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Background The objective of this study was to evaluate pattern and distribution of neovascularization of optic disc (NVD) and elsewhere (NVE) in proliferative diabetic retinopathy (PDR). Methods A cross-sectional study was conducted among freshly detected cases of PDR. Fundus fluorescein angiographic images of 61 eyes were assessed. Parameters studied for NVD were their number and location and for NVE were their number, location, type of leak, and distance from center of optic disc. Results Of 61 eyes, 29 eyes (47.5%) had NVD with a total of 49 leaks. Of these 49 NVD leaks, the maximum was concentrated in the superotemporal quadrant with 21 leaks (42.9%; 95%CI 28.8–57.8%). Of 61 eyes, 50 eyes (82%) had NVE with 97 leaks. Of 97 NVE leaks, 41 were found in the superotemporal quadrant (42.3%; 95%CI 32.3–52.7%). Maximum NVE was found within the circle of radius 3–6 mm centered on optic disc (p value = 0.001) with no leaks in central macula. Of 29 eyes with NVD, only 7 eyes had >1/3 area of disc involvement. Also, of 18 eyes with concurrent NVD and NVE, only 2 eyes had >1/3 area of disc involvement which is a high-risk characteristic of PDR. Conclusion Neovascular lesions have a predilection for superotemporal part for both NVD and NVE. NVE leaks were almost double the number of NVD leaks. Maximum NVE leaks were found at posterior pole with no central macular involvement. This study provides comprehensive data and further adds to knowledge of neovascularization for early diagnosis and management of PDR.

Purpose To describe two cases of catastrophic, bilateral retinal vascular occlusion following intravitreal (IVT) bevacizumab injection. Methods Case series. Main outcome measures included clinical and fluorescein angiography (FA) findings. Results Case 1 - A 65-year-old woman with calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasis (CREST) syndrome developed acute, severe, bilateral visual loss two weeks following bilateral IVT bevacizumab injection for proliferative diabetic retinopathy. Examination and FA revealed moderate anterior chamber inflammation, bilateral perivascular retinal hemorrhages and near total retinal vascular occlusion. Extensive testing revealed moderately elevated anti-B2 glycoprotein (antiphospholipid) antibodies. Case 2 - An 85-year-old man with polymyalgia rheumatica and left eye exudative age-related macular degeneration experienced severe, bilateral, sequential visual loss in the left then right eye approximately three weeks following IVT bevacizumab left eye injection. Examination revealed bilateral panuveitis, diffuse perivascular exudates, and intraretinal hemorrhages. FA showed diffuse venous leakage. Extensive testing revealed an elevated anti-nuclear antibody and mildly elevated anti-cardiolipin antibody. Conclusion Patients with underlying retinal vascular vulnerabilities may be at increased risk of catastrophic, bilateral retinal vascular occlusion following treatment with IVT bevacizumab. The moderate to severe intraocular inflammation in both cases, and the contralateral involvement following unilateral IVT injection in Case 2, suggest a possible delayed immune-mediated mechanism.

Diabetic Retinopathy (DR) is the condition caused due to uncontrolled diabetes that can lead to vision impairment. It greatly affects the retinal blood vessels and diminishes the fundus light-sensitive inner coating. Early diagnosis and regular screening of this disease are essential for prompt processing through artificial intelligence techniques. This paper targets assessing the latest techniques for screening and diagnosing DR, including 94 articles based on the Detection and grading of DR. For every analyzed approach, tables are summarized detailing imaging procedure used, datasets, performance metrics used. The research gaps are also highlighted in this paper. Despite the consistent progression and methods actualized in this field, a couple of issues actually should be centered on. The noise and contrast of the image in Image enhancement are still in the infancy stage for high resolution. This study covers a review of existing image techniques, the gold standard and private datasets available, performance measures used for detection and grading of DR. Now the future research focuses on the amalgamation of the dataset as well as techniques to make the generalized technique for detecting the lesion in DR through an automated system. Moreover, various research gaps have also been taken into account for further research. This review is beneficial to the researchers working in the field of medical imaging to screen and diagnose diseases.

In order to evaluate the accuracy of commercially available handheld fundus cameras for a variety of ophthalmic diagnoses, we conducted a systematic review, searching PubMed and PubMed Central and performing a bivariate analysis to determine the pooled sensitivity and specificity of handheld fundus cameras. Eleven studies validating handheld fundus cameras against a gold-standard method for disease diagnosis were included. For nonmydriatic images, pooled sensitivity was 83% (95% confidence interval (CI): 77-88%) and specificity was 92% (95% CI: 79-97%). For mydriatic images, pooled sensitivity was 87% (95% CI: 79-92%) and specificity was 90% (95% CI: 78-96%). Overall pooled sensitivity was 85% (95% CI: 80-89%) and specificity was 91% (95% CI: 83-95%). Of the 11 studies included, 5 assessed the diagnosis of diabetic retinopathy, for which sensitivity was 87% (95% CI: 80-92%) and specificity was 95% (95% CI: 85-98%). For all other diagnoses combined, sensitivity was 81% (95% CI: 74-87%) and specificity was 83% (95% CI: 76-89%). These findings suggest that handheld fundus cameras are capable of achieving acceptable sensitivity and specificity values for eye disease, with mydriatic images being more sensitive for disease. Diabetic retinopathy was the single diagnosis with the strongest data to support the use of handheld fundus cameras for disease screening.

Diabetic retinopathy (DR) is one of the most common retinal diseases that cause preventable blindness in diabetic patients. The timely screening and grading of retinal images minimize the possibility of vision loss. However, manual screening of retinal images, for detecting micro lesions in the early stages of DR, is time-consuming. This paper proposes an ensemble of deep convolutional neural network (CNN) models for accurate detection and grading of DR using fundus images. Each input image is divided into four patches at the first stage and passed on to pre-trained CNN models (InceptionV3, Xception) for training. The relevant features in the shallow-dense layers of CNN models are utilized as prior knowledge. The integration of shallow and dense layer features helps the model learn the significant information of DR images. At the second stage, a classifier based on artificial neural network is trained using the fused probability vectors of four patches. The results of individual CNN models are combined to generate the final decision in the third stage. This ensemble approach of multi-stage deep learning model improves the overall classification accuracy of diabetic retinopathy grading. Among the five different classification schemes presented in this paper, multistage patch-based deep CNN (MPDCNN), in which local patch-based and holistic details of fundus image are concatenated, provides the best classification accuracy. This ensemble classifier exhibits 96.2 % classification accuracy with fivefold cross-validation.

Background Diabetic retinopathy is a principal cause of visual damage and blindness, in which laser treatment offers proven therapy. The progressive degeneration of the retina, secondary to diabetes, is believed to cause postural instability although this is not well documented. The aim of this research was to assess how optic flow stimuli contribute to the control of stance in people with impaired retinal functions. Research question Does the different retinal functionality correspond to different specific patterns of movements and muscles recruitment? Methods Postural mechanisms and motor strategies were measured by testing subjects in quiet stance on a force platform with surface electromyography under different optic flow stimulations. Root mean square values of the center of pressure time-varying signals and normalized EMG values were used to evaluate the postural sway. Results People with diabetic retinopathy, and to a greater extent laser group, were more unstable than healthy subjects. The greater amplitude of the body sway observed in the retinopathy group, and especially in the laser group, could be an expression of the difficulty for this population in processing this kind of visual information. Significance The increase in muscle activity indicates that there are musculoskeletal and postural changes in the lower limb musculature with increasing severity of diabetic retinopathy. An impaired retinal function might negatively affect postural control in a way that is dependent on the severity of retinal damage.

Objective This study was designed to evaluate potential differences in circumpapillary retinal nerve fibre layer (cpRNFL) thickness and segmented macular retinal layers between dominant and nondominant eyes on spectral-domain optical coherence tomography in a pediatric population. Design Cross-sectional study. Participants 89 healthy children attending a general pediatric clinic. Methods Participants underwent sighting dominant testing and macular and cpRNFL spectral-domain optical coherence tomography. Segmented macular layer thicknesses and cpRNFL thickness were compared for individual patients based on their ocular dominance. Results Ocular dominance occurred particularly in the right eye (64.7%). Dominant and nondominant eyes did not differ significantly in axial length or spherical equivalent refraction; axial length: 22.99 ± 1.17 mm versus 22.98 ± 1.19 mm; p = 0.51 and spherical equivalent refraction: −0.09 ± 2.68 D versus 0.32 ± 2.93 D; p = 0.41. In the comparison of the macular ganglion layer the average thickness in the 1 mm central Early Treatment Diabetic Retinopathy Study area was significantly different between the dominant and nondominant eye (16.56 ± 6.02 μm vs 17.58 ± 8.32 μm; p = 0.02). However, when compensating with Bonferroni, this difference was no longer statistically significant. There were no differences in the analyses of average global and sectorial cpRNFL thickness in dominant and nondominant eyes. Conclusion Dominant eyes demonstrated no significantly thicker average macular retinal nerve fiber layer (mRNFL), Ganglion cell layer (GCL) thickness or cpRNFL thickness. No ocular characteristic was found to be associated with the relative dominance of an eye in eyes with low anisometropia.

