Heather Hancock

Vitreal penetration of oral moxifloxacin in humans.

Purpose: To investigate the vitreal penetration of moxifloxacin after oral administration. Design: Prospective, nonrandomized clinical series. Methods: Twenty-four patients (mean age = 62.8 years) undergoing elective pars plana vitrectomy were assigned to a dosing group: control (n = 3), which received no medication; single-dose (n = 11), which received one 400 mg oral dose of moxifloxacin 3 hours before surgery; and five-dose (n = 10), which received one 400 mg dose on each of the 4 days preceding surgery and a fifth dose 3 hours before surgery. Vitreous samples were obtained and analyzed. Results: Control, below quantifiable levels; single-dose, 0.572 ± 0.239 μg/mL; and five-dose, 1.200 ± 0.645 μg/mL. Conclusions: Five doses of oral moxifloxacin lead to higher intravitreal drug concentrations than single-dose administration. Both regimens, however, achieve levels that exceed the MIC90 of many bacteria implicated in postoperative endophthalmitis.

Whole exome sequencing identification of novel candidate genes in patients with proliferative diabetic retinopathy

&NA; Rare or novel gene variants in patients with proliferative diabetic retinopathy may contribute to disease development. We performed whole exome sequencing (WES) on patients at the phenotypic extremes of diabetic retinal complications: 57 patients diagnosed with proliferative diabetic retinopathy (PDR) as cases and 13 patients with no diabetic retinopathy despite at least 10 years of type 2 diabetes as controls. Thirty‐one out of the 57 cases and all 13 controls were from the African American Proliferative Diabetic Retinopathy Study (AA). The rest of the cases were of mixed ethnicities (ME). WES identified 721 candidate genes with rare or novel non‐synonymous variants found in at least one case with PDR and not present in any controls. After filtering for genes with null alleles in greater than two cases, 28 candidate genes were identified in our ME cases and 16 genes were identified in our AA cases. Our analysis showed rare and novel variants within these genes that could contribute to the development of PDR, including rare non‐synonymous variants in FAM132A, SLC5A9, ZNF600, and TMEM217. We also found previously unidentified variants in VEGFB and APOB. We found that VEGFB, VPS13B, PHF21A, NAT1, ZNF600, PKHD1L1 expression was reduced in human retinal endothelial cells (HRECs) cultured under high glucose conditions. In an exome sequence analysis of patients with PDR, we identified variants in genes that could contribute to pathogenesis. Six of these genes were further validated and found to have reduced expression in HRECs under high glucose conditions, suggestive of an important role in the development of PDR.

Risk Factors for Proliferative Diabetic Retinopathy in African Americans with Type 2 Diabetes

ABSTRACT Purpose: To assess personal and demographic risk factors for proliferative diabetic retinopathy in African Americans with type 2 diabetes. Methods: In this prospective, non-interventional, cross-sectional case-control study, 380 African Americans with type 2 diabetes were enrolled. Participants were recruited prospectively and had to have either: (1) absence of diabetic retinopathy after ≥10 years of type 2 diabetes, or (2) presence of proliferative diabetic retinopathy when enrolled. Dilated, 7-field fundus photographs were graded using the Early Treatment Diabetic Retinopathy Study scale. Covariates including hemoglobin A1C (HbA1C), blood pressure, height, weight and waist circumference were collected prospectively. Multivariate regression models adjusted for age, sex and site were constructed to assess associations between risk factors and proliferative diabetic retinopathy. Results: Proliferative diabetic retinopathy was associated with longer duration of diabetes (odds ratio, OR, 1.62, p < 0.001), higher systolic blood pressure (OR 1.65, p < 0.001) and insulin use (OR 6.65, p < 0.001) in the multivariate regression analysis. HbA1C was associated with proliferative diabetic retinopathy in the univariate analysis (OR 1.31, p = 0.002) but was no longer significant in the multivariate analysis. Conclusions: In this case-control study of African Americans with type 2 diabetes, duration of diabetes, systolic hypertension and insulin use were strong risk factors for the development of proliferative diabetic retinopathy. Interestingly, HbA1C did not confer additional risk in this cohort.

OPTICAL COHERENCE TOMOGRAPHY CHARACTERISTICS OF MACULAR EDEMA AND HARD EXUDATES AND THEIR ASSOCIATION WITH LIPID SERUM LEVELS IN TYPE 2 DIABETES.

Purpose: To determine whether hyperreflective foci (HF) and macular thickness on spectral domain ocular coherence tomography are associated with lipid levels in patients with Type 2 diabetes. Methods: Two hundred and thirty-eight participants from four sites had fundus photographs and spectral domain ocular coherence tomography images graded for hard exudates and HF, respectively. Regression models were used to determine the association between serum lipid levels and 1) presence of HF and hard exudates and 2) central subfield macular thickness, central subfield macular volume, and total macular volume. Results: All patients with hard exudates on fundus photographs had corresponding HF on spectral domain ocular coherence tomography, but 57% of patients with HF on optical coherence tomography did not have hard exudates detected in their fundus photographs. Presence of HF was associated with higher total cholesterol (odds ratio = 1.13, 95% confidence interval = 1.01–1.27, P = 0.03) and higher low-density lipoprotein levels (odds ratio = 1.17, 95% confidence interval = 1.02–1.35, P = 0.02) in models adjusting for other risk factors. The total macular volume was also associated with higher total cholesterol (P = 0.009) and triglyceride (P = 0.02) levels after adjusting for other risk factors. Conclusion: Higher total and low-density lipoprotein cholesterol were associated with presence of HF on spectral domain ocular coherence tomography. Total macular volume was associated with higher total cholesterol and triglyceride levels.

African Ancestry Analysis and Admixture Genetic Mapping for Proliferative Diabetic Retinopathy in African Americans

PURPOSE To examine the relationship between proportion of African ancestry (PAA) and proliferative diabetic retinopathy (PDR) and to identify genetic loci associated with PDR using admixture mapping in African Americans with type 2 diabetes (T2D). METHODS Between 1993 and 2013, 1440 participants enrolled in four different studies had fundus photographs graded using the Early Treatment Diabetic Retinopathy Study scale. Cases (n = 305) had PDR while controls (n = 1135) had nonproliferative diabetic retinopathy (DR) or no DR. Covariates included diabetes duration, hemoglobin A1C, systolic blood pressure, income, and education. Genotyping was performed on the Affymetrix platform. The association between PAA and PDR was evaluated using logistic regression. Genome-wide admixture scanning was performed using ANCESTRYMAP software. RESULTS In the univariate analysis, PDR was associated with increased PAA (odds ratio [OR] = 1.36, 95% confidence interval [CI] = 1.16-1.59, P = 0.0002). In multivariate regression adjusting for traditional DR risk factors, income and education, the association between PAA and PDR was attenuated and no longer significant (OR = 1.21, 95% CI = 0.59-2.47, P = 0.61). For the admixture analyses, the maximum genome-wide score was 1.44 on chromosome 1. CONCLUSIONS In this largest study of PDR in African Americans with T2D to date, an association between PAA and PDR is not present after adjustment for clinical, demographic, and socioeconomic factors. No genome-wide significant locus (defined as having a locus-genome statistic > 5) was identified with admixture analysis. Further analyses with even larger sample sizes are needed to definitively assess if any admixture signal for DR is present.

Genetically determined plasma lipid levels and risk of diabetic retinopathy: A mendelian randomization study

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.

A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes

Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy.