Glaucoma: now and beyond.

The glaucomas are a group of conditions leading to irreversible sight loss and characterised by progressive loss of retinal ganglion cells. Although not always elevated, intraocular pressure is the only modifiable risk factor demonstrated by large clinical trials. It remains the leading cause of irreversible blindness, but timely treatment to lower intraocular pressure is effective at slowing the rate of vision loss from glaucoma. Methods for lowering intraocular pressure include laser treatments, topical medications, and surgery. Although modern surgical innovations aim to be less invasive, many have been introduced with little supporting evidence from randomised controlled trials. Many cases remain undiagnosed until the advanced stages of disease due to the limitations of screening and poor access to opportunistic case finding. Future research aims to generate evidence for intraocular pressure-independent neuroprotective treatments, personalised treatment through genetic risk profiling, and exploration of potential advanced cellular and gene therapies.

Association between Glucagon-like Peptide-1 Receptor Agonists and the Risk of Glaucoma in Individuals with Type 2 Diabetes.

PURPOSE: To examine the association between glucagon-like peptide-1 receptor agonist (GLP-1RA) use and the development of glaucoma in individuals with type 2 diabetes. DESIGN: Nationwide, nested case-control study. PARTICIPANTS: From a nationwide cohort of 264 708 individuals, we identified 1737 incident glaucoma cases and matched them to 8685 glaucoma-free controls, all aged more than 21 years and treated with metformin and a second-line antihyperglycemic drug formulation, with no history of glaucoma, eye trauma, or eye surgery. METHODS: Cases were incidence-density-matched to 5 controls by birth year, sex, and date of second-line treatment initiation. MAIN OUTCOME MEASURES: Conditional logistic regression was used to calculate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for glaucoma, defined by first-time diagnosis, first-time use of glaucoma-specific medication, or first-time glaucoma-specific surgical intervention. RESULTS: Compared with the reference group, who received treatments other than GLP-1RA, individuals who were exposed to GLP-1RA treatment exhibited a lower risk of incident glaucoma (HR, 0.81; CI, 0.70-0.94; P = 0.006). Prolonged treatment extending beyond 3 years lowered the risk even further (HR, 0.71; CI, 0.55-0.91; P = 0.007). Treatment with GLP-1RA for 0 to 1 year (HR, 0.89; CI, 0.70-1.14; P = 0.35) and 1 to 3 years (HR, 0.85; CI, 0.67-1.06; P = 0.15) was not significant. CONCLUSIONS: Exposure to GLP-1RA was associated with a lower risk of developing glaucoma compared with receiving other second-line antihyperglycemic medication. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Potential Retinal Biomarkers in Alzheimer's Disease.

Alzheimer's disease (AD) represents a major diagnostic challenge, as early detection is crucial for effective intervention. This review examines the diagnostic challenges facing current AD evaluations and explores the emerging field of retinal alterations as early indicators. Recognizing the potential of the retina as a noninvasive window to the brain, we emphasize the importance of identifying retinal biomarkers in the early stages of AD. However, the examination of AD is not without its challenges, as the similarities shared with other retinal diseases introduce complexity in the search for AD-specific markers. In this review, we address the relevance of using the retina for the early diagnosis of AD and the complex challenges associated with the search for AD-specific retinal biomarkers. We provide a comprehensive overview of the current landscape and highlight avenues for progress in AD diagnosis by retinal examination.

Distinct Metabolic Profiles of Ocular Hypertensives in Response to Hypoxia.

