The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy reduced the development and progression of retinopathy in type 1 diabetes (T1D) compared with conventional ...therapy. The Epidemiology of Diabetes Interventions and Complications (EDIC) study observational follow-up showed persistent benefits. In addition to glycemia, we now examine other potential retinopathy risk factors (modifiable and nonmodifiable) over more than 30 years of follow-up in DCCT/EDIC.
The retinopathy outcomes were proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), and ocular surgery. The survival (event-free) probability was estimated using the Kaplan-Meier method. Cox proportional hazards models assessed the association between risk factors and subsequent risk of retinopathy. Both forward- and backward-selection approaches determined the multivariable models.
Rate of ocular events per 1,000 person-years was 12 for PDR, 14.5 for CSME, and 7.6 for ocular surgeries. Approximately 65%, 60%, and 70% of participants remained free of PDR, CSME, and ocular surgery, respectively. The greatest risk factors for PDR in descending order were higher mean HbA
, longer duration of T1D, elevated albumin excretion rate (AER), and higher mean diastolic blood pressure (DBP). For CSME, risk factors, in descending order, were higher mean HbA
, longer duration of T1D, and greater age and DBP and, for ocular surgeries, were higher mean HbA
, older age, and longer duration of T1D.
Mean HbA
was the strongest risk factor for the progression of retinopathy. Although glycemic control is important, elevated AER and DBP were other modifiable risk factors associated with the progression of retinopathy.
The Diabetes Control and Complications Trial (DCCT) demonstrated that a mean of 6.5 years of intensive therapy aimed at near-normal glucose levels reduced the risk of development and progression of ...retinopathy by as much as 76% compared with conventional therapy. The Epidemiology of Diabetes Interventions and Complications study (EDIC) observational follow-up showed that the risk of further progression of retinopathy 4 years after the DCCT ended was also greatly reduced in the former intensive group, despite nearly equivalent levels of HbA1c, a phenomenon termed metabolic memory. Metabolic memory was shown to persist through 10 years of follow-up. We now describe the risk of further progression of retinopathy, progression to proliferative diabetic retinopathy, clinically significant macular edema, and the need for intervention (photocoagulation or anti-VEGF) over 18 years of follow-up in EDIC. The cumulative incidence of each retinal outcome continues to be lower in the former intensive group. However, the year-to-year incidence of these outcomes is now similar, owing in large part to a reduction in risk in the former conventional treatment group.
To examine possible differences in clinical outcomes between pars plana vitrectomy (PPV) and scleral buckling (SB) for uncomplicated rhegmatogenous retinal detachment (RRD).
Meta-analysis.
Adult ...patients with uncomplicated RRD from previously reported randomized controlled trials of PPV and SB.
A comprehensive literature search using the Cochrane Collaboration methodology to identify randomized controlled trials comparing PPV with SB for uncomplicated RRD.
Analysis was divided into phakic and pseudophakic/aphakic patients. Primary outcome parameters included proportion of primary reattachment and difference of means of best-corrected visual acuity (BCVA) at 6 months or more between the PPV and SB groups. Secondary outcome parameters included the proportion of secondary reattachment and complications between the PPV and SB groups.
Seven studies were identified and analyzed for comparing PPV (636 eyes) with SB (670 eyes) for uncomplicated RRD. In the phakic group, there were no significant differences in the proportion of primary reattachments (odds ratio OR, 1.00; 95% confidence interval CI, 0.69-1.46) or secondary reattachments (OR, 0.99; 95% CI, 0.34-2.87) between the PPV and SB groups. Meta-analysis showed a statistically significant difference in the logarithm of the minimum angle of resolution (logMAR) BCVA at 6 months between the PPV-treated and SB-treated phakic eyes (mean deviation, 0.14; 95% CI, 0.06-0.21; P<0.0004). In the pseudophakic/aphakic group, there were no significant differences in the proportion of primary reattachments (OR, 1.46; 95% CI, 0.79-2.71) or logMAR BCVA at 6 months between the PPV and SB groups (mean deviation, -0.03; 95% CI, -0.10 to 0.04). A statistically significant difference was noted in the proportion of secondary reattachments (OR, 2.08; 95% CI, 1.08-4.03; P = 0.03) between the PPV and SB groups in pseudophakic/aphakic eyes. Meta-analysis showed a statistically significant rate of cataract progression in the PPV group (OR, 4.11; 95% CI, 2.70-6.25; P<0.00001).
