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Hellen CS Römkens, Henny JM Beckers, Jan SAG Schouten, Tos TJM Berendschot, Carroll AB Webers Department of Ophthalmology, Maastricht University Medical Center+, Maastricht, the Netherlands Purpose: The aim of this study is to generate reference values for anterior chamber morphometrics to facilitate the interpretation of anterior chamber images acquired with swept-source optical coherence tomography (SS-OCT) in a Caucasian population.Materials and methods: Non-glaucomatous Caucasian subjects, who were newly referred to the outpatient department of the University Eye Clinic Maastricht UMC+, were asked to undergo anterior segment assessment with SS-OCT imaging prior to routine eye examination (including visual acuity and refractive error measurements, Goldmann applanation tonometry, slit lamp examination and funduscopy).Results: A total of 647 Caucasian subjects, aged 40–80 years, were included. Mean age (± standard deviation) was 61.7±10.3 years, and 294 were male (45%). Mean refractive error was -0.63±3.17 D. OCT images and measurements were obtained in all cases. The mean temporal trabecular iris angle at 500 µm (TIA500) was 27.04°±12.04°, the mean nasal TIA500 was 27.43°±11.75°, the mean anterior chamber depth (ACD) was 2.75±0.39 mm and the mean lens vault (LV) was 0.44±0.30 mm. A smaller temporal TIA500, shallower ACD and higher LV were found in female and hyperopic subjects.Conclusion: Reference values for anterior chamber morphometrics in Caucasians were generated, quantified and presented. These values offer tools for the interpretation of anterior segment images of Caucasians and differentiation between presumed mechanisms of angle closure. Keywords: reference value, anterior chamber, optical coherence tomography, Caucasian

P Mokhles, JSAG Schouten, HJM Beckers, CAB Webers University Eye Clinic Maastricht, Maastricht, the Netherlands Purpose: Blindness in glaucoma is difficult to assess with merely the use of the current World Health Organization (WHO) definition (a visual field restricted to 10° in a radius around central fixation), as this criterion does not cover other types of visual field loss that are encountered in clinical practice and also depict blindness. In this study, a 5-point ordinal scale was developed for the assessment of common visual field defect patterns, with the purpose of comparing blindness as outcome to the findings with the WHO criterion when applied to the same visual fields. The scores with the two methods were compared between two ophthalmologists. In addition, the variability between these assessors in assessing the different visual field types was determined.Methods: Two glaucoma specialists randomly assessed a sample of 423 visual fields from 77 glaucoma patients, stripped of all indices and masked for all patient variables. They applied the WHO criterion and a 5-point ordinal scale to all visual fields for the probability of blindness.Results: The WHO criterion was mostly found applicable and in good agreement for both assessors to visual fields depicting central island of vision or a temporal crescent. The percentage of blindness scores was higher when using the ordinal scale, 21.7% and 19.6% for assessors A and B, respectively, versus 14.4% and 11.3% for the WHO criterion. However, Kappa was lower, 0.71 versus 0.78 for WHO.Conclusions: The WHO criterion is strictly applied and shows good agreement between assessors; however, blindness does not always fit this criterion. More visual fields are labeled as blind when a less stringent criterion is used, but this leads to more interobserver variability. A new criterion that describes the extent, location, and depth of visual field defects together with their consequence for the patient’s quality of life is needed for the classification of glaucoma blindness. Keywords: glaucoma, blindness, visual fields, World Health Organization

Background: Microvascular dysfunction (MVD) is an important contributor to major clinical disease such as stroke, dementia, depression, retinopathy, and chronic kidney disease. Alcohol consumption may be a determinant of MVD., Objective: Main objectives were (1) to study whether alcohol consumption was associated with MVD as assessed in the brain, retina, skin, kidney and in the blood; and (2) to investigate whether associations differed by history of cardiovascular disease or sex., Design: We used cross-sectional data from The Maastricht Study (N = 3,120 participants, 50.9% men, mean age 60 years, and 27.5% with type 2 diabetes [the latter oversampled by design]). We used regression analyses to study the association between total alcohol (per unit and in the categories, i.e. none, light, moderate, high) and MVD, where all measures of MVD were combined into a total MVD composite score (expressed in SD). We adjusted all associations for potential confounders; and tested for interaction by sex, and history of cardiovascular disease. Additionally we tested for interaction with glucose metabolism status., Results: The association between total alcohol consumption and MVD was non-linear, i.e. J-shaped. Moderate versus light total alcohol consumption was significantly associated with less MVD, after full adjustment (beta [95% confidence interval], -0.10 [-0.19; -0.01]). The shape of the curve differed with sex (P interaction  = 0.03), history of cardiovascular disease (P interaction  < 0.001), and glucose metabolism status (P interaction  = 0.02)., Conclusions: The present cross-sectional, population-based study found evidence that alcohol consumption may have an effect on MVD. Hence, although increasing alcohol consumption cannot be recommended as a policy, this study suggests that prevention of MVD may be possible through dietary interventions., (© 2023. The Author(s).)

