Oral Peroxisome Proliferator-Activated Receptor-α Agonist Enhances Corneal Nerve Regeneration in Patients With Type 2 Diabetes.

Diabetic corneal neuropathy (DCN) is a common complication of diabetes. However, there are very limited therapeutic options. We investigated the effects of a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, fenofibrate, on 30 patients (60 eyes) with type 2 diabetes. On in vivo confocal microscopy evaluation, there was significant stimulation of corneal nerve regeneration and a reduction in nerve edema after 30 days of oral fenofibrate treatment, as evidenced by significant improvement in corneal nerve fiber density (CNFD) and corneal nerve fiber width, respectively. Corneal epithelial cell morphology also significantly improved in cell circularity. Upon clinical examination, fenofibrate significantly improved patients' neuropathic ocular surface status by increasing tear breakup time along with a reduction of corneal and conjunctival punctate keratopathy. Tear substance P (SP) concentrations significantly increased after treatment, suggesting an amelioration of ocular surface neuroinflammation. The changes in tear SP concentrations was also significantly associated with improvement in CNFD. Quantitative proteomic analysis demonstrated that fenofibrate significantly upregulated and modulated the neurotrophin signaling pathway and linolenic acid, cholesterol, and fat metabolism. Complement cascades, neutrophil reactions, and platelet activation were also significantly suppressed. Our results showed that fenofibrate could potentially be a novel treatment for patients with DCN.

Towards Next-Generation Sequencing for HIV-1 Drug Resistance Testing in a Clinical Setting.

The HIV genotypic resistance test (GRT) is a standard of care for the clinical management of HIV/AIDS patients. In recent decades, population or Sanger sequencing has been the foundation for drug resistance monitoring in clinical settings. However, the advent of high-throughput or next-generation sequencing has caused a paradigm shift towards the detection and characterization of low-abundance covert mutations that would otherwise be missed by population sequencing. This is clinically significant, as these mutations can potentially compromise the efficacy of antiretroviral therapy, causing poor virologic suppression. Therefore, it is important to develop a more sensitive method so as to reliably detect clinically actionable drug-resistant mutations (DRMs). Here, we evaluated the diagnostic performance of a laboratory-developed, high-throughput, sequencing-based GRT using 103 archived clinical samples that were previously tested for drug resistance using population sequencing. As expected, high-throughput sequencing found all the DRMs that were detectable by population sequencing. Significantly, 78 additional DRMs were identified only by high-throughput sequencing, which is statistically significant based on McNemar's test. Overall, our results complement previous studies, supporting the notion that the two methods are well correlated, and the high-throughput sequencing method appears to be an excellent alternative for drug resistance testing in a clinical setting.

Evaluation of Strip Meniscometry and Association with Clinical and Demographic Variables in a Community Eye Study (in Bangladesh).

Strip meniscometry (SM) is a relatively new technique for evaluating inferior tear meniscus. We described SM in an epidemiology study and its potential associations with clinical and tear parameters. This cross-sectional study involved 1050 factory garment workers in Gazipur, Bangladesh. The Ocular Surface Disease Index (OSDI) questionnaire and a standard examination for dry eye and meibomian gland dysfunction (MGD), including the five-second SM, were performed by a single ophthalmologist. The participants' ages were 35.56 ± 12.12 years (range 18-59), with 53.8% women. The overall SM was 7.7 ± 3.6 mm, with skewness of 0.126 and kurtosis of 1.84 in frequency distribution. SM values were significantly lower in men than women, and significantly correlated with schirmers (r = 0.71) and tear break up time (TBUT) (r = 0.89). A lower SM value was associated with higher OSDI, lower Schirmer test, increased MG severity and lower TBUT. In multivariable analysis, when adjusted by age, SM values remained associated with schirmers and TBUT, and inversely associated with OSDI. In a separate regression model, higher SM was associated with increasing age, reduced severity of MGD grading, and increased TBUT. To conclude, SM is a rapid clinical test associated with dry eye symptoms and signs, with findings affected by both tear secretion and tear stability.

Prevalence and Risk Factors of Severe Dry Eye in Bangladesh-Based Factory Garment Workers.

