Association between deep learning measured retinal vessel calibre and incident myocardial infarction in a retrospective cohort from the UK Biobank.

BACKGROUND: Cardiovascular disease is a leading cause of global death. Prospective population-based studies have found that changes in retinal microvasculature are associated with the development of coronary artery disease. Recently, artificial intelligence deep learning (DL) algorithms have been developed for the fully automated assessment of retinal vessel calibres. METHODS: In this study, we validate the association between retinal vessel calibres measured by a DL system (Singapore I Vessel Assessment) and incident myocardial infarction (MI) and assess its incremental performance in discriminating patients with and without MI when added to risk prediction models, using a large UK Biobank cohort. RESULTS: Retinal arteriolar narrowing was significantly associated with incident MI in both the age, gender and fellow calibre-adjusted (HR=1.67 (95% CI: 1.19 to 2.36)) and multivariable models (HR=1.64 (95% CI: 1.16 to 2.32)) adjusted for age, gender and other cardiovascular risk factors such as blood pressure, diabetes mellitus (DM) and cholesterol status. The area under the receiver operating characteristic curve increased from 0.738 to 0.745 (p=0.018) in the age-gender-adjusted model and from 0.782 to 0.787 (p=0.010) in the multivariable model. The continuous net reclassification improvements (NRIs) were significant in the age and gender-adjusted (NRI=21.56 (95% CI: 3.33 to 33.42)) and the multivariable models (NRI=18.35 (95% CI: 6.27 to 32.61)). In the subgroup analysis, similar associations between retinal arteriolar narrowing and incident MI were observed, particularly for men (HR=1.62 (95% CI: 1.07 to 2.46)), non-smokers (HR=1.65 (95% CI: 1.13 to 2.42)), patients without DM (HR=1.73 (95% CI: 1.19 to 2.51)) and hypertensive patients (HR=1.95 (95% CI: 1.30 to 2.93)) in the multivariable models. CONCLUSION: Our results support DL-based retinal vessel measurements as markers of incident MI in a predominantly Caucasian population.

Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial.

BACKGROUND: Intravitreal aflibercept 8 mg could improve treatment outcomes and provide sustained disease control in patients with neovascular age-related macular degeneration (nAMD), with extended dosing compared with aflibercept 2 mg. METHODS: PULSAR is a phase 3, randomised, three-group, double-masked, non-inferiority, 96-week trial conducted across 223 sites worldwide. Adults with nAMD were randomised 1:1:1 to aflibercept 8 mg every 12 weeks (8q12), aflibercept 8 mg every 16 weeks (8q16), or aflibercept 2 mg every 8 weeks (2q8), following three initial monthly doses in all groups. From week 16, patients in the aflibercept 8 mg groups had their dosing interval shortened if pre-specified dose regimen modification criteria denoting disease activity were met. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48. All patients with at least one dose of study treatment were included in the efficacy and safety analyses. This trial is registered with ClinicalTrials.gov (NCT04423718) and is ongoing. FINDINGS: Of 1011 patients randomised to aflibercept 8q12 (n=336), 8q16 (n=338), or 2q8 (n=337) between Aug 11, 2020, and July 30, 2021, 1009 patients received study treatment (aflibercept 8q12 n=335; aflibercept 8q16 n=338; and aflibercept 2q8 n=336). Aflibercept 8q12 and 8q16 showed non-inferior BCVA gains versus aflibercept 2q8 (mean BCVA change from baseline +6·7 [SD 12·6] and +6·2 [11·7] vs +7·6 [12·2] letters). The least squares mean differences between aflibercept 8q12 versus 2q8 and 8q16 versus 2q8, respectively, were -0·97 (95% CI -2·87 to 0·92) and -1·14 (-2·97 to 0·69) letters (non-inferiority margin at 4 letters). The incidence of ocular adverse events in the study eye was similar across groups (aflibercept 8q12 n=129 [39%]; aflibercept 8q16 n=127 [38%]; and aflibercept 2q8 n=130 [39%]). INTERPRETATION: Aflibercept 8 mg showed efficacy and safety with extended dosing intervals, which has the potential to improve the management of patients with nAMD. FUNDING: Bayer AG and Regeneron Pharmaceuticals.

