Social Risk Groups in Patients With Diabetes With Differing Eye Care Utilization and Vision Outcomes.

Purpose: To evaluate whether latent class analysis on social determinants of health (SDoH) data can identify social risk groups that differ by adverse SDoH and vision outcomes in patients with diabetes. Methods: This was a prospective cohort study of adults ≥18 years with diabetes who completed a SDoH survey. Latent class analysis was used to cluster patients into social risk groups. The association of social risk group and severity of diabetic retinopathy, history of lapses in diabetic retinopathy care, and visual acuity was evaluated. Results: A total of 1006 participants were included. The three social risk groups differed by sociodemographic characteristics. The average age was 65, 60, and 54 in Groups 1, 2, and 3 respectively. Most (51%) patients in group 1 were non-Hispanic White, 66% in group 2 were non-Hispanic Black, and 80% in group 3 were Hispanic. Group 1 had the lowest burden of adverse SDoH per person (average 3.6), group 2 had 8.2, and group 3 had 10.5. In general, group 1 lacked diabetic retinopathy knowledge, group 2 had financial insecurity and difficulties with transportation, and group 3 had financial insecurity and did not have health insurance. Social risk group was associated with a history of lapses in diabetic retinopathy care, and presenting with worse vision. Conclusions and Translational Relevance: We identified distinct social risk groups among patients seeking care for diabetic retinopathy that differed by social needs, eye care utilization, and vision. Identifying these groups and their specific needs can help guide interventions to effectively address adverse SDoH and improve eye care utilization and vision outcomes among patients with diabetes.

NOD1 deficiency ameliorates the progression of diabetic retinopathy by modulating bone marrow-retina crosstalk.

BACKGROUND: Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) plays a pivotal role in inducing metabolic inflammation in diabetes. Additionally, the NOD1 ligand disrupts the equilibrium of bone marrow-derived hematopoietic stem/progenitor cells, a process that has immense significance in the development of diabetic retinopathy (DR). We hypothesized that NOD1 depletion impedes the advancement of DR by resolving bone marrow dysfunction. METHODS: We generated NOD1-/--Akita double-mutant mice and chimeric mice with hematopoietic-specific NOD1 depletion to study the role of NOD1 in the bone marrow-retina axis. RESULTS: Elevated circulating NOD1 activators were observed in Akita mice after 6 months of diabetes. NOD1 depletion partially restored diabetes-induced structural changes and retinal electrical responses in NOD1-/--Akita mice. Loss of NOD1 significantly ameliorated the progression of diabetic retinal vascular degeneration, as determined by acellular capillary quantification. The preventive effect of NOD1 depletion on DR is linked to bone marrow phenotype alterations, including a restored HSC pool and a shift in hematopoiesis toward myelopoiesis. We also generated chimeric mice with hematopoietic-specific NOD1 ablation, and the results further indicated that NOD1 had a protective effect against DR. Mechanistically, loss of hematopoietic NOD1 resulted in reduced bone marrow-derived macrophage infiltration and decreased CXCL1 and CXCL2 secretion within the retina, subsequently leading to diminished neutrophil chemoattraction and NETosis. CONCLUSIONS: The results of our study unveil, for the first time, the critical role of NOD1 as a trigger for a hematopoietic imbalance toward myelopoiesis and local retinal inflammation, culminating in DR progression. Targeting NOD1 in bone marrow may be a potential strategy for the prevention and treatment of DR.

Molecular Mechanisms and Therapeutic Implications of Human Pericyte-like Adipose-Derived Mesenchymal Stem Cells in an In Vitro Model of Diabetic Retinopathy.

The blood-retinal barrier (BRB) is strongly compromised in diabetic retinopathy (DR) due to the detachment of pericytes (PCs) from retinal microvessels, resulting in increased permeability and impairment of the BRB. Western blots, immunofluorescence and ELISA were performed on adipose mesenchymal stem cells (ASCs) and pericyte-like (P)-ASCs by co-cultured human retinal endothelial cells (HRECs) under hyperglycemic conditions (HG), as a model of DR. Our results demonstrated that: (a) platelet-derived growth factor receptor (PDGFR) and its activated form were more highly expressed in monocultured P-ASCs than in ASCs, and this expression increased when co-cultured with HRECs under high glucose conditions (HG); (b) the transcription factor Nrf2 was more expressed in the cytoplasmic fraction of ASCs and in the P-ASC nuclear fraction, under normal glucose and, even more, under HG conditions; (c) cytosolic phospholipase A2 activity and prostaglandin E2 release, stimulated by HG, were significantly reduced in P-ASCs co-cultured with HRECs; (d) HO-1 protein content was significantly higher in HG-P-ASCs/HRECs than P-ASCs/HRECs; and (e) VEGF-A levels in media from HG-co-cultures were reduced in P-ASCs/HRECs with respect to ASCs/HRECs. The data obtained highlighted the potential of autologous differentiated ASCs in future clinical applications based on cell therapy to counteract the damage induced by DR.