Background Circulation miRNAs have emerged as new biomarkers for identifying and monitoring the microvascular complications of diabetes. The aim of this study is to evaluate the levels of five candidate miRNAs (miR-29c-3p, miR-18a, miR-31, miR-181 and miR-20a) in patients with diabetic retinopathy (DR) and their relationship with disease severity. Methods The study included 31 diabetes patients without DR (NDR group), 68 patients with DR (DR group) and 30 healthy controls (HC group). Twenty-five of patients with DR were proliferative DR (PDR group) and 43 were non-proliferative DR (NPDR group) patients. Metabolic parameters and serum vascular endothelial growth factor (VEGF) levels of all participants were measured. Circulating miRNAs levels were determined by quantitative realtime PCR. Fundus examinations of all patients were performed by a single ophthalmologist. Results VEGF levels were significantly higher in the NDR and DR groups compared to HC group (p=0.011 and p=0.014, respectively). Plasma miR-29c-3p was downregulated in diabetic patients with retinopathy and without retinopathy. This downregulation was more prominent in diabetic patients without retinopathy compared to those with retinopathy (p=0.016). There was no significant difference in plasma levels of miR-18a, miR-20a, miR-18a and miR-31 between diabetic subjects with and without retinopathy (p>0.05). There was no correlation between DR severity and the levels of miRNAs (p>0.05). In multivariate logistic regression analysis, it was found that changes in plasma miR-29c-3p expression of diabetic patients increased DR risk independent of other risk factors. Conclusions Plasma miR-29c-3p expression is downregulated in diabetic patients with and without retinopathy, and changes in this miRNA are an independent risk factor for the development of DR.

Purpose To report two cases of secondary eccentric macular holes that developed following vitrectomy and present their outcomes. Methods Retrospective, observational case report CASE DESCRIPTION:: A 69-year-old female and a 57-year-old male developed secondary paracentral retinal hole following vitrectomy surgery for stage 4 macular hole and proliferative diabetic retinopathy respectively. In case 1, the hole was left untreated while in case 2, laser photocoagulation was done around the paracentral retinal hole. In both cases, spontaneous closure of the paracentral retinal holes was noted 12-week and 3-week following presentation respectively. Conclusions Secondary eccentric retinal holes are extremely rare following vitrectomy. The pathogenesis of MHs in our cases is most consistent with contraction of the residual ILM or preretinal fibrous tissue. Spontaneous closure of small eccentric retinal holes can occur as well which to the best of our knowledge has not yet been reported in literature.

Concomitant vitamin D deficiency (VDD) is speculated to aggravate diabetic macular edema (DME). We aimed to determine the effect of hypovitaminosis D correction on the outcome of treatment with intravitreal bevacizumab (IVB) in DME eyes.In this randomized clinical trial, 83 eyes of 83 patients with DME were recruited and divided into three groups: normal vitamin D levels + IVB administration (Group 1), vitamin D insufficient/deficient + IVB administration (Group 2), and vitamin D insufficient/deficient + IVB administration + oral vitamin D supplementation (Group 3). Participants were followed for 6 months after the intervention. Visual (corrected distance visual acuity, CDVA) and anatomical (central macular thickness, CMT) outcomes of intervention were evaluated 1, 3, and 6 months after three monthly loading doses of IVB were given. Serum vitamin D levels were measured 1 and 6 months after the third IVB administration.A total of 29, 26, and 28 eyes were enrolled in groups 1, 2, and 3, respectively. In months 1, 3, and 6, after the three basic loading doses of IVB, visual acuity and CMT improved in all three groups, but improvements (both functional and anatomical) in groups 1 and 3 in month 6 were more significant than in group 2 (mean CDVA LogMAR changes: - 0.18 ± 0.03, - 0.14 ± 0.05, and - 0.2 ± 0.06; mean CMT reductions: - 82.24 ± 11.43, - 66.62 ± 14.34, and - 86.14 ± 18.36, in groups 1, 2, and 3, respectively; p 0.001). The mean number of IVB injections during follow-up was 5.33 (range 4-7), which did not differ between the groups.Correction of vitamin D deficiency in DME patients with type 2 diabetes and vitamin D deficiency, in addition to IVB injections, may play a role in improving CDVA and CMT. However, this beneficial effect seems to be delayed by several months.Iranian Registry of Clinical Trials (IRCT), IRCT20200407046978N1, registered on April 11, 2020, retrospectively registered ( https://en.irct.ir/trial/46999 ).

PURPOSE: To investigate the cost-effectiveness of prophylactic treatments against cystoid macular edema (CME) after cataract surgery in diabetic patients.SETTING: Seven ophthalmology clinics in the Netherlands and Belgium.DESIGN: Prospective trial-based cost-effectiveness analysis using data from a European multicenter randomized clinical trial.METHODS: Diabetic patients (n=163) undergoing uncomplicated cataract surgery were randomized to perioperative subconjunctival triamcinolone acetonide (n=36), perioperative intravitreal bevacizumab (n=36), combination treatment (n=45), or no additional treatment (control group, n=46). The cost analysis was performed from a healthcare perspective within a 12-week postoperative time horizon. The main effectiveness outcome was quality-adjusted life years (QALYs). The main cost-effectiveness outcome was the incremental cost-effectiveness ratio (ICER; cost per QALY).RESULTS: Mean total healthcare costs and QALYs were: Triamcinolone € 1827 (US$ 2295) / 0.166; Bevacizumab € 2050 (US$ 2575) / 0.144; Combination € 2027 (US$ 2546) / 0.166; Control € 2041 (US$ 2564) / 0.156. Bevacizumab and control treatment were most costly and least effective. The ICER was € 321,984 (US$ 404,503) per QALY for the combination group compared to the triamcinolone group. Assuming the willingness-to-pay is € 20,000 (US$ 25,126) per QALY, the cost-effectiveness probability was 70% and 23% in the triamcinolone and combination groups, respectively. No patient that received triamcinolone developed clinically significant macular edema (CSME). A secondary cost-effectiveness analysis based on this outcome showed a clear preference for triamcinolone.CONCLUSIONS: In diabetic patients, subconjunctival triamcinolone was effective in preventing CSME after cataract surgery. The cost-effectiveness analysis showed triamcinolone is also cost-effective.

Aim To determine the association and the prognostic value of soluble ST2 (sST2) levels in the development of diabetic retinopathy (DR), diabetic macular oedema (DMO) or diabetic nephropathy (DN), in a cohort of patients with type 1 diabetes (T1D). Methods A total of 269 individuals with T1D (154 males and 115 females) were recruited. The overall mean age was 43.2 ± 14.9 years, and the diabetes duration was 17.1 ± 12.1 years. Levels of sST2 in serum were evaluated, and the presence as well as the degree of DR, DMO and DN was recorded. Additionally, other clinical and analytical parameters including demographic variables were recovered from patients’ electronic health record. Ten years later, the presence and stage of DR, DMO and DN were again recorded under the same criteria. The association between previously mentioned parameters with DR and DN was analysed by univariate and multivariate logistic regression. The variables in the final multivariate models were adjusted from complete models via backward elimination and maintained only when significant. Results An increase of 10 ng/ml in the levels of sST2 was associated with a 1.50 (1.02–2.19) and 1.48 (1.05–2.08) prevalence odds ratio (OR) in DMO and DR, respectively. There was no association between sST2 levels and DN. Meanwhile, sST2 levels did not display a prognostic effect in any of the microangiopathic diabetic complications studied. Conclusions Levels of sST2 are associated with the presence of DR and DMO, they do not seem to be predictive for the development or deterioration of DR, DMO or DN.

Background: Diabetic retinopathy (DR) is a severe complication of diabetes; however, the pathogenesis of DR has not been completely clarified, which is mostly dependent on the molecular pathology. To investigate key serum-derived miRNAs associated with DR. Methods: miRNA expression profile arrays of human umbilical vein endothelial cells (HUVECs) treated with glucose were downloaded from the Gene Expression Omnibus (GEO) database (GSE74296). Weighted gene co-expression network analysis (WGCNA) was performed to obtain hub miRNAs, which were verified in HUVECs treated with 40 mM and 5 mM glucose, respectively. Meanwhile, serum samples of patients with DR and healthy controls were collected, and EVs were extracted from the patients’ serum by ultracentrifugation. Hub miRNAs associated with endothelial dysfunction were verified in healthy individuals before and after treatment of patients with DR, by qRT-PCR. Results: These miRNAs were categorized into six modules, among which miR-26b-5p had a strong association with other modules. This miRNA was also one of the hyperglycemia-induced miRNAs related to endothelial dysfunction. miR-26b-5p was upregulated in HUVECs treated with 40 mM glucose and in the serum of patients with DR before and after treatment Furthermore, miR-26b-5p was slightly up-regulated in serum-derived EVs but not in serum without EVs in DM patients. Conclusion: Our results suggest that EVs derived from miR-26b-5p are up-regulated in the serum of patients with DR.

