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BackgroundCaffeine has a well-established effect on intraocular pressure (IOP) and ocular perfusion pressure (OPP); however, the possible differences between low- and high-caffeine consumers remain unknown.MethodsIn this placebo-controlled, double-blind, and balanced crossover study, 40 healthy individuals were divided in low- (n = 21) and high (n = 19)-caffeine consumers, according to their daily caffeine consumption. All participants ingested either caffeine (4 mg/kg) or placebo, and IOP and OPP were measured after 30, 60, and 90 min of ingesting caffeine or placebo. Subjective feelings of arousal were also obtained.ResultsCaffeine induced an acute IOP rise (p < 0.001, ƞp2 = 0.408), whereas habitual caffeine demonstrated a mediating effect on the IOP changes induced by caffeine intake, with high-caffeine consumers showing a less accentuated IOP rise in comparison to low-caffeine consumers. The greatest IOP change induced by caffeine intake was reached after 90 min from capsule ingestion, being more accentuated for the low-caffeine consumers (+ 3.4 mmHg) than for the high-caffeine consumers (+ 1.2 mmHg). Consequently, the participants reported higher levels of perceived arousal after ingesting caffeine in comparison to placebo (p = 0.002, ƞp2 = 0.222); however, similar responses were given by high- and low-caffeine consumers (p = 0.256). Our data did not reveal any effect of caffeine consumption on OPP (p = 0.304).ConclusionsThese results suggest that IOP responsiveness to caffeine ingestion is subject to tolerance, which could have important implication in the management of glaucoma. This finding may be due to alterations in the adenosine receptor system caused by chronic caffeine consumption. Future studies are needed to assess if these findings are also applicable to patients with glaucoma.

Treatments for open-angle glaucoma aim to prevent vision loss through lowering of intraocular pressure, but to our knowledge no placebo-controlled trials have assessed visual function preservation, and the observation periods of previous (unmasked) trials have typically been at least 5 years. We assessed vision preservation in patients given latanoprost compared with those given placebo. In this randomised, triple-masked, placebo-controlled trial, we enrolled patients with newly diagnosed open-angle glaucoma at ten UK centres (tertiary referral centres, teaching hospitals, and district general hospitals). Eligible patients were randomly allocated (1:1) with a website-generated randomisation schedule, stratified by centre and with a permuted block design, to receive either latanoprost 0·005% (intervention group) or placebo (control group) eye drops. Drops were administered from identical bottles, once a day, to both eyes. The primary outcome was time to visual field deterioration within 24 months. Analyses were done in all individuals with follow-up data. The Data and Safety Monitoring Committee (DSMC) recommended stopping the trial on Jan 6, 2011 (last patient visit July, 2011), after an interim analysis, and suggested a change in primary outcome from the difference in proportions of patients with incident progression between groups to time to visual field deterioration within 24 months. This trial is registered, number ISRCTN96423140. We enrolled 516 individuals between Dec 1, 2006, and March 16, 2010. Baseline mean intraocular pressure was 19·6 mm Hg (SD 4·6) in 258 patients in the latanoprost group and 20·1 mm Hg (4·8) in 258 controls. At 24 months, mean reduction in intraocular pressure was 3·8 mm Hg (4·0) in 231 patients assessed in the latanoprost group and 0·9 mm Hg (3·8) in 230 patients assessed in the placebo group. Visual field preservation was significantly longer in the latanoprost group than in the placebo group: adjusted hazard ratio (HR) 0·44 (95% CI 0·28–0·69; p=0·0003). We noted 18 serious adverse events, none attributable to the study drug. This is the first randomised placebo-controlled trial to show preservation of the visual field with an intraocular-pressure-lowering drug in patients with open-angle glaucoma. The study design enabled significant differences in vision to be assessed in a relatively short observation period. Pfizer, UK National Institute for Health Research Biomedical Research Centre.

