Role of Systemic Factors in Improving the Prognosis of Diabetic Retinal Disease and Predicting Response to Diabetic Retinopathy Treatment.

Topic: To review clinical evidence on systemic factors that might be relevant to update diabetic retinal disease (DRD) staging systems, including prediction of DRD onset, progression, and response to treatment. Clinical relevance: Systemic factors may improve new staging systems for DRD to better assess risk of disease worsening and predict response to therapy. Methods: The Systemic Health Working Group of the Mary Tyler Moore Vision Initiative reviewed systemic factors individually and in multivariate models for prediction of DRD onset or progression (i.e., prognosis) or response to treatments (prediction). Results: There was consistent evidence for associations of longer diabetes duration, higher glycosylated hemoglobin (HbA1c), and male sex with DRD onset and progression. There is strong trial evidence for the effect of reducing HbA1c and reducing DRD progression. There is strong evidence that higher blood pressure (BP) is a risk factor for DRD incidence and for progression. Pregnancy has been consistently reported to be associated with worsening of DRD but recent studies reflecting modern care standards are lacking. In studies examining multivariate prognostic models of DRD onset, HbA1c and diabetes duration were consistently retained as significant predictors of DRD onset. There was evidence of associations of BP and sex with DRD onset. In multivariate prognostic models examining DRD progression, retinal measures were consistently found to be a significant predictor of DRD with little evidence of any useful marginal increment in prognostic information with the inclusion of systemic risk factor data apart from retinal image data in multivariate models. For predicting the impact of treatment, although there are small studies that quantify prognostic information based on imaging data alone or systemic factors alone, there are currently no large studies that quantify marginal prognostic information within a multivariate model, including both imaging and systemic factors. Conclusion: With standard imaging techniques and ways of processing images rapidly evolving, an international network of centers is needed to routinely capture systemic health factors simultaneously to retinal images so that gains in prediction increment may be precisely quantified to determine the usefulness of various health factors in the prognosis of DRD and prediction of response to treatment. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

CLINICAL CHARACTERIZATION OF AQUEOUS AND VITREOUS RETINOL-BINDING PROTEIN 3 CONCENTRATIONS IN RELATION TO DIABETIC RETINOPATHY SEVERITY, RETINAL STRUCTURES, AND SYSTEMIC COMPLICATIONS.

PURPOSE: To evaluate Retinol-Binding Protein 3 (RBP3) from photoreceptors in aqueous and its association with vitreous concentrations, diabetic retinopathy (DR) severity, retinal layer thickness, and clinical characteristics in people with diabetes. METHODS: RBP3 concentration was measured by custom-developed enzyme-linked immunosorbent assay in aqueous and correlated with vitreous concentrations in patients from the 50-Year Medalist study and Beetham Eye Institute at Joslin Diabetes Center. RESULTS: Aqueous RBP3 concentration (N = 131) was elevated in eyes with no to mild DR (mean ± SD 0.7 nM ± 0.2) and decreased in eyes with moderate to severe DR (0.65 nM ± 0.3) and proliferative DR (0.5 nM ± 0.2, P < 0.001) compared to eyes without diabetes. Aqueous and vitreous RBP3 concentrations correlated with each other (r = 0.34, P = 0.001) and between fellow eyes (P < 0.0001). History of retinal surgery did not affect aqueous RBP3 concentrations, but cataract surgery affected both vitreous and aqueous levels. Elevated aqueous RBP3 concentration associated with increased thickness of the outer nuclear layer (P = 0.004) and correlated with hemoglobin A1c, whereas vitreous RBP3 concentrations correlated with diabetic systemic complications. CONCLUSION: These findings suggest that aqueous RBP3 concentration may be an important endogenous clinical retinal protective factor, a biomarker for DR severity, and a promising VEGF-independent clinical intervention target in DR.

Retinal artery to vein ratio is associated with cerebral microbleeds in individuals with type 1 diabetes.

