UNASSIGNED: Hyperglycemia is a major risk factor for early lesions of diabetic retinal disease (DRD). Updating the DRD staging system to incorporate relevant basic and cellular mechanisms pertinent to DRD is necessary to better address early disease, disease progression, the use of therapeutic interventions, and treatment effectiveness.
UNASSIGNED: We sought to review preclinical and clinical evidence on basic and cellular mechanisms potentially pertinent to DRD that might eventually be relevant to update the DRD staging system.
UNASSIGNED: Not applicable.
UNASSIGNED: The Basic and Cellular Mechanisms Working Group (BCM-WG) of the Mary Tyler Moore Vision Initiative carefully and extensively reviewed available preclinical and clinical evidence through multiple iterations and classified these.
UNASSIGNED: Classification was made into evidence grids, level of supporting evidence, and anticipated future relevance to DRD.
UNASSIGNED: A total of 40 identified targets based on pathophysiology and other parameters for DRD were grouped into concepts or evaluated as specific candidates. VEGFA, peroxisome proliferator-activated receptor-alpha related pathways, plasma kallikrein, and angiopoietin 2 had strong agreement as promising for use as biomarkers in diagnostic, monitoring, predictive, prognostic, and pharmacodynamic responses as well as for susceptibility/risk biomarkers that could underlie new assessments and eventually be considered within an updated DRD staging system or treatment, based on the evidence and need for research that would fit within a 2-year timeline. The BCM-WG found there was strong reason also to pursue the following important concepts regarding scientific research of DRD acknowledging their regulation by hyperglycemia: inflammatory/cytokines, oxidative signaling, vasoprotection, neuroprotection, mitophagy, and nutrients/microbiome.
UNASSIGNED: Promising targets that might eventually be considered within an updated DRD staging system or treatment were identified. Although the BCM-WG recognizes that at this stage little can be incorporated into a new DRD staging system, numerous potential targets and important concepts deserve continued support and research, as they may eventually serve as biomarkers and/or therapeutic targets with measurable benefits to patients with diabetes.
UNASSIGNED: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

To identify specific markers indicative of macular neural and microvascular alterations in individuals with Type 2 Diabetes Mellitus (T2DM) without clinically observable retinopathy.
Prospective cross-sectional study.
Using the PLEX Elite 9000, all eyes underwent swept-source optical coherence tomography (SS-OCT) angiography. Quantitative analysis of acquired images compared macular neural and microvascular alterations in T2DM patients without retinopathy to age-matched controls. Precise assessments encompassed measuring the thickness of each individual retinal layer and evaluating macular vascular indices within different capillary plexuses.
Forty-nine T2DM patients and 51 age-matched controls participated. T2DM patients exhibited a significant reduction in the mean macular thickness of the ganglion cell-inner plexiform layer (GC-IPL) (82.5 ± 5.5 µm vs 86.2 ± 5.0 µm, P = .001) and macular retinal nerve fiber layer (RNFL) (45.8 ± 3.0 µm vs 48.1 ± 3.7 µm, P = .001). Furthermore, macular full retinal thickness was significantly lower in diabetic eyes than controls (324.9 ± 16.3 µm vs 332.8 ± 13.7 µm, P = .009). Vascular measurements revealed subtle changes in macular vascular skeleton density within the total capillary plexuses in T2DM patients (0.132 ± 0.005 vs 0.135 ± 0.005, P = .019).
Metrics derived from SS-OCT, particularly macular RNFL and GC-IPL thicknesses, emerged as superior indicators for the early detection of diabetic retinal disease in individuals with T2DM without clinically observable retinopathy. Further investigations are warranted to comprehensively understand the clinical implications of these findings.

UNASSIGNED: The goal of this review was to summarize the current level of evidence on biomarkers to quantify diabetic retinal neurodegeneration (DRN) and diabetic macular edema (DME).
UNASSIGNED: With advances in retinal diagnostics, we have more data on patients with diabetes than ever before. However, the staging system for diabetic retinal disease is still based only on color fundus photographs and we do not have clear guidelines on how to incorporate data from the relatively newer modalities into clinical practice.
UNASSIGNED: In this review, we use a Delphi process with experts to identify the most promising modalities to identify DRN and DME. These included microperimetry, full-field flash electroretinogram, spectral-domain OCT, adaptive optics, and OCT angiography. We then used a previously published method of determining the evidence level to complete detailed evidence grids for each modality.
UNASSIGNED: Our results showed that among the modalities evaluated, the level of evidence to quantify DRN and DME was highest for OCT (level 1) and lowest for adaptive optics (level 4).
UNASSIGNED: For most of the modalities evaluated, prospective studies are needed to elucidate their role in the management and outcomes of diabetic retinal diseases.
UNASSIGNED: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