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.

Erythropoietin (EPO) is a glycoprotein hormone that regulates hematopoiesis in the human body. The presence of EPO and its receptors in different tissues indicates that this hormone has extramedullary effects in other tissues, including the eye. We focus on the biological roles of this hormone in the development and normal physiologic functions of the eye. Furthermore, we explore the role of EPO in the management of different ocular diseases – including diabetic retinopathy, retinopathy of prematurity, inherited retinal degeneration, branch and central retinal vein occlusion, retinal detachment, traumatic optic neuropathy, optic neuritis, methanol optic neuropathy, nonarteritic anterior ischemic optic neuropathy, glaucoma, and scleral necrosis.

Purpose To determine if plasma levels of six arginine and citrulline-related metabolites (arginine, citrulline, asymmetric dimethylarginine [ADMA], ornithine, proline, and argininosuccinate) differ between patients with type 2 diabetes and diabetic retinopathy (DR) and type 2 diabetic controls or between patients with proliferative DR (PDR) and non-proliferative DR (NPDR). Design Cross-sectional study Methods Adults with type 2 diabetes were recruited from the Vanderbilt Eye Institute. Exclusion criteria included non-diabetic retinal disease. Plasma metabolite levels were quantified in 159 diabetic controls and 156 DR patients (92 NPDR, 64 PDR) using isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS). Metabolite levels were compared using Wilcoxon Rank Sum test and logistic regressions adjusting for age, sex, hemoglobin A1c, diabetes duration, statin use, and angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use. A secondary analysis that included creatinine in the regression model was performed for the subset of patients with available creatinine values (135 diabetic controls, 100 DR patients [58 NPDR, 42 PDR]). Results Multivariable logistic regression analyses determined arginine (OR = 1.20, [1.06-1.38], P = 0.0067) and citrulline (OR = 1.53, [1.20-1.98], P = 0.0025) were significantly elevated in DR patients compared to diabetic controls. While ADMA differed between NPDR and PDR patients in the primary analysis (OR = 1.56, [1.15-2.16], P = 0.0051), it was not significantly different when adjusting for creatinine (OR = 1.30, [0.90-1.91], P = 0.15). Conclusions Plasma arginine and citrulline were significantly elevated in type 2 diabetic patients with DR compared to diabetic controls. None of the tested metabolites significantly differed between NPDR and PDR patients in the adjusted analysis.

PURPOSE To compare outcomes of glaucoma drainage device (GDD) implantation and trabeculectomies with and without postoperative intravitreal injections (IVIs) in glaucoma patients with a history of preoperative IVIs. DESIGN Retrospective cohort study. PARTICIPANTS A total of 133 eyes of 133 glaucoma patients who underwent GDD implantation or trabeculectomy with at least 1 IVI preoperatively between January 2005 and October 2020 at Massachusetts Eye and Ear. METHODS Chart review of glaucoma patients with traditional glaucoma surgery and at least 1 IVI before surgery. All statistical analyses were conducted with R statistical programming software. MAIN OUTCOME MEASURES Intraocular pressure (IOP), medication burden, best-corrected visual acuity (BCVA), Kaplan-Meier success rates, adjusted hazard ratios (HRs), and complications. RESULTS Baseline demographics were similar between the groups with and without postoperative IVIs. The group with postoperative IVIs had a higher proportion of diabetic retinopathy and retinal vascular occlusions than the group without postoperative IVIs, which had more eyes with age-related macular degeneration. Intraocular pressure, medication burden, and visual acuity were similar between groups at all time points except for IOP at 6 weeks, which was lower in the group with postoperative IVIs. The group with postoperative IVIs had significantly more preoperative IVIs than the group without postoperative IVIs (6.6 vs. 3.3, P = 0.017). For success defined as IOP reduction ≥ 20% with 5 < IOP ≤ 21 mmHg, Kaplan-Meier analyses demonstrated similar success rates between groups with and without IVIs. When stratified by the number of IVIs, success rates for the group with 7 or more IVIs were significantly higher than the success rates for the group with 0-6 IVIs (P = 0.005). Each additional postoperative IVI resulted in a 7.2% decrease in the hazard of failure to achieve our stated success criteria. With regard to late complications, the group with postoperative IVIs had a higher incidence of vitreous hemorrhage (18.5% vs. 3.2%, P = 0.039) than the group without postoperative IVIs. CONCLUSIONS A higher number of postoperative IVIs, specifically 7 or more IVIs, may be associated with improved success rates of traditional glaucoma surgery in glaucoma patients who received IVIs before surgery.

Screening for silent coronary artery disease in asymptomatic patients with diabetes mellitus (DM) is challenging and controversial. In this context, it seems crucial to identify early markers of coronary artery disease.The aim of this study was to investigate the incremental value of resting left ventricular (LV) global longitudinal strain (GLS) for the prediction of positive results on stress (exercise or dobutamine) transthoracic echocardiography in 273 consecutive asymptomatic high-risk patients with DM. Positive results on stress transthoracic echocardiography were defined as stress-induced LV wall motion abnormalities (new or worsening preexisting abnormalities).Compared with patients with negative stress results, those with positive stress results (n = 28 [10%]) more frequently had cardiovascular risk factors, complications of DM, vascular disease, moderate and severe calcification of the aortic valve and mitral annulus, and worse resting LV GLS (-16.7 ± 2.9% vs -19.0 ± 1.9%, P .001). On multivariable logistic regression analysis, DM duration10 years, diabetic retinopathy, LV hypertrophy, and impaired LV GLS (odds ratio, 1.39 [95% CI, 1.14-1.70] per percentage increase; odds ratio, 5.16 [95% CI, 1.96-13.59] for LV GLS worse than -18%) were independently associated with positive results on stress transthoracic echocardiography. The area under the curve to predict positive results was 0.74 for LV GLS with a cutoff of -18.0% (sensitivity 68%, specificity 78%). The area under the curve of the multivariable model to predict test results was improved by the addition of LV GLS (P .001), with a bias-corrected area under the curve after bootstrapping of 0.842 [95% CI, 0.753-0.893].The present findings show that resting LV GLS is associated with the presence of silent ischemia and could be useful to better identify asymptomatic patients with DM who might benefit from coronary artery disease screening.

Purpose To calculate costs required to prevent center-involved diabetic macular edema (CI-DME) or proliferative diabetic retinopathy (PDR), and to improve the diabetic retinopathy severity score (DRSS) with intravitreal anti-VEGF injections as reported for aflibercept in two randomized control trials. Design Cost-effectiveness analysis modeling based on published data Subjects None Methods Results from PANORAMA and the Diabetic Retinopathy Clinical Research Network ( DRCR.net ) Protocol W were analyzed. Parameters collected included DRSS score, risk reduction of PDR, risk reduction of CI-DME, and number of treatments required. Costs were modeled based on 2020 Medicare reimbursement data practice settings of hospital-based facility and non-facility. Main Outcome Measure Cost to prevent case of PDR and CI-DME, and to improve DRSS stage Results Over 2 years in Protocol W, the cost required to prevent 1 case of PDR was $83,000 ($72,400) in the facility (non-facility) setting; in PANORAMA, the corresponding 2 year costs were $89,400 ($75,000) for the 2Q16 arm, and $91,200 ($89,900) for the 2Q8PRN arm. To prevent 1 case of CI-DME with vision loss in Protocol W, the cost was $154,000 ($133,000). For all CI-DME, with and without vision loss; in PANORAMA, the costs to prevent a case were $70,900 ($59,500) for the 2Q16 arm, and $90,000 ($88,800) for the 2Q8PRN arm. In Protocol W, the overall accumulated total for cost /DRSS unit change at the 2 year point for facility (non-facility) setting was $2700 ($2400)/DRSS. In the first year alone, it was $2100 ($1800)/DRSS and in the second year alone, $6100 ($5300)/DRSS. Conclusion There is a considerable cost associated with the prevention of PDR and CI-DME with intravitreal aflibercept injections. A price per unit of change in diabetic retinopathy severity score is a new parameter which might serve as a benchmark in future utility analyses that could be used to bring perspective to cost-utility considerations.

