Weighing in Ocular Perfusion Pressure in Managing Glaucoma

The role of vascular risk factors in glaucoma is increasingly being supported by the literature, with the association between low ocular perfusion pressure (PP) and glaucoma being the most consistent result. However, we need to be cautious when interpreting these results and consider all possible confounders in the observed associations. While we assess PP through its principal components, the weight of intraocular pressure (IOP) and blood pressure (BP) in the PP equation remains unknown. Also, the role of PP in glaucoma needs to be elucidated with regards to IOP and BP fluctuation during the 24hour period and the effect of IOP-lowering and BP-lowering treatment. The complexity of the interaction of PP with other potential risk factors for glaucoma means that PP cannot be currently considered in the assessment of an individual patient. The role of PP in glaucoma warrants further research and randomized clinical trials assessing PP should include vision and/or structure preservation as end-points and ideally address all of the above issues

An Interpretable Multiple-Instance Approach for the Detection of referable Diabetic Retinopathy from Fundus Images

Diabetic Retinopathy (DR) is a leading cause of vision loss globally. Yet despite its prevalence, the majority of affected people lack access to the specialized ophthalmologists and equipment required for assessing their condition. This can lead to delays in the start of treatment, thereby lowering their chances for a successful outcome. Machine learning systems that automatically detect the disease in eye fundus images have been proposed as a means of facilitating access to DR severity estimates for patients in remote regions or even for complementing the human expert's diagnosis. In this paper, we propose a machine learning system for the detection of referable DR in fundus images that is based on the paradigm of multiple-instance learning. By extracting local information from image patches and combining it efficiently through an attention mechanism, our system is able to achieve high classification accuracy. Moreover, it can highlight potential image regions where DR manifests through its characteristic lesions. We evaluate our approach on publicly available retinal image datasets, in which it exhibits near state-of-the-art performance, while also producing interpretable visualizations of its predictions.Comment: 11 page

Factors Associated With Retinal Vessel Diameters in an Elderly Population: the Thessaloniki Eye Study

Purpose: To identify the factors associated with retinal vessel diameters in the population of the Thessaloniki Eye Study. Methods: Cross-sectional population-based study (age ≥ 60 years). Subjects with glaucoma, late age-related macular degeneration, and diabetic retinopathy were excluded from the analyses. Retinal vessel diameters were measured using the IVAN software, and measurements were summarized to central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), and arteriole to venule ratio (AVR). Results: The analysis included 1614 subjects. The hypertensive group showed lower values of CRAE (P = 0.033) and AVR (P = 0.0351) compared to the normal blood pressure (BP) group. On the contrary, the group having normal BP under antihypertensive treatment did not have different values compared to the normal BP group. Diastolic BP (per mm Hg) was negatively associated with CRAE (P < 0.0001) and AVR (P < 0.0001), while systolic BP (per mm Hg) was positively associated with CRAE (P = 0.001) and AVR (P = 0.0096). Other factors significantly associated included age, sex, alcohol, smoking, cardiovascular disease history, ophthalmic medication, weight, and IOP; differences were observed in a stratified analysis based on BP medication use. Conclusions: Our study confirms previous reports about the association of age and BP with vessel diameters. The negative correlation between BP and CRAE seems to be guided by the effect of diastolic BP as higher systolic BP is independently associated with higher values of CRAE. The association of BP status with retinal vessel diameters is determined by diastolic BP status in our population. Multiple other factors are also independently associated with retinal vessel diameters

Guanylyl cyclase activation reverses resistive breathing–induced lung injury and inflammation