This study sought to evaluate the prevalence of dry eye and meibomian gland dysfunction (MGD) and the associated factors of severe dry eye symptoms (SDES) among garments worker of Gazipur, Bangladesh. We prospectively collected cross-sectional data for 1050 garments workers of a factory (70% response). All participants had an evaluation of the Ocular Surface Disease Index (OSDI), and a detailed ophthalmic examination including tear breakup time (TBUT), ocular surface fluorescein staining, and Schirmer's I test. MGD grading was based on the viscosity/color and ease of manual expression of meibum. Mean age of participants was 35.5 ± 12.1 years; 53.8% were women. The prevalence of dry eye (OSDI > 12) was 64.2% (95% CI 61.2-67.1%). OSDI was not significantly different between sex or age-groups but associated with increasing MGD grade (p < 0.001), reduced TBUT (<5 s) [p < 0.001], and reduced Schirmer's test (<5 mm) [p < 0.001]. Thirty-five percent had SDES (OSDI > 32). Using univariate logistic regressions, SDES was associated with older age (Odds Ratio (OR) 1.01, 95% Confidence Interval [1.005-1.03] per year increase) and male sex (OR 1.76, 95% CI: 1.36-2.27). When adjusted for age and sex, SDES were strongly associated with increase in MGD severity grading (OR 188, 95% CI: 91-390). However, in multivariate regression, TBUT, but not MGD severity, became the only significant determinant of SDES (OR 13.0, 95% CI: 6.3-27.0, for every 1 s decrease in TBUT). MGD is common in garments workers, contributing to dry eye symptoms in addition to other tear parameters. Reduced tear stability is associated with SDES.

Meibomian gland dysfunction is the primary determinant of dry eye symptoms: Analysis of 2346 patients.

PURPOSE: To determine relative contributions of various ocular surface clinical signs and predisposing factors to the magnitude of dry eye symptoms. METHODS: Clinical audit data were prospectively collected for newly referred dry eye patients. All 2346 patients had an initial visit evaluation of the Ocular Surface Disease Index (OSDI), and a detailed ophthalmic examination including tear breakup time (TBUT), ocular surface fluorescein staining, Schirmer's I test. Among the participants, 1414 had number of liquid meibum expressing glands (NLMEG) evaluated on standard force expression. Other variables collected included history of glaucoma or glaucoma surgery, and history of allergies. RESULTS: In patients aged 46.2 ± 14.8 years, 77.4% were women and 87.1% Chinese. The mean ± SD OSDI was 35.2 ± 21.7. On univariate analysis, higher OSDI was associated with glaucoma diagnosis (p = 0.003), glaucoma surgery (p = 0.002), greater temporal corneal staining (p = 0.002), reduced NLMEG (p < 0.001), and higher inferior forniceal papillary grade (p < 0.001). OSDI was not significantly associated with gender, TBUT, Schirmer's I test values, or the use of cyclosporine eyedrops. On multivariate regression, higher OSDI scores were associated with fewer NLMEG (p = 0.002) and increased lower eyelid forniceal papillary grading (p = 0.002). Corneal staining, glaucoma status and glaucoma surgery were not significantly associated with OSDI. Logistic regression showed that severe symptoms (OSDI>32) was associated with <2 NLMEG [OR(95%CI): 1.34(1.08-1.66)], and presence of inferior eyelid forniceal papillae [1.50(1.17-1.91)]. CONCLUSIONS: Meibomian gland dysfunction (MGD) and lower forniceal papillary reaction had significant contributions to the severity of symptoms, in contrast to traditional dry eye signs. MGD should be objectively assessed and treated to improve symptoms.

Spatial Distribution of Noninvasive Break Up Times and Clinical Relevance in Healthy Participants and Mild Dry Eye.

PURPOSE: Noninvasive keratograph break up times (NIKBUTs) are preferred to dye-based methods to evaluate tear stability in translational medicine. We analyzed the NIKBUTs in different regions of the precorneal tear by using a common imaging technology and explored potential correlations with clinical parameters. METHODS: We tested NIKBUTs of 120 participants (62.5% females, aged 61.0 ± 13.8 years) with the Keratograph 5M, with standardized symptoms, ocular surface evaluation, and tear lipid layer interferometry. NIKBUTs were obtained from color maps in up to 165 spatial zones corresponding to 7 concentric rings. RESULTS: The lowest NIKBUT of tested zones averaged 7.8 ± 7.4 seconds (median, 4.5; range, 1.5-24 seconds), with the lowest NIKBUT measuring <2 seconds in many inferior zones. A mean of 5 zones had broken up by 2 seconds compared to a mean of about 50 zones by 10 seconds. NIKBUTs in specific inferior peripheral zones were significantly directly correlated to tear lipid thicknesses. The receiver operating characteristics for detecting reduced tear lipid thickness were better than overall NIKBUTs for participants with readings in these zones. Weaker correlations of NIKBUTs with symptoms were observed in two other zones. Overall, the NIKBUT displayed by keratograph was not significantly associated with any clinical parameters. CONCLUSIONS: Decreased NIKBUTs in specific peripheral locations may be associated with lower lipid thicknesses. Future measurements of NIKBUTs should ideally be determined in smaller defined zones than current maps. TRANSLATIONAL RELEVANCE: An understanding of how to evaluate tear stability allows a more robust clinical evaluation of new drugs and medical devices for dry eye.