There were no significant differences in the proportions of primary reattachment in the PPV and SB groups in phakic eyes. The SB-treated phakic eyes had better postoperative BCVA at 6 months or more. This is most likely related to higher rates of cataract progression in PPV-treated phakic eyes. There were no significant differences in proportions of primary reattachment and postoperative BCVA at 6 months or more in pseudophakic/aphakic eyes.
We sought to assess a smartphone-based, gold nanoparticle–based colorimetric lateral flow immunoassay paper sensor for quantifying urine 8-hydroxy-2′-deoxyguanosine (8-OHdG) as a biomarker for ...diabetic retinopathy (DR) screening.
Paper strips incorporate gold nanoparticle–8-OHdG antibody conjugates that produce color changes that are proportional to urine 8-OHdG and that are discernible on a smartphone camera photograph. Paper strip accuracy, precision, and stability studies were performed with 8-OHdG solutions of varying concentrations. Urine was collected from 97 patients with diabetes who were receiving DR screening examinations, including 7-field fundus photographs. DR was graded by standard methods as either low risk (no or mild DR) or high risk (moderate or severe DR). Paper sensor assays were performed on urine samples from patients and 8-OHdG values were correlated with DR grades. The differences in 8-OHdG values between the low- and high-risk groups were analyzed for outliers to identify the threshold 8-OHdG value that would minimize false-negative results.
Lateral flow immunoassay paper strips quantitatively measure 8-OHdG and were found to be accurate, precise, and stable. Average urine 8-OHdG concentrations in study patients were 22 ± 10 ng/mg of creatinine in the low-risk group and 55 ± 11 ng/mg of creatinine in the high-risk group. Screening cutoff values of 8-OHdG >50 ng/mg of creatinine or urine creatinine >1.5 mg minimized screen failures, with 91% sensitivity and 81% specificity.
Urinary 8-OHdG is a useful biomarker to screen DR. Quantitative 8-OHdG detection with the lateral flow immunoassay paper sensor and smartphone camera demonstrates its potential in DR screening. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.
Diabetic retinopathy (DR) is an ocular complication of diabetes mellitus (DM). International Diabetic Federations (IDF) estimates up to 629 million people with DM by the year 2045 worldwide. Nearly ...50% of DM patients will show evidence of diabetic-related eye problems. Therapeutic interventions for DR are limited and mostly involve surgical intervention at the late-stages of the disease. The lack of early-stage diagnostic tools and therapies, especially in DR, demands a better understanding of the biological processes involved in the etiology of disease progression. The recent surge in literature associated with NOD-like receptors (NLRs) has gained massive attraction due to their involvement in mediating the innate immune response and perpetuating inflammatory pathways, a central phenomenon found in the pathogenesis of ocular diseases including DR. The NLR family of receptors are expressed in different eye tissues during pathological conditions suggesting their potential roles in dry eye, ocular infection, retinal ischemia, cataract, glaucoma, age-related macular degeneration (AMD), diabetic macular edema (DME) and DR. Our group is interested in studying the critical early components involved in the immune cell infiltration and inflammatory pathways involved in the progression of DR. Recently, we reported that NLRP3 inflammasome might play a pivotal role in the pathogenesis of DR. This comprehensive review summarizes the findings of NLRs expression in the ocular tissues with special emphasis on its presence in the retinal microglia and DR pathogenesis.