Retinal vessel caliber and cognitive performance: the multi-ethnic study of atherosclerosis (MESA).

Retinal vessel calibers share anatomic and physiologic characteristics with the cerebral vasculature and can be visualized noninvasively. In light of the known microvascular contributions to brain health and cognitive function, we aimed to determine if, in a community based-study, retinal vessel calibers and change in caliber over 8 years are associated with cognitive function or trajectory. Participants in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort who completed cognitive testing at Exam 5 (2010-2012) and had retinal vascular caliber measurements (Central Retinal Artery and Vein Equivalents; CRAE and CRVE) at Exam 2 (2002-2004) and Exam 5 were included. Using multivariable linear regression, we evaluated the association of CRAE and CRVE from Exam 2 and Exam 5 and their change between the two exams with scores on tests of global cognitive function (Cognitive Abilities Screening Instrument; CASI), processing speed (Digit Symbol Coding; DSC) and working memory (Digit Span; DS) at Exam 5 and with subsequent change in cognitive scores between Exam 5 and Exam 6 (2016-2018).The main effects are reported as the difference in cognitive test score per SD increment in retinal vascular caliber with 95% confidence intervals (CI). A total of 4334 participants (aged 61.6 ± 9.2 years; 53% female; 41% White) completed cognitive testing and at least one retinal assessment. On multivariable analysis, a 1 SD larger CRAE at exam 5 was associated with a lower concomitant CASI score (- 0.24, 95% CI - 0.46, - 0.02). A 1 SD larger CRVE at exam 2 was associated with a lower subsequent CASI score (- 0.23, 95%CI - 0.45, - 0.01). A 1 SD larger CRVE at exam 2 or 5 was associated with a lower DSC score [(- 0.56, 95% CI - 1.02, - 0.09) and - 0.55 (95% CI - 1.03, - 0.07) respectively]. The magnitude of the associations was relatively small (2.8-3.1% of SD). No significant associations were found between retinal vessel calibers at Exam 2 and 5 with the subsequent score trajectory of cognitive tests performance over an average of 6 years. Wider retinal venular caliber was associated with concomitant and future measures of slower processing speed but not with later cognitive trajectory. Future studies should evaluate the utility of these measures in risk stratification models from a clinical perspective as well as for screening on a population level.

Optical coherence tomography in the management of diabetic macular oedema.

Diabetic macular oedema (DMO) is the major cause of visual impairment in people with diabetes. Optical coherence tomography (OCT) is now the most widely used modality to assess presence and severity of DMO. DMO is currently broadly classified based on the involvement to the central 1 mm of the macula into non-centre or centre involved DMO (CI-DMO) and DMO can occur with or without visual acuity (VA) loss. This classification forms the basis of management strategies of DMO. Despite years of research on quantitative and qualitative DMO related features assessed by OCT, these do not fully inform physicians of the prognosis and severity of DMO relative to visual function. Having said that, recent research on novel OCT biomarkers development and re-defined classification of DMO show better correlation with visual function and treatment response. This review summarises the current evidence of the association of OCT biomarkers in DMO management and its potential clinical importance in predicting VA and anatomical treatment response. The review also discusses some future directions in this field, such as the use of artificial intelligence to quantify and monitor OCT biomarkers and retinal fluid and identify phenotypes of DMO, and the need for standardisation and classification of OCT biomarkers to use in future clinical trials and clinical practice settings as prognostic markers and secondary treatment outcome measures in the management of DMO.

Association of fractal dimension and other retinal vascular network parameters with cognitive performance and neuroimaging biomarkers: The Multi-Ethnic Study of Atherosclerosis (MESA).