Purpose To evaluate the long-term efficacy and safety of ripasudil-brimonidine fixed-dose combination (RBFC), a new intraocular pressure (IOP)-lowering medication for glaucoma and ocular hypertension (OHT). Methods This prospective, multicentre (23 sites in Japan), open-label study enrolled patients with primary open-angle glaucoma (POAG), OHT or exfoliative glaucoma and assigned them to one of four combination therapy cohorts, based on previous treatment(s) received: prostaglandin (PG) analogue (Cohort 1); PG analogue and beta-adrenoceptor blocker (β-blocker) (Cohort 2); PG analogue, β-blocker and carbonic anhydrase inhibitor (Cohort 3); or other/no treatment (Cohort 4). After a ≥ 4-week screening period, eligible patients received twice-daily RBFC for 52 weeks in addition to the treatments they were already receiving. Efficacy was assessed by change in IOP from baseline through week 52. Adverse events and adverse drug reactions (ADRs) were monitored throughout. Results In total, 179 patients from Cohort 1 ( n = 48), Cohort 2 ( n = 44), Cohort 3 ( n = 41) and Cohort 4 ( n = 46) entered the RBFC treatment period. For all cohorts, mean IOP was significantly reduced at 11:00 (2 h after instillation of RBFC) through week 52 with the changes from baseline at week 52 of − 2.7 to − 4.1 mmHg across cohorts; all p < 0.001. Common ADRs were conjunctival hyperaemia (58%), allergic conjunctivitis (18%) and blepharitis (17%), most of which were mild in severity. Conclusion These data demonstrated the long-term efficacy and safety of RBFC, both alone and in combination with other anti-glaucoma agents. RBFC may offer a new treatment option for the long-term management of glaucoma and OHT. Trial registration Japan Registry of Clinical Trials Identifier: jRCT2080225063. Date of registration 17 February 2020.

Lowering of intraocular pressure is currently the only therapeutic measure for Glaucoma management. Many longterm, randomized trials have shown the efficacy of lowering IOP, either by a percentage of baseline, or to a specified level. This has lead to the concept of 'Target\" IOP, a range of IOP on therapy, that would stabilize the Glaucoma/prevent further visual field loss, without significantly affecting a patient's quality of life. A clinical staging of Glaucoma by optic nerve head evaluation and perimetric parameters, allows a patient's eye to be categorized as having - mild, moderate or severe Glaucomatous damage. An initial attempt should be made to achieve the following IOP range for both POAG or PACG after an iridotomy. In mild glaucoma the initial target IOP range could be kept as 15-17 mmHg, for moderate glaucoma 12-15 mmHg and in the severe stage of glaucomatous damage 10-12 mmHg. Factoring in baseline IOP, age, vascular perfusion parameters, and change on perimetry or imaging during follow up, this range may be reassessed over 6 months to a year. \"Target\" IOP requires further lowering when the patient continues to progress or develops a systemic disease such as a TIA. Conversely, in the event of a very elderly or sick patient with stable nerve and visual field over time, the target IOP could be raised and medications reduced. An appropriate use of medications/laser/surgery to achieve such a \"Target\" IOP range in POAG or PACG can maintain visual fields and quality of life, preventing Glaucoma blindness.

Purpose To evaluate the efficacy and safety of dexamethasone implantation in the supraciliary (SC) space, a novel and potential effective implantation site, compared to intravitreal (IV) application. Methods This prospective study included 39 eyes of 38 patients with macular oedema (ME) who underwent SC and IV dexamethasone implantation (SC-DEX and IV-DEX). Patients were randomly assigned to treatment groups and followed for 3 months. Preoperative and postoperative assessments included maximum retinal thickness (MRT), change in central retinal thickness between consecutive visits (ΔCRT), intraocular pressure (IOP), and best corrected visual acuity (BCVA). Results Both SC-DEX and IV-DEX groups showed significant MRT reductions during at follow-up. In the SC group, MRT significantly decreased at 1st and 3rd months ( p  = 0.0002 for both), but not at 1st week ( p  = 0.2517). In the IV-DEX group, significant reductions in MRT were observed at all postoperative visits: 1st week ( p  = 0.0002), 1st month ( p  = 0.0004), and 3rd month ( p  = 0.0003). There were no significant differences in the change in ΔCRT between the SC-DEX and IV-DEX groups at any visit ( p  > 0.05). IOP did not show significant changes ( p  > 0.05). BCVA improved significantly in the SC group compared to the IV-DEX group during the first week ( p  = 0.014). No other perioperative or postoperative sight-threatening complications were noted in either group, including hypotony or endophthalmitis. Conclusion SC-DEX shows promise as an alternative for managing ME, offering similar effectiveness to IV-DEX with safe profile. Further studies are needed to confirm its long-term safety and efficacy.

