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Aims/hypothesis The aim of the study was to examine the association of retinal vessel morphometry with BP, body composition and biochemistry, and to determine whether these associations differ by diabetes status. Methods The UK Biobank ocular assessment included 68,550 participants aged 40-70 years who underwent non-mydriatic retinal photography, BP and body composition measurements, and haematological analysis. A fully automated image analysis program provided measurements of retinal vessel diameter and tortuosity. The associations between retinal vessel morphology and cardiometabolic risk factors by diabetes status were examined using multilevel linear regression, to provide absolute differences in vessel diameter and percentage differences in tortuosity (allowing for within-person clustering). Results A total of 50,233 participants (a reduction from 68,550) were included in these analyses. Overall, those with diabetes had significantly more tortuous venules and wider arteriolar diameters compared with those without. Associations between venular tortuosity and cardiometabolic risk factors differed according to diabetes status (p interaction 1c, C-reactive protein, white cell count and granulocyte count. For example, a unit rise in white cell count was associated with a 0.18% increase (95% CI 0.05, 0.32%) in venular tortuosity for those without diabetes and a 1.48% increase (95% CI 0.90, 2.07%) among those with diabetes. For arteriolar diameter, significant interactions were evident for systolic BP, diastolic BP, mean arterial pressure (MAP) and LDL-cholesterol. For example, a 10 mmHg rise in systolic BP was associated with a −0.92 μm difference (95% CI −0.96 to −0.88 μm) in arteriolar diameter for those without diabetes, and a −0.58 μm difference (95% CI −0.76 to −0.41 μm) among those with diabetes. No interactions were observed for arteriolar tortuosity or venular diameters. Conclusions/interpretation We provide clear evidence of the modifying effect of diabetes on cardiometabolic risk factor associations with retinal microvascular architecture. These observations suggest the occurrence of preclinical disease processes, and may be a sign of impaired autoregulation due to hyperglycaemia, which has been suggested to play a pivotal role in the development of diabetes-related microvascular complications. Data Availability The data supporting the results reported here are available through the UK Biobank (https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access). Graphical abstract

We report the sensitivity and specificity of van Herick (VH) grading in detecting gonioscopically-defined primary angle closure suspects (PACS) among subjects screened for participation in a population-based trial in southern China. A cut-off of VH≤25% was found to have sensitivity and specificity rates of 98.2% and 25.9%, respectively. Rates were adjusted for missing gonioscopy data, resulting in a sensitivity and specificity of 92.5% and 61.5%, respectively.

Purpose: Serum lipids are modifiable, routinely collected blood test features associated with cardiovascular health. We examined the association of commonly collected serum lipid measures (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and triglycerides) with intraocular pressure (IOP). Design: Cross-sectional study in the UK Biobank and European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohorts. Participants: We included 94 323 participants from the UK Biobank (mean age, 57 years) and 6230 participants from the EPIC-Norfolk (mean age, 68 years) cohorts with data on TC, HDL-C, LDL-C, and triglycerides collected between 2006 and 2009. Methods: Multivariate linear regression adjusting for demographic, lifestyle, anthropometric, medical, and ophthalmic covariables was used to examine the associations of serum lipids with corneal-compensated IOP (IOPcc). Main Outcome Measures: Corneal-compensated IOP. Results: Higher levels of TC, HDL-C, and LDL-C were associated independently with higher IOPcc in both cohorts after adjustment for key demographic, medical, and lifestyle factors. For each 1-standard deviation increase in TC, HDL-C, and LDL-C, IOPcc was higher by 0.09 mmHg (95% confidence interval [CI], 0.06–0.11 mmHg; P < 0.001), 0.11 mmHg (95% CI, 0.08–0.13 mmHg; P < 0.001), and 0.07 mmHg (95% CI, 0.05–0.09 mmHg; P < 0.001), respectively, in the UK Biobank cohort. In the EPIC-Norfolk cohort, each 1-standard deviation increase in TC, HDL-C, and LDL-C was associated with a higher IOPcc by 0.19 mmHg (95% CI, 0.07–0.31 mmHg; P = 0.001), 0.14 mmHg (95% CI, 0.03–0.25 mmHg; P = 0.016), and 0.17 mmHg (95% CI, 0.06–0.29 mmHg; P = 0.003). An inverse association between triglyceride levels and IOP in the UK Biobank (–0.05 mmHg; 95% CI, –0.08 to –0.03; P < 0.001) was not replicated in the EPIC-Norfolk cohort (P = 0.30). Conclusions: Our findings suggest that serum TC, HDL-C, and LDL-C are associated positively with IOP in 2 United Kingdom cohorts and that triglyceride levels may be associated negatively. Future research is required to assess whether these associations are causal in nature.

To examine the association of alcohol consumption and type of alcoholic beverage with incident cataract surgery in 2 large cohorts.Longitudinal, observational study.We included 469 387 participants of UK Biobank with a mean age of 56 years and 23 162 participants of European Prospective Investigation of Cancer (EPIC)-Norfolk with a mean age of 59 years.Self-reported alcohol consumption at baseline was ascertained by a touchscreen questionnaire in UK Biobank and a food-frequency questionnaire in EPIC-Norfolk. Cases were defined as participants undergoing cataract surgery in either eye as ascertained via data linkage to National Health Service procedure statistics. We excluded participants with cataract surgery up to 1 year after the baseline assessment visit or those with self-reported cataract at baseline. Cox proportional hazards models were used to examine the associations of alcohol consumption with incident cataract surgery, adjusted for age, sex, ethnicity, Townsend deprivation index, body mass index (BMI), smoking, and diabetes status.Incident cataract surgery.There were 19 011 (mean cohort follow-up of 95 months) and 4573 (mean cohort follow-up of 193 months) incident cases of cataract surgery in UK Biobank and EPIC-Norfolk, respectively. Compared with nondrinkers, drinkers were less likely to undergo cataract surgery in UK Biobank (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.85-0.93) and EPIC-Norfolk (HR, 0.90; 95% CI, 0.84-0.97) after adjusting for covariables. Among alcohol consumers, greater alcohol consumption was associated with a reduced risk of undergoing cataract surgery in EPIC-Norfolk (P0.001), whereas a U-shaped association was observed in the UK Biobank. Compared with nondrinkers, subgroup analysis by type of alcohol beverage showed the strongest protective association with wine consumption; the risk of incident cataract surgery was 23% and 14% lower among those in the highest category of wine consumption in EPIC-Norfolk and UK Biobank, respectively.Our findings suggest a lower risk of undergoing cataract surgery with low to moderate alcohol consumption. The association was particularly apparent with wine consumption. We cannot exclude the possibility of residual confounding, and further studies are required to determine whether this association is causal in nature.

The aim of this study was to assess whether adiposity or body composition relates to microvascular characteristics of the retina, indicative of cardiometabolic function. A fully automated QUARTZ software processed retinal images from 68,550 UK Biobank participants (aged 40-69 years). Differences in retinal vessel diameter and tortuosity with body composition measures from the Tanita analyzer were obtained by using multilevel regression analyses adjusted for age, sex, ethnicity, clinic, smoking, and Townsend deprivation index. Venular tortuosity and diameter increased by approximately 2% (P

Background/AimsThis work aimed to study the effect of long-term intraocular pressure (IOP) fluctuation on visual field (VF) progression 8 years post-trabeculectomy in Asian eyes.MethodsThis was a retrospective analysis of 8-year post-trabeculectomy data from The Singapore 5-Fluorouracil (5-FU) Study. VFs were analysed using Progressor software (Medisoft, Leeds, UK). Outcome measures included mean slope for VF per year, number of progressing points and mean slope for progressing points per year. Multivariate regression analyses were performed adjusting for age, gender, ethnicity, glaucoma type, intraoperative 5-FU, diabetes mellitus, hypertension, best pre-trabeculectomy VF mean deviation, post-trabeculectomy mean IOP, IOP reduction and IOP fluctuation (SD of IOPs at 6-monthly timepoints).Results127 (52.3%) subjects completed 8-year follow-up with ≥5 reliable VFs and ≥8 6-monthly IOP measurements. Mean age was 61.8±9.6 years. Post-operatively, mean IOP was 14.2±2.8 mm Hg and mean IOP fluctuation was 2.53±1.20 mm Hg. Higher IOP fluctuation was associated with greater mean slope for field (B=−0.071; p=0.013), number of progressing points (B=0.963; p=0.014) and VF progression as defined by ≥1 progressing point (OR=1.585; p=0.029). There was also a trend towards eyes with higher IOP fluctuation having ≥3 adjacent progressing points in the same hemifield (OR=1.489; p=0.055). Greater mean IOP reduction post-trabeculectomy was associated only with a lower mean slope for progressing points per year (B=−0.026; p=0.028). There was no significant effect of intra-operative 5-FU compared with placebo for all outcome measures.ConclusionIn post-trabeculectomy Asian eyes with well-controlled IOP, higher long-term IOP fluctuation may be associated with greater VF progression.