UNASSIGNED: Several patient-reported outcome measures (PROMs) are available to measure health-related quality of life (HRQoL) in patients with late-stage clinical diabetic retinal diseases (DRDs). However, an understanding of the psychometric properties of PROMs is needed to assess how they could relate to severity levels of a revised DRD grading system. This narrative review assessed the available generic-, vision-, and DRD-related PROMs used in DRD research and highlights areas for improvement.
UNASSIGNED: Diabetic retinal disease is a common complication of diabetes and can lead to sight-threatening complications with a devastating effect on HRQoL.
UNASSIGNED: The Quality of Life working group is one of 6 working groups organized for the DRD Staging System Update Effort, a project of the Juvenile Diabetes Research Foundation Mary Tyler Moore Vision Initiative. PubMed, Cochrane Library, Embase, and Google Scholar databases were searched using core keywords to retrieve ophthalmology-related review articles, randomized clinical trials, and prospective, observational, and cross-sectional studies in the English language. A detailed review of 12 PROMs (4 QoL questionnaires and 8 utilities) that met a minimum level of evidence (LOE) was conducted. The relevance of each PROM to DRD disease stage and Biomarker Qualification guidelines (Biomarkers, EndpointS, and other Tools) categories was also defined.
UNASSIGNED: The National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25), Impact of vision impairment-computerized adaptive testing, and Diabetic Retinopathy and Macular Edema Computerized Adaptive Testing System had a LOE of II in detecting change due to late-stage DRD (diabetic macular edema), although several areas for improvement (e.g., psychometrics and generalizability) were identified. Other PROMs, particularly the utilities, had a LOE of III due to cross-sectional evidence in late-stage clinical DRD. Although the NEI VFQ-25 has been the most widely used PROM in late-stage DRD, more work is required to improve its multidimensional structure and other psychometric limitations. No PROM was deemed relevant for subclinical or early/mid-DRD.
UNASSIGNED: This narrative review found that the most commonly used PROM is NEI VFQ-25, but none meets the ideal psychometric, responsiveness, and clinical setting digital administration requirements that could be included in an updated DRD staging system for diagnosis and monitoring of DRD progression.
UNASSIGNED: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

UNASSIGNED: In the pivotal clinical trial that led to Food and Drug Administration De Novo \"approval\" of the first fully autonomous artificial intelligence (AI) diabetic retinal disease diagnostic system, a reflexive dilation protocol was used. Using real-world deployment data before implementation of reflexive dilation, we identified factors associated with nondiagnostic results. These factors allow a novel predictive dilation workflow, where patients most likely to benefit from pharmacologic dilation are dilated a priori to maximize efficiency and patient satisfaction.
UNASSIGNED: Retrospective review of patients who were assessed with autonomous AI at Johns Hopkins Medicine (8/2020 to 5/2021). We constructed a multivariable logistic regression model for nondiagnostic results to compare characteristics of patients with and without diagnostic results, using adjusted odds ratio (aOR). P < .05 was considered statistically significant.
UNASSIGNED: Of 241 patients (59% female; median age = 59), 123 (51%) had nondiagnostic results. In multivariable analysis, type 1 diabetes (T1D, aOR = 5.82, 95% confidence interval [CI]: 1.45-23.40, P = .01), smoking (aOR = 2.86, 95% CI: 1.36-5.99, P = .005), and age (every 10-year increase, aOR = 2.12, 95% CI: 1.62-2.77, P < .001) were associated with nondiagnostic results. Following feature elimination, a predictive model was created using T1D, smoking, age, race, sex, and hypertension as inputs. The model showed an area under the receiver-operator characteristics curve of 0.76 in five-fold cross-validation.
UNASSIGNED: We used factors associated with nondiagnostic results to design a novel, predictive dilation workflow, where patients most likely to benefit from pharmacologic dilation are dilated a priori. This new workflow has the potential to be more efficient than reflexive dilation, thus maximizing the number of at-risk patients receiving their diabetic retinal examinations.

Diabetic retinal disease (DRD) remains a leading cause of vision loss and blindness globally. Although treatments can be effective when given at vision-threatening stages of DRD, there is a lack of knowledge about the earliest mechanisms leading to the development of clinically evident DRD. Recent advances in retinal imaging methods for patients with diabetes allow a more precise and granular characterization of the different stages of DRD than is provided by the classic Diabetic Retinopathy Severity Scale based on fundus photographs. In addition, recent clinical studies have yielded more information on how to adjust blood glucose levels, lipid levels and blood pressure to minimize the risk of DRD. Given the incomplete success of current therapies, there is a critical need for better understanding of the mechanisms underlying DRD and novel treatment targets that address the entire neurovascular retina. Moreover, the causes for interindividual variability in the development of DRD in patients with similar glycemic history and other metabolic factors are not yet clarified either. Finally, greater focus on patients\' experience with visual disabilities and treatment effects should be addressed in research in this field.