The aim of this study was to examine differences between adolescents and adults in persistence of the benefits of intensive therapy 10 years after completion of the Diabetes Control and Complications ...Trial (DCCT).
During the Epidemiology of Diabetes Interventions and Complications (EDIC) study, progression of retinopathy from DCCT closeout to EDIC year 10 was evaluated in 1,055 adults and 156 adolescents.
During 10 years of follow-up, HbA(1c) (A1C) was similar between original intensive (INT) and conventional (CON) groups and between former adolescents and adults. At EDIC year 10, adults in the former INT group continued to show slower progression of diabetic retinopathy than those in the CON group (adjusted hazard reduction 56%, P < 0.0001), whereas in adolescents this beneficial effect had disappeared (32%, P = 0.13). Seventy-nine percent of observed differences in the prolonged treatment effect between adults and adolescents at year 10 were explained by differences in mean A1C during DCCT between adolescents and adults (8.9 vs. 8.1%), particularly between INT adolescents and adults (8.1 vs. 7.2%).
Prior glycemic control during DCCT is vital for the persistence of the beneficial effects of INT therapy 10 years later. Lowering A1C to as close to normal as safely possible without severe hypoglycemia and starting as early as possible should be attempted for all subjects with type 1 diabetes. These results underscore the importance of maintaining A1C at target values for as long as possible because the benefits of former INT treatment wane over time if A1C levels rise.
Enzyme-linked immunosorbent assay (ELISA) is a widely used technique for detecting and quantifying target analytes in clinical and research laboratories. One of the main drawbacks of ELISA is the ...involvement of multiple washing steps that desorbs the capture antigen/antibody off the polystyrene plate, thereby producing inconsistent and erroneous data. To overcome the problem of desorption, we hypothesized that gelatin nanoparticles (GelNP) could serve as a “plate-adherent” substrate to irreversibly adhere the capture antigen/antibody of interest. We tested our hypothesis using GelNP-based substrate (Gel–BSA–OHG) to adhere 8-hydroxy-2′-deoxyguanosine (8-OHdG) to the polystyrene plate and assayed this molecule using the ELISA technique. The stability and ELISA performance of Gel–BSA–OHG was evaluated in comparison to the conventional substrate (BSA–OHG). Importantly, the Gel–BSA–OHG substrate was found to be more wash-resistant and consequently resulted in improved sensitivity, accuracy, and precision in the ELISA analysis of 8-OHdG. Finally, the scope of Gel–BSA–OHG substrate-based ELISA for clinical application was demonstrated by validating its ability to detect 8-OHdG in an artificial urine sample with high specificity.
To determine whether individuals with type 1 diabetes (T1D) who develop any retinopathy at any time prior to 5 years of diabetes duration have an increased subsequent risk for further progression of ...retinopathy or onset of proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), diabetes-related retinal photocoagulation, or anti-vascular endothelial growth factor injections. Additionally, to determine the influence of HbA1c and other risk factors in these individuals.
Diabetic retinopathy (DR) was assessed longitudinally using standardized stereoscopic seven-field fundus photography at time intervals of 6 months to 4 years. Early-onset DR (EDR) was defined as onset prior to 5 years of T1D duration. Cox models assessed the associations of EDR with subsequent risk of outcomes.
In unadjusted models, individuals with EDR (n = 484) had an increased subsequent risk of PDR (hazard ratio HR 1.51 95% CI 1.12, 2.02, P = 0.006), CSME (HR 1.44 1.10, 1.88, P = 0.008), and diabetes-related retinal photocoagulation (HR 1.48 1.12, 1.96, P = 0.006) compared with individuals without EDR (n = 369). These associations remained significant when adjusted for HbA1c, but only the association with PDR remained significant after adjustment for age, duration of T1D, HbA1c, sex, systolic/diastolic blood pressure, pulse, use of ACE inhibitors, albumin excretion rate, and estimated glomerular filtration rate (HR 1.47 95% CI 1.04, 2.06, P = 0.028).