OBJECTIVES: A third of asymptomatic individuals with type 1 diabetes (T1D) show signs of cerebrovascular disease in brain MRI. These signs associate with advanced stages of diabetic retinal disease, but not in mild or moderate retinopathy. We aimed to evaluate a wider spectrum of retinal changes by exploring the relationship between quantitative measures of retinal vessel parameters (RVP) and cerebrovascular changes in T1D. METHODS: We included 146 neurologically asymptomatic individuals with T1D [51% women, median age 40 (33.0-45.1) years] and 24 healthy, sex-matched and age-matched controls. All individuals underwent a clinical and biochemical work-up and brain MRI, which was evaluated for cerebral microbleeds (CMBs), white matter hyperintensities, and lacunar infarcts. RVPs, including central retinal arteriole (CRAE) and central retinal vein (CRVE) equivalents and the ratio of the two variables (arteriovenous ratio, AVR) were assessed quantitatively by a computer-assisted method (IVAN software, version 3.2.6) from fundus images. RESULTS: Among T1D participants, those with CMBs had a lower arteriovenous ratio (AVR) compared with those without CMBs ( P  = 0.023). AVR was inversely associated with the amount of CMBs ( r  = -0.063, P  = 0.035). CMB prevalence was higher in those with AVR below the median (31%) compared with above the median (16%, P  < 0.001), and this difference was significant also after individuals with only no-to-mild retinopathy were included (28 vs. 16%, P  = 0.005). A correlation between blood pressure and CRAE ( r  = -0.19, P  = 0.025) appeared among those with T1D. CONCLUSION: Regardless of the severity of diabetic retinopathy, AVR is associated with the existence of CMBs in T1D.

Automated Machine Learning for Predicting Diabetic Retinopathy Progression From Ultra-Widefield Retinal Images.

Importance: Machine learning (ML) algorithms have the potential to identify eyes with early diabetic retinopathy (DR) at increased risk for disease progression. Objective: To create and validate automated ML models (autoML) for DR progression from ultra-widefield (UWF) retinal images. Design, Setting and Participants: Deidentified UWF images with mild or moderate nonproliferative DR (NPDR) with 3 years of longitudinal follow-up retinal imaging or evidence of progression within 3 years were used to develop automated ML models for predicting DR progression in UWF images. All images were collected from a tertiary diabetes-specific medical center retinal image dataset. Data were collected from July to September 2022. Exposure: Automated ML models were generated from baseline on-axis 200° UWF retinal images. Baseline retinal images were labeled for progression based on centralized reading center evaluation of baseline and follow-up images according to the clinical Early Treatment Diabetic Retinopathy Study severity scale. Images for model development were split 8-1-1 for training, optimization, and testing to detect 1 or more steps of DR progression. Validation was performed using a 328-image set from the same patient population not used in model development. Main Outcomes and Measures: Area under the precision-recall curve (AUPRC), sensitivity, specificity, and accuracy. Results: A total of 1179 deidentified UWF images with mild (380 [32.2%]) or moderate (799 [67.8%]) NPDR were included. DR progression was present in half of the training set (590 of 1179 [50.0%]). The model's AUPRC was 0.717 for baseline mild NPDR and 0.863 for moderate NPDR. On the validation set for eyes with mild NPDR, sensitivity was 0.72 (95% CI, 0.57-0.83), specificity was 0.63 (95% CI, 0.57-0.69), prevalence was 0.15 (95% CI, 0.12-0.20), and accuracy was 64.3%; for eyes with moderate NPDR, sensitivity was 0.80 (95% CI, 0.70-0.87), specificity was 0.72 (95% CI, 0.66-0.76), prevalence was 0.22 (95% CI, 0.19-0.27), and accuracy was 73.8%. In the validation set, 6 of 9 eyes (75%) with mild NPDR and 35 of 41 eyes (85%) with moderate NPDR progressed 2 steps or more were identified. All 4 eyes with mild NPDR that progressed within 6 months and 1 year were identified, and 8 of 9 (89%) and 17 of 20 (85%) with moderate NPDR that progressed within 6 months and 1 year, respectively, were identified. Conclusions and Relevance: This study demonstrates the accuracy and feasibility of automated ML models for identifying DR progression developed using UWF images, especially for prediction of 2-step or greater DR progression within 1 year. Potentially, the use of ML algorithms may refine the risk of disease progression and identify those at highest short-term risk, thus reducing costs and improving vision-related outcomes.