INTRODUCTION: Retinal vascular network changes may reflect the integrity of the cerebral microcirculation, and may be associated with cognitive impairment. METHODS: Associations of retinal vascular measures with cognitive function and MRI biomarkers were examined amongst Multi-Ethnic Study of Atherosclerosis (MESA) participants in North Carolina who had gradable retinal photographs at Exams 2 (2002 to 2004, n = 313) and 5 (2010 to 2012, n = 306), and detailed cognitive testing and MRI at Exam 6 (2016 to 2018). RESULTS: After adjustment for covariates and multiple comparisons, greater arteriolar fractal dimension (FD) at Exam 2 was associated with less isotropic free water of gray matter regions (ß = -0.0005, SE = 0.0024, p = 0.01) at Exam 6, while greater arteriolar FD at Exam 5 was associated with greater gray matter cortical volume (in mm3 , ß = 5458, SE = 20.17, p = 0.04) at Exam 6. CONCLUSION: Greater arteriolar FD, reflecting greater complexity of the branching pattern of the retinal arteries, is associated with MRI biomarkers indicative of less neuroinflammation and neurodegeneration.

Application of a Deep Learning System to Detect Papilledema on Nonmydriatic Ocular Fundus Photographs in an Emergency Department.

PURPOSE: The Fundus photography vs Ophthalmoscopy Trial Outcomes in the Emergency Department (FOTO-ED) studies showed that ED providers poorly recognized funduscopic findings in patients in the ED. We tested a modified version of the Brain and Optic Nerve Study Artificial Intelligence (BONSAI) deep learning system on nonmydriatic fundus photographs from the FOTO-ED studies to determine if the deep learning system could have improved the detection of papilledema had it been available to ED providers as a real-time diagnostic aid. DESIGN: Retrospective secondary analysis of a cohort of patients included in the FOTO-ED studies. METHODS: The testing data set included 1608 photographs obtained from 828 patients in the FOTO-ED studies. Photographs were reclassified according to the optic disc classification system used by the deep learning system ("normal optic discs," "papilledema," and "other optic disc abnormalities"). The system's performance was evaluated by calculating the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity using a 1-vs-rest strategy, with reference to expert neuro-ophthalmologists. RESULTS: The BONSAI deep learning system successfully distinguished normal from abnormal optic discs (AUC 0.92 [95% confidence interval {CI} 0.90-0.93]; sensitivity 75.6% [73.7%-77.5%] and specificity 89.6% [86.3%-92.8%]), and papilledema from normal and others (AUC 0.97 [0.95-0.99]; sensitivity 84.0% [75.0%-92.6%] and specificity 98.9% [98.5%-99.4%]). Six patients with missed papilledema in 1 eye were correctly identified by the deep learning system as having papilledema in the other eye. CONCLUSIONS: The BONSAI deep learning system was able to reliably identify papilledema and normal optic discs on nonmydriatic photographs obtained in the FOTO-ED studies. Our deep learning system has excellent potential as a diagnostic aid in EDs and non-ophthalmology clinics equipped with nonmydriatic fundus cameras. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

A deep learning system for retinal vessel calibre improves cardiovascular risk prediction in Asians with chronic kidney disease.

Backgraund: Cardiovascular disease (CVD) and mortality is elevated in chronic kidney disease (CKD). Retinal vessel calibre in retinal photographs is associated with cardiovascular risk and automated measurements may aid CVD risk prediction. Methods: Retrospective cohort study of 860 Chinese, Malay and Indian participants aged 40-80 years with CKD [estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2] who attended the baseline visit (2004-2011) of the Singapore Epidemiology of Eye Diseases Study. Retinal vessel calibre measurements were obtained by a deep learning system (DLS). Incident CVD [non-fatal acute myocardial infarction (MI) and stroke, and death due to MI, stroke and other CVD] in those who were free of CVD at baseline was ascertained until 31 December 2019. Risk factors (established, kidney, and retinal features) were examined using Cox proportional hazards regression models. Model performance was assessed for discrimination, fit, and net reclassification improvement (NRI). Results: Incident CVD occurred in 289 (33.6%) over mean follow-up of 9.3 (4.3) years. After adjusting for established cardiovascular risk factors, eGFR [adjusted HR 0.98 (95% CI: 0.97-0.99)] and retinal arteriolar narrowing [adjusted HR 1.40 (95% CI: 1.17-1.68)], but not venular dilation, were independent predictors for CVD in CKD. The addition of eGFR and retinal features to established cardiovascular risk factors improved model discrimination with significantly better fit and better risk prediction according to the low (<15%), intermediate (15-29.9%), and high (30% or more) risk categories (NRI 5.8%), and with higher risk thresholds (NRI 12.7%). Conclusions: Retinal vessel calibre measurements by DLS were significantly associated with incident CVD independent of established CVD risk factors. Addition of kidney function and retinal vessel calibre parameters may improve CVD risk prediction among Asians with CKD.

Faricimab Treat-and-Extend for Diabetic Macular Edema: Two-Year Results from the Randomized Phase 3 YOSEMITE and RHINE Trials.

PURPOSE: To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2 and vascular endothelial growth factor (VEGF) A pathway inhibition with intravitreal faricimab according to a personalized treat-and-extend (T&E)-based regimen with up to every-16-week dosing in the YOSEMITE and RHINE (ClinicalTrials.gov identifiers, NCT03622580 and NCT03622593, respectively) phase 3 trials of diabetic macular edema (DME). DESIGN: Randomized, double-masked, noninferiority phase 3 trials. PARTICIPANTS: Adults with visual acuity loss (best-corrected visual acuity [BCVA] of 25-73 letters) due to center-involving DME. METHODS: Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks, faricimab 6.0 mg T&E (previously referred to as personalized treatment interval), or aflibercept 2.0 mg every 8 weeks. The T&E up to every-16-week dosing regimen was based on central subfield thickness (CST) and BCVA change. MAIN OUTCOME MEASURES: Included changes from baseline in BCVA and CST, number of injections, durability, absence of fluid, and safety through week 100. RESULTS: In YOSEMITE and RHINE (n = 940 and 951, respectively), noninferior year 1 visual acuity gains were maintained through year 2; mean BCVA change from baseline at 2 years (weeks 92, 96, and 100 average) with faricimab every 8 weeks (YOSEMITE and RHINE, +10.7 letters and +10.9 letters, respectively) or T&E (+10.7 letters and +10.1 letters, respectively) were comparable with aflibercept every 8 weeks (+11.4 letters and +9.4 letters, respectively). The median number of study drug injections was lower with faricimab T&E (YOSEMITE and RHINE, 10 and 11 injections, respectively) versus faricimab every 8 weeks (15 injections) and aflibercept every 8 weeks (14 injections) across both trials during the entire study. In the faricimab T&E arms, durability was improved further during year 2, with > 60% of patients receiving every-16-week dosing and approximately 80% receiving every-12-week or longer dosing at week 96. Almost 80% of patients who achieved every-16-week dosing at week 52 maintained every-16-week dosing without an interval reduction through week 96. Mean CST reductions were greater (YOSEMITE/RHINE weeks 92/96/100 average: faricimab every 8 weeks -216.0/-202.6 µm, faricimab T&E -204.5/-197.1 µm, aflibercept every 8 weeks -196.3/-185.6 µm), and more patients achieved absence of DME (CST < 325 µm; YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 87%-92%/88%-93%, faricimab T&E 78%-86%/85%-88%, aflibercept every 8 weeks 77%-81%/80%-84%) and absence of intraretinal fluid (YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 59%-63%/56%-62%, faricimab T&E 43%-48%/45%-52%, aflibercept every 8 weeks 33%-38%/39%-45%) with faricimab every 8 weeks or T&E versus aflibercept every 8 weeks through year 2. Overall, faricimab was well tolerated, with a safety profile comparable with that of aflibercept. CONCLUSIONS: Clinically meaningful visual acuity gains from baseline, anatomic improvements, and extended durability with intravitreal faricimab up to every 16 weeks were maintained through year 2. Faricimab given as a personalized T&E-based dosing regimen supports the role of dual angiopoietin-2 and VEGF-A inhibition to promote vascular stability and to provide durable efficacy for patients with DME. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Retinal microvasculature and incident dementia over 10 years: The Three-City-Alienor cohort.

Introduction: We explored the longitudinal relationship between retinal vascular features and dementia incidence over 10 years. Methods: Among 584 participants from the Three-City-Alienor (3C-Alienor) population-based cohort, quantitative retinal vascular features (caliber, tortuosity, fractal dimension) were measured using semi-automated software. Dementia was actively diagnosed over the follow-up period. Results: One hundred twenty-eight participants (21.9%) developed dementia over a median of 7.1 years. In Cox proportional hazards models adjusted for sociodemographic characteristics, apolipoprotein E (APOE) ε4, and vascular factors, increased retinal arteriolar tortuosity was associated with all-cause dementia (hazard ratio per standard deviation increase, 1.21; 95% confidence interval: 1.02-1.44). Wider retinal calibers and a higher venular tortuosity were associated with mixed/vascular dementia, but not Alzheimer's disease. Fractal dimensions were not associated with dementia. Discussion: Changes in the retinal microvasculature were associated with dementia risk. More studies are needed to replicate these findings and determine which features might help identify persons at risk at an early stage. HIGHLIGHTS: The retinal microvasculature might reflect the brain microvasculatureWe explored the association between retinal vascular features and incident dementia584 participants from the Three-City-Alienor cohort were followed-up over 10 yearsIncreased arteriolar tortuosity and venular calibers were associated with dementia riskRetinal imaging might help identify persons at risk of future dementia.

Influence of secondhand smoke exposure on the retinal vasculature of children in Hong Kong.

BACKGROUND: A recent prospective demonstrated that cardiovascular risk factors in early childhood were associated with later cardiovascular events. However, the impact of secondhand smoke (SHS) on children is unclear. The aims of this study is to determine the effects of SHS exposure on the retinal vasculature of children. METHODS: This is a population-based cross-sectional study of children aged 6 to 8 years. All participants received comprehensive ophthalmic examinations and retinal photography. Data on SHS exposure was derived from a validated questionnaire. A validated deep-learning system was used to automatically estimate retinal arteriolar and venular calibers from retinal photographs. Associations of quantitative retinal vessel caliber values with SHS exposure, number of smokers in the household, and total number of cigarettes smoked were determined by analyses of covariance (ANCOVA) after adjusting for potential confounders. Test of trend was determined by treating categorical risk factors as continuous ordinal variables. RESULTS: Here we show children exposed to SHS have wider retinal arteriolar (CRAE 152.1 µm vs. 151.3 µm, p < 0.001) and venular (CRVE 216.7 µm vs. 215.5 µm, p < 0.001) calibers compared to those in smoke-free homes, after adjustment for different factors. Wider arteriolar and venular calibers are also associated with increasing number of smokers in the family (p trend < 0.001) and more cigarettes smoked among family smokers (p trend<0.001). CONCLUSIONS: Exposure to SHS at home is associated with changes in retinal vasculature among children. This reinforces the adverse effect of secondhand smoking around children though further research incorporating comprehensive assessment of potential confounders is necessary.

Exposure to secondhand smoke can be harmful, particularly for our heart and lung health as adults. However, the impact of secondhand smoke on children is less clear. Here, we looked at the effects of secondhand smoke exposure on vessels within children's eyes. The health of these vessels is a potential indicator of overall eye health and is also associated with cardiovascular disease. Pictures were taken of children's eyes and analyzed using a computer program. We looked at the association between vessel measurements in the eye and how much secondhand smoke the children are exposed to. We observed differences in the vessels in children exposed to secondhand smoke, compared to those from smoke-free homes. These findings indicate that secondhand smoke may affect the health of children's eyes and highlight the need to promote smoke-free home environments.

The Impact of Hearing Impairment on Health Indicators in a Multiethnic Population of Older Adults in Singapore.

Background and Objectives: To determine the impact of hearing impairment (HI) on health indicators in a multiethnic Singaporean population of older adults. Research Design and Methods: In this cross-sectional, population-based study, pure-tone averages of air-conduction thresholds at 500 Hz, 1,000 Hz, 2,000 Hz, and 4,000 Hz were calculated for each ear. Eight categories of HI were defined ranging from: 1: No HI to 8: Bilateral severe HI. Health indicators included hearing-related quality of life (H-QoL), depressive symptoms, frailty, gait speed, instrumental activities of daily living, sarcopenia, and cognitive impairment. Multivariable regression models determined the independent associations between HI and outcomes. Results: A total of 2,503 older adults (mean age ± SD 73.4 ± 8.4; 55.2% female participants) were enrolled. Of these, 289 (11.6%), 259 (10.4%), 798 (31.9%), 303 (12.1%), 515 (20.6%), 52 (2.1%), 155 (6.2%), and 115 (4.6%) had hearing levels in Cats 1 to 8, respectively; and 20 (0.8%) used a hearing aid. Compared to those with no HI, participants with unilateral mild HI (Cat 2) had a 107% reduction in H-QoL (ß: 0.63; CI: 0.18, 1.09, p = .006), increasing to a 2,816% reduction (ß: 16.78; CI: 13.25, 20.31, p < .001) in those with bilateral severe HI-Cat 8 (p-trend < .001). Those with Cat 8 also had lower gait speed and we observed a nonsignificant increase in odds of frailty as HI worsened. Discussion and Implications: H-QoL is affected across the spectrum of severity and laterality of HI. Interventions to alleviate the effects of HI and provision of QoL support are warranted. Other health indicators were only affected in late stages, suggesting that slowing disease progression is crucial in clinical management.

Evaluating the outcome of screening for glaucoma using colour fundus photography-based referral criteria in a teleophthalmology screening programme for diabetic retinopathy.

AIMS: To evaluate the effectiveness of glaucoma screening using glaucoma suspect (GS) referral criteria assessed on colour fundus photographs in Singapore's Integrated Diabetic Retinopathy Programme (SiDRP). METHODS: A case-control study. This study included diabetic subjects who were referred from SiDRP with and without GS between January 2017 and December 2018 and reviewed at Singapore National Eye Centre. The GS referral criteria were based on the presence of a vertical cup-to-disc ratio (VCDR) of ≥0.65 and other GS features. The final glaucoma diagnosis confirmed from electronic medical records was retrospectively matched with GS status. The sensitivity, specificity and positive predictive value (PPV) of the test were evaluated. RESULTS: Of 5023 patients (2625 with GS and 2398 without GS) reviewed for glaucoma, 451 (9.0%, 95% CI 8.2% to 9.8%) were confirmed as glaucoma. The average follow-up time was 21.5±10.2 months. Using our current GS referral criteria, the sensitivity, specificity and PPV were 81.6% (95% CI 77.7% to 85.1%), 50.6% (95% CI 49.2% to 52.1%) and 14.0% (95% CI 13.4% to 14.7%), respectively, resulting in 2257 false positive cases. Increasing the VCDR cut-off for referral to ≥0.80, the specificity increased to 93.9% (95% CI 93.1% to 94.5%) but the sensitivity decreased to 11.3% (95% CI 8.5% to 14.6%), with a PPV of 15.4% (95% CI 12.0% to 19.4%). CONCLUSIONS: Opportunistic screening for glaucoma in a lower VCDR group could result in a high number of unnecessary referrals. If healthcare infrastructures are limited, targeting case findings on a larger VCDR group with high specificity will still be beneficial.

Diabetic retinopathy in China: Epidemiology, screening and treatment trends-A review.

