopathy.

PURPOSE: To evaluate and compare the retinal and choroidal spectral-domain optic coherence tomography (SD-OCT) findings of treatment-naïve diabetic macular edema (DME) secondary to non-proliferative and proliferative diabetic retinopathy (NPDR-PDR). MATERIAL AND METHODS: A hundred and thirty-eight eyes of 138 patients with DME were evaluated. Best-corrected visual acuity was recorded, biomicroscopic anterior and posterior segment examination, SD-OCT imaging, and fundus fluorescein angiography (FFA) were performed. Demographic features, OCT characteristics, FFA, and visual acuity measurements were evaluated and compared between the two groups. RESULTS: Sixteen eyes were excluded from the study due to the lack of FFA images. Data of 122 eyes were analyzed for the study. Sixty-five eyes with NPDR (Group 1) and 57 eyes with PDR (Group 2) were enrolled in the study. There was no significant difference in central macular thicknesses (CMT) between the two groups. The eyes with DME + PDR showed a higher rate of the diffuse type of macular edema with more para and peri-foveal extension accompanied by larger cysts than the eyes with DME + NPDR. Disorganization of retinal inner layers, disrupted ellipsoid zone, and the epiretinal membrane were more prominent in the eyes with PDR. Also, there were more prominent macular ischemia on FFA and worse initial visual acuity measurements in the eyes with PDR than those with NPDR. Choroidal thickness (CT) was significantly reduced in the PDR group. CONCLUSION: SD-OCT features of treatment-naïve DME in patients with NPDR and PDR presented some differences. These variations may be related to diabetic retinopathy severity and may provide information about prognosis.

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.

Review of the management of sight-threatening diabetic retinopathy during pregnancy.

Diabetes mellitus (DM) is a noncommunicable disease reaching epidemic proportions around the world. It affects younger individuals, including women of childbearing age. Diabetes can cause diabetic retinopathy (DR), which is potentially sight threatening when severe nonproliferative DR (NPDR), proliferative DR (PDR), or sight-threatening diabetic macular oedema (STDME) develops. Pregnancy is an independent risk factor for the progression of DR. Baseline DR at the onset of pregnancy is an important indicator of progression, with up to 10% of women with baseline NPDR progressing to PDR. Progression to sight-threatening DR (STDR) during pregnancy causes distress to the patient and often necessitates ocular treatment, which may have a systemic effect. Management includes prepregnancy counselling and, when possible, conventional treatment prior to pregnancy. During pregnancy, closer follow-up is required for those with a long duration of DM, poor baseline control of blood sugar and blood pressure, and worse DR, as these are risk factors for progression to STDR. Conventional treatment with anti-vascular endothelial growth factor agents for STDME can potentially lead to foetal loss. Treatment with laser photocoagulation may be preferred, and surgery under general anaesthesia should be avoided. This review provides a management plan for STDR from the perspective of practising ophthalmologists. A review of strategies for maintaining the eyesight of diabetic women with STDR with emphasis on prepregnancy counselling and planning, monitoring and safe treatment during pregnancy, and management of complications is presented.