Bias and Non-Diversity of Big Data in Artificial Intelligence: Focus on Retinal Diseases.

Artificial intelligence (AI) applications in healthcare will have a potentially far-reaching impact on patient care, however issues regarding algorithmic bias and fairness have recently surfaced. There is a recognized lack of diversity in the available ophthalmic datasets, with 45% of the global population having no readily accessible representative images, leading to potential misrepresentations of their unique anatomic features and ocular pathology. AI applications in retinal disease may show less accuracy with underrepresented populations that may further widen the gap of health inequality if left unaddressed. Beyond disease symptomatology, social determinants of health must be integrated into our current paradigms of disease understanding, with the goal of more personalized care. AI has the potential to decrease global healthcare inequality, but it will need to be based on a more diverse, transparent and responsible use of healthcare data.

Frontiers in diabetic retinal disease.

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.

Circulatory Biomarkers and Diabetic Retinopathy in Racial and Ethnic Populations.

Clinical staging systems for diagnosis and treatment of diabetic retinopathy (DR) must closely relate to endpoints that are both relevant for patients and feasible for physicians to implement. Current DR staging systems for clinical eye care and research provide detailed phenotypic characterization to predict patient outcomes in diabetes but have limitations. Biochemical biomarkers provide a rich pool of potential candidates for new DR staging systems that can be readily measured in accessible fluids. Circulating biomarkers that are specific to the retina and relate to angiogenesis and inflammation have been suggested as relevant for DR. Although there is a lack of multi-ethnic studies evaluating circulatory biomarkers in DR, variability in circulatory biomarkers have been reported in people from different ethnic and racial backgrounds. Therefore, there is a need for future studies to evaluate individual or combinations of biomarkers in diverse populations with DR from different ethnic and racial backgrounds.

Elevated Retinol Binding Protein 3 Concentrations Are Associated With Decreased Vitreous Inflammatory Cytokines, VEGF, and Progression of Diabetic Retinopathy.

OBJECTIVE: To correlate inflammatory cytokines and vascular endothelial growth factor (VEGF) in vitreous and plasma with vitreous retinol binding protein 3 (RBP3), diabetic retinopathy (DR) severity, and DR worsening in a population with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: RBP3, VEGF, and inflammatory cytokines were measured in plasma and vitreous samples (n = 205) from subjects of the Joslin Medalist Study and Beetham Eye Institute. RESULTS: Higher vitreous RBP3 concentrations were associated with less severe DR (P < 0.0001) and a reduced risk of developing proliferative DR (PDR) (P < 0.0001). Higher RBP3 correlated with increased photoreceptor segment thickness and lower vitreous interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α), and TNF-ß (P < 0.05). PDR was associated with lower vitreous interferon-γ and IL-10 and higher VEGF, IL-6, and IL-15 (P < 0.05), but was not associated with their plasma concentrations. CONCLUSIONS: Higher vitreous RBP3 concentrations are associated with less severe DR and slower rates of progression to PDR, supporting its potential as a biomarker and therapeutic agent for preventing DR worsening, possibly by lowering retinal VEGF and inflammatory cytokines.

Association of Cognitive Function and Retinal Neural and Vascular Structure in Type 1 Diabetes.