Structured Counselling and Regular Telephonic follow up to improve Referral flow and compliance in Nepal for Diabetic Retinopathy(SCREEN-D Study): a randomised controlled trial.

BACKGROUND: Diabetic Retinopathy (DR) is an emerging public health issue, leading to severe visual impairment or blindness. Early identification and prompt treatment play a key role in achieving good visual outcomes. The objective of the study was to estimate the effectiveness of SCREEN package on improving referral compliance from peripheral centres to a tertiary eye centre in Nepal. METHODS: In this facility-based cluster-randomized trial, ten out of 19 referring centres of the tertiary eye care centre in Lumbini zone, Nepal were randomized into intervention and control groups. A SCREEN packagewereprovided as intervention for DR patients who require advanced treatment in the tertiary centres and was compared with the current practice of the control arm, where structured counselling and follow-up mechanism are absent. Compliance was estimated by a weekly follow-up between the referring centre and the referred hospital. RESULTS: We recruited 302 participantsof whom 153 were in the intervention arm. The mean age of the participants was 57.8 years (Standard deviation [SD]±11.7 years). With implementation of SCREEN package71.2% (n=109) in the intervention group and 42.9% (n=64) in the control group were compliant till three months of follow-up (Difference 28.3%, 95% CI: 17.6- 39.0, p<0.05). Compliance was 43% (n=66) with counselling alone, and 66% (n=103) with first telephonic follow-up in the intervention arm. The mean duration to reach the referral centre was 14.7 days (SD± 9.4 days) and 18.2 days (SD± 9.1 days) in the intervention and the control arm, respectively (Difference 3.5 days, 95% CI: 0.7 to 6.4 days). CONCLUSIONS: Counselling& follow-up to patients is the key factor to improve the utilization of the health services by patients with DR. Health systems must be strengthened by optimizing the existing referral structure in Nepal. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Registration and Results System, ClinicalTrials.gov Identifier: NCT04834648 , 08/04/2021.

Healthcare Resource Utilization and Costs in an At-Risk Population With Diabetic Retinopathy.

Purpose: Several investigators have suggested the cost-effectiveness of earlier screening, management of risk factors, and early treatment for diabetic retinopathy (DR). We aimed to evaluate the extent of health care utilization and cost of delayed care by insurance type in a vulnerable patient population. Methods: A retrospective analysis of patients with DR was conducted using electronic medical record (EMR) data from January 2014 to December 2020 at Denver Health Medical Center, a safety net institution. Patients were classified by disease severity and insurance status. DR-specific costs were assessed via Current Procedural Terminology (CPT) codes over a 24-month follow-up period. Results: Among the 313 patients, a higher proportion of non-English speaking patients were uninsured. Rates of proliferative DR at presentation differed across insurance groups (62% of uninsured, 42% of discount plan, and 33% of Medicare/Medicaid, P = 0.016). There was a significant difference in the total median cost between discount plan patients ($1258, interquartile range [IQR] = $0 - $5901) and both Medicare patients ($751, IQR = $0, $7148, P = 0.037) and Medicaid patients ($593, IQR = $0 - $6299, P = 0.025). Conclusions: There were higher rates of proliferative DR at presentation among the uninsured and discount plan patients and greater total median cost in discount plan patients compared to Medicare or Medicaid. These findings prioritize mitigating gaps in insurance coverage and barriers to preventative care among vulnerable populations. Translational Relevance: Advanced diabetic disease and increased downstream health care utilization and cost vary across insurance type, suggesting improved access to preventative care is needed in these specific at-risk populations.

Acute and Chronic Adverse Outcomes of Type 1 Diabetes.

Type 1 diabetes is associated with both acute and chronic complications. Acute complications include diabetic ketoacidosis and severe hypoglycemia. Chronic complications can be microvascular or macrovascular. Microvascular complications include retinopathy, nephropathy, and neuropathy. The pathophysiology of microvascular complications is complex. Hyperglycemia is a common underlying risk factor, underscoring the importance of optimizing glycemic management. Patients with type 1 diabetes are also at increased risk of macrovascular complications including coronary artery disease and vascular disease. The American Diabetes Association provides screening guidelines for chronic complications of diabetes. Adherence to these guidelines is an important aspect of diabetes care.