Background: If retinal indices of neurodegeneration are to be biomarkers for the monitoring of cerebral neurodegeneration, it is important to establish whether potentially modifiable risk factors for dementia are associated with retinal neurodegenerative changes., Objective: To study associations of dementia risk factors with retinal sensitivity, an index of retinal neural function, and retinal nerve fiber layer (RNFL) thickness, an index of retinal neural structure., Methods: We used cross-sectional data from The Maastricht Study (up to 5,666 participants, 50.5% men, mean age 59.7), and investigated associations with regression analyses (adjusted for potential confounders)., Results: Most risk factors under study (i.e., hyperglycemia, unhealthy diet, lower cardiorespiratory fitness, smoking, alcohol consumption, and hypertension) were significantly associated with lower retinal sensitivity and lower RNFL thickness., Conclusion: Findings of this population-based study support the concept that retinal neural indices may be biomarkers for the monitoring of therapeutic strategies that aim to prevent early-stage cerebral neurodegeneration and, ultimately, dementia.

Retinopathy and neuropathy in type 2 diabetes are preceded by retinal nerve fibre layer (RNFL) thinning, an index of neurodegeneration. We investigated whether glucose metabolism status (GMS), measures of glycaemia, and daily glucose variability (GV) are associated with RNFL thickness over the entire range of glucose tolerance. We used cross-sectional data from The Maastricht Study (up to 5455 participants, 48.9% men, mean age 59.5 years and 22.7% with type 2 diabetes) to investigate the associations of GMS, measures of glycaemia (fasting plasma glucose [FPG], 2-h post-load glucose [2-h PG], HbA1c, advanced glycation endproducts [AGEs] assessed as skin autofluorescence [SAF]) and indices of daily GV (incremental glucose peak [IGP] and continuous glucose monitoring [CGM]-assessed standard deviation [SD]) with mean RNFL thickness. We used linear regression analyses and, for GMS, P for trend analyses. We adjusted associations for demographic, cardiovascular risk and lifestyle factors, and, only for measures of GV, for indices of mean glycaemia. After full adjustment, type 2 diabetes and prediabetes (versus normal glucose metabolism) were associated with lower RNFL thickness (standardized beta [95% CI], respectively - 0.16 [- 0.25; - 0.08]; - 0.05 [- 0.13;  0.03]; P trend  = 0.001). Greater FPG, 2-h PG, HbA1c, SAF, IGP, but not CGM-assessed SD, were also associated with lower RNFL thickness (per SD, respectively - 0.05 [- 0.08; - 0.01]; - 0.06 [- 0.09; - 0.02]; - 0.05 [- 0.08; - 0.02]; - 0.04 [- 0.07; - 0.01]; - 0.06 [- 0.12; - 0.01]; and - 0.07 [- 0.21; 0.07]). In this population-based study, a more adverse GMS and, over the entire range of glucose tolerance, greater glycaemia and daily GV were associated with lower RNFL thickness. Hence, early identification of individuals with hyperglycaemia, early glucose-lowering treatment, and early monitoring of daily GV may contribute to the prevention of RNFL thinning, an index of neurodegeneration and precursor of retinopathy and neuropathy., (© 2022. The Author(s).)

Purpose: To investigate the cost-effectiveness of prophylactic treatments against cystoid macular edema after cataract surgery in diabetic patients., Setting: 7 ophthalmology clinics in the Netherlands and Belgium., Design: Prospective trial-based cost-effectiveness analysis using data from a European multicenter randomized clinical trial., Methods: Diabetic patients (n = 163) undergoing uneventful cataract surgery were randomized to perioperative subconjunctival triamcinolone acetonide (n = 36), perioperative intravitreal bevacizumab (n = 36), combination treatment (n = 45), or no additional treatment (control group, n = 46). The cost analysis was performed from a healthcare perspective within a 12-week postoperative time horizon. The main effectiveness outcome was quality-adjusted life years (QALYs). The main cost-effectiveness outcome was the incremental cost-effectiveness ratio (ICER; cost per QALY)., Results: The mean total healthcare costs and QALYs were as follows: triamcinolone group €1827 (U.S. dollars [$] 2295)/0.166; bevacizumab group €2050 ($2575)/0.144; combination group €2027 ($2546)/0.166; and control group €2041 ($2564)/0.156. Bevacizumab and control treatment were most costly and least effective. The ICER was €321 984 ($404 503) per QALY for the combination group compared with that of the triamcinolone group. Assuming the willingness-to-pay as €20 000 ($25 126) per QALY, the cost-effectiveness probability was 70% and 23% in the triamcinolone and combination groups, respectively. No patient who received triamcinolone developed clinically significant macular edema (CSME). A secondary cost-effectiveness analysis based on this outcome showed a clear preference for triamcinolone., Conclusions: In diabetic patients, subconjunctival triamcinolone was effective in preventing CSME after cataract surgery. The cost-effectiveness analysis showed that triamcinolone is also cost-effective., (Copyright © 2021 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

Purpose: The trabecular meshwork (TM) is situated in the most frontal part of the eye and is thought to play an important role in the regulation of the eye pressure. However, this tissue is rather difficult to harvest for research. The purpose of this study is therefore to integrate the existing gene expression data of the healthy TM to increase sample size and identify its signature genes and pathways. This provides a robust reference for the study of molecular disease processes and supports the selection of candidate target genes for new treatments., Methods: A systematic search identified microarray data of healthy TM tissue. After quality control, datasets of low quality and deviating samples were excluded. Remaining individuals were jointly normalized and integrated into one database. The average gene expression of each tested gene over all individuals was calculated. The 25% genes with the highest average expression were identified as the most active genes in the healthy TM and used as input for pathway and network analysis. Additionally, ubiquitous pathways and genes were identified and excluded from the results. Lastly, we identified genes which are likely to be TM-specific., Results: The gene expression data of 44 individuals, obtained from 18 datasets, were jointly normalized. Ubiquitous genes (n = 688) and ubiquitous pathways (n = 73) were identified and excluded. Following, 1882 genes and 211 pathways were identified as the signature genes and pathways of the healthy TM. Pathway analysis revealed multiple molecular processes of which some were already known to be active in the TM, for example extracellular matrix and elastic fiber formation. Forty-six candidate TM-specific genes were identified. These consist mainly of pseudogenes or novel transcripts of which the function is unknown., Conclusions: In this comprehensive meta-analysis we identified non-ubiquitous genes and pathways that form the signature of the functioning of the healthy TM. Additionally, 46 candidate TM-specific genes were identified. This method can also be used for other tissues that are difficult to obtain for study., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the usefulness of water drinking test and dark room provocative testing (WDT + DRPT) in current clinical practice by evaluating input parameters from Swept-source Optical Coherence Tomography (SS-OCT) images, and to determine if clinical factors like axial length, central endothelial cell count (CECC) and retinal nerve fibre layer thickness (RNFL) thickness are associated with a positive WDT + DRPT., Methods: SS-OCT examination was performed in consecutive subjects presenting as new patients in the outpatient clinic aged > 40 years. If at least one eye met the inclusion criteria (anterior chamber angles <20° and anterior chamber depth < 2.5 mm on SS-OCT), subjects were included in this study and WDT + DRPT was carried out. The eye with the smallest angle was analysed. The difference in parameters between eyes with a positive (≥8 mmHg) and negative (<8 mmHg) increase in intraocular pressure (IOP) after WDT + DRPT were statistically analysed. Second, the correlation between IOP increase after WDT + DRPT and anterior chamber angle parameters (RNFL thickness, CECC and axial length) was studied., Results: A total of 95 subjects with a mean age of 64 years were included. There was an association between IOP increase after WDT + DRPT and anterior chamber angle characteristics, however this was not of clinical significance. No positive results after WDT + DRPT were found in patients with anterior chamber angles ≥ 20°., Conclusions: The present findings indicate that this combined provocative test has no definite correlative or predictive value in angle closure disease. Further, the test is not useful in predicting early diagnosis or possible CECC or RNFL loss., (© 2021. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Importance: Whether neurodegeneration contributes to the early pathobiology of late-life depression remains incompletely understood., Objective: To investigate whether lower retinal nerve fiber layer (RNFL) thickness, a marker of neurodegeneration, is associated with the incidence of clinically relevant depressive symptoms and depressive symptoms over time., Design, Setting, and Participants: This is a population-based cohort study from the Netherlands (The Maastricht Study) with baseline examination between 2010 and 2020 and median (IQR) follow-up of 5.0 (3.0-6.0) years. Participants were recruited from the general population. Individuals with type 2 diabetes were oversampled by design. Data analysis was performed from September 2020 to January 2021., Exposures: RNFL, an index of neurodegeneration, assessed with optical coherence tomography., Main Outcomes and Measures: Depressive symptoms were assessed with the Patient Health Questionnaire (PHQ)-9 (continuous score, 0-27) at baseline and over time via annual assessments. The presence of clinically relevant depressive symptoms was defined as a PHQ-9 score of 10 or higher., Results: We used data from 4934 participants with depressive symptoms over time (mean [SD] age, 59.7 [8.4] years; 2159 women [50.8%]; 870 had type 2 diabetes [20.5%]). Lower RNFL thickness was associated with higher incidence of clinically relevant depressive symptoms (per 1 SD, hazard ratio 1.11; 95% CI, 1.01-1.23) and more depressive symptoms over time (per 1 SD, rate ratio, 1.04; 95% CI, 1.01-1.06), after adjustment for demographic, cardiovascular, and lifestyle factors., Conclusions and Relevance: The findings of this study suggest that lower RNFL thickness is associated with higher incidence of clinically relevant depressive symptoms and more depressive symptoms over time. Hence, neurodegeneration may be associated with the early pathobiology of late-life depression.

Purpose: To investigate whether higher blood pressure and greater arterial stiffness are associated with the presence of macular cysts and whether this association is already present in the absence of micro-aneurysms in individuals with and without type 2 diabetes., Methods: Using spectral domain optical coherence tomography (OCT), we performed a macular volume scan in 2647 individuals (mean age 60 ± 8 years, 50% men, 27% type 2 diabetes). The association between macular cysts and 24-hour systolic and diastolic blood pressure, pulse pressure, mean arterial blood pressure, carotid-femoral pulse wave velocity and carotid distensibility was assessed by use of logistic regression., Results: Twenty-four hours systolic blood pressure was associated with the presence of macular cysts [OR = 1.03 (95% CI 1.00-1.05) per 1 mmHg, p = 0.03]. 24 hr pulse pressure [OR = 1.61 (95% CI 1.11-2.34) per 10 mmHg, p = 0.01] and carotid-femoral pulse wave velocity [OR = 1.16 (95% CI 1.02-1.32) per 1 m/s, p = 0.02] were associated with macular cysts, while carotid distensibility was not [OR = 1.03 (95% CI 0.96-1.11) per 1.0*10 -3 /kPa, p = 0.45]. Associations were similar in individuals with and without type 2 diabetes and were already present in the absence of micro-aneurysms., Conclusion: Twenty-four hours systolic blood pressure, 24 hr pulse pressure and carotid-femoral pulse wave velocity are associated with the presence of OCT-detected macular cysts in individuals with and without type 2 diabetes, even in the absence of micro-aneurysms. Therefore, blood pressure and aortic stiffness are potential factors contributing to macular cysts., (© 2020 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Objective: This study investigated whether arterial stiffening is a determinant of subtle retinal microvascular changes that precede diabetic retinopathy., Research Design and Methods: This study used cross-sectional data from the Maastricht Study, a type 2 diabetes-enriched population-based cohort study. We used multivariable linear regression analysis to investigate, in individuals without and with type 2 diabetes, the associations of carotid distensibility coefficient and carotid-femoral pulse wave velocity with retinal microvascular diameters and flicker light-induced dilation and adjusted for cardiovascular and lifestyle risk factors., Results: The retinal microvascular diameter study population consisted of N = 2434 participants (51.4% men, mean ± SD age 59.8 ± 8.1 years, and 28.1% type 2 diabetes). No measures of arterial stiffness were significantly associated with microvascular diameters. Greater carotid distensibility coefficient (i.e., lower carotid stiffness) was significantly associated with greater retinal arteriolar flicker light-induced dilation (per standard deviation, standardized beta [95% CI] 0.06 [0.00; 0.12]) and non-significantly, but directionally similarly, associated with greater retinal venular flicker light-induced dilation (0.04 [-0.02; 0.10]). Carotid-femoral pulse wave velocity (i.e., aortic stiffness) was not associated with retinal microvascular flicker light-induced dilation. The associations between carotid distensibility coefficient and retinal arteriolar and venular flicker light-induced dilation were two- to threefold stronger in individuals with type 2 diabetes than in those without., Conclusion: In this population-based study greater carotid, but not aortic, stiffness was associated with worse retinal flicker light-induced dilation and this association was stronger in individuals with type 2 diabetes. Hence, carotid stiffness may be a determinant of retinal microvascular dysfunction., (© 2021 The Authors. Microcirculation published by John Wiley & Sons Ltd.)

Aim: To assess the visual acuity at the end of life in glaucoma suspect patients, ocular hypertension, and patients treated for glaucoma and to find factors contributing to a reduced visual acuity in this cohort of deceased patients., Methods: In a cohort of 3883 medically treated glaucoma patients, glaucoma suspect, or patients with ocular hypertension assembled in 2001-2004, 1639 were deceased. Patient data were collected from electronic and paper patient files. The files of 1378 patients were studied and the last measured visual acuity and ocular comorbidities influencing the visual acuity were extracted., Results: Our results show that only 37.2% of patients had no visual impairment in either eye, 30.5% was visually impaired or blind in both eyes and 4.1% was blind in both eyes, all based on VA. The most common contributing factors for severe visual impairment or blindness (prevalence ≥ 1%) were: glaucoma, retinal vein occlusion, dry and exudative age-related macular degeneration, past retinal detachment, amblyopia, diabetic retinopathy, anterior ischemic optic neuropathy, trauma, decompensated cornea, past keratitis, enucleation, corneal transplantation, and macular hole., Conclusions: Despite the current advanced treatment modalities for glaucoma, 30.5% of patients had a VA < 0.5 in both eyes and 4.1% was blind in both eyes. However, this disability cannot be confidently attributed only to glaucoma. Besides glaucoma, most common contributing factors were among others retinal and macular diseases. Patient management in glaucoma should be based on more than lowering the intraocular pressure to prevent blindness at the end of life.

Purpose: To investigate the cost-effectiveness of prophylactic treatments against cystoid macular edema (CME) after cataract surgery in patients without diabetes., Setting: Seven ophthalmology clinics in the Netherlands and Belgium., Design: Prospective cost-effectiveness analysis using data from a European multicenter randomized clinical trial (ESCRS PREMED)., Methods: Patients without diabetes planned for expected uneventful cataract surgery were randomized to topical bromfenac (Yellox, n = 242), topical dexamethasone (n = 242), or a combination treatment (n = 238). All relevant resources from a healthcare perspective were included in the cost analysis within a time horizon of 12 weeks postoperatively. The main effectiveness outcome was quality-adjusted life years (QALYs). The main cost-effectiveness outcome was the incremental cost-effectiveness ratio (ICER) based on the cost per QALY., Results: The study comprised 722 patients without diabetes. Total healthcare costs and QALYs were € 447 (US $562) and 0.174 in the bromfenac group, €421 (US $529) and 0.179 in the dexamethasone group, and €442 (US $565) and 0.182 in the combination group. Bromfenac was most costly and least effective (ie, strongly dominated). The ICER was €6544 (US $8221) per QALY for the combination group compared with the dexamethasone group. Assuming that the willingness to pay is € 20 000 (US $25 126) per QALY, the cost-effectiveness probability was 3%, 32%, and 65% in the bromfenac, dexamethasone, and combination groups, respectively., Conclusions: In patients without diabetes, combination treatment with topical bromfenac and dexamethasone was effective and cost-effective in preventing CME after cataract surgery compared with treatment with either drug alone., (Copyright © 2021 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

Background: Microvascular dysfunction (MVD) contributes to stroke, dementia, depression, retinopathy and chronic kidney disease. However, the determinants of MVD are incompletely understood. Greater blood pressure variability (BPV) may be one such determinant., Methods and Results: We used cross-sectional data of The Maastricht Study (n = 2773, age 59.9 years; 51.9% men) to investigate whether greater very short- to mid-term BPV is associated with various MVD measures. We standardized and averaged within-visit, 24-h and 7-day BPV into a systolic and a diastolic BPV composite score. MVD measures included a composite score of MRI cerebral small vessel disease (CSVD) features (total brain parenchymal volume, white matter hyperintensity volume, lacunar infarcts and cerebral microbleeds), a composite score of flicker light-induced retinal arteriolar and venular dilation response, albuminuria, heat-induced skin hyperemia and a composite score of plasma biomarkers of MVD (sICAM-1, sVCAM-1, sE-selectin and von Willebrand Factor). We used linear regression adjusted for age, sex, glucose metabolism status, mean 24-h systolic or DBP, cardiovascular risk factors and antihypertensive medication. We found that higher systolic and diastolic BPV composite scores (per SD) were associated with higher albuminuria [higher ratio, 1.04 (95% CI 1.00-1.08) and 1.07 (1.03-1.11), respectively], but not with other measures of MVD tested., Conclusion: Greater systolic and diastolic BPV was associated with higher albuminuria, but not with CSVD features, flicker light-induced retinal arteriolar and venular dilation response, heat-induced skin hyperemia and plasma biomarkers of MVD. This suggests that the microvasculature of the kidneys is most vulnerable to the detrimental effects of greater BPV.

Purpose: In individuals with diabetes, injury to the corneal nerve fibres predisposes to delayed corneal epithelial healing, reduced corneal sensitivity and corneal erosion. We investigated to what extent a reduction in corneal nerve fibre length (CNFL) is present in individuals with prediabetes or type 2 diabetes (DM2) compared with individuals with normal glucose metabolism (NGM)., Methods: Using composite images acquired by corneal confocal microscopy, we assessed total CNFL per mm 2 in the subbasal nerve plexus of the cornea in 134 participants (mean age 59 ± 8 years, 49% men, 87 NGM, 20 prediabetes, 27 DM2). Multivariable linear regression was used to assess the association between CNFL and glucose metabolism status, adjusted for age and sex., Results: In individuals with type 2 diabetes, the mean CNFL was significantly reduced [β = -1.86 mm/mm 2 (95% CI -3.64 to -0.08), p = 0.04], as compared with individuals with normal glucose metabolism after adjustment for age and sex. Part of the reduction was present in individuals with prediabetes [β = -0.96 mm/mm 2 (95% CI -2.91 to 0.99), p = 0.34], with a linear trend of corneal nerve fibre reduction with severity of glucose metabolism status (p trend = 0.04)., Conclusions: A significant reduction in CNFL was found in individuals with DM2 compared with individuals with NGM. A trend of reduction in CNFL was observed between individuals with NGM and prediabetes. The reduction in corneal nerve fibre length could contribute to a delayed corneal healing and an increased risk for corneal complications after surgery., (© 2020 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: To identify processes that contribute to corticosteroid-induced ocular hypertension and candidate target genes for treatment., Methods: A systematic search identified five human microarray datasets investigating the effect of dexamethasone versus a control medium on trabecular meshwork (TM) tissue. After thorough quality control, samples of low quality were removed, and the datasets were integrated. Additionally, a bovine RNA-sequencing dataset allowed to investigate differences in gene expression profiling between cows with and without corticosteroid-induced ocular hypertension (responders vs. nonresponders). The obtained datasets were used as input for parallel pathway analyses. Significantly changed pathways were clustered into functional categories and the results were further investigated. A network visualizing the differences between the responders and nonresponders was created., Results: Seven functional pathway clusters were found to be significantly changed in TM cells exposed to dexamethasone versus a control medium and in TM cells of responders versus nonresponders: collagen, extracellular matrix, adhesion, WNT-signaling, inflammation, adipogenesis, and glucose metabolism. In addition, cell cycle and senescence were only significantly changed in responders versus nonresponders. The network of the differential gene expression between responders and nonresponders shows many connections between the identified processes via shared genes., Conclusions: Nine functional pathway clusters synthesize the molecular response to dexamethasone exposure in TM cells and are likely to be involved in the pathogenesis of corticosteroid-induced ocular hypertension.

Purpose: To identify risk factors for the development of ocular hypertension after keratoplasty., Methods: A systematic search in PubMed and Embase identified 67 relevant articles published between January 1990 and 2019. We preferentially searched for data on an intraocular pressure increase above 21 mmHg at 6 months or a threshold or time point close to that and reported whether the preoperative or intraoperative status of risk factors was defined. The results were presented in evidence tables, visualizing the direction of the association, whether univariate and/or multivariate analysis was performed, and the significance level (P < 0.05). Four researchers, blinded for the risk factors, independently assigned a level of evidence (definitely, probably, possibly, not associated). Consensus was met during group meetings., Results: From the 110 studied risk factors, pre-existing glaucoma, high preoperative IOP and combined keratoplasty with removal or exchange of an intraocular lens (IOL) were definitely associated with an increased risk. In addition, if the pre-or postoperative lens status was undefined, aphakia and pseudophakia with the IOL in the anterior or posterior chamber were also definitely associated with an increased risk when compared to phakia. Glaucoma in the contralateral eye, indication of bullous keratopathy, African American descent, preoperative treatment with cyclosporine or olopatadine 0.1%, postoperative treatment with prednisolone acetate 1%, and combined surgery in general (ie, the type of surgeries undefined in primary studies) were probably associated. Multiple other identified risk factors lack sufficient evidence and need additional investigation., Conclusions: Risk factors with a definite association can help clinicians select patients at risk and adjust their follow-up and treatment. The other factors need further investigation.

Purpose: Performing bioinformatics analyses using trabecular meshwork (TM) gene expression data in order to further elucidate the molecular pathogenesis of primary open-angle glaucoma (POAG), and to identify candidate target genes., Methods: A systematic search in Gene Expression Omnibus and ArrayExpress was conducted, and quality control and preprocessing of the data was performed with ArrayAnalysis.org. Molecular pathway overrepresentation analysis was performed with PathVisio using pathway content from three pathway databases: WikiPathways, KEGG and Reactome. In addition, Gene Ontology (GO) analysis was performed on the gene expression data. The significantly changed pathways were clustered into functional categories which were combined into a network of connected genes., Results: Ninety-two significantly changed pathways were clustered into five functional categories: extracellular matrix (ECM), inflammation, complement activation, senescence and Rho GTPase signalling. ECM included pathways involved in collagen, actin and cell-matrix interactions. Inflammation included pathways entailing NF-κB and arachidonic acid. The network analysis showed that several genes overlap between the inflammation cluster on the one hand, and the ECM, complement activation and senescence clusters on the other hand. GO analysis, identified additional clusters, related to development and corticosteroids., Conclusion: This study provides an overview of the processes involved in the molecular pathogenesis of POAG in the TM. The results show good face validity and confirm findings from histological, biochemical, genome-wide association and transcriptomics studies. The identification of known points of action for drugs, such as Rho GTPase, arachidonic acid, NF-κB, prostaglandins and corticosteroid clusters, supports the value of this approach to identify potential drug targets., (© 2019 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Background: Following the principles of value-based health care, outcomes and processes of daily-practice eye care need to be systematically evaluated. We illustrate an approach that can be used to support data-driven quality improvements. We used patient data regarding the treatment of neovascular age-related macular degeneration (nAMD)., Methods: In a cohort study, we reviewed medical records of patients with nAMD confirmed on fluorescein angiography (FA). Patients were treated with intravitreal injections with bevacizumab; ranibizumab; or photodynamic therapy (PDT). Visual acuity (VA), ophthalmic exam results and treatments were recorded. VA was compared between treatments by linear mixed model. Diagnosis was re-evaluated on the original FAs. Outcome analysis was performed by 1) selecting VA as the relevant outcome parameter; 2) Preventing selection by comparing treatments with historical untreated cohort and cohorts from the literature, 3) correcting for confounding due to lesion type, and 4) identifying relevant process variables that affect the outcome. These were severity of disease at presentation, and doctor- and patient dependent process variables., Results: In total, 473 eyes were included. At 12 months, change in VA was 0.54, 0.48, 0.09, and 0.07 LogMAR in the no-treatment, photodynamic therapy (PDT), bevacizumab, and ranibizumab groups, respectively. Lesion type on FA differed between groups. Diagnosis of nAMD could not be confirmed in 104 patients. Patient delay, inaccurate diagnosis and treatment intervals may have impacted outcomes., Conclusions: The effect of PDT was small to absent. Anti-VEGFs were effective and appeared as effective as in RCTs. Correct selection of a comparator cohort and addressing confounding, including confounding by indication and effect modification, are needed to achieve valid results and interpretation. Patient delay, diagnosis accuracy, indication for and application of treatment can potentially be improved to improve treatment outcomes. In a value-based care perspective, systematic evaluation of diagnostic accuracy, treatment indication, protocols, and outcomes of new interventions is needed at an early stage to improve outcomes.

Purpose: Ophthalmologists increasingly depend on new drugs to advance their treatment options. These options are limited by restraints on reimbursements for new and expensive drugs. These restraints are put in place through health policy decisions based on cost-effectiveness analyses (CEA). Cost-effectiveness analyses need to be valid and of good quality to support correct decisions to create new treatment opportunities. In this study, we report the quality, validity and usefulness of CEAs for therapies for nAMD., Methods: A systematic review in PubMed, EMBASE and Cochrane was performed to include CEAs. Quality and validity assessment was based on current general quality criteria and on elements that are specific to the field of ophthalmology., Results: Forty-eight CEAs were included in the review. Forty-four CEAs did not meet four basic model quality and validity criteria specific to CEAs in the field of ophthalmology (both eyes analysed instead of one; a time horizon extending beyond 4 years; extrapolating VA and treatment intervals beyond trial data realistically; and including the costs of low-vision). Four CEAs aligned with the quality and validity criteria. In two of these CEAs bevacizumab as-needed (PRN) was more cost-effective than bevacizumab monthly; aflibercept (VIEW); or ranibizumab monthly or PRN. In two CEAs, ranibizumab (PRN or treat and extent) was dominant over aflibercept. In two other CEAs, aflibercept was either more cost-effective or dominant over ranibizumab monthly or PRN., Conclusion: Two of the CEAs of sufficient quality and validity show that bevacizumab PRN is the most cost-effective treatment. Comparing ranibizumab and aflibercept, either treatment can be more cost-effective depending on the assumptions used for drug prices and treatment frequencies. The majority of the published CEAs are of insufficient quality and validity. They wrongly inform decision-makers at the cost of opportunities for ophthalmologists to treat patients. As such, they may negatively influence overall patient outcomes and societal costs. For future ophthalmic treatments, CEAs need to be improved and only published when they are of sufficient quality and validity., (© 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

In this small cross-sectional study of predominantly well-treated participants with relatively short-term type 2 diabetes duration, HbA1c > 7% (53 mmol/mol) was associated with lower cortical density and thickness and higher cortical porosity at the distal radius, lower trabecular thickness at the distal tibia, and higher trabecular number at both sites., Introduction: To examine the association between diabetes status and volumetric bone mineral density (vBMD), bone microarchitecture and strength of the distal radius and tibia as assessed with HR-pQCT. Additionally-in participants with type 2 diabetes (T2DM), to examine the association between HbA1c, diabetes duration, and microvascular disease (MVD) and bone parameters., Methods: Cross-sectional data from 410 (radius) and 198 (tibia) participants of The Maastricht Study (mean age 58 year, 51% female). Diabetes status (normal glucose metabolism, prediabetes, or T2DM) was based on an oral glucose tolerance test and medication history., Results: After full adjustment, prediabetes and T2DM were not associated with vBMD, bone microarchitecture, and strength of the radius and tibia, except for lower trabecular number (Tb.N) of the tibia (- 4%) in prediabetes and smaller cross-sectional area of the tibia (- 7%) in T2DM. In T2DM, HbA1c > 7% was associated with lower cortical vBMD (- 5%), cortical thickness (- 16%), higher cortical porosity (+ 20%) and Tb.N (+ 9%) of the radius, and higher Tb.N (+ 9%) and lower trabecular thickness (- 13%) of the tibia. Diabetes duration > 5 years was associated with higher Tb.N (+ 6%) of the radius. The presence of MVD was not associated with any bone parameters., Conclusions: In this study with predominantly well-treated T2DM participants with relatively short-term diabetes duration, inadequate blood glucose control was negatively associated with cortical bone measures of the radius. In contrast, trabecular number was increased at both sites. Studies of larger sample size are warranted for more detailed investigations of bone density and bone quality in patients with T2DM.

Purpose: To calculate the prevalence of all vitreomacular interface (VMI) disorders and stratify according to age, sex and (pre)diabetes status., Methods: The presence of VMI disorders was assessed in 2660 participants aged between 40 and 75 years from The Maastricht Study who had a gradable macular spectral-domain optical coherence tomography (SD-OCT) volume scan in at least one eye [mean 59.7 ± 8.2 years, 50.2% men, 1531 normal glucose metabolism (NGM), 401 prediabetes, 728 type 2 diabetes (DM2, oversampled)]. A stratified and multivariable logistic regression analysis was used., Results: The prevalence of the different VMI disorders for individuals with NGM, prediabetes and DM2 was, respectively, 5.7%, 6% and 6.7% for epiretinal membranes; 6%, 9.6% and 6.8% for vitreomacular traction; 1.1%, 0.7% and 0.3% for lamellar macular holes; 0.1%, 0% and 0% for pseudoholes; 1.1%, 1.9% and 5.5% for macular cysts. None of the participants was diagnosed with a macular hole. The prevalence of epiretinal membranes, vitreomacular traction and macular cysts was higher with age (p < 0.001). Vitreomacular traction and lamellar macular holes were more frequent in women (p < 0.01). DM2 is positively associated [OR = 3.9 (95% CI 2.11-7.22, p < 0.001)] with macular cysts and negatively associated with lamellar macular holes [OR = 0.2 (95% CI 0.04-0.9, p = 0.036)] after adjustment for age and sex. The calculated prevalence of VMI disorders was 15.9%., Conclusions: The calculated prevalence of VMI disorders in individuals aged between 40 and 75 years is 15.9%. The prevalence depends on age, sex and glucose metabolism status for several types of VMI disorders., (© 2018 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: The purpose of this study is to evaluate the effect of early phacoemulsification on the management of acute angle closure glaucoma in patients with coexisting cataract after initial treatment with medical therapy and laser peripheral iridotomy., Patients and Methods: This study involved a retrospective analysis of patients presenting to the Maastricht University Medical Center+ with acute angle closure and coexisting cataract between 2005 and 2015. Patients were included after initial treatment with a standard protocol comprising topical and systemic medical therapy and laser peripheral iridotomy. Patients underwent small-incision phacoemulsification with intraocular lens implantation into the capsular bag by experienced surgeons within 3 months of the acute angle closure episode. The effect on intraocular pressure, number of glaucoma medications, visual acuity, and complications was assessed., Results: A total 35 patients were included in the study (mean age, 71±10 y; 20% male; mean refractive error, +1.6±1.8 diopters). The mean duration between acute angle closure episode and phacoemulsification was 37±22 days. There were no complications. Intraocular pressure decreased in all patients from 17.0±8.2 mm Hg to 13.2±3.9 mm Hg after 3 months (P=0.008), whereas the mean number of glaucoma medications decreased from 2.9±1.1 to 0.7±0.9 (P<0.001), with 56% of patients discontinuing all medications. Visual acuity improved from 0.9±0.9 logMAR to 0.2±0.3 logMAR (P<0.001)., Conclusions: Early phacoemulsification with intraocular lens implantation results in a reduced intraocular pressure and number of glaucoma medications after an acute angle closure glaucoma crisis in patients with coexisting cataract. Although surgery may be challenging, the results are promising, with significant improvement in visual acuity in most patients.