Glaucoma is a neurodegenerative disease that affects the retinal ganglion cells (RGCs). The main risk factor is elevated intraocular pressure (IOP), but the actual cause of the disease remains unknown. Emerging evidence indicates that metabolic dysfunction plays a central role. The aim of the current study was to determine and compare the effect of universal hypoxia on the metabolomic signature in plasma samples from healthy controls (n = 10), patients with normal-tension glaucoma (NTG, n = 10), and ocular hypertension (OHT, n = 10). By subjecting humans to universal hypoxia, we aim to mimic a state in which the mitochondria in the body are universally stressed. Participants were exposed to normobaric hypoxia for two hours, followed by a 30 min recovery period in normobaric normoxia. Blood samples were collected at baseline, during hypoxia, and in recovery. Plasma samples were analyzed using a non-targeted metabolomics approach based on liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS). Multivariate analyses were conducted using principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA), and univariate analysis using the Wilcoxon signed-rank test and false discovery rate (FDR) correction. Unique metabolites involved in fatty acid biosynthesis and ketone body metabolism were upregulated, while metabolites of the kynurenine pathway were downregulated in OHT patients exposed to universal hypoxia. Differential affection of metabolic pathways may explain why patients with OHT initially do not suffer or are more resilient from optic nerve degeneration. The metabolomes of NTG and OHT patients are regulated differently from control subjects and show dysregulation of metabolites important for energy production. These dysregulated processes may potentially contribute to the elevation of IOP and, ultimately, cell death of the RGCs.

Girl Power in Glaucoma: The Role of Estrogen in Primary Open Angle Glaucoma.

Estrogen is essential in maintaining various physiological features in women, and a decline in estrogen levels are known to give rise to numerous unfortunate symptoms associated with menopause. To alleviate these symptoms hormone replacement therapy with estrogen is often used, and has been shown to be fruitful in improving quality of life in women suffering from postmenopausal discomforts. An often forgotten condition associated with menopause is the optic nerve disorder, glaucoma. Thus, estrogen may also have an impact in maintaining the retinal ganglion cells (RGCs), which make up the optic nerve, thereby preventing glaucomatous neurodegeneration. This review aims to provide an overview of possible associations of estrogen and the glaucoma subtype, primary open-angle glaucoma (POAG), by evaluating the current literature through a PubMed-based literature search. Multiple in vitro and in vivo studies of RGC protection, as well as clinical and epidemiological data concerning the well-defined retinal neurodegenerative disorder POAG have been reviewed. Over all, deficiencies in retinal estrogen may potentially instigate RGC loss, visual disability, and eventual blindness. Estrogen replacement therapy may therefore be a beneficial future treatment. However, more studies are needed to confirm the relevance of estrogen in glaucoma prevention.

Decreased Glucose Metabolism and Glutamine Synthesis in the Retina of a Transgenic Mouse Model of Alzheimer's Disease.

Visual changes are some of the earliest symptoms that patients with Alzheimer's disease (AD) experience. Pathophysiological processes such as amyloid-ß plaque formation, vascular changes, neuroinflammation, and loss of retinal ganglion cells (RGCs) have been detected in the retina of AD patients and animal models. However, little is known about the molecular processes that underlie retinal neurodegeneration in AD. The cellular architecture and constant sensory activity of the retina impose high metabolic demands. We thus hypothesized that energy metabolism might be compromised in the AD retina similarly to what has been observed in the AD brain. To address this question, we explored cellular alterations and retinal metabolic activity in the 5 × FAD mouse model of AD. We used 8-month-old female 5 × FAD mice, in which the AD-related pathology has been shown to be apparent. We observed that RGC density is selectively affected in the retina of 5 × FAD mice. To map retinal metabolic activity, we incubated isolated retinal tissue with [U-13C] glucose and analyzed tissue extracts by gas chromatography-mass spectrometry. We found that the retinas of 5 × FAD mice exhibit glucose hypometabolism. Moreover, we detected decreased glutamine synthesis in 5 × FAD retinas but no changes in the expression of markers of Müller glia, the main glial cell type responsible for glutamate uptake and glutamine synthesis in the retina. These findings suggest that AD presents with metabolic alterations not only in the brain but also in the retina that may be detrimental to RGC activity and survival, potentially leading to the visual impairments that AD patients suffer.

Rho kinase inhibitor for primary open-angle glaucoma and ocular hypertension.

BACKGROUND: Glaucoma is a group of optic neuropathies characterized by progressive degeneration of the retinal ganglion cells, axonal loss and irreversible visual field defects. Glaucoma is classified as primary or secondary, and worldwide, primary glaucoma is a leading cause of irreversible blindness. Several subtypes of glaucoma exist, and primary open-angle glaucoma (POAG) is the most common. The etiology of POAG is unknown, but current treatments aim to reduce intraocular pressure (IOP), thus preventing the onset and progression of the disease. Compared with traditional antiglaucomatous treatments, rho kinase inhibitors (ROKi) have a different pharmacodynamic. ROKi is the only current treatment that effectively lowers IOP by modulating the drainage of aqueous humor through the trabecular meshwork and Schlemm's canal. As ROKi are introduced into the market more widely, it is important to assess the efficacy and potential AEs of the treatment. OBJECTIVES: To compare the efficacy and safety of ROKi with placebo or other glaucoma medication in people diagnosed with open-angle glaucoma (OAG), primary open-angle glaucoma (POAG) or ocular hypertension (OHT). SEARCH METHODS: We used standard Cochrane methods and searched databases on 11 December 2020. SELECTION CRITERIA: We included randomized clinical trials examining commercially available ROKi-based monotherapy or combination therapy compared with placebo or other IOP-lowering medical treatments in people diagnosed with (P)OAG or OHT. We included trials where ROKi were administered according to official glaucoma guidelines. There were no restrictions regarding type, year or status of the publication. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently screened studies, extracted data, and evaluated risk of bias by using Cochrane's RoB 2 tool.  MAIN RESULTS: We included 17 trials with 4953 participants diagnosed with (P)OAG or OHT. Fifteen were multicenter trials and 15 were masked trials. All participants were aged above 18 years. Trial duration varied from 24 hours to 12 months. Trials were conducted in the USA, Canada and Japan. Sixteen trials were funded by pharmaceutical companies, and one trial provided no information about funding sources. The trials compared ROKi monotherapy (netarsudil or ripasudil) or combination therapy with latanoprost (prostaglandin analog) or timolol (beta-blocker) with placebo, timolol, latanoprost or netarsudil. Reported outcomes were IOP and safety. Meta-analyses were applied to 13 trials (IOP reduction from baseline) and 15 trials (ocular AEs).  Of the trials evaluating IOP, seven were at low risk, three had some concerns, and three were at high risk of bias. Three trials found that netarsudil monotherapy may be superior to placebo (mean difference [MD] 3.11 mmHg, 95% confidence interval [CI] 2.59 to 3.62; I2 = 0%; 155 participants; low-certainty evidence). Evidence from three trials found that timolol may be superior to netarsudil with an MD of 0.66 mmHg (95% CI 0.41 to 0.91; I2 = 0%; 1415 participants; low-certainty evidence). Evidence from four trials found that latanoprost may be superior to netarsudil with an MD of 0.97 mmHg (95% CI 0.67 to 1.27; I2 = 4%; 1283 participants; moderate-certainty evidence).  Evidence from three trials showed that, compared with monotherapy with latanoprost, combination therapy with netarsudil and latanoprost probably led to an additional pooled mean IOP reduction from baseline of 1.64 mmHg (95% CI -2.16 to -1.11; 1114 participants). Evidence from three trials showed that, compared with monotherapy with netarsudil, combination therapy with netarsudil and latanoprost probably led to an additional pooled mean IOP reduction from baseline of 2.66 mmHg (95% CI -2.98 to -2.35; 1132 participants). The certainty of evidence was moderate. One trial showed that,  compared with timolol monotherapy, combination therapy with ripasudil and timolol may lead to an IOP reduction from baseline of 0.75 mmHg (95% -1.29 to -CI 0.21; 208 participants). The certainty of evidence was moderate. Of the trials assessing total ocular AEs, three were at low risk, four had some concerns, and eight were at high risk of bias.  We found very low-certainty evidence that netarsudil may lead to more ocular AEs compared with placebo, with 66 more ocular AEs per 100 person-months (95% CI 28 to 103; I2 = 86%; 4 trials, 188 participants). We found low-certainty evidence that netarsudil may lead to more ocular AEs compared with latanoprost, with 29 more ocular AEs per 100 person-months (95% CI 17 to 42; I2 = 95%; 4 trials, 1286 participants).  We found moderate-certainty evidence that, compared with timolol, netarsudil probably led to 21 additional ocular AEs (95% CI 14 to 27; I2 = 93%; 4 trials, 1678 participants). Data from three trials (1132 participants) showed no evidence of differences in the incidence rate of AEs between combination therapy with netarsudil and latanoprost and netarsudil monotherapy (1 more event per 100 person-months, 95% CI 0 to 3); however, the certainty of evidence was low. Similarly, we found low-certainty evidence that, compared with latanoprost, combination therapy with netarsudil and latanoprost may cause 29 more ocular events per 100 person-months (95% CI 11 to 47; 3 trials, 1116 participants). We found moderate-certainty evidence that, compared with timolol monotherapy, combination therapy with ripasudil and timolol probably causes 35 more ocular events per 100 person-months (95% CI 25 to 45; 1 trial, 208 participants). In all included trials, ROKi was reportedly not associated with any particular serious AEs. AUTHORS' CONCLUSIONS: The current evidence suggests that in people diagnosed with OHT or (P)OAG, the hypotensive effect of netarsudil may be inferior to latanoprost and slightly inferior to timolol. Combining netarsudil and latanoprost probably further reduces IOP compared with monotherapy. Netarsudil as mono- or combination therapy may result in more ocular AEs. However, the certainty of evidence was very low or low for all comparisons except timolol. In general, AEs were described as mild, transient, and reversible upon treatment discontinuation. ROKi was not associated with any particular serious AEs. Future trials of sufficient size and follow-up should be conducted to provide reliable information about glaucoma progression, relevant IOP measurements and a detailed description of AEs using similar terminology. This would ensure the robustness and confidence of the results and assess the intermediate- and long-term efficacy and safety of ROKi.

Bidirectional association between atopic dermatitis, conjunctivitis, and other ocular surface diseases: A systematic review and meta-analysis.

BACKGROUND: Conjunctivitis and several other ocular surface diseases (OSDs) have been linked to atopic dermatitis (AD) and its treatment. OBJECTIVES: To examine the association between AD, conjunctivitis, and other OSDs. METHODS: A systematic review and meta-analysis was performed. Two authors independently searched EMBASE, PubMed, SCOPUS, and Web of Science and performed title/abstract and full-text review and data abstraction. Pooled random-effects prevalence and odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. RESULTS: The search yielded 5719 nonduplicate articles; 134 were included in the quantitative analysis. AD was associated with conjunctivitis compared to reference individuals (OR, 2.78; 95% CI, 2.33-3.32); the prevalences of conjunctivitis in patients with AD and reference individuals were 31.7% (95% CI, 27.7-35.9) and 13.3% (95% CI, 11.0-15.7), respectively. Keratoconus (OR, 3.71; 95% CI, 1.99-6.94) and ocular herpes simplex (OR, 3.65; 95% CI 2.04-6.51) were also associated with AD. LIMITATIONS: Disease definitions differed and often relied on self-reports. Few studies provided data concerning AD phenotype or OSDs other than conjunctivitis. CONCLUSIONS: Conjunctivitis is the most common ocular comorbidity in AD. Signs and symptoms of conjunctivitis and other OSDs in AD may be underreported, making proactive inquiry and examination by physicians treating patients with AD important.

Phase 3, Randomized, 20-Month Study of Bimatoprost Implant in Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 1).