Glaucoma, a leading cause of irreversible blindness, is a highly heritable human disease. Previous genome-wide association studies have identified over 100 loci for the most common form, primary open-angle glaucoma. Two key glaucoma-associated traits also show high heritability: intraocular pressure and optic nerve head excavation damage quantified as the vertical cup-to-disc ratio. Here, since much of glaucoma heritability remains unexplained, we conducted a large-scale multitrait genome-wide association study in participants of European ancestry combining primary open-angle glaucoma and its two associated traits (total sample size over 600,000) to substantially improve genetic discovery power (263 loci). We further increased our power by then employing a multiancestry approach, which increased the number of independent risk loci to 312, with the vast majority replicating in a large independent cohort from 23andMe, Inc. (total sample size over 2.8 million; 296 loci replicated at P  < 0.05, 240 after Bonferroni correction). Leveraging multiomics datasets, we identified many potential druggable genes, including neuro-protection targets likely to act via the optic nerve, a key advance for glaucoma because all existing drugs only target intraocular pressure. We further used Mendelian randomization and genetic correlation-based approaches to identify novel links to other complex traits, including immune-related diseases such as multiple sclerosis and systemic lupus erythematosus. Multitrait genome-wide association analyses identify hundreds of risk loci for primary open-angle glaucoma. Integration with other data types highlights potential new drug targets, including proteins likely to act via the optic nerve.

The etiology of primary open angle glaucoma is constituted by both intraocular pressure-dependent and intraocular pressure-independent mechanisms. However, GWASs of traits affecting primary open angle glaucoma through mechanisms independent of intraocular pressure remains limited. Here, we address this gap by subtracting the genetic effects of a GWAS for intraocular pressure from a GWAS for primary open angle glaucoma to reveal the genetic contribution to primary open angle glaucoma via intraocular pressure-independent mechanisms. Seventeen independent genome-wide significant SNPs were associated with the intraocular pressure-independent component of primary open angle glaucoma. Of these, 7 are located outside known normal tension glaucoma loci, 11 are located outside known intraocular pressure loci, and 2 are novel primary open angle glaucoma loci. The intraocular pressure-independent genetic component of primary open angle glaucoma is associated with glaucoma endophenotypes, while the intraocular pressure-dependent component is associated with blood pressure and vascular permeability. A genetic risk score for the intraocular pressure-independent component of primary open angle glaucoma is associated with 26 different retinal micro-vascular features, which contrasts with the genetic risk score for the intraocular pressure-dependent component. Increased understanding of these intraocular pressure-dependent and intraocular pressure-independent components provides insights into the pathogenesis of glaucoma. The mechanisms connecting intraocular pressure to glaucoma remain unclear. Here, the authors use GWAS by subtraction to reveal intraocular pressure-independent aspects of glaucoma.