Purpose: To compare the efficacy of perioperative treatment strategies, in addition to topical bromfenac 0.09% and dexamethasone 0.1%, to reduce the risk for developing cystoid macular edema (CME) after uneventful cataract surgery in diabetic patients., Setting: Twelve European study centers., Design: Randomized clinical trial., Methods: Diabetic patients having phacoemulsification cataract surgery were randomly allocated to receive no additional treatment, a subconjunctival injection with 40 mg triamcinolone acetonide, an intravitreal injection with 1.25 mg bevacizumab, or a combination of both. The main outcomes were the difference in central subfield mean macular thickness, corrected distance visual acuity, and the incidence of CME and clinically significant macular edema within 6 and 12 weeks postoperatively., Results: The study comprised 213 patients. At 6 and 12 weeks postoperatively, the central subfield mean macular thickness was 12.3 μm and 9.7 μm lower, respectively, in patients who received subconjunctival triamcinolone acetonide than patients who did not (P = .007 and P = .014, respectively). No patient who received subconjunctival triamcinolone acetonide developed CME. Intravitreal bevacizumab had no significant effect on macular thickness., Conclusions: Diabetic patients who received a subconjunctival injection with triamcinolone acetonide at the end of cataract surgery had a lower macular thickness and macular volume at 6 and 12 weeks postoperatively than patients who did not. Intravitreal bevacizumab had no significant effect., (Copyright © 2018 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.)

Objective: Albuminuria is thought to be a biomarker of microvascular and macrovascular endothelial dysfunction. However, direct evidence for an association of microvascular endothelial dysfunction with albuminuria is limited. In addition, experimental data suggest a stronger association of microvascular endothelial dysfunction with albuminuria in individuals with than in those without diabetes., Methods: We examined cross-sectional associations of flicker light-induced retinal arteriolar dilation (n = 2095) and heat-induced skin hyperemia (n = 1508) with 24-h albuminuria in the population-based, diabetes-enriched Maastricht Study. We used linear regression analyses to adjust for age, sex, type 2 diabetes, and cardiovascular disease risk factors. In addition, we tested for statistical interaction with type 2 diabetes., Results: Median [interquartile range] albuminuria was 6.5 [3.9-11.6] mg/24 h and 8.2% had albuminuria at least 30 mg/24 h. After adjustment, albuminuria was 1.168 (95% confidence interval, 1.046-1.303) times greater in participants in the quartile with the smallest flicker light-induced retinal arteriolar dilation relative to those with the greatest dilation, and this association was stronger in participants with type 2 diabetes (Pinteraction < 0.10). Further, each 100 percentage points lower heat-induced skin hyperemia was associated with a 1.022 (1.010-1.035) times greater albuminuria in participants with type 2 diabetes, whereas it was not associated with albuminuria in nondiabetic participants (Pinteraction < 0.10)., Conclusion: This is the first population-based study that provides direct evidence that microvascular endothelial dysfunction is associated with albuminuria, and that this association is stronger in individuals with than in those without type 2 diabetes.

Purpose: To compare the efficacy of a topical nonsteroidal antiinflammatory drug, topical corticosteroid, and a combination of both drugs to prevent the occurrence of cystoid macular edema (CME) after cataract surgery in nondiabetic patients., Setting: Twelve European study centers., Design: Randomized clinical trial., Methods: Nondiabetic patients having uneventful cataract surgery were included in this study. Patients were randomized to receive topical bromfenac 0.09% twice daily for 2 weeks or dexamethasone 0.1% 4 times daily with 1 drop less per day every following week, or a combination of both. The primary outcome was the difference in central subfield mean macular thickness 6 weeks postoperatively. Secondary outcome measures included corrected distance visual acuity as well as the incidence of CME and clinically significant macular edema (CSME) within 6 weeks and 12 weeks postoperatively., Results: This study comprised 914 patients. Six weeks postoperatively, the central subfield mean macular thickness was 288.3 μm, 296.0 μm, and 284.5 μm in the bromfenac group, dexamethasone group, and combination treatment group, respectively (overall P = .006). The incidence of clinically significant macular edema within 12 weeks postoperatively was 3.6%, 5.1%, and 1.5%, respectively (overall P = .043)., Conclusion: Patients treated with a combination of topical bromfenac 0.09% and dexamethasone 0.1% had a lower risk for developing CSME after cataract surgery than patients treated with a single drug., (Copyright © 2018 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.)

Background: The aim of is to determine the association of vitamins with glaucoma by performing a systematic review and meta-analyses., Methods: Studies on the relation of vitamins and glaucoma published up to December 2017 were identified in the PubMed and Embase database. Data on vitamins (method of assessment), glaucoma (type and method of assessment), study characteristics and quality were recorded. In case of multiple studies for one nutrient a meta-analysis was performed., Results: A total of 629 articles were identified of which 36 were included in the systematic review. The meta-analysis included five of them (940 open-angle glaucoma (OAG) cases and 123,697 controls in total) and resulted in an odds ratio [95% confidence interval] (OR [95% CI]) of 0.58 [0.37-0.91] for dietary vitamin A, though heterogeneity was high (I² = 51%). After omitting studies that contributed significantly to the heterogeneity, the pooled OR [95% CI] was 0.45 [0.30-0.68] for dietary vitamin A on OAG (I² = 0%). For vitamin B1, C and E no significant association with OAG was found (OR [95% CI]: 0.84 [0.47-1.51]; 0.68 [0.38-1.22]; 0.95 [0.75-1.19]; respectively). However, after addressing heterogeneity, vitamin C showed a protective effect as well. Especially, foods high in these vitamins (e.g., dark green vegetables) were protective for OAG., Conclusions: Dietary intake of vitamin A and C showed a beneficial association with OAG; however, findings on blood levels of vitamins do not show a clear relation with OAG., Competing Interests: The authors declare no conflict of interest.