Inspiratory resistive breathing (RB), encountered in obstructive lung diseases, induces lung injury. The soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway is down-regulated in chronic and acute animal models of RB, such as asthma, chronic obstructive pulmonary disease, and in endotoxin-induced acute lung injury. Our objectives were to: (1) characterize the effects of increased concurrent inspiratory and expiratory resistance in mice via tracheal banding; and (2) investigate the contribution of the sGC/cGMP pathway in RB-induced lung injury. Anesthetized C57BL/6 mice underwent RB achieved by restricting tracheal surface area to 50% (tracheal banding). RB for 24 hours resulted in increased bronchoalveolar lavage fluid cellularity and protein content, marked leukocyte infiltration in the lungs, and perturbed respiratory mechanics (increased tissue resistance and elasticity, shifted static pressure–volume curve right and downwards, decreased static compliance), consistent with the presence of acute lung injury. RB down-regulated sGC expression in the lung. All manifestations of lung injury caused by RB were exacerbated by the administration of the sGC inhibitor, 1H-[1,2,4]oxodiazolo[4,3-]quinoxalin-l-one, or when RB was performed using sGCα1 knockout mice. Conversely, restoration of sGC signaling by prior administration of the sGC activator BAY 58-2667 (Bayer, Leverkusen, Germany) prevented RB-induced lung injury. Strikingly, direct pharmacological activation of sGC with BAY 58-2667 24 hours after RB reversed, within 6 hours, the established lung injury. These findings raise the possibility that pharmacological targeting of the sGC–cGMP axis could be used to ameliorate lung dysfunction in obstructive lung diseases

Associations between Serum Vitamin D and Genetic Variants in Vitamin D Pathways and Age-Related Macular Degeneration in the European Eye Study.

PURPOSE: To study associations between early and late age-related macular degeneration (AMD) and neovascular AMD (nvAMD) with serum 25-hydroxy vitamin D (25(OH)D) and genetic variants in vitamin D pathway genes. DESIGN: Population-based, cross-sectional study in a random sample aged 65 years or older from 7 European countries. PARTICIPANTS: Of 4753 participants, 4496 (2028 men and 2468 women), with a mean age of 73 years, provided a blood sample; 2137 had no signs of AMD, 2209 had early AMD, and 150 had late AMD, of whom 104 had nvAMD. METHODS: Participants were interviewed to determine smoking and alcohol use, sunlight exposure, and diet; underwent fundus photography. Fundus images were graded using the International Classification System for Age-Related Maculopathy. The 25(OH)D was measured by liquid chromatography-tandem mass spectrometry and categorized as deficient (<30 nmol/l), insufficient (30-50 nmol/l), or adequate (≥50 nmol/l). Genotyping was performed on a subsample of 1284 AMD cases and controls for 93 single nucleotide polymorphisms (SNPs) from 7 genes. Associations were investigated by linear or logistic regression adjusted for potential confounders. MAIN OUTCOME MEASURES: Adjusted odds ratio (OR) for 3 outcomes (early AMD, late AMD, nvAMD). RESULTS: No linear association was found with 25(OH)D and early or late AMD or nvAMD. There was no association between insufficient or deficient status with early or late AMD. Deficient status was associated with nvAMD (adjusted OR, 1.27; 95% confidence interval, 1.1-1.45; P < 0.0001). Significant (P < 0.05) associations with 25(OH)D were found for SNPs in genes GC, VDR, CYP2R1, and CYP27B1. Two SNPs (VDR) were associated with early AMD, 4 SNPs (RXRA) and 1 SNP (VDR) were associated with nvAMD, and 1 SNP (RXRA), 2 SNPs (VDR), and 1 SNP (CYP2R1) were associated with late AMD. After Bonferroni correction, no SNPs were associated with early AMD, late AMD, or nvAMD. CONCLUSIONS: Deficiency in 25(OH)D was associated with nvAMD, but the adjusted OR was small, and we cannot exclude residual confounding. The hypothesis of a causal association of vitamin D with AMD is not supported by clear evidence for an association of vitamin D SNPs with early AMD, late AMD, or nvAMD

Mediterranean Diet Score and Its Association with Age-Related Macular Degeneration: The European Eye Study

To examine associations between adherence to a Mediterranean diet and prevalence of age-related macular degeneration (AMD) in countries ranging from Southern to Northern Europe. Cross-sectional, population-based epidemiologic study. Of 5060 randomly sampled people aged 65 years or older from 7 study centers across Europe (Norway, Estonia, United Kingdom, France, Italy, Greece, and Spain), full dietary data were available in 4753. The mean age of participants was 73.2 years (standard deviation, 5.6), and 55% were women. Participants underwent an eye examination and digital retinal color photography. The images were graded at a single center. Dietary intake during the previous 12 months was assessed by using a semiquantitative food-frequency questionnaire (FFQ). A previously published Mediterranean Diet Score (MDS) was used to classify participants according to their responses on the FFQ. Multivariable logistic regression was used to investigate the association of the MDS score and AMD, taking account of potential confounders and the multicenter study design. Images were graded according to the International Classification System for age-related maculopathy and stratified using the Rotterdam staging system into 5 exclusive stages (AMD 0-4) and a separate category of large drusen (≥125 μm). Age-related macular degeneration 4 included neovascular AMD (nvAMD) and geographic atrophy (GA). Increasing MDS was associated with reduced odds of nvAMD in unadjusted and confounder-adjusted analysis. Compared with the lowest MDS adherence (≤4 score), those in the highest category MDS adherence (&gt;6 score) showed lower odds of nvAMD (odds ratio, 0.53; 0.27-1.04; P trend = 0.01). The association with MDS did not differ by Y204H risk allele (P = 0.89). For all early AMD (grade 1-3), there was no relationship with MDS (P trend = 0.9). There was a weak trend (P = 0.1) between MDS and large drusen; those in the highest category of MDS had 20% reduced odds compared with those in the lowest (P = 0.05). This study adds to the limited evidence of the protective effect of adherence to a Mediterranean dietary pattern in those with late AMD, although it does not support previous reports of a relationship with genetic susceptibility. Interventions to encourage the adoption of the Mediterranean diet should be developed, and methods by which such behavior change can be achieved and maintained investigated

Association Between Myopia, Ultraviolet B Radiation Exposure, Serum Vitamin D Concentrations, and Genetic Polymorphisms in Vitamin D Metabolic Pathways in a Multicountry European Study.

IMPORTANCE: Myopia is becoming increasingly common globally and is associated with potentially sight-threatening complications. Spending time outdoors is protective, but the mechanism underlying this association is poorly understood. OBJECTIVE: To examine the association of myopia with ultraviolet B radiation (UVB; directly associated with time outdoors and sunlight exposure), serum vitamin D concentrations, and vitamin D pathway genetic variants, adjusting for years in education. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional, population-based random sample of participants 65 years and older was chosen from 6 study centers from the European Eye Study between November 6, 2000, to November 15, 2002. Of 4187 participants, 4166 attended an eye examination including refraction, gave a blood sample, and were interviewed by trained fieldworkers using a structured questionnaire. Myopia was defined as a mean spherical equivalent of -0.75 diopters or less. Exclusion criteria included aphakia, pseudophakia, late age-related macular degeneration, and vision impairment due to cataract, resulting in 371 participants with myopia and 2797 without. EXPOSURES: Exposure to UVB estimated by combining meteorological and questionnaire data at different ages, single-nucleotide polymorphisms in vitamin D metabolic pathway genes, serum vitamin D3 concentrations, and years of education. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) of UVB, serum vitamin D3 concentrations, vitamin D single-nucleotide polymorphisms, and myopia estimated from logistic regression. RESULT: Of the included 3168 participants, the mean (SD) age was 72.4 (5) years, and 1456 (46.0%) were male. An SD increase in UVB exposure at age 14 to 19 years (OR, 0.81; 95% CI, 0.71-0.92) and 20 to 39 years (OR, 0.7; 95% CI, 0.62-0.93) was associated with a reduced adjusted OR of myopia; those in the highest tertile of years of education had twice the OR of myopia (OR, 2.08; 95% CI, 1.41-3.06). No independent associations between myopia and serum vitamin D3 concentrations nor variants in genes associated with vitamin D metabolism were found. An unexpected finding was that the highest quintile of plasma lutein concentrations was associated with a reduced OR of myopia (OR, 0.57; 95% CI, 0.46-0.72). CONCLUSIONS AND RELEVANCE: Increased UVB exposure was associated with reduced myopia, particularly in adolescence and young adulthood. The association was not altered by adjusting for education. We found no convincing evidence for a direct role of vitamin D in myopia risk. The relationship between high plasma lutein concentrations and a lower risk of myopia requires replication