This systematic review and meta-analysis summarizes evidence relating to the prevalence of diabetic retinopathy (DR) among Indigenous and non-Indigenous Australians.Indigenous Australians suffer disproportionately from diabetes-related complications. Exploring ethnic variation in disease is important for equitable distribution of resources and may lead to identification of ethnic-specific modifiable risk factors. Existing DR prevalence studies comparing Indigenous and non-Indigenous Australians have shown conflicting results.This study was conducted following Joanna Briggs Institute guidance on systematic reviews of prevalence studies (PROSPERO ID: CRD42022259048). We performed searches of Medline (Ovid), EMBASE, and Web of Science until October 2021, using a strategy designed by an information specialist. We included studies reporting DR prevalence among diabetic patients in Indigenous and non-Indigenous Australian populations. Two independent reviewers performed quality assessments using a 9-item appraisal tool. Meta-analysis and meta-regression were performed using double arcsine transformation and a random-effects model comparing Indigenous and non-Indigenous subgroups.Fifteen studies with 8219 participants met criteria for inclusion. The Indigenous subgroup scored lower on the appraisal tool than the non-Indigenous subgroup (mean score 50% vs. 72%, P = 0.04). In the unadjusted meta-analysis, DR prevalence in the Indigenous subgroup (30.2%; 95% confidence interval [CI], 24.9-35.7) did not differ significantly (P = 0.17) from the non-Indigenous subgroup (23.7%; 95% CI, 16.8-31.4). After adjusting for age and quality, DR prevalence was higher in the Indigenous subgroup (P0.01), with prevalence ratio point estimates ranging from 1.72 to 2.58, depending on the meta-regression model. For the secondary outcomes, prevalence estimates were higher in the Indigenous subgroup for diabetic macular edema (DME) (8.7% vs. 2.7%, P = 0.02) and vision-threatening DR (VTDR) (8.6% vs. 3.0%, P = 0.03) but not for proliferative DR (2.5% vs. 0.8%, P = 0.07).Indigenous studies scored lower for methodological quality, raising the possibility that systematic differences in research practices may be leading to underestimation of disease burden. After adjusting for age and quality, we found a higher DR prevalence in the Indigenous subgroup. This contrasts with a previous review that reported the opposite finding of lower DR prevalence using unadjusted pooled estimates. Future epidemiological work exploring DR burden in Indigenous communities should aim to address methodological weaknesses identified by this review.

Importance: Understanding the effects of modifiable risk factors on risk for multiple sclerosis (MS) and associated neurodegeneration is important to guide clinical counseling. Objective: To investigate associations of alcohol use, smoking, and obesity with odds of MS diagnosis and macular ganglion cell layer and inner plexiform layer (mGCIPL) thickness. Design, Setting, and Participants: This cross-sectional study analyzed data from the community-based UK Biobank study on health behaviors and retinal thickness (measured by optical coherence tomography in both eyes) in individuals aged 40 to 69 years examined from December 1, 2009, to December 31, 2010. Risk factors were identified with multivariable logistic regression analyses. To adjust for intereye correlations, multivariable generalized estimating equations were used to explore associations of alcohol use and smoking with mGCIPL thickness. Finally, interaction models explored whether the correlations of alcohol and smoking with mGCIPL thickness differed for individuals with MS. Data were analyzed from February 1 to July 1, 2021. Exposures: Smoking status (never, previous, or current), alcohol intake (never or special occasions only [low], once per month to ≤4 times per week [moderate], or daily/almost daily [high]), and body mass index. Main Outcomes and Measures: Multiple sclerosis case status and mGCIPL thickness. Results: A total of 71 981 individuals (38 685 women [53.7%] and 33 296 men [46.3%]; mean [SD] age, 56.7 [8.0] years) were included in the analysis (20 065 healthy control individuals, 51 737 control individuals with comorbidities, and 179 individuals with MS). Modifiable risk factors significantly associated with MS case status were current smoking (odds ratio [OR], 3.05 [95% CI, 1.95-4.64]), moderate alcohol intake (OR, 0.62 [95% CI, 0.43-0.91]), and obesity (OR, 1.72 [95% CI, 1.15-2.56]) compared with healthy control individuals. Compared with the control individuals with comorbidities, only smoking was associated with case status (OR, 2.30 [95% CI, 1.48-3.51]). High alcohol intake was associated with a thinner mGCIPL in individuals with MS (adjusted β = -3.09 [95% CI, -5.70 to -0.48] μm; P = .02). In the alcohol interaction model, high alcohol intake was associated with thinner mGCIPL in control individuals (β = -0.93 [95% CI, -1.07 to -0.79] μm; P

Angle-closure glaucoma is a major cause of blindness worldwide that carries an excessive risk of severe, bilateral visual impairment. A common concern among clinicians is the precipitation of acute angle-closure (AAC) attacks because of mydriasis. We evaluated the risk of AAC after pharmacologic dilation in Chinese individuals classified as having bilateral primary angle-closure suspects (PACSs).Randomized, interventional, controlled trial.A total of 889 patients with bilateral PACSs, aged between 50 and 70 years, were identified through community screening in Guangzhou, China, and enrolled in the study.In the Zhongshan Angle-Closure Prevention Trial, bilateral PACSs were treated with laser peripheral iridotomy (LPI) in 1 randomly selected eye, with the fellow eye serving as an untreated control. Over 72 months of follow-up, the participants had their pupils pharmacologically dilated 6 times with 5% phenylephrine and 0.5% tropicamide.Incidence and risk of post-mydriasis AAC in LPI-treated and untreated, control eyes classified as PACSs.One bilateral AAC attack occurred after mydriasis at the 2-week post-LPI visit. No other AAC events occurred in the LPI-treated eyes. In the untreated eyes, 4 additional attacks occurred: 2 occurred after dilation (1 at 54 months and 1 at 72 months of follow-up) and 2 occurred spontaneously. The risk of post-mydriasis AAC in the untreated eyes was 1 attack in 1587 dilations. The risk of spontaneous AAC in the untreated eyes was 0.44 per 1000 eye-years (95% confidence interval, 0.11-1.77 per 1000 eye-years).The risk of incident AAC attacks in PACSs was extremely low, even in a higher-risk group that underwent repeated pharmacologic pupillary dilation over 6 years of follow-up. Prophylactic LPI reduced this small but real risk. This trial was registered at ISRCTN.com as ISRCTN45213099.

Purpose Air pollution is associated with chronic diseases of later life. Cataract is the most common cause of blindess globally. It is biologically plausible that cataract risk is increased by pollution exposure. Therefore, the relationship between air pollution and incident cataract surgery was examined. Methods This was a prospective, observational study involving 433,727 UK Biobank participants. Ambient air pollution measures included particulates, nitrogen dioxide (NO2) and nitrogen oxides (NOx). Outdoor air pollution was estimated based on land use regression models. Participants undergoing cataract surgery in either eye were ascertained via data linkage to the National Health Service procedure statistics. Those undergoing cataract surgery within 1 year of baseline assessment and those reporting cataract at baseline were excluded. Cox proportional hazards models were used to examine the associations between air pollutants and incident cataract surgery, adjusting for sociodemographic and lifestyle factors. Results There were 16,307 incident cases of cataract surgery. Higher exposure to PM2.5 was associated with a 5% increased risk of incident cataract surgery (per interquartile range [IQR] increase). Compared to the lowest quartile, participants with exposures to PM2.5, NO2, and NOx in the highest quartile were 14%, 11%, and 9% more likely to undergo cataract surgery, respectively. A continuous exposure-response relationship was observed, with the likelihood of undergoing cataract surgery being progressively higher with greater levels of PM2.5, NO2, and NOx (P for trend P < 0.001). Conclusions Although the results of our study showed a 5% increased risk of future cataract surgery following an exposure to PM2.5, NO2, and NOx, the effect estimates were relatively small. Further research is required to determine if the associations identified are causal.