PURPOSE: To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10- and 15-µg bimatoprost implant in subjects with open-angle glaucoma (OAG) and ocular hypertension (OHT) after initial and repeated administrations. DESIGN: Randomized, 20-month, multicenter, subject- and efficacy evaluator-masked, parallel-group, phase 3 clinical study. PARTICIPANTS: Adults with OAG or OHT in each eye, open iridocorneal angle inferiorly in the study eye, and study eye baseline IOP (hour 0; 8 am) of 22-32 mmHg after washout. METHODS: Study eyes received bimatoprost implant 10 µg (n = 198) or 15 µg (n = 198) on day 1 with readministration at weeks 16 and 32, or twice-daily topical timolol maleate 0.5% (n = 198). Intraocular pressure was measured at hours 0 and 2 at each visit. MAIN OUTCOME MEASURES: Primary end points were IOP and change from baseline IOP through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD). RESULTS: Both dose strengths of bimatoprost implant were noninferior to timolol in IOP lowering after each administration. Mean diurnal IOP was 24.0, 24.2, and 23.9 mmHg at baseline and from 16.5-17.2, 16.5-17.0, and 17.1-17.5 mmHg through week 12 in the 10-µg implant, 15-µg implant, and timolol groups, respectively. The incidence of corneal and inflammatory TEAEs of interest (e.g., corneal endothelial cell loss, iritis) was higher with bimatoprost implant than timolol and highest with the 15-µg dose strength. Incidence of corneal TEAEs increased after repeated treatment; with 3 administrations at fixed 16-week intervals, incidence of ≥20% CECD loss was 10.2% (10-µg implant) and 21.8% (15-µg implant). Mean best-corrected visual acuity (BCVA) was stable; 3 implant-treated subjects with corneal TEAEs had >2-line BCVA loss at their last visit. CONCLUSIONS: Both dose strengths of bimatoprost implant met the primary end point of noninferiority to timolol through week 12. One year after 3 administrations, IOP was controlled in most subjects without additional treatment. The risk-benefit assessment favored the 10-µg implant over the 15-µg implant. Ongoing studies are evaluating other administration regimens to reduce the potential for CECD loss. The bimatoprost implant has potential to improve adherence and reduce treatment burden in glaucoma.

Can DMCO Detect Visual Field Loss in Neurological Patients? A Secondary Validation Study.

Unrecognized visual field loss is caused by a range of blinding eye conditions as well as serious brain diseases. The commonest cause of asymptomatic visual field loss is glaucoma. No screening tools have been proven cost-effective. Damato Multifixation Campimetry Online (DMCO), an inexpensive online test, has been evaluated as a future cost-beneficial tool to detect glaucoma. To further validate DMCO, this study aimed to test DMCO in a preselected population with neurological visual field loss. METHODS: The study design was an evaluation of a diagnostic test. Patients were included if they had undergone surgery for epilepsy during 2011-2014, resulting in visual field loss. They were examined with DMCO and results were compared with those obtained with the Humphrey Field Analyzer (30:2 SITA-Fast). DMCO sensitivity and specificity were estimated with 95% confidence intervals. RESULTS: The cohort comprised 40 patients (25 female and 15 male) with a mean age of 39 years (range 17-60 years). The mean visual acuity was >1.0 and all eyes had an intraocular pressure <21 mm Hg. Sensitivity and specificity of DMCO compared to the reference standard were 72.7 and 96.3%, respectively. CONCLUSIONS: DMCO detects moderate-to-severe homonymous quadrantanopia; it can be useful in settings where the current practice is confrontation visual field examination, and where standard conventional perimetry is not available.

Lactate Transport and Receptor Actions in Retina: Potential Roles in Retinal Function and Disease.

In retina, like in brain, lactate equilibrates across cell membranes via monocarboxylate transporters and in the extracellular space by diffusion, forming a basis for the action of lactate as a transmitter of metabolic signals. In the present paper, we argue that the lactate receptor GPR81, also known as HCAR1, may contribute importantly to the control of retinal cell functions in health and disease. GPR81, a G-protein coupled receptor, is known to downregulate cAMP both in adipose and nervous tissue. The receptor also acts through other down-stream mechanisms to control functions, such as excitability, metabolism and inflammation. Recent publications predict effects of the lactate receptor on neurodegeneration. Neurodegenerative diseases in retina, where the retinal ganglion cells die, notably glaucoma and diabetic retinopathy, may be linked to disturbed lactate homeostasis. Pilot studies reveal high GPR81 mRNA in retina and indicate GPR81 localization in Müller cells and retinal ganglion cells. Moreover, monocarboxylate transporters are expressed in retinal cells. We envision that lactate receptors and transporters could be useful future targets of novel therapeutic strategies to protect neurons and prevent or counteract glaucoma as well as other retinal diseases.