Objective Owing to limited research, the effect of non-alcoholic fatty liver disease (NAFLD) on type 2 diabetes outcomes remains unclear. This study aimed to investigate the association between NAFLD and microvascular complications in hospitalized patients with type 2 diabetes. Methods We included 1982 patients with type 2 diabetes. NAFLD was defined as hepatic steatosis detected by ultrasound without secondary causes of fat accumulation. The diagnosis of diabetic retinopathy (DR), diabetic kidney disease (DKD) and diabetic neuropathy was based on clinical medical records. Risk for advanced liver fibrosis was categorized as “low risk,” “indeterminate risk,” and “high risk,” based on the NAFLD Fibrosis Score (NAFLD-FS). Logistic regression was used to test the association between NAFLD, risk for advanced fibrosis and the presence of DR, DKD, and diabetic neuropathy. Results The prevalence of NAFLD was 61.3%. The presence of DR (odds ratio [OR]: 0.749, 95% confidence interval [CI]: 0.578–0.971), and DKD (OR: 0.667, 95% CI: 0.515–0.864) was inversely associated with NAFLD, after adjusting for covariates. The presence of DR and DKD was higher in the “indeterminate risk” (DR: OR: 1.237, 95% CI: 0.730–2.096; DKD: OR: 1.009, 95% CI: 0.640–1.591, respectively) and “high risk” group (DR: OR: 1.341, 95% CI: 0.730–2.463; DKD: OR: 1.732, 95% CI: 1.021–2.940, respectively) than in the “low risk” group, after adjusting for the same covariates. Only the presence of DKD significantly increased with high NAFLD-FS (P=0.01 for trend). Conclusion The presence of DR and DKD was inversely associated with NAFLD among hospitalized patients with type 2 diabetes. DKD was closely associated with high NAFLD-FS among patients with NAFLD.

Widefield swept-source optical coherence tomography (OCT) imaging was used to characterize choroidal thickness and vascularity at baseline in proliferative diabetic retinopathy (PDR) and longitudinally after panretinal photocoagulation (PRP).Patients with treatment-naive PDR were imaged at baseline and at 1 week, 1 month, and 3 months after PRP. Previously validated algorithms were used to calculate the mean choroidal thickness (MCT) and choroidal vascularity index (CVI) in 5 regions of 12 mm × 12 mm scans.Fourteen PDR eyes were included. Baseline MCT in PDR eyes did not differ significantly from normal eyes, but CVI measurements in PDR eyes were lower in all regions (P0.001-0.008). After PRP, MCT measurements in PDR eyes were significantly lower at 1 month and 3 months in all regions (P0.001-0.005) except the fovea (P = 0.074). However, CVI measurements did not change over time in any region after PRP.The choroid in PDR eyes has a smaller CVI than that in normal eyes. After PRP, the choroidal thickness decreases outside the fovea, but the CVI remains constant, which suggests that a relative decrease in choroidal vascularity persists. These widefield swept-source OCT results are consistent with choroidal alterations found in histopathological reports of diabetic choroidopathy.

Purpose: To evaluate the efficacy and complications of intravitreal dexamethasone with simultaneous silicone tamponade after combined phacoemulsification and pars plana vitrectomy (PPV) in severe d...

Purpose: To determine the clinical significance of choroidal thickness and evaluate changes in choroidal thickness over time in eyes affected by ocular ischemic syndrome (OIS).Methods: Medical records of 16 patients diagnosed with OIS between November 2017 and August 2019 were retrospectively reviewed. In every nine areas of the Early Treatment Diabetic Retinopathy Study grid, we compared the differences in choroidal thickness between the eyes with OIS and unaffected eyes, and its change in the OIS eyes during the follow-up period using swept-source optical coherence tomography. We analyzed the best-corrected visual acuity, intraocular pressure, fluorescein angiography (FAG) parameters, systemic diseases, and the duration of symptoms. Correlation between FAG parameters and the choroidal thickness value ratio in the OIS eyes and the unaffected eyes, and changes in the choroidal thickness in the OIS eyes during follow-up were investigated.Results: Median age of the subjects was 67.5 years. In the OIS eyes, all FAG parameters were delayed at the initial examination. Best-corrected visual acuity and intraocular pressure were significantly different between the OIS and unaffected eyes. While the choroidal thickness in every nine areas of Early Treatment Diabetic Retinopathy Study in the OIS eyes was lesser than the unaffected eyes, the choroidal thickness of inner temporal, outer nasal, and outer temporal area showed statistically significant difference. During follow-up, changes in choroidal thickness of OIS eyes as well as correlation between the FAG parameters and the choroidal thickness value ratio between the OIS eyes and the unaffected eyes were not found to be statistically significant.Conclusions: The choroidal thickness of the eyes with OIS was significantly less compared with the unaffected eyes. We inferred that choroidal thinning takes place in the early phase of the disease as the changes in choroidal thickness during the follow-up period were not significant.

Purpose This analysis of the pivotal phase 3 HAWK and HARRIER trials aimed to provide insights on the timing of presentation, management, and outcomes of intraocular inflammation (IOI)-related adverse events (AEs), as reported by investigators in these trials. Design Post hoc analysis of investigator-reported IOI-related AEs in HAWK and HARRIER. Participants Of 1088 brolucizumab-treated eyes (3 or 6 mg), 49 eyes demonstrated at least 1 IOI-related AE and were included in this analysis. Methods Reports of IOI-related AEs were analyzed and descriptive statistics were provided for outcome measures. Main Outcome Measures Incidence and description of eyes with IOI-related AEs, timing of presentation, management, clinical outcomes, and brolucizumab treatment after the first IOI-related AE. Results Seventy IOI-related AEs were reported in 49 eyes. Before the onset of first IOI-related AE, eyes received a mean ± standard deviation (SD) of 3.9 ± 2.2 brolucizumab injections. Median time to first IOI-related AE from the last administered brolucizumab injection was 18.0 days (interquartile range, 4.0–29.0 days). Of the 70 AEs, 61 (87.1%) were treated, most with topical corticosteroids; systemic and intraocular corticosteroids were used for 3 AEs each. Overall, inflammation resolved completely in 39 eyes (79.6%), resolved with sequelae in 5 eyes (10.2%), and did not resolve in 5 eyes (10.2%) by end-of-study (EOS). Overall, the mean ± SD best-corrected visual acuity (BCVA) change from baseline to EOS, before AE to the lowest BCVA in 3 months after AE, and from before AE to EOS were −0.84 ± 20.6 , −16.31 ± 17.6, and −0.22 ± 18.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, respectively. Of the 36 eyes (73.5%) that continued with brolucizumab therapy after the first IOI-related AE, 24 completed the trials and 12 discontinued; mean ± SD BCVA change in these eyes was 2.6 ± 17.6, 7.8 ± 13.2, and −7.7 ± 21.3 ETDRS letters, respectively, from baseline to EOS. The remaining 13 eyes (26.5%) were not treated with brolucizumab after first IOI-related AE and showed a mean ± SD BCVA change of −10.4 ± 25.5 ETDRS letters from baseline to EOS. Conclusions Findings of this analysis highlight the need for continued vigilance and monitoring for any signs of IOI-related events in patients receiving brolucizumab.

Background: The purpose of this study was to investigate the feasibility and effectiveness of an innovative telemedicine community-based intervention to increase detection of previously undiagnosed...

Abstract: Diabetic retinopathy is a posterior eye disorder in which damage occurs to the light sensitive retina due to diabetes mellitus. This disorder specifically affects people aged between 18-64 with type ІІ diabetes. This disease progresses through different pathophysiological pathways, which include oxidative stress, inflammation, stimulation of the growth factor in the eye’s vasculature, isoforms of protein kinase C, and also the activation of the hexosamine pathway. It starts as micro aneurysms and advances in complicated stage, which results in retinal detachment. Treatment of posterior eye diseases has complications due to the structural design of the eye and physiological barriers present. The current treatment approach involves the use of intravitreal anti- VEGFs, corticosteroids implants, laser and surgery; these treatment methods have drawbacks attributed to them despite their benefits. The development of a robust delivery system with minimal or no invasion to tackle the issues of diabetic retinopathy will be of considerable benefit to patients having diabetic retinopathy; the dependency on ophthalmologists for multiple injections will significantly reduce and provide a promising approach in drug delivery. In this review article, the authors provided information related to existing treatment methods available for diabetic retinopathy, the most significant among which is nanotechnology approach through which local delivery via the ocular route to posterior eye can be achieved. It also possesses the various carriers studied for the non-invasive approach for retinal delivery of medicaments. Non-invasive approach for delivery of drugs can be considered as potential for the treatment of diabetic retinopathy.