AimTo report efficacy and safety measures for XEN45 in a National Health Service setting after 24-month follow-up.MethodsThis is a retrospective, non-comparative audit of records of patients who underwent XEN45 procedure between June 2015 and May 2017. The main outcome measures were intraocular pressure (IOP) reduction and number of antihypertensive medications at each timepoint. Failure was defined as requiring further surgery or removal of XEN. Success was defined as 20% reduction of IOP without additional glaucoma medications or reduction in antihypertensive medications without increase in baseline IOP. Needling rates were assessed and subgroup analysis was performed.ResultsA total of 151 eyes were included in the study. The main diagnoses were primary open angle glaucoma (84.1%), angle closure glaucoma (8.6%) and refractory glaucoma (7.3%). Stand-alone procedure was performed in 62.3% and combined phaco-XEN was done in 37.7%. The mean IOP at baseline was 22.1±6.5 mm Hg, and the mean IOP at 12 and 24 months was 15.4±5.9 mm Hg and 14.5±3.3 mm Hg, respectively (p<0.001). The mean number of medications was 2.77±1.1 at baseline, and 0.3±0.7 and 0.5±1.0 medications at 12 and 24 months, respectively (p<0.001). 25% of patients failed at the 24-month timepoint. Needling was required in 37.7% of patients at 24 months. Non-Caucasian ethnicity was found to be related to higher failure rate. No significant adverse events were noted.ConclusionXEN45 is a viable, effective and safe procedure after 2 years of follow-up. Patients should be advised regarding failure rate as well as possible need for bleb revisions and medication use.

Primary congenital glaucoma (PCG) is a severe disease characterized by developmental defects in the trabecular meshwork (TM) and Schlemm’s canal (SC), comprising the conventional aqueous humor outflow pathway of the eye. Recently, heterozygous loss of function variants in TEK and ANGPT1 or compound variants in TEK / SVEP1 were identified in children with PCG. Moreover, common variants in ANGPT1 and SVEP1 have been identified as risk alleles for primary open angle glaucoma (POAG) in GWAS studies. Here, we show tissue-specific deletion of Angpt1 or Svep1 from the TM causes PCG in mice with severe defects in the adjacent SC. Single-cell transcriptomic analysis of normal and glaucomatous Angpt1 deficient eyes allowed us to identify distinct TM and SC cell populations and discover additional TM-SC signaling pathways. Furthermore, confirming the importance of angiopoietin signaling in SC, delivery of a recombinant ANGPT1-mimetic promotes developmental SC expansion in healthy and Angpt1 deficient eyes, blunts intraocular pressure (IOP) elevation and RGC loss in a mouse model of PCG and lowers IOP in healthy adult mice. Our data highlight the central role of ANGPT1-TEK signaling and TM-SC crosstalk in IOP homeostasis and provide new candidates for SC-targeted glaucoma therapy. Primary congenital glaucoma (PCG) is characterised by increased intraocular pressure, and variants in ANGPT1 , or SVEP1 have been identified as risk alleles. Here, the authors show that deletion of these genes induces glaucoma in mice, and that activation of ANGPT1-TEK signaling ameliorates disease progression in mouse models.

In the central nervous system, glycogen-derived bioenergetic resources in astrocytes help promote tissue survival in response to focal neuronal stress. However, our understanding of the extent to which these resources are mobilized and utilized during neurodegeneration, especially in nearby regions that are not actively degenerating, remains incomplete. Here we modeled neurodegeneration in glaucoma, the world’s leading cause of irreversible blindness, and measured how metabolites mobilize through astrocyte gap junctions composed of connexin 43 (Cx43). We elevated intraocular pressure in one eye and determined how astrocyte-derived metabolites in the contralateral optic projection responded. Remarkably, astrocyte networks expand and redistribute metabolites along distances even 10 mm in length, donating resources from the unstressed to the stressed projection in response to intraocular pressure elevation. While resource donation improves axon function and visual acuity in the directly stressed region, it renders the donating tissue susceptible to bioenergetic, structural, and physiological degradation. Intriguingly, when both projections are stressed in a WT animal, axon function and visual acuity equilibrate between the two projections even when each projection is stressed for a different length of time. This equilibration does not occur when Cx43 is not present. Thus, Cx43-mediated astrocyte metabolic networks serve as an endogenous mechanism used to mitigate bioenergetic stress and distribute the impact of neurodegenerative disease processes. Redistribution ultimately renders the donating optic nerve vulnerable to further metabolic stress, which could explain why local neurodegeneration does not remain confined, but eventually impacts healthy regions of the brain more broadly.