Calcium-independent phospholipase A2, group VIA, is critical for RPE cell survival.

PURPOSE: To investigate the significance of calcium-independent phospholipase A2, group VIA (iPLA2-VIA), in RPE cell survival following responses to sodium iodate (SI) in cell cultures. METHODS: The human retinal pigment epithelium (RPE) cell line (ARPE-19) cells and primary mouse-RPE cultures were treated with SI to induce cell death. Cells were transfected with an iPLA2-VIA promoter-luciferase construct to evaluate the regulation of iPLA-VIA after exposure to SI. PCR analysis, western blot analysis, and activity assays were performed to evaluate the mRNA level, protein level, and activity levels of iPLA2-VIA after SI exposure. Inhibitors of iPLA2-VIA were used to explore a potential protective role in cells exposed to SI. Primary RPE cell cultures were grown from iPLA2-VIA knockout mice and wild-type mice. The cultures were exposed to SI to investigate a possible increased protection against SI in iPLA2-VIA knockout mice compared to wild-type mice. RESULTS: The study revealed upregulation of iPLA2-VIA expression (promoter activity, iPLA2-VIA mRNA, iPLA2-VIA protein, and iPLA2-VIA protein activity) in ARPE-19 cells exposed to SI. SI-induced cell death was shown to be inhibited by iPLA2-VIA-specific inhibitors in ARPE-19 cell cultures. RPE cultures from iPLA2-VIA knockout mice were less vulnerable to SI-induced cell death compared to RPE cultures from wild-type mice. CONCLUSIONS: SI -induced RPE cell death involves iPLA2-VIA upregulation and activation, and amelioration of SI-induced RPE cell death can be facilitated by inhibitors of iPLA2-VIA. Thus, we suggest iPLA2-VIA as a possible pharmaceutical target to treat RPE-related retinal diseases.

Limited energy supply in Müller cells alters glutamate uptake.

The viability of retinal ganglion cells (RGC) is essential for the maintenance of visual function. RGC homeostasis is maintained by the surrounding retinal glial cells, the Müller cells, which buffer the extracellular concentration of neurotransmitters and provide the RGCs with energy. This study evaluates if glucose-deprivation of Müller cells interferes with their ability to remove glutamate from the extracellular space. The human Müller glial cell line, Moorfields/Institute of Ophthalmology-Müller 1, was used to study changes in glutamate uptake. Excitatory amino acid transporter (EAAT) proteins were up-regulated in glucose-deprived Müller cells and glutamate uptake was significantly increased in the absence of glucose. The present findings revealed an up-regulation of EAAT1 and EAAT2 in glucose-deprived Müller cells as well as an increased ability to take up glutamate. Hence, glucose deprivation may result in an increased ability to protect RGCs from glutamate-induced excitotoxicity, whereas malfunction of glutamate uptake in Müller cells may contribute to retinal neurodegeneration.

Persistence and adherence with Latanoprost: A Danish register-based cohort study in older patients with glaucoma.

PURPOSE: This study aims to assess the association between switching patterns and adherence/persistence in Danish patients over the age of 65, who started their first-ever glaucoma treatment with latanoprost eye drops. METHODS: Patients were assigned to three different cohorts: (1) switchers, (2) non-switchers, and (3) preservative-free latanoprost (Monoprost®) users. Patients were followed for 1 year until the end of data coverage or censoring. Study covariates were used to compute the propensity score. In the adjusted analysis, the propensity score was added to the model as an independent variable. The Cox regression model was used to calculate the hazard ratio (HR) of discontinuation for the three cohorts (the non-switchers cohort was the reference level) in both adjusted and unadjusted analyses. RESULTS: Non-switchers had a statistically significant lower adherence (proportion of days covered, PDC 92%) than switchers (PDC 96%; p < 0.001) and users of Monoprost® (PDC 99%; p < 0.001). Switchers had a 53% lower risk of treatment discontinuation compared to the reference group within 1 year after the first redemption of latanoprost in both unadjusted (HR 0.47; 95% Confidence interval, 95% CI: 0.41-0.53; p < 0.001) and adjusted (HR 0.47; 95% CI: 0.42-0.53; p < 0.001) analyses. In comparison to the non-switchers, Monoprost® users had a 78% lower risk for the above result in both unadjusted (HR 0.22; 95% CI: 0.17-0.28; p < 0.001) and adjusted (HR 0.22; 95% CI: 0.17-0.29; p < 0.001) analyses. CONCLUSION: This study found increased adherence and persistence in latanoprost users among those who redeemed preservative-free latanoprost (Monoprost®) and among those who switched between different latanoprost formulations.