CONTEXT: Cognitive dysfunction is a growing and understudied public health issue in the aging type 1 diabetic population and is difficult and time-consuming to diagnose. Studies in long duration type 1 diabetes have reported the presence of proliferative diabetic retinopathy was associated with cognitive dysfunction. OBJECTIVE: This study assessed whether structural and vascular abnormalities of the retina, representing an extension of the central nervous system, are associated with cognitive impairment and other complications of type 1 diabetes. METHODS: An observational cross-sectional study of individuals with 50 or more years of type 1 diabetes (Joslin Medalist Study) was conducted at a university hospital in the United States. The study included 129 participants with complete cognitive testing. Validated cognitive testing measures included psychomotor speed, and immediate, and delayed memory. Optical coherence tomography (OCT) and OCT angiography (OCTA) were performed to obtain neural retinal layer thicknesses and vascular density for superficial (SCP) and deep retinal capillary plexus (DCP). Multivariable modeling was adjusted for potential confounders associated with outcomes in unadjusted analyses. RESULTS: Decreased vessel density of the SCP and DCP was associated with worse delayed memory (DCP: P = .002) and dominant hand psychomotor speed (SCP: P = .01). Thinning of the retinal outer nuclear layer was associated with worse psychomotor speed both in nondominant and dominant hands (P = .01 and P = .05, respectively). Outer plexiform layer thickness was associated with delayed memory (P = .04). CONCLUSION: These findings suggest that noninvasive retinal imaging using OCT and OCTA may assist in estimating the risks for cognitive dysfunction in people with type 1 diabetes.

Retinol binding protein 3 is increased in the retina of patients with diabetes resistant to diabetic retinopathy.

The Joslin Medalist Study characterized people affected with type 1 diabetes for 50 years or longer. More than 35% of these individuals exhibit no to mild diabetic retinopathy (DR), independent of glycemic control, suggesting the presence of endogenous protective factors against DR in a subpopulation of patients. Proteomic analysis of retina and vitreous identified retinol binding protein 3 (RBP3), a retinol transport protein secreted mainly by the photoreceptors, as elevated in Medalist patients protected from advanced DR. Mass spectrometry and protein expression analysis identified an inverse association between vitreous RBP3 concentration and DR severity. Intravitreal injection and photoreceptor-specific overexpression of RBP3 in rodents inhibited the detrimental effects of vascular endothelial growth factor (VEGF). Mechanistically, our results showed that recombinant RBP3 exerted the therapeutic effects by binding and inhibiting VEGF receptor tyrosine phosphorylation. In addition, by binding to glucose transporter 1 (GLUT1) and decreasing glucose uptake, RBP3 blocked the detrimental effects of hyperglycemia in inducing inflammatory cytokines in retinal endothelial and Müller cells. Elevated expression of photoreceptor-secreted RBP3 may have a role in protection against the progression of DR due to hyperglycemia by inhibiting glucose uptake via GLUT1 and decreasing the expression of inflammatory cytokines and VEGF.

Retinal proteome associated with bradykinin-induced edema.

The plasma kallikrein-stimulated generation of bradykinin (BK) has been implicated in diabetic macular edema (DME). This study characterizes the effects of BK on the ultrastructure and proteome of the rat retina. The effects of intravitreal injection of BK on retinal thickness and vascular ultrastructure in Sprague Dawley rats were analyzed and compared with the effects of VEGF using spectral-domain optical coherence tomography. At 24 h post intravitreal injection of BK or saline vehicle retina were harvested and solubilized proteins were analyzed by mass spectrometry-based proteomics. Proteins were identified using X!Tandem and spectral counts were used as a semiquantitative measurement of protein abundance. Proteins identified from retinal extracts were annotated by Gene Ontology (GO) slim terms and compared with a human DME vitreous proteome. Intravitreal injection of BK and VEGF induced transient increases in retinal thickness of 46 µm (24.6%, p = 0.015) and 39 µm (20.3%, p = 0.004), respectively at 24 h, which were resolved to baseline thicknesses at 96 h post injection. BK and VEGF also increased retinal vessel diameters and tortuosity at 24 h post intravitreal injection. Proteomic analyses identified 1757 non-redundant proteins in the rat retina, including 1739 and 1725 proteins from BK- and saline control-injected eyes, respectively. Eighteen proteins, including two proteins associated with intercellular junctions, filamin A and actinin alpha 4, were decreased by at least 50% (p < 0.05) in retina from BK-injected eyes compare with retina from eyes injected with saline. In addition, 32 proteins were increased by > 2-fold (p < 0.05) in retina from BK-injected eyes. Eight proteins, including complement C3, were identified to be increased in both BK-stimulated rat retina and in human DME vitreous. Western blot analysis showed that Complement 3 levels in vitreous from BK-injected eyes in rats and clinical DME samples were increased by 6.6-fold (p = 0.039) and 4.3-fold (p = 0.02), compared with their respective controls. In summary, this study identifies protein changes in rat retina that are associated with BK-induced retinal thickening, including 8 proteins that were previously reported to be increased in the human DME vitreous proteome.