Importance Efforts are underway to incorporate retinal neurodegeneration in the diabetic retinopathy severity scale. However, there is no established measure to quantify diabetic retinal neurodegeneration (DRN). Objective We compared total retinal, macular retinal nerve fiber layer (mRNFL) and ganglion cell-inner plexiform layer (GC-IPL) thickness among participants with and without diabetes (DM) in a population-based cohort. Design/setting/participants Cross-sectional analysis, using the UK Biobank data resource. Separate general linear mixed models (GLMM) were created using DM and glycated hemoglobin as predictor variables for retinal thickness. Sub-analyses included comparing thickness measurements for patients with no/mild diabetic retinopathy (DR) and evaluating factors associated with retinal thickness in participants with and without diabetes. Factors found to be significantly associated with DM or thickness were included in a multiple GLMM. Exposure Diagnosis of DM was determined via self-report of diagnosis, medication use, DM-related complications or glycated hemoglobin level of ≥ 6.5%. Main outcomes and measures Total retinal, mRNFL and GC-IPL thickness. Results 74,422 participants (69,985 with no DM; 4,437 with DM) were included. Median age was 59 years, 46% were men and 92% were white. Participants with DM had lower total retinal thickness (-4.57 μm, 95% CI: -5.00, -4.14; p Conclusion GC-IPL was thinner among participants with DM, compared to without DM. This difference persisted after adjusting for confounding variables and when considering only those with no/mild DR. This confirms that GC-IPL thinning occurs early in DM and can serve as a useful marker of DRN.

Purpose To examine retinal vasculometry associations with different glaucomas in older British people. Design Cross-sectional study. Methods A total of 8,623 European Prospective Investigation into Cancer-Norfolk Eye study participants were examined, who underwent retinal imaging, ocular biometry assessment, and clinical ascertainment of ocular hypertensive or glaucoma status (including glaucoma suspect [GS], high-tension open-angle glaucoma [HTG], and normal-tension glaucoma [NTG]). Automated measures of arteriolar and venular tortuosity, area, and width from retinal images were obtained. MainOutcomeMeasures: Associations between glaucoma and retinal vasculometry outcomes were analyzed using multilevel linear regression, adjusted for age, sex, height, axial length, intraocular and systemic blood pressure, and within-person clustering, to provide absolute differences in width and area, and percentage differences in vessel tortuosity. Presence or absence of within-person-between-eye differences in retinal vasculometry by diagnoses were examined. Results A total of 565,593 vessel segments from 5,947 participants (mean age 67.6 years, SD 7.6 years, 57% women) were included; numbers with HTG, NTG, and GS in at least 1 eye were 87, 82, and 439, respectively. Thinner arterioles (−3.2 μm; 95% confidence interval [CI] −4.4 μm, −1.9 μm) and venules (−2.7 μm; 95% CI −4.9 μm, −0.5 μm) were associated with HTG. Reduced venular area was associated with HTG (−0.2 mm2; 95% CI −0.3 mm2, −0.1 mm2) and NTG (−0.2 mm2; 95% CI −0.3 mm2, −0.0 mm2). Less tortuous retinal arterioles and venules were associated with all glaucomas, but only significantly for GS (−3.9%; 95% CI −7.7%, −0.1% and −4.8%; 95% CI −7.4%, −2.1%, respectively). There was no evidence of within-person-between-eye differences in retinal vasculometry associations by diagnoses. Conclusions Retinal vessel width associations with glaucoma and novel associations with vessel area and tortuosity, together with no evidence of within-person-between-eye differences in retinal vasculometry, suggest a vascular cause of glaucoma., Highlights • Retinal vessel measurements, including (as a first report) vessel tortuosity and area, were associated with high-tension glaucoma and other glaucoma-related outcomes. • Novel analyses showing that within-person-between-eye glaucoma diagnoses, intraocular pressure, and retinal vasculometry were uncorrelated provides further evidence that systemic microvascular changes may cause glaucoma.

Despite recent advances, our understanding of the aetiological mechanisms underlying glaucoma remains incomplete. Heavy metals toxicity has been linked to the development of neurodegenerative diseases and various ocular pathologies. Given the similarities in pathophysiology between glaucoma and some neurodegenerative disorders, it is plausible that heavy metal toxicity may play a role in the development of glaucoma. Heavy metal exposure may be occupational, or through water or dietary contamination. In this report, we review mechanisms for systemic and neurotoxicity for arsenic, cadmium, chromium, cobalt, lead, mercury, and manganese, and weigh the evidence for an association between glaucoma and the accumulation of heavy metals either in ocular tissues or in the central nervous system.摘要: 尽管近年来关于青光眼的发病机制的研究有所进展, 但我们对其认识仍不全面。已发现重金属毒性与神经的退行性病变与多种眼部疾病发生具有相关性。由于青光眼与一些退行性神经病变的病理生理机制相似, 因此推测重金属毒性可能与青光眼的发展有关。重金属暴露可能是职业性的原因, 也可能通过水及食物的污染。在这篇报道中我们分析了砷, 镉, 铬, 钴, 铅, 汞和锰对于全身和神经系统毒性的病理发病机制, 评估了重金属在眼部与中枢神经系统中的蓄积与青光眼发病之间的相关性。.

Background Primary angle-closure glaucoma affects 20 million people worldwide. People classified as primary angle closure suspects have a higher but poorly quantified risk of developing glaucoma. We aimed to assess efficacy and safety of laser peripheral iridotomy prophylaxis against primary angle-closure glaucoma in Chinese people classified as primary angle closure suspects. Methods In this randomised controlled trial, bilateral primary angle closure suspects aged 50-70 years were enrolled at the Zhongshan Ophthalmic Center, a tertiary specialised hospital in Guangzhou, China. Eligible patients received laser peripheral iridotomy in one randomly selected eye, with the other remaining untreated. The primary outcome was incident primary angle closure disease as a composite endpoint of elevation of intraocular pressure, peripheral anterior synechiae, or acute angle-closure during 72 months of follow-up in an intention-to-treat analysis between treated eyes and contralateral controls. This trial is registered with the ISRCTN registry, number ISRCTN45213099. Findings Of 11 991 screened individuals, 889 individuals were randomly assigned from June 19, 2008 (889 treated and 889 untreated eyes). Incidence of the primary outcome was 4·19 per 1000 eye-years in treated eyes compared with 7·97 per 1000 eye-years in untreated eyes (hazard ratio 0·53; 95% CI 0·30-0·92; p=0·024). A primary outcome event occurred in 19 treated eyes and 36 untreated eyes with a statistically significant difference using pair-wise analysis (p=0·0041). No serious adverse events were observed during follow-up. Interpretation Incidence of angle-closure disease was very low among individuals classified as primary angle closure suspects identified through community-based screening. Laser peripheral iridotomy had a modest, albeit significant, prophylactic effect. In view of the low incidence rate of outcomes that have no immediate threat to vision, the benefit of prophylactic laser peripheral iridotomy is limited; therefore, widespread prophylactic laser peripheral iridotomy for primary angle-closure suspects is not recommended. Funding Fight for Sight, the Sun Yat-Sen University 5010 Project Fund, Moorfields Eye Charity, and the National Natural Science Foundation of China.

This systematic review and meta-analysis summarizes the existing evidence for the association of alcohol use with intraocular pressure (IOP) and open-angle glaucoma (OAG).Understanding and quantifying these associations may aid clinical guidelines or treatment strategies and shed light on disease pathogenesis. The role of alcohol, a modifiable factor, in determining IOP and OAG risk also may be of interest from an individual or public health perspective.The study protocol was preregistered in the Open Science Framework Registries (https://osf.io/z7yeg). Eligible articles (as of May 14, 2021) from 3 databases (PubMed, Embase, Scopus) were independently screened and quality assessed by 2 reviewers. All case-control, cross-sectional, and cohort studies reporting a quantitative effect estimate and 95% confidence interval (CI) for the association between alcohol use and either IOP or OAG were included. The evidence for the associations with both IOP and OAG was qualitatively summarized. Effect estimates for the association with OAG were pooled using random effects meta-analysis. Studies not meeting formal inclusion criteria for systematic review, but with pertinent results, were also appraised and discussed. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.Thirty-four studies were included in the systematic review. Evidence from 10 studies reporting an association with IOP suggests that habitual alcohol use is associated with higher IOP and prevalence of ocular hypertension (IOP21 mmHg), although absolute effect sizes were small. Eleven of 26 studies, comprising 173 058 participants, that tested for an association with OAG met inclusion criteria for meta-analysis. Pooled effect estimates indicated a positive association between any use of alcohol and OAG (1.18; 95% confidence interval [CI], 1.02-1.36; P = 0.03; IAlthough this meta-analysis suggests a harmful association between alcohol use and OAG, our results should be interpreted cautiously given the weakness and heterogeneity of the underlying evidence base, the small absolute effect size, and the borderline statistical significance. Nonetheless, these findings may be clinically relevant, and future research should focus on improving the quality of evidence.

Visual impairment has emerged as a potential modifiable risk factor for dementia. However, there is a lack of large studies with objective measures of vision and with more than 10 years of follow-up. We investigated whether visual impairment is associated with an increased risk of incident dementia in UK Biobank and European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk). In both cohorts, visual acuity was measured using a “logarithm of the minimum angle of resolution” (LogMAR) chart and categorized as no (≤0.30 LogMAR), mild (>0.3 to ≤0.50 LogMAR), and moderate to severe (>0.50 LogMAR) impairment. Dementia was ascertained through linkage to electronic medical records. After restricting to those aged ≥60 years, without prevalent dementia and with eye measures available, the analytic samples consisted of 62 206 UK Biobank and 7 337 EPIC-Norfolk participants, respectively. In UK Biobank and EPIC-Norfolk, respectively, 1 113 and 517 participants developed dementia over 11 and 15 years of follow-up. Using multivariable Cox proportional-hazards models, the hazard ratios for mild and moderate to severe visual impairment were 1.26 (95% confidence interval [CI]: 0.92–1.72) and 2.16 (95% CI: 1.37–3.40), in UK Biobank, and 1.05 (95% CI: 0.72–1.53) and 1.93 (95% CI: 1.05–3.56) in EPIC-Norfolk, compared to no visual impairment. When excluding participants censored within 5 years of follow-up or with prevalent poor or fair self-reported health, the direction of the associations remained similar for moderate impairment but was not statistically significant. Our findings suggest visual impairment might be a promising target for dementia prevention; however, the possibility of reverse causation cannot be excluded.

Background and aimUndiagnosed glaucoma is an invisible but important public health issue. At least half of glaucoma cases are estimated to be undiagnosed in western populations. The aim of this study is to examine risk factors for previously undiagnosed primary open-angle glaucoma (POAG).DesignCross-sectional study within the European Prospective Investigation of Cancer-Norfolk Eye Study, a large-scale cohort study in the UK.Participants314 study participants with POAG in either eye.MethodsLogistic regression was used to examine associations with previously undiagnosed POAG compared with previously diagnosed POAG. The factors examined included sociodemographic, ocular, physical and economic factors that could be barriers to eye care access.Results217 participants had previously diagnosed POAG and 107 participants were newly diagnosed with POAG during the study. After adjusting for covariables, the factors significantly associated with previously undiagnosed POAG were: a lower pretreatment intraocular pressure (IOP) (OR 0.71/mm Hg, 95% CI 0.63 to 0.80, pConclusionsThe risk factors for previously undiagnosed POAG identified in this study highlight the over-reliance on IOP level in glaucoma screening and the risk of missing glaucoma among lower IOP cases. It also suggests a role in improving glaucoma awareness in the community.

This systematic review summarizes evidence for associations between female reproductive factors (age at menarche, parity, oral contraceptive [OC] use, age at menopause, and postmenopausal hormone [PMH] use) and intraocular pressure (IOP) or open-angle glaucoma (OAG).Understanding the associations between female reproductive factors and glaucoma may shed light on the disease pathogenesis and aid clinical prediction and personalized treatment strategies. Importantly, some factors are modifiable, which may lead to new therapies.Two reviewers independently extracted articles in MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials databases to identify relevant studies. Eligibility criteria included studies with human subjects aged18 years; a measured outcome of either IOP or OAG; a cohort, case-control, cross-sectional, or randomized controlled trial design; a reported measure of association, such as the hazard ratio, relative risk, odds ratio, or mean difference, with an associated confidence interval; and a measured exposure of at least 1 of the following variables: age at menarche, parity, OC use, age at menopause, or PMH use.We included a total of 27 studies. Substantial differences in study designs, exposure and treatment levels, treatment durations, and variable reporting precluded a meaningful quantitative synthesis of the identified studies. Overall, relatively consistent associations between PMH use and a lower IOP were identified. Estrogen-only PMH use may be associated with lower OAG risk, which may be modified by race. No significant associations were found with combined estrogen-and-progesterone PMH use. No strong associations between parity or age at menarche and glaucoma were found, but a younger age at menopause was associated with an increased glaucoma risk, and adverse associations were identified with a longer duration of OC use, though no overall association with OC use was found.The association between PMH use and lower IOP or OAG risk is a potentially clinically relevant and modifiable risk factor and should be investigated further, although this needs to be interpreted in the context of a high risk of bias across included studies. Future research should examine associations with IOP specifically and how the relationship between genetic factors and OAG risks may be influenced by female reproductive factors.

To examine the efficacy of laser peripheral iridotomy (LPI) in patients who received a diagnosis of primary angle-closure suspect (PACS).Prospective, randomized controlled trial.This multicenter, randomized controlled trial (ClinicalTrials.gov identifier, NCT00347178) enrolled 480 patients older than 50 years from glaucoma clinics in Singapore with bilateral asymptomatic PACS (defined as having ≥2 quadrants of appositional angle closure on gonioscopy).Each participant underwent prophylactic LPI in 1 randomly selected eye, whereas the fellow eye served as a control. Patients were followed up yearly for 5 years.The primary outcome measure was development of primary angle closure (PAC; defined as presence of peripheral anterior synechiae, intraocular pressure [IOP] of21 mmHg, or both or acute angle closure [AAC]) or primary angle-closure glaucoma (PACG) over 5 years.Of the 480 randomized participants, most were Chinese (92.7%) and were women (75.8%) with mean age of 62.8 ± 6.9 years. Eyes treated with LPI reached the end point less frequently after 5 years (n = 24 [5.0%]; incidence rate [IR], 11.65 per 1000 eye-years) compared with control eyes (n = 45 [9.4%]; IR, 21.84 per 1000 eye-years; P = 0.001). The adjusted hazard ratio (HR) for progression to PAC was 0.55 (95% confidence interval [CI], 0.37-0.83; P = 0.004) in LPI-treated eyes compared with control eyes. Older participants (per year; HR, 1.06; 95% CI, 1.03-1.10; P0.001) and eyes with higher baseline IOP (per millimeter of mercury; HR, 1.35; 95% CI, 1.22-1.50; P0.0001) were more likely to reach an end point. The number needed to treat to prevent an end point was 22 (95% CI, 12.8-57.5).In patients with bilateral asymptomatic PACS, eyes that underwent prophylactic LPI reached significantly fewer end points compared with control eyes over 5 years. However, the overall incidence of PAC or PACG was low.

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function., Author summary The thickness of the inner retinal layers is one of the biomarkers for glaucoma, the leading cause of irreversible blindness globally. Here we utilised the large-scale of the UK Biobank and the images of the retina it contains to look for genetic variants that effect the thickness of the inner retina. We find many variants associated with this variable, but surprisingly only one that also affects glaucoma. Further analysis shows that glaucoma and genetically determined inner retinal thickness are not on the same genetic pathway and it is rather the change of thickness over time that is indicative of the disease. This is important as it invites the potential for the discovered variants to be used as a representation of baseline thickness in the clinic in the future. We also show that foveal hypoplasia, the lack of the normal valley-like shape of the central retina, is present at a population level in a mild form and is affected by three variants that also affect visual acuity. This is an interesting discovery as foveal hypoplasia was previously thought of as an outcome of rare Mendelian disease.

Summary Genome-wide association studies (GWASs) require accurate cohort phenotyping, but expert labeling can be costly, time intensive, and variable. Here, we develop a machine learning (ML) model to predict glaucomatous optic nerve head features from color fundus photographs. We used the model to predict vertical cup-to-disc ratio (VCDR), a diagnostic parameter and cardinal endophenotype for glaucoma, in 65,680 Europeans in the UK Biobank (UKB). A GWAS of ML-based VCDR identified 299 independent genome-wide significant (GWS; p ≤ 5 × 10−8) hits in 156 loci. The ML-based GWAS replicated 62 of 65 GWS loci from a recent VCDR GWAS in the UKB for which two ophthalmologists manually labeled images for 67,040 Europeans. The ML-based GWAS also identified 93 novel loci, significantly expanding our understanding of the genetic etiologies of glaucoma and VCDR. Pathway analyses support the biological significance of the novel hits to VCDR: select loci near genes involved in neuronal and synaptic biology or harboring variants are known to cause severe Mendelian ophthalmic disease. Finally, the ML-based GWAS results significantly improve polygenic prediction of VCDR and primary open-angle glaucoma in the independent EPIC-Norfolk cohort.

PURPOSE: To assess anatomical changes after laser peripheral iridotomy (LPI) and predictors of angle widening based on anterior segment OCT (AS-OCT) and angle opening based on gonioscopy in mainland Chinese primary angle closure suspects (PACS). DESIGN: Prospective observational study. PARTICIPANTS: 454 subjects aged 50 to 70 years with PACS. METHODS: Subjects received clinical examinations including gonioscopy and AS-OCT imaging at baseline and 2 weeks after LPI as part of the Zhongshan Angle Closure Prevention (ZAP) Trial. PACS was defined as inability to visualize pigmented trabecular meshwork in two or more quadrants on static gonioscopy. LPI was performed on one eye per subject in a superior (between 11 to 1 o’clock) or temporal or nasal (at or below 10:30 or 1:30 o’clock) location. Biometric parameters in horizontal and vertical AS-OCT scans were measured and averaged. Multivariable linear and logistic regression modeling were performed to determine predictors of angle widening, defined as change in continuous measurements of mean angle opening distance (AOD750), poor angle widening, defined as the lowest quintile of change in mean AOD750, and poor angle opening, defined as residual PACS after LPI based on gonioscopy. MAIN OUTCOME MEASURES: Anatomical changes and predictors of angle widening and opening after LPI. RESULTS: 454 subjects were included in the analysis. 219 received superior LPIs and 235 received temporal or nasal LPIs. There were significant changes among most biometric parameters (p

We report cases of acute angle closure in 2 young highly myopic siblings with Knobloch syndrome. To our knowledge, this is the first report of acute angle closure in Knobloch syndrome. Both patients were homozygous for a likely pathogenic variant in COL18A1. Both responded to treatment with cyclophotocoagulation and remained stable despite declining or being medically unfit for clear lens extraction. We argue that the recent implication of heterozygous mutations in COL18A1 in familial angle closure supports the argument that acute angle closure in these 2 patients was likely to be a thus far unreported feature of Knobloch syndrome. In addition, these cases also support the hypothesis that pathogenic variants in COL18A1 may be a risk factor for acute angle closure.

Identifying biomarkers of Alzheimer’s disease (AD) will accelerate the understanding of its pathophysiology, facilitate screening and risk stratification, and aid in developing new therapies. Developments in non-invasive retinal imaging technologies, including optical coherence tomography (OCT), OCT angiography and digital retinal photography, have provided a means to study neuronal and vascular structures in the retina in people with AD. Both qualitative and quantitative measurements from these retinal imaging technologies (eg, thinning of peripapillary retinal nerve fibre layer, inner retinal layer, and choroidal layer, reduced capillary density, abnormal vasodilatory response) have been shown to be associated with cognitive function impairment and risk of AD. The development of computer algorithms for respective retinal imaging methods has further enhanced the potential of retinal imaging as a viable tool for rapid, early detection and screening of AD. In this review, we present an update of current retinal imaging techniques and their potential applications in AD research. We also discuss the newer retinal imaging techniques and future directions in this expanding field.

Purpose To examine associations between retinal vessel morphometry and cardiometabolic risk factors in older British men and women. Design Retinal imaging examination as part of the European Prospective Investigation into Cancer—Norfolk Eye Study. Participants Retinal imaging and clinical assessments were carried out in 7411 participants. Retinal images were analyzed using a fully automated validated computerized system that provides novel measures of vessel morphometry. Methods Associations between cardiometabolic risk factors, chronic disease, and retinal markers were analyzed using multilevel linear regression, adjusted for age, gender, and within-person clustering, to provide percentage differences in tortuosity and absolute differences in width. Main Outcomes Measures Retinal arteriolar and venular tortuosity and width. Results In all, 279 802 arterioles and 285 791 venules from 5947 participants (mean age, 67.6 years; standard deviation [SD], 7.6 years; 57% female) were analyzed. Increased venular tortuosity was associated with higher body mass index (BMI; 2.5%; 95% confidence interval [CI], 1.7%–3.3% per 5 kg/m 2 ), hemoglobin A1c (HbA1c) level (2.2%; 95% CI, 1.0%–3.5% per 1%), and prevalent type 2 diabetes (6.5%; 95% CI, 2.8%–10.4%); wider venules were associated with older age (2.6 μm; 95% CI, 2.2–2.9 μm per decade), higher triglyceride levels (0.6 μm; 95% CI, 0.3–0.9 μm per 1 mmol/l), BMI (0.7 μm; 95% CI, 0.4–1.0 per 5 kg/m 2 ), HbA1c level (0.4 μm; 95% CI, –0.1 to 0.9 per 1%), and being a current smoker (3.0 μm; 95% CI, 1.7–4.3 μm); smoking also was associated with wider arterioles (2.1 μm; 95% CI, 1.3–2.9 μm). Thinner venules were associated with high-density lipoprotein (HDL) (1.4 μm; 95% CI, 0.7–2.2 per 1 mmol/l). Arteriolar tortuosity increased with age (5.4%; 95% CI, 3.8%–7.1% per decade), higher systolic blood pressure (1.2%; 95% CI, 0.5%–1.9% per 10 mmHg), in females (3.8%; 95% CI, 1.4%–6.4%), and in those with prevalent stroke (8.3%; 95% CI, –0.6% to 18%); no association was observed with prevalent myocardial infarction. Narrower arterioles were associated with age (0.8 μm; 95% CI, 0.6–1.0 μm per decade), higher systolic blood pressure (0.5 μm; 95% CI, 0.4–0.6 μm per 10 mmHg), total cholesterol level (0.2 μm; 95% CI, 0.0–0.3 μm per 1 mmol/l), and HDL (1.2 μm; 95% CI, 0.7–1.6 μm per 1 mmol/l). Conclusions Metabolic risk factors showed a graded association with both tortuosity and width of retinal venules, even among people without clinical diabetes, whereas atherosclerotic risk factors correlated more closely with arteriolar width, even excluding those with hypertension and cardiovascular disease. These noninvasive microvasculature measures should be evaluated further as predictors of future cardiometabolic disease.

Refractive errors, in particular myopia, are a leading cause of morbidity and disability world-wide. Genetic investigation can improve understanding of the molecular mechanisms underlying abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies involving 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (AUC=0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes participating in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may make possible predicting refractive error and the development of personalized myopia prevention strategies in the future., Reporting summary Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Current estimates suggest 50% of glaucoma blindness worldwide is caused by primary angle-closure glaucoma (PACG) but the causative gene is not known. We used genetic linkage and whole genome sequencing to identify Spermatogenesis Associated Protein 13, SPATA13 (NM_001166271; NP_001159743, SPATA13 isoform I), also known as ASEF2 (Adenomatous polyposis coli-stimulated guanine nucleotide exchange factor 2), as the causal gene for PACG in a large seven-generation white British family showing variable expression and incomplete penetrance. The 9 bp deletion, c.1432_1440del; p.478_480del was present in all affected individuals with angle-closure disease. We show ubiquitous expression of this transcript in cell lines derived from human tissues and in iris, retina, retinal pigment and ciliary epithelia, cornea and lens. We also identified eight additional mutations in SPATA13 in a cohort of 189 unrelated PACS/PAC/PACG samples. This gene encodes a 1277 residue protein which localises to the nucleus with partial co-localisation with nuclear speckles. In cells undergoing mitosis SPATA13 isoform I becomes part of the kinetochore complex co-localising with two kinetochore markers, polo like kinase 1 (PLK-1) and centrosome-associated protein E (CENP-E). The 9 bp deletion reported in this study increases the RAC1-dependent guanine nucleotide exchange factors (GEF) activity. The increase in GEF activity was also observed in three other variants identified in this study. Taken together, our data suggest that SPATA13 is involved in the regulation of mitosis and the mutations dysregulate GEF activity affecting homeostasis in tissues where it is highly expressed, influencing PACG pathogenesis., Author summary Glaucoma is the leading cause of irreversible blindness globally. Angle closure glaucoma accounts for 50% of all glaucoma blindness impacting quality of life and burden on health services. A number of variations in DNA appear to influence the risk of the disease. However, the biological mechanism underlying this important disease remains unclear. In this paper, we report the identification and functional characterisation of the first gene, mutation in which causes primary angle closure glaucoma in a seven generation Caucasian family. We have identified other variants in the same gene in another family and individuals with the disease. This gene is involved in cell division and is highly expressed in parts of the eye affected by the disease. Mutations in this gene appear to affect important enzyme activity involved in cell division. Identification of the disease-causing role of mutations in this gene helps to further the understanding of glaucoma aetiology and identifies potential therapeutic targets for disease management.