The role of cadre in the community on diabetic retinopathy management and its challenges in low-middle income countries: a scoping review.

INTRODUCTION: Diabetes is a serious public health problem, with low- and middle-income countries (LMICs) bearing over 80% of the burden. Diabetic retinopathy (DR) is one of the most prevalent diabetic microvascular problems, and early diagnosis through eye screening programs for people with diabetes is critical to prevent vision impairment and blindness. Community-based treatments, including non-physician cadres have been recommended to enhance DR care. METHODS: The review protocol was determined and scoping review was conducted.The population, concept, and context were "cadre", "role of cadre in the management of DR", and LMICs". Data were collected from databases and searches, including grey literature. RESULTS: Cadre can motivate people to attend a diabetic eye screening event when the rate of eye examinations is about six times higher than before the start of the intervention. Health education is a possible area for task sharing, and the cadre reported could also perform the task of vision testing. The cadre could be a good supporter and a good reminder for society. However, several challenges have been faced in this study and inadequate infrastructure is the foremost challenge found in this study. Other challenges encountered in the studies include poverty, lack of community awareness, trust issues, and low education levels contributing to poor health. CONCLUSION: The current study highlighted significant gaps in the literature, which focus on the role of cadre as a community-based intervention in managing DR in LMICs. Further research is needed to develop evidence to support cost-effective screening services and cadre-related policy development in LMICs.

Optical coherence tomography in the management of diabetic macular oedema.

Diabetic macular oedema (DMO) is the major cause of visual impairment in people with diabetes. Optical coherence tomography (OCT) is now the most widely used modality to assess presence and severity of DMO. DMO is currently broadly classified based on the involvement to the central 1 mm of the macula into non-centre or centre involved DMO (CI-DMO) and DMO can occur with or without visual acuity (VA) loss. This classification forms the basis of management strategies of DMO. Despite years of research on quantitative and qualitative DMO related features assessed by OCT, these do not fully inform physicians of the prognosis and severity of DMO relative to visual function. Having said that, recent research on novel OCT biomarkers development and re-defined classification of DMO show better correlation with visual function and treatment response. This review summarises the current evidence of the association of OCT biomarkers in DMO management and its potential clinical importance in predicting VA and anatomical treatment response. The review also discusses some future directions in this field, such as the use of artificial intelligence to quantify and monitor OCT biomarkers and retinal fluid and identify phenotypes of DMO, and the need for standardisation and classification of OCT biomarkers to use in future clinical trials and clinical practice settings as prognostic markers and secondary treatment outcome measures in the management of DMO.

AAV-Based Strategies for Treatment of Retinal and Choroidal Vascular Diseases: Advances in Age-Related Macular Degeneration and Diabetic Retinopathy Therapies.

Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are vascular diseases with high prevalence, ranking among the leading causes of blindness and vision loss worldwide. Despite being effective, current treatments for AMD and DR are burdensome for patients and clinicians, resulting in suboptimal compliance and real risk of vision loss. Thus, there is an unmet need for long-lasting alternatives with improved safety and efficacy. Adeno-associated virus (AAV) is the leading vector for ocular gene delivery, given its ability to enable long-term expression while eliciting relatively mild immune responses. Progress has been made in AAV-based gene therapies for not only inherited retinal diseases but also acquired conditions with preclinical and clinical studies of AMD and DR showing promising results. These studies have explored several pathways involved in the disease pathogenesis, as well as different strategies to optimise gene delivery. These include engineered capsids with enhanced tropism to particular cell types, and expression cassettes incorporating elements for a targeted and controlled expression. Multiple-acting constructs have also been investigated, in addition to gene silencing and editing. Here, we provide an overview of strategies employing AAV-mediated gene delivery to treat AMD and DR. We discuss preclinical efficacy studies and present the latest data from clinical trials for both diseases.

MSC-Derived Small Extracellular Vesicles Alleviate Diabetic Retinopathy by Delivering miR-22-3p to Inhibit NLRP3 Inflammasome Activation.