Differential Association of Microvascular Attributions With Cardiovascular Disease in Patients With Long Duration of Type 1 Diabetes.

OBJECTIVE: Independent association of chronic kidney disease (CKD) and proliferative diabetic retinopathy (PDR) with cardiovascular disease (CVD) has not been established. In the Joslin 50-Year Medalist study, characterizing individuals with type 1 diabetes for 50 years or more, we examined the associations of CKD and PDR with CVD, which was validated by another cohort with type 1 diabetes from Finland. RESEARCH DESIGN AND METHODS: This cross-sectional study characterized U.S. residents (n = 762) with type 1 diabetes of 50 years or longer (Medalists) at a single site by questionnaire, clinical, ophthalmic, and laboratory studies. A replication cohort (n = 675) from the longitudinal Finnish Diabetic Nephropathy Study (FinnDiane) was used. CKD and PDR were defined as estimated glomerular filtration rate <45 mL/min/1.73 m2 (CKD stage 3b) and according to the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol, respectively. CVD was based on questionnaires and/or hospital discharge registers. Associations of CVD status with CKD and PDR were analyzed by multivariable logistic regression. RESULTS: CVD prevalence in the Medalists with CKD and without PDR (+CKD/-PDR) (n = 30) and CVD prevalence in the -CKD/+PDR group (n = 339) were half the prevalence in the +CKD/+PDR group (n = 66) (34.5% and 42.8% vs. 68.2%, P = 0.002). PDR status was independently associated with CVD (odds ratio 0.21 [95% CI 0.08-0.58], P = 0.003) in patients with CKD. Among the Finnish cohort, a trend toward a lower prevalence of CVD in the +CKD/-PDR group (n = 21) compared with the +CKD/+PDR group (n = 170) (19.1% vs. 37.1%, P = 0.10) was also observed. CONCLUSIONS: Absence of PDR in people with type 1 diabetes and CKD was associated with a decreased prevalence of CVD, suggesting that common protective factors for PDR and CVD may exist.

PREDICTIVE VALUE OF OPTICAL COHERENCE TOMOGRAPHIC FEATURES IN THE BEVACIZUMAB AND RANIBIZUMAB IN PATIENTS WITH DIABETIC MACULAR EDEMA (BRDME) STUDY.

PURPOSE: To establish the predictive value of specific optical coherence tomography retinal features on visual outcomes and retinal thickness during anti-vascular endothelial growth factor treatment in patients with diabetic macular edema. METHODS: Post hoc analysis of compound data of a prospective, 6-month, multicenter, randomized controlled trial of 119 patients with diabetic macular edema receiving either intravitreal bevacizumab or ranibizumab were analyzed to assess the associations between baseline retinal morphologic parameters and change in best-corrected visual acuity and central subfield thickness. Based on the study protocol of the core study, best-corrected visual acuity and central subfield thickness were obtained before each mandatory monthly injection during 6 months. RESULTS: The presence of serous retinal detachment at baseline was associated with significant improvement in best-corrected visual acuity letter score at Month 3 and Month 6 (P < 0.001 and P = 0.01, respectively). In addition, the presence of disorganization of retinal inner layers was associated with lower best-corrected visual acuity letter score at Month 3 and Month 6 (P < 0.05 and P = 0.01, respectively). CONCLUSION: This study found that serous retinal detachment and disorganization of retinal inner layers were associated with different treatment responses to anti-vascular endothelial growth factor therapy in patients with diabetic macular edema.