Diabetic retinal disease (DRD), the most common complication of diabetes and a leading cause of blindness in working age individuals, is now understood to be a form of sensory neuropathy or neurovascular degeneration. Current treatments are focused on advanced vision-threatening disease and a single molecular target, vascular endothelial growth factor, has an approved therapy. We trace the evolution of understanding of DRD pathogenesis, identify new approaches to clinical assessment, trials infrastructure and design, and target identification to accelerate selection and evaluation of new therapeutics that will speed development of potentially curative interventions. Critically, the \"Restoring Vision Moonshot\" framework will address gaps in knowledge to be filled to achieve the goal of restoring sight and preventing vision loss in persons with diabetes.

Optical coherence tomography Angiography (OCT-A) represents a revolution in the noninvasive evaluation of retinal and choroidal circulation especially in detecting early clinical signs of diabetic retinal disease (DRD). With appropriate use, OCT-A characteristics and measurements have the potential to become new imaging biomarkers in managing and treating DRD. Major challenges include (a) provision of standardized outputs from different OCT-A instruments providing standardized terminology to correctly interpret data; (b) the presence of artifacts; (c) the absence of standardized grading or interpretation method in the evaluation of DRD, similar to that already established in fundus photography; and (d) establishing how OCT-A might be able to provide surrogate markers to demonstrate blood retinal barrier breakdown and vascular leakage, commonly associated with DRD. In fact, OCT-A guidelines for DRD are still evolving. The outputs of quantitative OCT-A data offer a unique opportunity to develop tools based on artificial intelligence to assist the clinicians in diagnosing, monitoring, and managing patients with diabetes. In addition, OCT-A has the potential to become a useful tool for the evaluation of cardiovascular diseases and different neurological diseases including cognitive impairment. This article written by the members of Diabetic Retinopathy expert committee of the European Vision Clinical Research network will review the available evidence on the use of OCT-A as an imaging biomarker in DRD and discuss the limits and the current application as well as future developments for its use in both clinical practice and research trials of DRD.

Diabetic retinal disease (DRD) remains the most common cause of vision loss in adults of working age. Progress on the development of new therapies for DRD has been limited by the complexity of the human eye, which constrains the utility of traditional research techniques, including animal and tissue culture models-a problem shared by those in the field of kidney disease research. By contrast, significant progress in the study of diabetic kidney disease (DKD) has resulted from the successful employment of systems biology approaches. Systems biology is widely used to comprehensively understand complex human diseases through the unbiased integration of genetic, environmental, and phenotypic aspects of the disease with the functional and structural manifestations of the disease. The application of a systems biology approach to DRD may help to clarify the molecular basis of the disease and its progression. Acquiring this type of information might enable the development of personalized treatment approaches, with the goal of discovering new therapies targeted to an individual\'s specific DRD pathophysiology and phenotype. Furthermore, recent efforts have revealed shared and distinct pathways and molecular targets of DRD and DKD, highlighting the complex pathophysiology of these diseases and raising the possibility of therapeutics beneficial to both organs. The objective of this review is to survey the current understanding of DRD pathophysiology and to demonstrate the investigative approaches currently applied to DKD that could promote a more thorough understanding of the structure, function, and progression of DRD.

Diabetic retinal disease (DR) is the main cause of visual disability and blindness in adults with diabetes mellitus. Currently, efficient prevention and treatment are still under investigation. MicroRNAs (miRNAs) are groups of short, non-coding RNAs that post-transcriptionally control their target genes\' expression through complementary binding to the 3\'UTR region. MiRNAs have been reported to play important roles in a variety of physiological and pathophysiological processes. However, the roles of miR-125b in DR are still unclear. In this study, we exposed human retinal pigment epithelial (RPE) cells to high glucose levels to mimic DR progression. Hyperglycemia induced RPE cell death in 1, 3 and 5 days. Meanwhile, we observed that miR-125b expressions were significantly downregulated by the high glucose treatments. We demonstrated elevated cellular glycolysis rates of RPE cells under hyperglycemia. The glycolysis key enzymes, GLUT1, Hexokinase 2 (HK2) and LDHA were upregulated by high glucose. Moreover, treatments of RPE cells with low-toxic dosages of the glycolysis inhibitor, 2-DG or Oxamate, rescued the high glucose-induced cell from death. We identified hexokinase 2 as a direct target of miR-125b in RPE cells by showing the binding of the miR-125b seed region to HK2 mRNA 3\'UTR. Notably, we demonstrated that the overexpression of miR-125b significantly attenuated hyperglycemia-induced RPE cell death. This study reveals a new mechanism for miRNA-mediated cellular protection against RPE cell death, representing an effective DR-treatment approach.