Novel quantitative pigmentation phenotyping enhances genetic association, epistasis, and prediction of human eye colour

Success of genetic association and the prediction of phenotypic traits from DNA are known to depend on the accuracy of phenotype characterization, amongst other parameters. To overcome limitations in the characterization of human iris pigmentation, we introduce a fully automated approach that specifies the areal proportions proposed to represent differing pigmentation types, such as pheomelanin, eumelanin, and non-pigmented areas within the iris. We demonstrate the utility of this approach using high-resolution digital eye imagery and genotype data from 12 selected SNPs from over 3000 European samples of seven populations that are part of the EUREYE study. In comparison to previous quantification approaches, (1) we achieved an overall improvement in eye colour phenotyping, which provides a better separation of manually defined eye colour categories. (2) Single nucleotide polymorphisms (SNPs) known to be involved in human eye colour variation showed stronger associations with our approach. (3) We found new and confirmed previously noted SNP-SNP interactions. (4) We increased SNP-based prediction accuracy of quantitative eye colour. Our findings exemplify that precise quantification using the perceived biological basis of pigmentation leads to enhanced genetic association and prediction of eye colour. We expect our approach to deliver new pigmentation genes when applied to genome-wide association testing

Association of Systemic Medication Use with Glaucoma and Intraocular Pressure:The European Eye Epidemiology Consortium

Purpose: To investigate the association of commonly used systemic medications with glaucoma and intraocular pressure (IOP) in the European population. Design: Meta-analysis of 11 population-based cohort studies of the European Eye Epidemiology Consortium. Participants: The glaucoma analyses included 143 240 participants and the IOP analyses included 47 177 participants. Methods: We examined associations of 4 categories of systemic medications—antihypertensive medications (β-blockers, diuretics, calcium channel blockers [CCBs], α-agonists, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers), lipid-lowering medications, antidepressants, and antidiabetic medications—with glaucoma prevalence and IOP. Glaucoma ascertainment and IOP measurement method were according to individual study protocols. Results of multivariable regression analyses of each study were pooled using random effects meta-analyses. Associations with antidiabetic medications were examined in participants with diabetes only. Main Outcome Measures: Glaucoma prevalence and IOP. Results: In the meta-analyses of our maximally adjusted multivariable models, use of CCBs was associated with a higher prevalence of glaucoma (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.08 to 1.39). This association was stronger for monotherapy of CCBs with direct cardiac effects (OR, 1.96; 95% CI, 1.23 to 3.12). No other antihypertensive medications, lipid-lowering medications, antidepressants, or antidiabetic medications were associated with glaucoma. Use of systemic β-blockers was associated with a lower IOP (β coefficient, −0.33 mmHg; 95% CI, −0.57 to −0.08 mmHg). Monotherapy of both selective systemic β-blockers (β coefficient, −0.45 mmHg; 95% CI −0.74 to −0.16 mmHg) and nonselective systemic β-blockers (β coefficient, −0.54 mmHg; 95% CI, −0.94 to −0.15 mmHg) was associated with lower IOP. A suggestive association was found between use of high-ceiling diuretics and lower IOP (β coefficient, −0.30 mmHg; 95% CI, −0.47 to −0.14 mmHg) but not when used as monotherapy. No other antihypertensive medications, lipid-lowering medications, antidepressants, or antidiabetic medications were associated with IOP. Conclusions: We identified a potentially harmful association between use of CCBs and glaucoma prevalence. Additionally, we observed and quantified the association of lower IOP with systemic β-blocker use. Both findings potentially are important, given that patients with glaucoma frequently use systemic antihypertensive medications. Determining causality of the CCB association should be a research priority. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.</p