Purpose: To determine the magnitude, determinants, and public health issues related to diabetic retinopathy (DR) in India using 2019 data from a for-profit telescreening program. Methods: Digital retinal images were captured using a nonmydriatic fundus camera and transferred via the telescreening program to a reading center. Ophthalmologists trained in DR image reading created the DR status reports. Age/sex-adjusted rates of DR, sight-threatening DR (STDR), and diabetic macular edema (DME) were calculated and correlated with known risk factors. Results: Images of 51,760 Indian diabetic patients (103,520 eyes) were reviewed. The prevalence of DR, STDR, and DME was 19.1% (95% confidence interval [CI]: 18.9-19.5), 5.1% (95% CI: 4.9-5.3), and 3.9% (95% CI: 3.7-4.1), respectively. Based on these data, we projected 14.7 million cases of DR, 3.9 million with STDR, and 3.0 million DME cases in India. Statistically significant risk factors for DR were male gender (odds ratio [OR] = 1.19, p < 0.001), older age (χ2 = 270, df = 3, p < 0.001), history of cataract surgery (OR = 2.0, p < 0.001), longer duration of diabetes (χ2 = 1084, p < 0.001), and type 1 diabetes (OR = 3.9, p = 0.01). There was a statistically significant variation of DR by geographic zones (χ2 = 310, p < 0.001). Laser treatment coverage for STDR was 22%. Duration of diabetes (p < 0.001), cataract surgery in the past (p = 0.02), and females (p = 0.001) were predictors of STDR. Conclusion: This model of telescreening for DR provides an additional pathway for screening and preventing diabetes-related visual morbidity in India. The data from this study can be used for epidemiologic and ophthalmic health policies related to diabetes.

PURPOSE: To investigate the natural disease course of retinal dystrophies associated with crumbs cell polarity complex component 1 (CRB1) and identify clinical end points for future clinical trials. DESIGN: Single-center, prospective case series. METHODS: An investigator-initiated nationwide collaborative study that included 22 patients with CRB1-associated retinal dystrophies. Patients underwent ophthalmic assessment at baseline and 2 years after baseline. Clinical examination included best-corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study charts, Goldmann kinetic perimetry (V4e isopter seeing retinal areas), microperimetry, full-field electroretinography, full-field stimulus threshold (FST), fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence imaging. RESULTS: Based on genetic, clinical, and electrophysiological data, patients were diagnosed with retinitis pigmentosa (19 [86%]), cone-rod dystrophy (2 [9%]), or isolated macular dystrophy (1 [5%]). Analysis of the entire cohort at 2 years showed no significant changes in BCVA (P = .069) or V4e isopter seeing retinal areas (P = .616), although signs of clinical progression were present in individual patients. Macular sensitivity measured on microperimetry revealed a significant reduction at the 2-year follow-up (P < .001). FST responses were measurable in patients with nonrecordable electroretinograms. On average, FST responses remained stable during follow-up. CONCLUSION: In CRB1-associated retinal dystrophies, visual acuity and visual field measures remain relatively stable over the course of 2 years. Microperimetry showed a significant decrease in retinal sensitivity during follow-up and may be a more sensitive progression marker. Retinal sensitivity on microperimetry may serve as a functional clinical end point in future human treatment trials for CRB1-associated retinal dystrophies.

Purpose To quantitatively and morphologically document enlarged neovascularization elsewhere (NVE) using widefield swept-source (SS) optical coherence tomography angiography (OCTA) with vitreoretinal interface (VRI) slab images. Design Retrospective observational imaging study. Participants The study included 46 NVEs in 25 eyes of 21 consecutive patients who presented with severe proliferative diabetic retinopathy with NVEs between March 2018 and June 2020 at Osaka University Hospital. Methods All patients underwent ophthalmologic examinations, including ultra-widefield fluorescein angiography (UWF-FA) imaging and widefield SS-OCTA scans. Main outcome measures We evaluated the area and the vascular density (VD) of NVEs detected on five 12×12 mm2 or two 15×9 mm2 SS-OCTA panoramic VRI slab images taken at the first and final visits. Results At baseline, the mean area of the NVEs on OCTA was 1.85 ±2.81 mm2, and the vascular density of the NVEs was 73.9 ± 14.6%. At the final visit, the mean area of the NVEs on OCTA was 2.14 ± 3.14 mm2, and the mean vascular density of the NVEs was 65.3 ± 17.1%. The average NVE size change (mm2/month) was significantly associated with the ischemic index (P=0.009). NVE growth could be classified into two patterns: round-shaped (61.8%) and ramified (38.2%). The round-shaped group tended to have a larger ischemic index at baseline than the ramified group (p=0.0375). Conclusions We quantified the size and density of NVEs over time. The NVE size increase was significantly associated with the severity of ischemic changes. Furthermore, the ramified growth pattern was significantly correlated with the ischemic index. These findings suggest that the morphology of NVE is associated with more severe ischemia.

Objective To compare the clinical profile of long-term survivors and non-survivors with T1D(T1D) in India. Research design and methods This is a retrospective study of 76 individuals with T1D who had survived for at least 40 years ('survivors') and 51 individuals with T1D who had died with shorter duration of diabetes ('non-survivors'), from diabetes clinics in different cities of India. Prevalence of complications in both groups and causes of death of the non-survivors were analyzed. Retinopathy was diagnosed by retinal photography; chronic kidney disease (CKD) by urinary albumin excretion (micro- or macroalbuminuria) and estimated glomerular filtration rate; peripheral vascular disease (PVD) by Doppler measurement of ankle-brachial pressure index; coronary artery disease (CAD) based on history of myocardial infarction or coronary revascularization and neuropathy by biothesiometry. Results Mean glycated hemoglobin (8.4±1.5 vs 10.7±2.2%, p

Purpose This trial was conducted to investigate the clinical equivalence of the proposed biosimilar FYB201 and reference ranibizumab in patients with treatment-naive, subfoveal choroidal neovascularization caused by neovascular age-related macular degeneration (nAMD). Design This was a prospective, multicenter, evaluation-masked, parallel-group, 48-week, phase III randomized study. Participants A total of 477 patients were randomly assigned to receive FYB201 (n = 238) or reference ranibizumab (n = 239). Methods Patients received FYB201 or ranibizumab 0.5 mg by intravitreal injection in the study eye every four weeks. Main Outcome Measures The primary end point was change from baseline in best corrected visual acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) letters at 8 weeks prior to the third monthly intravitreal injection. Biosimilarity of FYB201 to its originator was assessed via a two-sided equivalence test, with an equivalence margin in BCVA of 3 ETDRS letters. Results BCVA improved in both groups, with a mean improvement of +5.1 (FYB201) and +5.6 (reference ranibizumab) ETDRS letters at week 8. The analysis of covariance (ANCOVA) least squares mean difference for the change from baseline between FYB201 and reference ranibizumab was –0.4 ETDRS letters with a 90% confidence interval (CI) of –1.6 to 0.9. Primary end point was met as the 90% CI was within the predefined equivalence margin. Adverse events were comparable between treatment groups. Conclusions FYB201 is biosimilar to reference ranibizumab in terms of clinical efficacy and ocular and systemic safety in the treatment of patients with nAMD.

Purpose : To evaluate the effect of loss to follow up (LTFU) on outcomes in eyes with diabetic macular edema (DME) treated with anti-vascular endothelial growth factor (VEGF). Design : Retrospective cohort study Methods : Single-center study of 90 eyes of 73 patients with non-proliferative diabetic retinopathy (NPDR) and DME treated with anti-VEGF injections who were LTFU for >6 months. Main outcomes were the change in mean visual acuity (VA) and central foveal thickness (CFT) at the return and final visits compared to the visit before LTFU. Results : Mean age was 64.5 years, mean LTFU duration was 322 days, and mean follow-up duration after return was 502 days. Compared to the mean VA at the visit before LTFU (0.42, Snellen ∼20/52), mean VA worsened at the return visit (0.54, Snellen ∼20/69, p=0.004). No significant change in the mean VA was noted at the 3-month after return visit (0.50, Snellen ∼20/63), the 6-month after return visit (0.46, Snellen ∼20/57), the 12-month after return visit (0.42, Snellen ∼20/52) and the final follow up (0.47, Snellen ∼20/59). When analyzed by NPDR severity before LTFU, no difference in VA was found from the visit before LTFU to the final visit. Mean CFT increased when comparing the visit before LTFU (270 μm) to the return visit (305 μm, p=0.012), but no difference was found by the final visit [247 μm, p=0.07]. Conclusions : Anti-VEGF treated DME patients who were LTFU for a prolonged period experienced a modest decline in VA that recovered after restarting treatment.

The uncontrolled growth of blood vessels is a major pathological factor in human eye diseases that can result in blindness. This effect is termed ocular neovascularization and is seen in diabetic retinopathy, age-related macular degeneration, glaucoma and retinopathy of prematurity. Current treatments for these diseases include laser photocoagulation, topical injection of corticosteroids, intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents and vitreoretinal surgery. Although strategies to inhibit VEGF have proved to be dramatically successful in some clinical studies, there remains the possibility of significant adverse effects regarding the blockade of crucial physiological roles of VEGF and the invasive nature of the treatments. Moreover, it is evident that other pro-angiogenic factors also play important roles in the development of these diseases, as seen in cases in which anti-VEGF therapies have failed. Therefore, new types of effective treatments are required. In this review, we discuss a promising strategy for the treatment of ocular neovascular diseases, i.e., the inhibition of hypoxia-inducible factor (HIF), a master regulator of angiogenesis. We also summarize promising recently investigated HIF inhibitors as treatments for ocular diseases. This review will facilitate more comprehensive approaches to understanding the protective aspects of HIF inhibition in the prevention of ocular diseases.