PurposeTo determine the 10-year incidence of all forms of primary angle closure (PAC) in phakic eyes and its risk factors in an urban Chinese population aged 50 years and older.MethodsSurvivors of 1405 baseline participants were invited to attend the 10-year follow-up visit in the Liwan Eye Study. Participants with established baseline angle closure, including primary angle closure suspects (PACS), PAC and primary angle closure glaucoma (PACG), or those who underwent bilateral cataract surgery during the 10-year period, as well as those who did not tolerate gonioscopic examinations, were excluded from this analysis. Incident PAC was present when those with open angles at baseline developed angle closure in any form in either eye during the 10-year period.ResultsAmong 791 participants who returned during the 10-year follow-up visit, 620 (78.4%) provided data on PAC incidence. The 10-year cumulative incidence of any forms of PAC was 20.5% (127/620, 95% CI 17.4% to 24.9%), including 16.9%, 2.4% and 1.1% with incident PACS, PAC and PACG in either eye, respectively. In multiple logistic regression, significant risk factors for incident angle closure were greater baseline lens thickness (OR=1.82 per mm, p=0.003), shallower anterior chamber depth (OR=3.18 per mm decreased, p=0.010) and narrower angle width (OR=1.63 per decreased angle width, pConclusionsApproximately one in five people aged 50 years and older developed some form of angle closure over a 10-year period. Small ocular dimensions and hyperopia at baseline were associated with the development of angle closure.

To determine the incidence and baseline clinical and anterior segment optical coherence tomography (AS-OCT) predictors associated with residual angle closure as assessed by gonioscopy 1 year after laser peripheral iridotomy (LPI) in primary angle closure suspects (PACS).Subanalysis of randomized controlled trial data.AS-OCT images from 181 PACS subjects ≥50 years of age were analyzed using customized software before and 1 year after LPI. Other parameters assessed were intraocular pressure (IOP) and axial length (Axl). Residual angle closure was defined as the inability to see the posterior trabecular meshwork for at least 2 quadrants on gonioscopy after LPI. Multivariate regression analysis determined the baseline predictors of residual angle closure 1 year after LPI.The mean age of participants was 62.4 (standard deviation 9.9) years. The majority were female (137, 75.7%) and Chinese (174, 96.1%). At 1 year post LPI, 148 (81.8%) subjects had gonioscopic residual angle closure. Univariate analysis showed that baseline Axl, anterior chamber area, anterior chamber volume, angle opening distance at 750 μm from the scleral spur, and angle recess area were smaller while baseline lens vault and iris curvature were larger in residual angle closure subjects (all P.05). Multivariate analysis revealed that baseline iris volume (B = -0.08, P = .035) and baseline IOP (B = 0.23, P = .032) were predictors for residual angle closure.One year after LPI,80% of PACS had gonioscopic residual angle closure. Greater baseline iris volume and higher IOP at baseline are independent risk factors for residual gonioscopic angle closure.

The morphometric characteristics of the retinal vasculature are associated with future risk of many systemic and vascular diseases. However, analysis of data from large population based studies is needed to help resolve uncertainties in some of these associations. This requires automated systems that extract quantitative measures of vessel morphology from large numbers of retinal images. Associations between retinal vessel morphology and disease precursors/outcomes may be similar or opposing for arterioles and venules. Therefore, the accurate detection of the vessel type is an important element in such automated systems. This paper presents a deep learning approach for the automatic classification of arterioles and venules across the entire retinal image, including vessels located at the optic disc. This comprises of a convolutional neural network whose architecture contains six learned layers: three convolutional and three fully-connected. Complex patterns are automatically learnt from the data, which avoids the use of hand crafted features. The method is developed and evaluated using 835,914 centreline pixels derived from 100 retinal images selected from the 135,867 retinal images obtained at the UK Biobank (large population-based cohort study of middle aged and older adults) baseline examination. This is a challenging dataset in respect to image quality and hence arteriole/venule classification is required to be highly robust. The method achieves a significant increase in accuracy of 8.1% when compared to the baseline method, resulting in an arteriole/venule classification accuracy of 86.97% (per pixel basis) over the entire retinal image. Morphology of retinal vasculature associated with risk markers of many diseases.Large population based studies help to resolve uncertainties in these associations.Automated system extracts morphometric data from the UK Biobank cohort study.Detection of the vessel type is an important element in such automated systems.Deep learning approach for the automatic classification of arterioles and venules.

PurposeTo obtain consensus opinion for the development of a standards framework for the development and implementation of virtual clinics for glaucoma monitoring in the UK using a modified Delphi methodology.MethodsA modified Delphi technique was used that involved sampling members of the UK Glaucoma and Eire Society (UKEGS). The first round scored the strength of agreement to a series of standards statements using a 9-point Likert scale. The revised standards were subjected to a second round of scoring and free-text comment. The final standards were discussed and agreed by an expert panel consisting of seven glaucoma subspecialists from across the UK. A version of the standards was submitted to external stakeholders for a 3-month consultation.ResultsThere was a 44% response rate of UKEGS members to rounds 1 and 2, consisting largely of consultant ophthalmologists with a specialist interest in glaucoma. The final version of the standards document was validated by stakeholder consultation and contains four sections pertaining to the patient groups, testing methods, staffing requirements and governance structure of NHS secondary care glaucoma virtual clinic models.ConclusionsUse of a modified Delphi approach has provided consensus agreement for the standards required for the development of virtual clinics to monitor glaucoma in the UK. It is anticipated that this document will be useful as a guide for those implementing this model of service delivery.

PurposesTo evaluate the effect of YAG laser peripheral iridotomy (LPI) on corneal endothelial cell density (ECD) and morphology in primary angle closure suspects (PACS) over 72 months.MethodsThe Zhongshan Angle Closure Prevention Trial is a single-centre randomised controlled trial. Subjects with bilateral PACS received YAG LPI prophylactic treatment in one eye randomly, while the fellow eye served as control. Central corneal ECD and morphology were assessed using non-contact specular microscopy (SP-2000P, Topcon) at baseline, 6, 18, 36, 54 and 72 months postoperatively. Mixed model analysis was conducted to compare the difference between treated and fellow eyes.ResultsA total of 875 participants were included, with a mean age of 59.3±5.0 years and 83.5% female. The ECD declined significantly (pConclusionECD decreases over time primarily due to ageing effect. YAG LPI does not appear to cause clinically significant corneal endothelial damage over 72 months after treatment.Trial registration numberISRCTN45213099.

BackgroundGlaucoma is the most frequent cause of irreversible blindness worldwide. There is no cure, but early detection and treatment can slow the progression and prevent loss of vision. It has been suggested that artificial intelligence (AI) has potential application for detection and management of glaucoma.Sources of dataThis literature review is based on articles published in peer-reviewed journals.Areas of agreementThere have been significant advances in both AI and imaging techniques that are able to identify the early signs of glaucomatous damage. Machine and deep learning algorithms show capabilities equivalent to human experts, if not superior.Areas of controversyConcerns that the increased reliance on AI may lead to deskilling of clinicians.Growing pointsAI has potential to be used in virtual review clinics, telemedicine and as a training tool for junior doctors. Unsupervised AI techniques offer the potential of uncovering currently unrecognized patterns of disease. If this promise is fulfilled, AI may then be of use in challenging cases or where a second opinion is desirable.Areas timely for developing researchThere is a need to determine the external validity of deep learning algorithms and to better understand how the ‘black box’ paradigm reaches results.

Contains fulltext : 218893.pdf (Publisher’s version ) (Closed access) Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 x 10(-)(6)). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.

Supplemental Digital Content is available in the text., To examine the baseline associations of retinal vessel morphometry with blood pressure (BP) and arterial stiffness in United Kingdom Biobank. The United Kingdom Biobank included 68 550 participants aged 40 to 69 years who underwent nonmydriatic retinal imaging, BP, and arterial stiffness index assessment. A fully automated image analysis program (QUARTZ [Quantitative Analysis of Retinal Vessel Topology and Size]) provided measures of retinal vessel diameter and tortuosity. The associations between retinal vessel morphology and cardiovascular disease risk factors/outcomes were examined using multilevel linear regression to provide absolute differences in vessel diameter and percentage differences in tortuosity (allowing within person clustering), adjusted for age, sex, ethnicity, clinic, body mass index, smoking, and deprivation index. Greater arteriolar tortuosity was associated with higher systolic BP (relative increase, 1.2%; 95% CI, 0.9; 1.4% per 10 mmHg), higher mean arterial pressure, 1.3%; 0.9, 1.7% per 10 mmHg, and higher pulse pressure (PP, 1.8%; 1.4; 2.2% per 10 mmHg). Narrower arterioles were associated with higher systolic BP (−0.9 µm; −0.94, −0.87 µm per 10 mmHg), mean arterial pressure (−1.5 µm; −1.5, −1.5 µm per 10 mmHg), PP (−0.7 µm; −0.8, −0.7 µm per 10 mmHg), and arterial stiffness index (−0.12 µm; −0.14, −0.09 µm per ms/m2). Associations were in the same direction but marginally weaker for venular tortuosity and diameter. This study assessing the retinal microvasculature at scale has shown clear associations between retinal vessel morphometry, BP, and arterial stiffness index. These observations further our understanding of the preclinical disease processes and interplay between microvascular and macrovascular disease.