Finding Ophthalmic Risk and Evaluating the Value of Eye exams and their predictive Reliability (FOREVER)-A cohort study in a Danish high street optician setting: Design and methodology.

PURPOSE: The purpose of the study was to describe the rationale and design of Project FOREVER (Finding Ophthalmic Risk and Evaluating the Value of Eye exams and their predictive Reliability). DESIGN: Project FOREVER will build a comprehensive database of clinical eye and vision data collected from ~280 000 adults at 100 optician stores across Denmark. The FOREVER database (FOREVERdb) includes detailed data from refraction, visual acuity, intraocular pressure, corneal thickness, visual field assessments and retinal fundus images. Linkage to the comprehensive Danish national registries with, that is diagnostic and prescribing data permits investigation of rare associations and risk factors. 30 000 individuals over 50 also provide a saliva sample for later genetic studies and blood pressure measurements. Of these 30 000, 10 000 will also get optical coherence tomography (OCT) nerve and retinal scans. This subpopulation data is reviewed by ophthalmologists for disease detection. All participants will be asked to complete a questionnaire assessing lifestyle, self-perceived eye health and general health. Enrolment of participants began in April 2022. PERSPECTIVE: The FOREVERdb is a powerful tool to answer a wide range of research questions that can pave the way for better eye health. This database will provide valuable insights for future studies investigating the correlations between eye and general health in a Danish population cohort, enabling research to identify potential risk factors for a range of diseases.

Steroids and/or Non-Steroidal Anti-Inflammatory Drugs as Postoperative Treatment after Trabeculectomy-12-Month Results of a Randomized Controlled Trial.

This prospective randomized controlled trial aimed to compare the efficacy and safety of topical preservative-free diclofenac (DICLO) to dexamethasone (DEX) eyedrops, and their combination (DEX+DICLO) after trabeculectomy. Sixty-nine patients with medically uncontrolled glaucoma were randomized to receive topical postoperative treatment with DICLO (n = 23), DEX (n = 23), or a combination of DEX and DICLO (n = 23). The primary outcome was the intraocular pressure (IOP) 12 months postoperatively. Secondary outcomes included surgical success, failure, visual field, and visual acuity from baseline to 12 months postoperatively. IOP reached the lowest point one day after trabeculectomy. At 12 months, IOP was 10.0 mmHg (95% CI, 8.4-11.6 mmHg) for DICLO, 10.9 mmHg (95% CI, 9.4-12.3 mmHg) for DEX, and 11.2 mmHg (95% CI, 9.1-13.3 mmHg) for DEX+DICLO. There were no significant differences in IOP, surgical success, failure, visual field, or visual acuity between the DICLO, DEX, or DEX+DICLO groups. We found that topical diclofenac was not statistically different from topical dexamethasone in controlling IOP 12 months after trabeculectomy. Combining diclofenac and dexamethasone offered no added IOP control compared to dexamethasone alone.

Longitudinal associations of retinal vessel morphology with intraocular pressure and blood pressure at follow-up visit-Findings from a Danish eye and vision cohort, Project FOREVER.