Background/Aim. The relationship between the foveal avascular zone (FAV) and visual acuity (VA) in retinal dis-eases remains a matter of discussion. The aim of this study was to determine the impact of diabetic macular ischemia (DMI) on VA through the analysis of the perifoveal capillary network in various stages of diabetic retinopathy - DR (non-proliferative diabetic retinopathy ? NPDR and proliferative diabetic retinopathy ? PDR). Methods. Qualitative and quantitative analysis of 143 angiograms of patients with different stages of DR was performed. The degree of macular ischemia was assessed by the analysis of 2 parameters: perifoveal capillary ring, ie, the FAZ outline irregularity, and capillary loss. Finally, a comparison was made between the degree of macular ischemia with the best-corrected VA, depending on macular thickness. Results. In the eyes with mild and moderate NPDR, without significant macular thickening, no statistically significant decrease in VA caused by macular ischemia was noticed (p = 0.81). Opposite, in a subgroup with severe NPDR and PDR, without significant macular thickening, a statistically significant difference was presented among eyes with moderate and severe macular ischemia compared to eyes with lower grades of macular ischemia (p = 0.021 and p = 0.018, respectively). In the eyes with moderate NPDR and mild macular ischemia, the increase in macular thickness resulted in a statistically insignificant decrease in VA compared to eyes with a normal macular thickness (p = 0.088). However, in the eyes with severe NPDR, every pathological increase in macular thickness caused a statistically significant decrease in VA, regardless of the degree of macular ischemia (p = 0.018?0.040). A similar relationship was also found in the eyes with PDR (p = 0.017?0.042). In the eyes with a statistically significant decrease in VA, most of the examined eyes (98%) had the FAZ outline irregularity in the nasal perifoveal subfield. Conclusion. In the absence of significant macular thickening, the destruction of one-half of the perifoveal capillary network, or greater, is associated with reduced VA. The location of macular ischemic changes in the nasal parts of the perifoveal capillary ring plays a crucial role in its effects on visual function.

Background: Dynamic Contrast-enhanced Magnetic Resonance Imaging (DCE-MRI) technique could not only quantify blood-retinal barrier (BRB) breakdown leading to macular edema associated with diabetes, but also provide a two-dimensional imaging method that is not interfered by refracting media. Objective: The current study was aimed to evaluate the macular change in the patients with diabetic retinopathy using DCE-MRI technique. Methods: Twenty patients with Diabetic Retinopathy (DR) and 20 Normal Controls (NC) were included. The fast spoiled gradient echo sequence was used to perform dynamic contrast T1WI enhancement on 3.0T MR system. The macular region, optic papila and nasal retina were performed with quantitative DCE-MRI evaluation using Omni-Kinetics software. Results: The maximal concentration, the area under the concentration-time curve (AUCconcentration-time) and maximal slope of macular region were significantly higher in DR [0.270(0.03,1.20)mmol/ 100ml, 2.71(0.04,9.91) mmol*min and 0.38(0.06,3.18) mmol/min, respectively] than that [0.169(0.03,0.72) mmol/1.25(0.13,10.41) mmol*min and 0.245(0.06,1.34) mmol/min] in NC (U value = 515.00 and P value = 0.080, U value = 433.00 and P value = 0.000, and U value = 563.00 and P value = 0.023, respectively). The receiver operating characteristic curve (ROC) analysis demonstrated that the area under AUCconcentration-time was 0.729±0.058 with the cut-off value 1.479 mmol*min (sensitivity 80.00% and specificity 62.50%) for macular region. Conclusion: The quantitative DCE-MRI technique could be used to evaluate the maculopathy associated with diabetic retinopathy.

PURPOSE To investigate the recurrence rate of active macular neovascularization in patients with neovascular age-related macular degeneration (nAMD) previously followed up in a treat-and-extend (TE) regimen in which treatment had been stopped because of disease stability. DESIGN Prospective cohort study. PARTICIPANTS One hundred five patients with nAMD previously followed up in a TE regimen treated with aflibercept injections. METHODS All patients with a dry macula on 3 consecutive visits 12 weeks apart were eligible to participate in the study. Patients were examined at baseline and then monitored for disease recurrence 4, 6, 8, 10, and 12 months after the last injection. MAIN OUTCOME MEASURES The proportion of patients with recurrent disease within 12 months after the last injection. Change in best-corrected visual acuity (BCVA) at the time of recurrence and after resumed therapy. RESULTS Evidence of recurrent nAMD was seen in 54 of 102 patients (52.9%) after 12 months of follow-up. The mean time to recurrence after the last injection was 6.7 ± 2.2 months. The BCVA decreased from 71.7 ± 10.0 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at baseline to 68.1 ± 11.1 ETDRS letters at the recurrence (P = 0.12). After treatment resumed, BCVA increased to 71.4 ± 10.0 ETDRS letters (P = not significant compared with baseline). Patients with a pigment epithelial detachment (PED) at baseline showed a 74% (14/19) recurrence rate compared with 48% (40/83) in patients without a PED (P < 0.05). Only 22 of 54 patients (40.7%) with recurrent disease showed symptoms of visual loss or metamorphopsia. CONCLUSIONS Recurrent nAMD is common in previously stable patients for whom anti-VEGF injections have been suspended. It is difficult to predict which patients will experience a recurrence, and most of these patients do not show symptoms in the early stages of reactivation. Long-term follow-up is important, and early detection of recurrent disease can improve the chances for maintained visual function.

Background: Both type 1 diabetes mellitus (T1DM) and metabolic syndrome (MetS) are associated with an elevated risk of morbidity and mortality yet with increasing heterogeneity. This study primarily aimed to evaluate the prevalence of MetS among adult patients with T1DM in China and investigate its associated risk factors, and relationship with microvascular complications.Methods: We included adult patients who had been enrolled in the Guangdong T1DM Translational Medicine Study conducted from June 2010 to June 2015. MetS was defined according to the updated National Cholesterol Education Program criterion. Logistic regression models were used to estimate the odds ratio (OR) for the association between MetS and the risk of diabetic kidney disease (DKD) and diabetic retinopathy (DR).Results: Among the 569 eligible patients enrolled, the prevalence of MetS was 15.1%. While female gender, longer diabetes duration, higher body mass index, and glycosylated hemoglobin A1c (HbA1c) were risk factors associated with MetS (OR, 2.86, 1.04, 1.14, and 1.23, respectively), received nutrition therapy education was a protective factor (OR, 0.46). After adjustment for gender, age, diabetes duration, HbA1c, socioeconomic and lifestyle variables, MetS status was associated with an increased risk of DKD and DR (OR, 2.14 and 3.72, respectively; both P

Diabetic nephropathy (DN) is the most common complication of diabetic patients, and has become a global healthcare problem. In this study, we used diabetic mice to evaluate the effect of Losartan on DN, in which the experimental animals were divided into three groups: non-diabetic mice (db/m group), untreated-diabetic mice (db/db group), and Losartan-treated diabetic mice (db/db-losartan). Next, immunohistochemistry and immunofluorescence were used to detect Wilms tumor protein 1 (WT-1) and synaptopodin expression, respectively. Protein levels of WT-1, synaptopodin, claudin1, and Pax-2 were assessed by Western blotting and real-time PCR. The miR-193a mRNA levels were quantitated by real-time PCR. The results showed that albuminuria was increased in diabetic mice compared with control animals and was significantly ameliorated by treatment with Losartan. In addition, Losartan significantly upregulated the immunopositive cell numbers of WT-1, the expression of WT-1 and synaptopodin in renal tissue. By contrast, expression of claudin1 and Pax-2 in renal tissue were decreased in db/db-losartan group. Besides, expression of miR-193a was decreased significantly in db/db-losartan group compared with the untreated diabetic group. Thus, Losartan has renoprotective effects on the control of tissue damage possibly by inhibiting the expression of miR-193a, thereby promoting the repair of podocyte injury in mice with DN.

