Pericyte in retinal vascular diseases: A multifunctional regulator and potential therapeutic target.

Retinal vascular diseases (RVDs), in particular diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity, are leading contributors to blindness. The pathogenesis of RVD involves vessel dilatation, leakage, and occlusion; however, the specific underlying mechanisms remain unclear. Recent findings have indicated that pericytes (PCs), as critical members of the vascular mural cells, significantly contribute to the progression of RVDs, including detachment from microvessels, alteration of contractile and secretory properties, and excessive production of the extracellular matrix. Moreover, PCs are believed to have mesenchymal stem properties and, therefore, might contribute to regenerative therapy. Here, we review novel ideas concerning PC characteristics and functions in RVDs and discuss potential therapeutic strategies based on PCs, including the targeting of pathological signals and cell-based regenerative treatments.

[Biomechanics of diabetic vitreopapillary traction syndrome]. / Biomekhanika diabeticheskogo vitreopapillyarnogo traktsionnogo sindroma.

Diabetic vitreopapillary traction syndrome (VPT) is a variant of diabetic retinopathy (DR) that can lead to vision loss in advanced stages. This review reports on the biomechanics of the vitreous in the pathogenesis of proliferative DR, in particular diabetic VPT. The article analyzes and summarizes literature data, presents the views of different authors on this problem, and provides the results of Russian and foreign scientific research on this pathology. It is concluded that further research in this area can lead to a significant improvement in the results of therapy, timely diagnosis, and preservation of vision in patients with DR.

Factors influencing optimal diabetes care and clinical outcomes in Thai patients with type 2 diabetes mellitus: a multilevel modelling analysis.

BACKGROUND: Increasing levels of poor glycaemic control among Thai patients with type 2 diabetes mellitus (T2DM) motivated us to compare T2DM care between urban and suburban primary care units (PCUs), to identify gaps in care, and to identify significant factors that may influence strategies to enhance the quality of care and clinical outcomes in this population. METHODS: We conducted a cross-sectional study involving 2160 patients with T2DM treated at four Thai PCUs from 2019 to 2021, comprising one urban and three suburban facilities. Using mixed effects logistic regression, we compared care factors between urban and suburban PCUs. RESULTS: Patients attending suburban PCUs were significantly more likely to undergo eye (adjusted OR (AOR): 1.83, 95% CI 1.35 to 1.72), foot (AOR: 1.61, 95% CI 0.65 to 4.59) and HbA1c (AOR: 1.66, 95% CI 1.09 to 2.30) exams and achieved all ABC (HbA1c, blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C)) goals (AOR: 2.23, 95% CI 1.30 to 3.83). Conversely, those at an urban PCU were more likely to undergo albuminuria exams. Variables significantly associated with good glycaemic control included age (AOR: 1.51, 95% CI 1.31 to 1.79), T2DM duration (AOR: 0.59, 95% CI 0.41 to 0.88), FAACE (foot, HbA1c, albuminuria, LDL-C and eye) goals (AOR: 1.23, 95% CI 1.12 to 1.36) and All8Q (AOR: 1.20, 95% CI 1.05 to 1.41). Chronic kidney disease (CKD) was significantly linked with high triglyceride and HbA1c levels (AOR: 5.23, 95% CI 1.21 to 7.61). Elevated HbA1c levels, longer T2DM duration, insulin use, high systolic BP and high lipid profile levels correlated strongly with diabetic retinopathy (DR) and CKD progression. CONCLUSION: This highlights the necessity for targeted interventions to bridge urban-suburban care gaps, optimise drug prescriptions and implement comprehensive care strategies for improved glycaemic control, DR prevention and CKD progression mitigation among in Thai patients with T2DM. The value of the clinical target aggregate (ABC) and the process of care aggregate (FAACE) was also conclusively demonstrated.

A Rapid Review of Interventions to Improve Care for People Who Are Medically Underserved with Multiple Sclerosis, Diabetic Retinopathy, and Lung Cancer.