These data suggest that individuals with any sign of retinopathy within the first 5 years of T1D onset may be at higher risk of long-term development of advanced DR, especially PDR. Identification of early-onset DR may influence prognosis and help guide therapeutic management to reduce the risk of future visual loss in these individuals.
To determine the relationship between refractive error and diabetic retinopathy (DR).
Clinical trial.
Type I diabetes individuals with serial refractive error and DR stage measurements over 30 years ...in the Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study.
Stage of DR was measured every 6 months from standard fundus photographs, and refractive error was measured annually during the 6.5 years of DCCT; then, both were staggered every fourth year during EDIC with the full cohort measured at EDIC years 4 and 10. Outcomes of DR were 2- or 3-step progression, presence of proliferative DR (PDR), clinically significant macular edema (CSME), diabetic macular edema (DME), or ocular surgery. Myopia, emmetropia, and hyperopia were defined as a spherical equivalent of ≤-0.5, >-0.5 and <0.5, and ≥0.5, respectively.
For each outcome separately, Cox proportional hazard (PH) models assessed the association between the refractive error status and the subsequent risk of that outcome, both without and with adjustment for potential risk factors.
Hyperopia was associated with a higher risk of 2-step progression (hazard ratio HR, 1.29; 95% confidence interval CI, 1.05-1.59), 3-step progression (HR, 1.35; 95% CI, 1.05-1.73), and PDR (HR, 1.40; 95% CI, 1.02-1.92) compared with emmetropia in unadjusted models. These associations remained significant after adjustment for DCCT treatment group, cohort, age, sex, smoking, duration of diabetes, systolic and diastolic blood pressures, pulse, low-density lipoprotein, high-density lipoprotein, triglycerides, albumin excretion rate, and DCCT/EDIC mean updated hemoglobin A1c (HbA1c) (2-step progression: HR, 1.28; 95% CI, 1.03-1.58; 3-step progression: HR, 1.30; 95% CI, 1.00-1.68; PDR: HR, 1.38; 95% CI, 1.00-1.90). Myopia was not associated with any of the 5 DR outcomes in the unadjusted models and only marginally associated with 2-step progression (HR, 1.11; 95% CI, 1.00-1.24) in the adjusted models.
Myopia is not associated with DR progression risk. Hyperopia is an independent risk factor for 2-step and 3-step DR progression and PDR.
Retinal inflammation is an integral component of many retinal diseases including diabetic retinopathy (DR), age-related macular degeneration (AMD) and retinopathy of prematurity (ROP). Inflammation ...is commonly initiated and perpetuated by myeloid-derived immune cells. In the retina, microglial cells are resident macrophages with myeloid origins, which acts as the first responders involved in the innate immune system. To understand the disease pathogenesis, the use of isolated retinal cell culture model is vital for the examination of multiple cellular responses to injury or trauma. The pig retina resembles human retina in terms of tissue architecture, vasculature, and topography. Additionally, it is a better model than the rodent retina because of the presence of the pseudomacula. In the present study, we sought to establish and characterize pig retinal primary microglial cell (pMicroglia) culture. We used pig eyes from the local abattoir and optimized pMicroglia cultures using multiple cell culture conditions and methods. The best results were obtained by seeding cells in DMEM-high glucose media for 18 days followed by shaking of the culture plate. The resulting pMicroglia were characterized by cellular morphology, phenotype, and immunostaining with Iba-1, CD68, P2Y12, CD163, CD14, and Isolectin GS-IB4. Generated pMicroglia were found functionally active in phagocytosis assay and responsive to lipopolysaccharides (LPS) in dose-dependent production of IL-1β. Furthermore, they showed increased secretion of pro-inflammatory cytokines with LPS treatment. Thus, we report a novel and reproducible method for the isolation of primary microglial cells from pig eyes, which may be useful for studying retinal diseases.
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