Angle-closure glaucoma is an aggressive condition that causes millions to become blind worldwide. This review explores the use of prophylactic laser peripheral iridotomy (PI) in patients classified as primary angle-closure suspects (PACS), and additionally, the use of clear lens exchange as a primary treatment option in established angle-closure disease with or without glaucoma. As PI has a strong prophylactic effect in fellow eyes of patients who have had an acute attack, its use has been widely adopted in those patients classified as PACS, but with limited evidence to support this. A large randomised trial conducted in China has demonstrated that although PI reduces the risk of incident angle-closure disease, the incidence of disease that would threaten vision was much lower than anticipated. This suggests that the benefit of prophylactic PI is very limited. Health services data shows an association between rising cataract surgical rates and of decreasing rates of acute angle-closure. Age-related growth of the lens is a major component of angle-closure disease. Several studies have shown that clear lens extraction (CLE) effectively lowers IOP in angle-closure. The use of CLE as a primary treatment option has been tested against LPI in the EAGLE study, a large RCT that enroled people with angle-closure and an IOP 30 mmHg, and those with angle-closure glaucoma. The trial showed CLE to be superior to PI both for IOP control and patient reported quality of life. On these grounds, CLE should be considered for first-line treatment of more advanced angle-closure disease.摘要 : 原发性闭角型青光眼已成为严峻的社会公共卫生问题, 已引起全球百万人致盲 。本文旨在探讨预防性激光周边虹膜切除术(PI)在可疑原发性房角关闭(PACS)患者中的作用, 此外, 对于已确诊的伴或不伴有青光眼的原发性房角关闭的患者, 是否首选清亮晶状体摘除术。研究已证实预防性激光周边虹膜切除术(PI)可有效预防既往有急性发作史的患者对侧眼发作, 因此PI现已广泛应用于PACS的治疗, 但是尚缺乏更多有效证据。一项中国大型随机试验证实, 尽管PI降低了房角关闭发生的风险, 但是并未降低威胁视力的眼病的发病率, 这说明预防性PI的作用还是有限的。卫生服务数据提示白内障手术率的增加与急性房角关闭发生率下降具有相关性。随年龄增加晶体的改变与房角关闭具有相关性。多项研究表明, 尚未混浊的晶体摘除术 (CLE)可以有效降低房角关闭的眼压。在EAGLE研究中, 将CLE作为主要治疗方案与LPI进行了比较。这项大型的RCT研究纳入了闭角型青光眼患者与IOP30mmHg的房角关闭患者。研究认为在控制眼压以及提高生活质量方面, CLE较PI具有明显优势。因此, CLE可考虑作为严重房角关闭的一线治疗。.

Optic nerve head morphology is affected by several retinal diseases. We measured the vertical optic disc diameter (DD) of the UK Biobank (UKBB) cohort (N = 67 040) and performed the largest genome-wide association study (GWAS) of DD to date. We identified 81 loci (66 novel) for vertical DD. We then replicated the novel loci in International Glaucoma Genetic Consortium (IGGC, N = 22 504) and European Prospective Investigation into Cancer–Norfolk (N = 6005); in general the concordance in effect sizes was very high (correlation in effect size estimates 0.90): 44 of the 66 novel loci were significant at P

Background/aimsThe reason for visual impairment in patients with nanophthalmos and posterior microphthalmos is not completely understood. Therefore, this study aims to investigate foveal structure, and the impact of demographic, clinical and imaging parameters on best-corrected visual acuity (BCVA) in these conditions.MethodsSixty-two eyes of 33 patients with nanophthalmos (n=40) or posterior microphthalmos (n=22), and 114 eyes of healthy controls with high-resolution retinal imaging including spectral-domain or swept-source optical coherence tomography images were included in this cross-sectional case–control study. Foveal retinal layer thickness was determined by two independent readers. A mixed-effect model was used to perform structure–function correlations and predict the BCVA based on subject-specific variables.ResultsMost patients (28/33) had altered foveal structure associated with loss of foveal avascular zone and impaired BCVA. However, widening of outer nuclear layer, lengthening of photoreceptor outer segments, normal distribution of macular pigment and presence of Henle fibres were consistently found. Apart from the presence of choroidal effusion, which had significant impact on BCVA, the features age, refractive error, axial length and retinal layer thickness at the foveal centre explained 61.7% of the variability of BCVA.ConclusionThis study demonstrates that choroidal effusion, age, refractive error, axial length and retinal layer thickness are responsible for the majority of interindividual variability of BCVA as well as the morphological foveal heterogeneity in patients with nanophthalmos or posterior microphthalmos. This might give further insights into the physiology of foveal development and the process of emmetropisation, and support clinicians in the assessment of these disease entities.

Item does not contain fulltext Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

Background/aims To examine the agreement in clinical decisions of glaucoma status made in a virtual glaucoma clinic with those made during a face-to-face consultation. Methods A trained nurse and technicians entered data prospectively for 204 patients into a proforma. A subsequent face-to-face clinical assessment was completed by either a glaucoma consultant or fellow. Proformas were reviewed remotely by one of two additional glaucoma consultants, and 12 months later, by the clinicians who had undertaken the original clinical examination. The interobserver and intraobserver decision-making agreements of virtual assessment versus standard care were calculated. Results We identified adverse disagreement between face-to-face and virtual review in 7/204 (3.4%, 95% CI 0.9% to 5.9%) patients, where virtual review failed to predict a need to accelerated follow-up identified in face-to-face review. Misclassification events were rare, occurring in 1.9% (95% CI 0.3% to 3.8%) of assessments. Interobserver κ (95% CI) showed only fair agreement (0.24 (0.04 to 0.43)); this improved to moderate agreement when only consultant decisions were compared against each other (κ=0.41 (0.16 to 0.65)). The intraobserver agreement κ (95% CI) for the consultant was 0.274 (0.073 to 0.476), and that for the fellow was 0.264 (0.031 to 0.497). Conclusions The low rate of adverse misclassification, combined with the slowly progressive nature of most glaucoma, and the fact that patients will all be regularly reassessed, suggests that virtual clinics offer a safe, logistically viable option for selected patients with glaucoma.

Purpose: To describe and compare associations with macular retinal nerve fiber layer (mRNFL), ganglion cell complex (GCC), and ganglion cell–inner plexiform layer (GCIPL) thicknesses in a large cohort. Design: Cross-sectional study. Participants: We included 42 044 participants in the UK Biobank. The mean age was 56 years. Methods: Spectral-domain OCT macular images were segmented and analyzed. Corneal-compensated intraocular pressure (IOPcc) was measured with the Ocular Response Analyzer (Reichert, Corp., Buffalo, NY). Multivariable linear regression was used to examine associations with mean mRNFL, GCC, and GCIPL thicknesses. Factors examined were age, sex, ethnicity, height, body mass index (BMI), smoking status, alcohol intake, Townsend deprivation index, education level, diabetes status, spherical equivalent, and IOPcc. Main Outcome Measures: Thicknesses of mRNFL, GCC, and GCIPL. Results: We identified several novel independent associations with thinner inner retinal thickness. Thinner inner retina was associated with alcohol intake (most significant for GCIPL: –0.46 μm for daily or almost daily intake compared with special occasion only or never [95% confidence interval (CI), 0.61–0.30]; P = 1.1×10–8), greater social deprivation (most significant for GCIPL: –0.28 μm for most deprived quartile compared with least deprived quartile [95% CI, –0.42 to –0.14]; P = 6.6×10–5), lower educational attainment (most significant for mRNFL: –0.36 μm for less than O level compared with degree level [95% CI, –0.45 to 0.26]; P = 2.3×10–14), and nonwhite ethnicity (most significant for mRNFL comparing blacks with whites: –1.65 μm [95% CI, –1.86 to –1.43]; P = 2.4×10–50). Corneal-compensated intraocular pressure was associated most significantly with GCIPL (–0.04 μm/mmHg [95% CI, –0.05 to –0.03]; P = 4.0×10–10) and was not associated significantly with mRNFL (0.00 μm/mmHg [95% CI, –0.01 to 0.01]; P = 0.77). The variables examined explained a greater proportion of the variance of GCIPL (11%) than GCC (6%) or mRNFL (7%). Conclusions: The novel associations we identified may be important to consider when using inner retinal parameters as a diagnostic tool. Associations generally were strongest with GCIPL, particularly for IOP. This suggests that GCIPL may be the superior inner retinal biomarker for macular pathophysiologic processes and especially for glaucoma.