In the United States, patients with chronic conditions experience disparities in health outcomes across the care continuum. Among patients with multiple sclerosis, diabetic retinopathy, and lung cancer, there is a lack of evidence summarizing interventions to improve care and decrease these disparities. The aim of this rapid literature review was to identify interventions among patients with these chronic conditions to improve health and reduce disparities in screening, diagnosis, access to treatment and specialists, adherence, and retention in care. Using structured search terms in PubMed and Web of Science, we completed a rapid review of studies published in the prior five years conducted in the United States on our subject of focus. We screened the retrieved articles for inclusion and extracted data using a standard spreadsheet. The data were synthesized across clinical conditions and summarized. Screening was the most common point in the care continuum with documented interventions. Most studies we identified addressed interventions for patients with lung cancer, with half as many studies identified for patients with diabetic retinopathy, and few studies identified for patients with multiple sclerosis. Almost two-thirds of the studies focused on patients who identify as Black, Indigenous, or people of color. Interventions with evidence evaluating implementation in multiple conditions included telemedicine, mobile clinics, and insurance subsidies, or expansion. Despite documented disparities and a focus on health equity, a paucity of evidence exists on interventions that improve health outcomes among patients who are medically underserved with multiple sclerosis, diabetic retinopathy, and lung cancer.

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.

Clinical-grade human embryonic stem cell-derived mesenchymal stromal cells ameliorate diabetic retinopathy in db/db mice.

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) hold great promise in the treatment of diabetic retinopathy (DR), as evidenced by increasing preclinical and clinical studies. However, the absence of standardized and industrialized clinical-grade donor cells hampers the continued development and large-scale clinical application of MSCs-based therapies for DR. Previously, we have identified a unique population of MSCs generated from a clinical-grade human embryonic stem cell (hESC) line under Good Manufacturing Practice conditions that could be a potential source to address the issues. Here, we investigated the therapeutic potential of the clinical-grade hESC line-derived MSCs (hESC-MSCs) on db/db mice with DR. METHODS: hESC-MSCs were initially characterized by morphological assessment, flow cytometry analysis and trilineage differentiation assays. These cells (5 × 106 cells) were then transplanted intravenously into 12-week-old db/db mice via tail vein, with phosphate-buffered saline transplantation and untreated groups used as controls. The retinal alterations in neural functions and microvascular perfusions, and inflammatory responses in peripheral blood and retina were evaluated at 4 and 6 weeks after transplantation using electroretinography, optical coherence tomography angiography and flow cytometry, respectively. Body weight and fasting blood glucose (FBG) levels were also measured to investigate their systemic implications. RESULTS: Compared with controls, intravenous transplantation of hESC-MSCs could significantly: (i) enhance impaired retinal electroretinography functions (including amplitudes of a-, b-wave and oscillatory potentials) at 4 weeks after transplantation; (ii) alleviate microvascular dysfunctions, especially in the inner retina with significance (including reducing non-perfusion area and increasing vascular area density) at 4 weeks after transplantation; (iii) decrease FBG levels at 4 weeks after transplantation and induce weight loss up to 6 weeks after transplantation and (iv) increase both peripheral blood and retinal interleukin-10 levels at 4 weeks after transplantation and modulate peripheral blood inflammatory cytokines and chemokines levels, such as monocyte chemotactic protein-1, up to 6 weeks after transplantation. CONCLUSIONS: The findings of our study indicated that intravenous transplantation of hESC-MSCs ameliorated retinal neural and microvascular dysfunctions, regulated body weight and FBG and modulated peripheral blood and retinal inflammation responses in a mouse model of DR. These results suggest that hESC-MSCs could be a potentially effective clinical-grade cell source for the treatment of DR.

A nonparametric relative treatment effect for direct comparisons of censored paired survival outcomes.

A frequently addressed issue in clinical trials is the comparison of censored paired survival outcomes, for example, when individuals were matched based on their characteristics prior to the analysis. In this regard, a proper incorporation of the dependence structure of the paired censored outcomes is required and, up to now, appropriate methods are only rarely available in the literature. Moreover, existing methods are not motivated by the strive for insights by means of an easy-to-interpret parameter. Hence, we seek to develop a new estimand-driven method to compare the effectiveness of two treatments in the context of right-censored survival data with matched pairs. With the help of competing risks techniques, the so-called relative treatment effect is estimated. This estimand describes the probability that individuals under Treatment 1 have a longer lifetime than comparable individuals under Treatment 2. We derive hypothesis tests and confidence intervals based on a studentized version of the estimator, where resampling-based inference is established by means of a randomization method. In a simulation study, we demonstrate for numerous sample sizes and different amounts of censoring that the developed test exhibits a good power. Finally, we apply the methodology to a well-known benchmark data set from a trial with patients suffering from diabetic retinopathy.

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.

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.

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.

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.

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.

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.

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.