Interactions between physicians and the pharmaceutical industry generally and sales representatives specifically and their association with physicians' attitudes and prescribing habits: a systematic review.

OBJECTIVES: The objective of this review is to explore interactions between physicians and the pharmaceutical industry including sales representatives and their impact on physicians' attitude and prescribing habits. DATA SOURCES: PubMed, Embase, Cochrane Library and Google scholar electronic databases were searched from 1992 to August 2016 using free-text words and medical subject headings relevant to the topic. STUDY SELECTION: Studies included cross-sectional studies, cohort studies, randomised trials and survey designs. Studies with narrative reviews, case reports, opinion polls and letters to the editor were excluded from data synthesis. DATA EXTRACTION: Two reviewers independently extracted the data. Data on study design, study year, country, participant characteristics, setting and number of participants were collected. DATA SYNTHESIS: Pharmaceutical industry and pharmaceutical sales representative (PSR) interactions influence physicians' attitudes and their prescribing behaviour and increase the number of formulary addition requests for the company's drug. CONCLUSION: Physician-pharmaceutical industry and its sales representative's interactions and acceptance of gifts from the company's PSRs have been found to affect physicians' prescribing behaviour and are likely to contribute to irrational prescribing of the company's drug. Therefore, intervention in the form of policy implementation and education about the implications of these interactions is needed.

Association of Circulating Markers With Outcome Parameters in the Bevacizumab and Ranibizumab in Diabetic Macular Edema Trial.

Purpose: The purpose of this study was to evaluate selected candidate biomarkers as potential markers for patients with diabetic macular edema (DME) who receive antivascular endothelial growth factor (VEGF) therapy. Methods: Selected biomarkers included blood levels of messenger RNA (mRNA) of retinoschisin, RPE65, rhodopsin, and endothelial progenitor cell markers CD34 and CD133. Blood samples were obtained from 89 patients with DME according to the study protocol of the Bevacizumab and Ranibizumab in Diabetic Macular Edema (BRDME) study. During each monthly visit, patients underwent optical coherence tomography scanning and visual acuity was measured. Anti-VEGF injections were administered at fixed monthly intervals over 6 months. Analyses of covariance using simplified and linear mixed models were used to examine the correlations between candidate markers and changes in visual acuity and central subfield thickness. Results: Plasma mRNA levels of retinoschisin were negatively associated with visual acuity, and plasma mRNA levels of rhodopsin were positively associated with visual acuity in patients with DME (P < 0.01 and P < 0.05, respectively). In addition, changes in central subfield thickness between baseline and months 1, 2, and 3 during anti-VEGF treatment were associated with mRNA levels of retinoschisin, rhodopsin, and the ratio of retinoschisin-to-rhodopsin (P < 0.01, all). Conclusions: This prospective, multicenter study found that circulating mRNA levels of retinoschisin and rhodopsin are associated with visual acuity and changes in central subfield thickness during anti-VEGF therapy in patients with DME. (ClinicalTrials.gov number: NCT01635790.).

[A woman with Christmas in sight]. / Met kerst in zicht.

A 70-year-old woman was referred because of vision deterioration of her right eye since several months. With optimal spheric correction of +2.50 in her right eye she had a vision of 0.7. The intraocular pressure was 10 mmHg. There were no abnormalities in the anterior chamber of the eye. The right eye did show a palette of coloured needle-shaped opacities in the cortex and anterior nucleus of the lens, consistent with unilateral Christmas tree cataract.