PURPOSE: This study aimed to investigate the effect of mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) on diabetic retinopathy (DR) and its underlying mechanism. METHODS: In vivo, MSC-sEVs were injected intravitreally into diabetic rats to determine the therapeutic efficacy. In vitro, MSC-sEVs with/without miR-22-3p inhibition were cocultured with advanced glycation end-products (AGEs)-induced microglia with/without NLRP3 overexpression to explore the molecular mechanism. RESULTS: In vivo, MSC-sEVs inhibited NLRP3 inflammasome activation, suppressed microglial activation, decreased inflammatory cytokines levels in the retina, and alleviated DR as evidenced by improved histological morphology and blood-retinal barrier function. Based on miRNA sequencing of MSC-sEVs, bioinformatic software, and dual-luciferase reporter assay, miR-22-3p stood out as the critical molecule for the role of MSC-sEVs in regulating NLRP3 inflammasome activation. Diabetic rats had lower level of miR-22-3p in their retina than those of control and sEV-treated rats. Confocal microscopy revealed that sEV could be internalized by microglia both in vivo and in vitro. In vitro, compared with sEV, the anti-inflammation effect of sEVmiR-22-3p(-) on AGEs-induced microglia was compromised, as they gave a lower suppression of NLRP3 inflammasome activation and inflammatory cytokines. In addition, NLRP3 overexpression in microglia damped the anti-inflammatory effect of sEV. CONCLUSION: These results indicated that MSC-sEVs alleviated DR via delivering miR-22-3p to inhibit NLRP3 inflammasome activation. Our findings indicate that MSC-sEVs might be a potential therapeutic method for DR.

Exploring the role of retinal fluid as a biomarker for the management of diabetic macular oedema.

Anti-VEGF therapies are associated with significant gains in visual acuity and fluid resolution in the treatment of diabetic macular oedema (DMO) and have become the standard of care. However, despite their efficacy, outcomes can be unpredictable, vary widely between individual eyes, and a large proportion of patients have persistent fluid following initial treatment, with a negative impact on visual outcomes. Anatomical parameters measured by optical coherence tomography (OCT), in addition to visual acuity, are key to monitoring treatment effectiveness and guiding retreatment decisions; however, existing guidelines on the management of DMO lack clear recommendations for interpretation of OCT parameters, or proposed thresholds of various markers to guide retreatment decisions. Although central subfield thickness (CSFT) has been widely used as a marker for retreatment decisions in clinical trials in DMO, and a reduction in CSFT has generally been shown to accompany improvements in best-corrected visual acuity with treatment, analyses of the relationship between these parameters show that the correlation is small to moderate. A more direct relationship can be seen between an increased magnitude of CSFT fluctuations over time and poorer visual acuity, suggesting that control of CSFT could be important in maximising visual outcomes. The relationship between visual outcomes and qualitatively assessed intraretinal fluid and subretinal fluid is also unclear, although quantitative assessments of fluid parameters suggest that untreated intraretinal fluid and subretinal fluid negatively impact visual outcomes. These findings highlight a need for clearer guidelines on the management of retinal fluid to improve visual outcomes for patients with DMO.

[Evaluation of an experiment in ophthalmology telemedicine]. / Évaluation d'une expérimentation de télémédecine en ophtalmologie.

PURPOSE: To meet the need for access to eye care in an area with a lack of physicians, a telemedicine workstation in ophthalmology was created. The main objective was to measure the improved access to eye care via telemedicine consultation. METHODS: No criteria of age, sex or geographical location were defined. Depending on the cause for the consultation and the results of the examinations conducted by an ophthalmic technician physically present in the center, the patient might be given a telemedicine consultation with an ophthalmologist. Eleven indicators were defined to achieve the study objectives. Data were compared with a reference eye care center. RESULTS: The quality, safety of care, and medical benefits of telemedicine consultation were not inferior to those of the reference center. The consultations screened 25 cases of age-related macular degeneration, 240 glaucoma, 229 cataracts and 27 diabetic retinopathy. 88.5% of patients were included in a cooperative ophthalmologist/technician protocol, compared with 27.3% in the reference center (P<0.0001). DISCUSSION: The telemedicine workstation must be linked to a main center located at most a one-hour drive away. The equipment must be adapted to the use of telemedicine and to allow the technician to perform the necessary assessments and examinations. The number of emergency department visits after telemedicine consultation at the telemedicine workstation was higher than the reference center, which may lead to a subsequent study. CONCLUSION: Telemedicine consultation improves access to eye care in a medically under-served area.

The role of Keap1-Nrf2 signaling pathway during the progress and therapy of diabetic retinopathy.

Diabetic retinopathy is a complex and progressive ocular complication of diabetes mellitus and is a leading cause of blindness in people of working age worldwide. The pathophysiology of diabetic retinopathy involves multifactorial processes, including oxidative stress, inflammation and vascular abnormalities. Understanding the underlying molecular mechanisms involved in its pathogenesis is essential for the development of effective therapeutic interventions. One of the pathways receiving increasing attention is the Keap1-Nrf2 signaling pathway, which regulates the cellular response to oxidative stress by activating Nrf2. In this review, we analyze the current evidence linking Keap1-Nrf2 signaling pathway dysregulation to diabetic retinopathy. In addition, we explore the potential therapeutic implications and the challenges of targeting this pathway for disease management. A comprehensive understanding of the molecular mechanisms of diabetic retinopathy and the therapeutic potential of the Keap1-Nrf2 pathway may pave the way for innovative and effective interventions to combat this vision-threatening disease.