PURPOSE: To assess global, zonal, and local correlations between vessel density changes measured by optical coherence tomography angiography (OCTA) and retinal sensitivity measured by microperimetry across diabetic retinopathy severity. METHODS: Diabetic patients with and without retinopathy, and age matched non-diabetic controls, underwent OCTA imaging and microperimetry testing. Skeletonized vessel density (SVD) was computed from 3 mm x 3 mm OCTA images of the superficial capillary plexus, deep capillary plexus, and full retinal layer, excluding larger retinal vessels and the foveal avascular zone (FAZ). Pearson’s correlation was used to assess associations between average sensitivity and vessel density globally and in four parafoveal zones; centrally, average sensitivity was correlated with the FAZ area. Linear mixed effects modeling was used to assess relationships between local SVD measurements and their spatially corresponding retinal sensitivity measurements. RESULTS: Thirty-nine eyes from 39 participants were imaged. In all slabs, there was a statistically significant positive correlation between retinal sensitivities and SVDs on both global and zonal scales. No statistically significant correlation was found between central retinal sensitivities and the FAZ areas. Assessment of 1,136 spatially paired retinal sensitivity and SVD measurements revealed a statistically significant local relationship; this appeared to be driven by eyes with proliferative diabetic retinopathy that had reduced retinal sensitivities. CONCLUSIONS: Data from this study supports positive correlations between SVD and retinal sensitivity at global and zonal spatial scales in the parafovea of diabetic eyes. However, our analysis did not find evidence of statistically significant correlations between retinal sensitivity and SVD on a local scale until advanced diabetic retinopathy.

To analyze the effect of transfer learning for classification of diabetic retinopathy (DR) by fundus photography and select retinal diseases by spectral domain optical coherence tomography (SD-OCT).Five widely used open-source deep neural networks and four customized simpler and smaller networks, termed the CBR family, were trained and evaluated on two tasks: 1) classification of DR using fundus photography and 2) classification of drusen, choroidal neovascularization, and diabetic macular edema using SD-OCT. For DR classification, the quadratic weighted Kappa coefficient was used to measure the level of agreement between each network and ground truth-labeled test cases. For SD-OCT-based classification, accuracy was calculated for each network. Kappa and accuracy were compared between iterations with and without use of transfer learning for each network to assess for its effect.For DR classification, Kappa increased with transfer learning for all networks (range of increase 0.152-0.556). For SD-OCT-based classification, accuracy increased for four of five open-source deep neural networks (range of increase 1.8%-3.5%), slightly decreased for the remaining deep neural network (-0.6%), decreased slightly for three of four CBR networks (range of decrease 0.9%-1.8%), and decreased by 9.6% for the remaining CBR network.Transfer learning improved performance, as measured by Kappa, for DR classification for all networks, although the effect ranged from small to substantial. Transfer learning had minimal effect on accuracy for SD-OCT-based classification for eight of the nine networks analyzed. These results imply that transfer learning may substantially increase performance for DR classification but may have minimal effect for SD-OCT-based classification.

AIM AND OBJECTIVES:Diabetes Mellitus is considered as one of the five leading causes of death in the world. An epidemic by all standards, nearly 250 million people suffer from diabetes across the world. Synthetic anti-diabetic drugs increase the insulin secretion or decrease the blood glucose level but they are also producing many harmful effects. Since, increase in the use of these drugs in diabetes therapy leads to many side effects and undesirable hazards, there is worldwide trend to go back to natural resources, i.e., traditional plant. In industrialized countries the people are seeking for safer alternative to allopathic medicine because of the increasing realization on the adverse side effects of many modern remedies. The current interest in and demand for herbs is a worldwide phenomenon, WHO currently encourages, recommends and promotes traditional/ herbal remedies in national healthcare programmes because such drugs are easily available at low cost, are comparatively safe and people have faith in such remedies On the other hand, the therapeutic approach of several traditional medicinal systems is more holistic. The fundamental mechanisms of these medicinal systems are still unexplainable using modern tools. The medicinal preparations in traditional medicines contain a variety of herbal and non-herbal ingredients that are thought to act on a variety of targets by various modes and mechanisms. Based upon ethanopharmacological survey, the aim of the present work is to evaluate the anti-hyperglycemic and anti-oxidant activities of Lantana camara Leaves by using streptozotocin model in rats.DISCUSSION: Diabetes mellitus is a serious complex chronic condition that is a major source of ill health worldwide. This metabolic disorder is characterized by hyperglycemia and disturbances of carbohydrate, protein and fat metabolisms, secondary to an absolute or relative lack of the hormone insulin85. The number of people in the world with diabetes has increased dramatically over recent years. Indeed, by 2010 it has been estimated that the diabetic population will increase to 221 million around the world86. Present number of diabetics worldwide is 150 million and this is likely to increase to 300 million or more by the year 202587. Reasons for this rise include increase in sedentary lifestyle, consumption of energy rich diet, obesity, higher life span, etc.88. Regions with greatest potential are Asia and Africa, where diabetes mellitus (DM) rates could rise to 2–3-folds than the present rates89. Many herbal medicines have been recommended for the treatment of diabetes90. Plant drugs are frequently considered to be less toxic and freer from side effects than synthetic ones91. STZ induced diabetes cause an increase in blood glucose level in rats92. Our studies show that oral administration of 50 % ethanolic Lantana camara Leaves extract decreases blood glucose in diabetic rats. The increase in the level of lipid peroxides in plasma generally is thought to be the consequence of increased production of and liberation in to the circulation of tissue lipid peroxides due to pathological changes93. This action shows the anti-peroxidative effect of LCE. Changes in the levels of antioxidants are observed in diabetic conditions94. Free radical-induced LPO has been associated with a number of disease processes including diabetes mellitus95. The increase in oxygen-free radicals in diabetes could be due to increase in blood glucose levels, which generate free radicals upon autoxidation96. Glucose auto-oxidases in the presence of transition metal ions generating oxygen-free radicals which make the membrane vulnerable to oxidative damage. The action of diabetes-inducing agents produces reactive free radicals, which have been shown to be cytotoxic to the s cells of the pancreas97 .The diabetogenic action can be prevented by the superoxide dismutase, catalase and other hydroxyl radical scavengers, such as ethanol and dimethyl urea, hence there is evidence to suggest that the incidence of diabetes involves superoxide anion and hydroxyl radicals. The deleterious effects of superoxide anion and hydroxyl radicals can be counteracted by antioxidant enzymes, such as SOD, CAT etc. There is clear cut evidence to show the role of free radicals in diabetes and studies indicate that tissue injury in diabetes may be due to free radicals98. The capacity of NAE to significantly decrease the elevated blood glucose close to normal level is an essential trigger for the liver to revert to its normal homeostasis during experimental diabetes. These findings coincide with those of the earlier studies which report the antidiabetic activity of the plant by clinical studies99. LPO is also one of the features of chronic diabetes and lipid peroxide-mediated damage has been observed in both type I and type II diabetes mellitus. Under physiological conditions, low concentrations of lipid peroxides are found in tissues, which stimulate the secretion of insulin100 .The involvement of free radicals in diabetes and the role of these toxic species in LPO and the antioxidant defense system have been studied. Depletion of tissue glutathione and increase in LPO have been observed in diabetes. CONCLUSION: The number of people with diabetes is increasing due to population growth, aging, urbanization, and increasing prevalence of obesity and physical inactivity. Quantifying the prevalence of diabetes and the number of people affected by diabetes, now and in the future, is important to allow rational planning and allocation of resources. Diabetes is a disorder of carbohydrate, fat and protein metabolism attributed to diminished production of insulin or mounting resistance to its action. Herbal treatments for diabetes have been used in patients with insulin-dependent and non-insulin-dependant diabetes, diabetic retinopathy, diabetic peripheral neuropathy, etc. Scientific validation of several Indian plant species has proved the efficacy of the botanicals in reducing the sugar level. From the reports on their potential effectiveness against diabetes, it is assumed that the botanicals have a major role to play in the management of diabetes. In recent year several authors evaluated and identified the anti-diabetic potential of traditionally used Indian medicinal plants using experimental animals. Previous studies confirmed the efficacy of several medicinal plants in the modulation of oxidative stress associated with diabetes mellitus. Effect of 50 % aqueous alcoholic extract of plants on serum glucose, lipid profile and antioxidant status in streptozotocin induced diabetic rats was studied. Based on this, potentiation of dreaded disease like diabetes mellitus may shows a ray for better protocol for future treatment. The efficacy of Lantana camara Leaves in experiment showed the significant decrease in the blood glucose level, increase the antioxidant efficacy in streptozotocin induced diabetes. It was demonstrated that the oral administration of the 50% ethanolic Lantana camara Leaves extract to streptozotocin diabetic rats is useful for the treatment of diabetes induced by streptozotocin, because there were significant positive changes in the biochemical and physiological parameters related to carbohydrate, protein and lipids metabolism., the strong anti-hyperglycemic and antioxidant effect observed in STZ induced diabetic rats justifies the use of Lantana camara Leaves for the treatment of diabetes related complications. The present study showed that the ethanolic extract of Lantana camara Leaves not only possess anti-hyperglycemic properties but also antioxidant activity in diabetic condition. These observation and description of mechanism of Lantana camara Leaves, which interplay with diabetes biology and pharmacology lead to rapid development in diabetes treatment. In addition to this, studies on molecular aspect of diabetic therapy will give mechanistic information in diabetes therapy and also critical balance should be there between the animal model and clinical research. This holds great promise for future research in human beings.