Elevated intraocular pressure (IOP) is an important risk factor for glaucoma. Mechanisms involved in its homeostasis are not well understood, but associations between metabolic factors and IOP have been reported. To investigate the relationship between levels of circulating metabolites and IOP, we performed a metabolome-wide association using a machine learning algorithm, and then employing Mendelian Randomization models to further explore the strength and directionality of effect of the metabolites on IOP. We show that O-methylascorbate, a circulating Vitamin C metabolite, has a significant IOP-lowering effect, consistent with previous knowledge of the anti-hypertensive and anti-oxidative role of ascorbate compounds. These results enhance understanding of IOP control and may potentially benefit future IOP treatment and reduce vision loss from glaucoma., Highlights • Vitamin C and its metabolites are highly concentrated in human brain and eye tissues. • Multi-omics analysis finds evidence for association between ascorbic acid metabolism and intraocular pressure. • O-methylascorbate lowers intraocular pressure in the general population. • O-methylascorbate's role in intraocular pressure regulation is likely mediated by its anti-photooxidative properties.

BACKGROUND: The availability and reduced cost of genotyping has improved gene susceptibility testing and our scientific understanding of disease pathophysiology. Whilst several personalised translational models exist within medical frameworks, genetic-based surgical therapy is a translational application not widely used in surgical specialties. METHOD: We present a clinical series of five patients with genetically confirmed bestrophinopathy and malignant glaucoma (MG). Patients were followed up for 12 months or more after receiving surgical intervention to manage refractory intraocular pressure (IOP) resistant to medical treatment. FINDINGS: Patients with BEST1 gene mutations are at higher risk of MG after filtration surgery. A multi-disciplinary approach after four patients experienced poor outcomes concluded that traditional first-line glaucoma surgery was not sufficient to prevent visual loss. A fifth patient presenting with the identified at-risk phenotype underwent primary pars plana vitrectomy, with pars plana Baerveldt tube insertion, successfully preventing MG and had no glaucoma progression after 5 years. INTERPRETATION: We provide proof-of-principle that genetic analysis can be used to inform the selection of surgical therapy to improve outcomes. In this case, a refinement of current surgical methods to avoid MG. Although challenges remain, personalised surgery has the potential to improve clinical outcomes beyond the scope of current surgical practice.

BackgroundTo describe the surgical technique and refractive outcomes following clear lens extraction (CLE) in the Effectiveness, in Angle-closure Glaucoma, of Lens Extraction trial.MethodsReview of prospectively collected data from a multicentre, randomised controlled trial comparing CLE and laser peripheral iridotomy. Eligible participants were ≥50 years old and newly diagnosed with (1) primary angle closure (PAC) with intraocular pressure above 30 mm Hg or (2) PAC glaucoma. We report the postoperative corrected distance visual acuity (CDVA) and refractive outcomes at 12 and 36 months postoperatively for those who underwent CLE.ResultsOf the 419 participants, 208 were randomised to CLE. Mean baseline CDVA was 77.9 (SD 12.4) letters and did not change significantly at 36 months when mean CDVA was 79.9 (SD 10.9) letters. Mean preoperative spherical equivalents were +1.7 (SD 2.3) and +0.08 (SD 0.95) diopters (D) at 36 months. Fifty-nine per cent and 85% eyes were within ±0.5D and ±1.0D of predicted refraction, respectively, at 36 months.ConclusionsMean CDVA in patients undergoing CLE for angle-closure glaucoma appeared stable over the 3-year study period. Refractive error was significantly reduced with surgery but refractive predictability was suboptimal.Trial registration number

AIM: Crowdsourcing is the process of simplifying and outsourcing numerous tasks to many untrained individuals. Our aim was to assess the performance and repeatability of crowdsourcing in the classification of normal and glaucomatous discs from optic disc images.METHODS: Optic disc images (N = 127) with pre-determined disease status were selected by consensus agreement from grading experts from a large cohort study. After reading brief illustrative instructions, we requested that knowledge workers (KWs) from a crowdsourcing platform (Amazon MTurk) classified each image as normal or abnormal. Each image was classified 20 times by different KWs. Two study designs were examined to assess the effect of varying KW experience and both study designs were conducted twice for consistency. Performance was assessed by comparing the sensitivity, specificity and area under the receiver operating characteristic curve (AUC).RESULTS: Overall, 2,540 classifications were received in under 24 hours at minimal cost. The sensitivity ranged between 83-88% across both trials and study designs, however the specificity was poor, ranging between 35-43%. In trial 1, the highest AUC (95%CI) was 0.64(0.62-0.66) and in trial 2 it was 0.63(0.61-0.65). There were no significant differences between study design or trials conducted.CONCLUSIONS: Crowdsourcing represents a cost-effective method of image analysis which demonstrates good repeatability and a high sensitivity. Optimisation of variables such as reward schemes, mode of image presentation, expanded response options and incorporation of training modules should be examined to determine their effect on the accuracy and reliability of this technique in retinal image analysis.

PurposeTo describe the results of darkroom prone provocative testing (DRPPT) in primary angle closure suspects (PACS) and to compare the findings to controls with open angles.Methods889 subjects with PACS in the Zhongshan Angle Closure Prevention Trial (a randomised controlled trial to compare prophylactic laser iridotomy to no treatment in PACS) and 89 with open angles in the 5-year follow-up of Liwan Eye Study were placed in a darkroom face down for 15 min. Intraocular pressure (IOP) was measured immediately before and after DRPPT.ResultsPACS participants were of similar age than controls (59.3 vs 60.5), more often female (82.9% vs 58.4%) and had lower IOP (14.3 vs 15.2 mm Hg). The average IOP increases after DRPPT was 4.3±3 mm Hg in PACS and 5.2±2.8 in controls (pConclusionsA modified DRPPT failed to separate PACS from those with open angle. Although the test resulted in greater IOP elevation among those PACS participants with all four quadrants closed than in those with two or three closed quadrants, it did not offer any insight into the risk of developing acute or chronic angle closure disease over 6-year follow-up.

PURPOSE: A common missense variant in the SIX6 gene (rs33912345) is strongly associated with primary open-angle glaucoma (POAG). We aimed to examine the association of rs33912345 with optic disc and retinal nerve fiber layer (RNFL) measures in a European population. METHODS: We examined participants of the population-based EPIC-Norfolk Eye Study. Participants underwent confocal laser scanning tomography (Heidelberg Retina Tomograph II, HRT) to estimate optic disc rim area and vertical cup-disc ratio (VCDR). Scanning laser polarimetry (GDxVCC) was used to estimate average RNFL thickness. The mean of right and left eye values was considered for each participant. Genotyping was performed using the Affymetrix UK Biobank Axiom Array. Multivariable linear regression with the optic nerve head parameter as outcome variable and dosage of rs33912345 genotype as primary explanatory variable was used, adjusted for age, sex, disc area, axial length and intraocular pressure. We further repeated analyses stratified into age tertiles. RESULTS: In total, 5,433 participants with HRT data and 3,699 participants with GDxVCC data were included. Each “C” allele of rs33912345 was associated with a smaller rim area (-0.030mm(2) [95% CI -0.040, -0.020], P=5.4x10(-9)), a larger VCDR (0.025 [95% CI 0.017, 0.033], P=3.3x10(-10)) and a thinner RNFL (-0.39μm [95% CI -0.62, -0.15], P=0.001). The RNFL association was strongest in the oldest age tertile, whereas rim area and VCDR associations were strongest in the youngest and oldest age tertiles. CONCLUSIONS: The protein coding SIX6 variant rs33912345, previously associated with POAG, has a functional effect on glaucoma-associated optic nerve head traits in Europeans.

We evaluated the prevalence of visual impairment (VI) and blindness among Chinese adults in the Singapore Chinese Eye Study (SCES, 2009–2011), and compared the trends with the Tanjong Pagar Survey, Singapore (TPS), conducted a decade earlier. The SCES comprised of 3,353 Chinese adults aged ≥40 years (response rate, 72.8%). Participants underwent standardized examinations, including measurements of presenting, and best-corrected visual acuity (VA). Bilateral VI (VA P ≤ 0.025). These findings will be useful for the planning of eye care services and resource allocation.