PURPOSE: To characterise the retinal vasculometry of a Danish eye and vision cohort and examine associations with systolic blood pressure (BP), diastolic BP, mean arterial BP, and intraocular pressure (IOP). DESIGN: Longitudinal study. METHODS: The retinal vasculature of fundus images from the FOREVER (Finding Ophthalmic Risks and Evaluating the Value of Eye exams and their predictive Reliability) cohort was analysed using a fully automated image analysis program. Longitudinal associations of retinal vessel morphology at follow-up visit with IOP (baseline and follow-up) and BP (follow-up) were examined using multilevel linear regression models adjusting for age, sex and retinal vasculometry at baseline as fixed effects and person as random effect. Width measurements were additionally adjusted for the spherical equivalent. RESULTS: A total of 2089 subjects (62% female) with a mean age of 61 (standard deviation 8) years and a mean follow-up period of 4.1 years (SD 0.6 years) were included. The mean arteriolar diameter was approximately 20% thinner than the mean venular diameter, and venules were about 21%-23% less tortuous than arterioles. BP at follow-up was associated with decreased arteriolar diameter from baseline to follow-up. After adjusting for baseline IOP, IOP at follow-up was associated with increased arteriolar tortuosity above baseline (0.59%, 95% CI 0.08-1.10, p-value 0.024). CONCLUSION: In a Danish eye and vision cohort, variations in BP and alterations in IOP over time were associated with changes in the width and tortuosity of retinal vessels. Our findings contribute novel insights into retinal vascular alterations over time.

Topical glaucoma medications - Possible implications on the meibomian glands.

One of the most common causes of blindness on a global scale is glaucoma. There is a strong association between glaucoma and increased intraocular pressure (IOP). Because of this, adequate IOP-lowering is the most important treatment strategy, mostly through topical eyedrops. Well-functioning meibomian glands are paramount for maintaining a stable tear film, and their dysfunction is the most common cause of dry eye disease. There is a growing concern that both topical glaucoma medications themselves and their added preservatives damage the meibomian glands, and consequently, the ocular surface. Preserved topical glaucoma medications appear to cause dysfunction and atrophy of the meibomian glands. Upon comparison, preserved formulations caused more symptoms of dry eye, tear film instability, inflammatory changes and meibomian gland dropout than the preservative-free counterpart. However, although seemingly less detrimental, unpreserved alternatives may diminish glandular efficacy, and, depending on the active ingredient, lead to glandular death. This negatively impacts quality of life, adherence to treatment regimens and prognosis. In this review, we explore the available evidence regarding the effects of IOP-lowering eye drops on the meibomian glands.

Comparing the effect of benzalkonium chloride-preserved, polyquad-preserved, and preservative-free prostaglandin analogue eye drops on cultured human conjunctival goblet cells.

PURPOSE: To investigate the effect of benzalkonium chloride (BAK)-preserved latanoprost and bimatoprost, polyquad (PQ)-preserved travoprost, and preservative-free (PF) latanoprost and tafluprost, all prostaglandin analogues (PGAs), on human conjunctival goblet cell (GC) survival. Furthermore, to investigate the effect of BAK-preserved and PF latanoprost on the cytokine secretion from GC. METHODS: Primary human conjunctival GCs were cultivated from donor tissue. Lactate dehydrogenase (LDH) and tetrazolium dye colorimetric (MTT) assays were used for the assessment of GC survival. A cytometric bead array was employed for measuring secretion of interleukin (IL)-6 and IL-8 from GC. RESULTS: BAK-preserved latanoprost and bimatoprost reduced cell survival by 28% (p = 0.0133) and 20% (p = 0.0208), respectively, in the LDH assay compared to a negative control. BAK-preserved latanoprost reduced cell proliferation by 54% (p = 0.003), BAK-preserved bimatoprost by 45% (p = 0.006), PQ-preserved travoprost by 16% (p = 0.0041), and PF latanoprost by 19% (p = 0.0001), in the MTT assay compared to a negative control. Only PF tafluprost did not affect the GCs in either assay. BAK-preserved latanoprost caused an increase in the secretion of pro-inflammatory IL-6 and IL-8 (p = 0.0001 and p = 0.0019, respectively) compared to a negative control, which PF latanoprost did not. CONCLUSION: BAK-preserved PGA eye drops were more cytotoxic to GCs than PQ-preserved and PF PGA eye drops. BAK-preserved latanoprost induced an inflammatory response in GC. Treatment with PF and PQ-preserved PGA eye drops could mean better tolerability and adherence in glaucoma patients compared to treatment with BAK-preserved PGA eye drops.