Abstract: The cardiovascular complications of type 2 diabetes mellitus (T2DM) including myocardial infarction, heart failure, peripheral vascular disease and, stroke and retinopathy, nephropathy and neuropathy are microvascular complications. While the newer therapies like glitazones or even dipeptidylpeptidase- IV (DPP-IV) inhibitors increase the risk of therapy, the Glucagon Like Peptide-1 Receptor Agonists (GLP-1RAs), were reported as suitable alternates. The GLP-1RAs reduce major adverse cardiovascular events (MACE), have anti-atherogenic potential, and possess pleiotropic activity. The GLP-1RAs were found to improve neuroprotection, enhance neuronal growth, reduce the incidence of stroke, and improve central insulin resistance. The GLP-1RAs are beneficial in improving the glycemic profile, preventing macroalbuminuria and reducing the decline in eGFR and enhancing renal protection. The renal benefits of add-on therapy of GLP-1RAs with SGLT-2 inhibitors have composite renal outcomes such as suppression of inflammatory pathways, improvement in natriuresis, diuresis, found to be nephroprotective. Improvement in glycemic control with a reduction in body weight and intraglomerular pressure and prevention of tubular injury makes the GLP-1RAs as suitable add-on therapies in improving cardiorenal outcomes. Obesity, an important contributor to insulin resistance and a reduction in weight, is an essential therapeutic option in addressing diabetic-obesity. It also reduces the damage to blood-retinal-barrier, thus beneficial in halting the development of diabetic retinopathy. In diabetic complications, glycemic control, addressing insulin resistance through weight loss, controlling atherosclerosis through anti-inflammatory effects and cardio-renal-neuro protection, makes GLP-1RAs a suitable therapeutic strategy on long-term treatment of T2DM. This review discusses the role of GLP-1RAs in diabetes, the dosage, mono or combination therapy with other antidiabetics in long-term treatment and its effect in uncontrolled diabetes.

AIM: To quantitatively detect aqueous levels of angiopoietin-like (ANGPTL)3, ANGPTL4, and ANGPTL6 and investigate their correlation with optical coherence tomography angiography (OCTA) findings in patients with diabetic macular edema (DME). METHODS: This cross-sectional study included 23 patients (27 eyes) with type 2 diabetes and 16 control subjects (20 eyes). All patients underwent OCTA imaging and ultra-wide field fundus photography. Diabetic patients were categorized into two groups according to the presence or absence of diabetic retinopathy (DME group, 14 patients, 16 eyes); and non-diabetic retinopathy (NDR) group, 9 patients, 11 eyes, respectively. Aqueous levels of ANGPTL3, ANGPTL4, and ANGPTL6 were assessed using suspension array technology, and foveal-centered 3×3 mm2 OCTA scans were automatically graded to determine the central, inner, and full vessel density (CVD, IVD, FVD); central, inner, and full perfusion density (CPD, IPD, FPD), foveal avascular zone (FAZ) area, FAZ perimeter, and FAZ circularity index (FAZ-CI) on superficial capillary plexuses. Additionally, central subfield thickness (CST), cube volume (CV), and cube average thickness (CAT) were measured in a model of macular cube 512×128. RESULTS: Aqueous ANGPTL3 levels were not significantly different among the three groups (P>0.05). ANGPTL4 levels were significantly higher in the DME group than the control and NDR groups (P

The purpose of current study was to evaluate different optical coherence tomography angiography (OCTA) metrics in eyes with diabetic retinopathy with and without diabetic macular edema (DME). In this retrospective study, macular OCTA images of eyes with non-proliferative or proliferative diabetic retinopathy were evaluated. Vascular density, vascular complexity and non-perfusion densities were compared between eyes with and without DME. One-hundred-thirty-eight eyes of 92 diabetic patients including 49 eyes with DME were included. In multivariate analysis, the presence of DME was positively associated with geometric perfusion deficit (GPD) in superficial capillary plexus (SCP), capillary non-perfusion (CNP) of SCP, and GPD in deep capillary plexus (DCP) (all P

Discovery of robust, selective and specific biomarkers are important for early diagnosis and monitor progression of human diseases. Eye being a common target for several human diseases, vision impediment and complications are often associated with systemic and ocular diseases. Tears are bodily fluids that are closest to eye and are rich in protein content and other metabolites. As a biomarker repository, it advantages over other bodily fluids due to the ability to collect it non-invasively. In this review, we highlight some recent advancements in identification of tear-based protein biomarkers like lacryglobin and cystatin SA for cancer; interleukin-6 and immunoglobulin-A antibody for COVID-19; tau, amyloid-β-42 and lysozyme-C for Alzheimer's disease; peroxiredoxin-6 and α-synuclein for Parkinson's disease; kallikrein, angiotensin converting enzyme and lipocalin-1 for glaucoma; lactotransferrin and lipophilin-A for diabetic retinopathy and zinc-alpha-2 glycoprotein-1, prolactin and calcium binding protein-A4 for eye thyroid disease. We also discussed identification of tear based non-protein biomarkers like lysophospholipids and acetylcarnitine for glaucoma, 8-hydroxy-2'-deoxyquanosine and malondialdehyde for thyroid eye disease. We elucidate technological advancement in developing tear-based biosensors for diagnosis and monitoring diseases such as diabetes, diabetic retinopathy and Alzheimer's disease. Altogether, the study of tears as potential biomarkers for early diagnosis of human diseases is promising.

DNA methylation is considered to play an important role in the development of diabetic retinopathy. Here, our goal was to investigate the precise role of methyl-CpG binding domain protein 2 (Mbd2) in the apoptosis of retinal ganglion cells (RGCs) in the early diabetic retina. Mbd2 was significantly upregulated after high glucose (HG) treatment and played a proapoptotic role in RGCs during HG-induced apoptosis. Combining ChIP and gene microarray datasets, the results showed that Mbd2 possessed potential binding sites for miR-345-5p, thereby elevating the expression levels of miR-345-5p via the enhancement of promoter demethylation. Activating transcription factor 1 (Atf1) played an anti-apoptotic role during the process of apoptosis in RGCs and acted as the target gene for miR-345-5p. Furthermore, the number of surviving RGCs in the diabetic retina was increased in Mbd2-knockout mice when compared with wild-type mice and the visual function became better accordingly. Collectively, our data demonstrated that the HG-induced overexpression of Mbd2 in the retina was partly responsible for the apoptosis of retinal neuronal cells through the miR-345-5p/Atf1 axis. Therefore, the targeting of Mbd2 might represent a novel therapeutic strategy for the treatment of neurodegeneration in the early diabetic retina., Graphical abstract, Methyl-CpG binding domain protein 2 (Mbd2) played a proapoptotic role in retinal ganglion cells (RGCs) during high glucose (HG) treatment via the miR-345-5p/Atf1 axis. This may provide a new therapeutic target for the prevention of neurodegeneration in the early diabetic retina.

PURPOSE: We describe the large-scale self-initiated recruitment of patients to a self-monitoring initiative for macular pathologic features during the coronavirus disease 2019 (COVID-19) pandemic. DESIGN: Observational study with retrospective analysis. PARTICIPANTS: A total of 2272 patients from the Singapore National Eye Centre (SNEC) whose visits were rescheduled over lockdown (April 13-June 1, 2020) were offered participation in a self-monitoring initiative administered by SNEC with the Alleye application (Switzerland) as the testing instrument. METHODS: This was an observational study with retrospective analysis. Demographics and characteristics were compared between those who signed up and those who did not. Similar comparisons were made between patients who complied with the initiative versus those who did not. Outcomes were tracked for 6 months starting from the commencement of lockdown. MAIN OUTCOME MEASURES: Participation and compliance rates and characteristics of patients who were more likely to participate and comply with the initiative. RESULTS: Seven hundred thirty-two patients (32%) participated in this self-monitoring initiative. Those who participated were younger (62 years of age vs. 68 years of age; P < 0.001), men, and living with family. Patients not receiving treatment and those with poorer vision in the worse-seeing eye were more likely to participate. When grouped according to diagnosis, the proportion who participated was highest for diabetic macular edema (52%), nonneovascular age-related macular degeneration (AMD; 42%), diabetic retinopathy (35%), retinal vein occlusions (18%), and neovascular AMD (15%; P < 0.001). Testing compliance rate was 43% (315/732). Patients who complied with the initiative were older, were receiving treatment, and had poorer vision in the worse-seeing eye. Trigger events occurred in 33 patients, with 5 patients having clinically verified disease progression (1.6%). CONCLUSIONS: We provide clinical data on characteristics of patients with stable retinal diseases who were offered, participated in, and complied with a self-monitoring program. The lower participation rate compared with standardized clinical studies reflects the difficulties in implementation for such initiatives in clinical settings. Despite this, self-monitoring continues to show promise in relieving clinic resources, suggesting the feasibility of scaling such programs beyond the COVID-19 pandemic.