Changes in activity impairment and work productivity after treatment for vitreous hemorrhage due to proliferative diabetic retinopathy: Secondary outcomes from a randomized controlled trial (DRCR Retina Network Protocol AB).

BACKGROUND: Vitreous hemorrhage from proliferative diabetic retinopathy can cause severe vision loss. DRCR Retina Network Protocol AB was a randomized clinical trial comparing intravitreal aflibercept versus vitrectomy with panretinal photocoagulation and found no difference in the average rate of visual recovery over 104 weeks. Herein, we describe patient-reported outcome measures from Protocol AB. METHODS: Secondary analysis of a multicenter (39 sites) randomized clinical trial. The Work Productivity and Activity Impairment Questionnaire was administered at 4, 12, 24, 36, 52, 68, 84, and 104 weeks. Main outcomes were mean change in activity impairment and work productivity loss over 24 and 104 weeks (area under the curve). RESULTS: Mean (SD) activity impairment at baseline was 58% (27%) in the aflibercept group (N = 99) and 56% (30%) in the vitrectomy group (N = 105). The mean reduction in activity impairment from baseline over 24 weeks was 21% (25%) in the aflibercept group and 27% (31%) in the vitrectomy group (adjusted difference = -6.8% [95% CI, -12.7% to -0.9%], P = .02); over 104 weeks, the adjusted mean difference was -3.1% (95% CI, -9.2% to 3.0%, P = .31). Mean work productivity loss at baseline was 51% (28%) in the aflibercept group (N = 44) and 58% (30%) in the vitrectomy group (N = 43). The mean reduction in work productivity loss from baseline over 24 weeks (area under the curve) was 19% (23%) in the aflibercept group and 31% (24%) in the vitrectomy group (adjusted difference = -8.3% [95% CI, -16.8% to 0.2%], P = .06); over 104 weeks, the adjusted mean difference was -9.1% (95% CI, -18.4% to 0.2%, P = .05). CONCLUSIONS: Participants with vitreous hemorrhage from proliferative diabetic retinopathy had less activity impairment over 24 weeks when treated initially with vitrectomy and panretinal photocoagulation versus intravitreal aflibercept. The trend was similar for work productivity but not statistically significant. By 104 weeks, the improvements were similar in the two treatment groups. TRIAL REGISTRATION: ClinicalTrials.gov NCT02858076.

Diabetic Macular Edema - Diagnostics and Treatment Guidelines.

Together with diabetic retinopathy, diabetic macular edema (DME) ranks among the most common causes of severe loss of vision in working adults. Due to recent developments in imaging methods, new classification schemes of DME have been created. In addition to this, new treatment options have been introduced (new intravitreal drugs as well as treatment protocols). At the same time laser, surgical as well as combination therapy is still available. In this paper we evaluate the current knowledge about DME diagnostic and treatment options and formulate recommended guidelines for the management of DME.

Diabetic Retinopathy ­ Diagnostics and Treatment Guidelines

Diabetic retinopathy is one of the most common complications of diabetes mellitus and represents a serious health, social and economic problem. With the expected increase in the number of patients with diabetes, it is becoming the leading cause of severe vision loss in the working-age population.  The presented guidelines summarize the current knowledge about this disease in order to standardize and update the procedures for the diagnosis, classification and treatment of diabetic retinopathy.

Report From the 2022 Mary Tyler Moore Vision Initiative Diabetic Retinal Disease Clinical Endpoints Workshop.

The Mary Tyler Moore Vision Initiative Diabetic Retinal Disease (DRD) Clinical Endpoints Workshop was held on October 22, 2022 to accelerate progress toward establishment of useful clinical and research endpoints and development of new therapeutics that have important relevance across the full spectrum of DRD pathology. More than 90 patient representatives, clinicians, scientists, funding and regulatory agencies, diagnostic, therapeutic and biotech industry representatives discussed the needs for new diagnostic and therapeutic approaches to prevent and restore retinal neurovascular unit integrity. Phase I of the MTM Vision Initiative plans, notably updating the DRD staging system and severity scale, establishing a human ocular biorepository and resource, and clinical endpoints and biomarker development and validation, was emphasized.