Diabetic retinopathy (DR) is the leading cause of vision impairment in the global working-age population. In China, with one-third of the world's diabetes population estimated at 141 million, the blindness prevalence due to DR has increased significantly. The country's geographic variations in socioeconomic status have led to prominent disparities in DR prevalence, screening and management. Reported risk factors for DR in China include the classic ones, such as long diabetes duration, hyperglycaemia, hypertension and rural habitats. There is no national-level DR screening programme in China, but significant pilot efforts are underway for screening innovations. Novel agents with longer durations, noninvasive delivery or multi-target are undergoing clinical trials in China. Although optimised medical insurance policies have enhanced accessibility for expensive therapies like anti-VEGF drugs, further efforts in DR prevention and management in China are required to establish nationwide cost-effective screening programmes, including telemedicine and AI-based solutions, and to improve insurance coverage for related out-of-pocket expenses.

Hypertensive retinopathy and cardiovascular disease risk: 6 population-based cohorts meta-analysis.

Background: The cardiovascular risk associated with different levels of hypertensive retinopathy, including mild, remains unclear. We performed an individual participant meta-analysis from 6 population-based cohort studies to determine the relationship of hypertensive retinopathy with incident cardiovascular outcomes. Methods: We identified cohort studies that objectively assessed hypertensive retinopathy from photographs, documented incident cardiovascular outcomes, and were population-based. Six studies contributed data from 11,013 individuals at baseline with 5-13 years follow-up. Participants were recruited if they had hypertension and did not have confounding conditions such as diabetic retinopathy. Main outcome measures were incident coronary heart disease (CHD), stroke and a composite endpoint of cardiovascular disease (CHD or stroke). Pooled estimates of incident risk ratios (IRR) were obtained after adjusting for age, gender, systolic blood pressure, serum total cholesterol, high density lipoprotein and smoking. Results: Among eligible participants with hypertension and without diabetes, there were 1018/9662 (10.5%) incident CHD events, 708/11,013 (6.4%) incident stroke events and 1317/9378 (14.0%) incident CVD events. Mild hypertensive retinopathy was associated with increased risk of CVD (IRR 1.13, 95% CI 1.00 to 1.27) and CHD (IRR 1.17, 95% CI 1.02 to 1.34) but not stroke; moderate hypertensive retinopathy was associated with increased risk of CVD (IRR 1.25 95% CI 1.02 to 1.53) but not stroke or CHD individually. Conclusions: In persons with hypertension, both mild and moderate hypertensive retinopathy were associated with higher CVD risk.

Emerging therapeutic strategies for unmet need in neovascular age-related macular degeneration.

Neovascular age-related macular degeneration (nAMD) is a major cause of visual impairment and blindness. Anti-vascular endothelial growth factor (VEGF) agents, such as ranibizumab, bevacizumab, aflibercept, brolucizumab and faricimab have revolutionized the clinical management of nAMD. However, there remains an unmet clinical need for new and improved therapies for nAMD, since many patients do not respond optimally, may lose response over time or exhibit sub-optimal durability, impacting on real world effectiveness. Evidence is emerging that targeting VEGF-A alone, as most agents have done until recently, may be insufficient and agents that target multiple pathways (e.g., aflibercept, faricimab and others in development) may be more efficacious. This article reviews issues and limitations that have arisen from the use of existing anti-VEGF agents, and argues that the future may lie in multi-targeted therapies including alternative agents and modalities that target both the VEGF ligand/receptor system as well as other pathways.

Effective refractive error coverage in adults aged 50 years and older: estimates from population-based surveys in 61 countries.

BACKGROUND: In 2021, WHO Member States endorsed a global target of a 40-percentage-point increase in effective refractive error coverage (eREC; with a 6/12 visual acuity threshold) by 2030. This study models global and regional estimates of eREC as a baseline for the WHO initiative. METHODS: The Vision Loss Expert Group analysed data from 565 448 participants of 169 population-based eye surveys conducted since 2000 to calculate eREC (met need/[met need + undermet need + unmet need]). A binary logistic regression model was used to estimate eREC by Global Burden of Disease (GBD) Study super region among adults aged 50 years and older. FINDINGS: In 2021, distance eREC was 79·1% (95% CI 72·4-85·0) in the high-income super region; 62·1% (54·7-68·8) in north Africa and Middle East; 49·5% (45·0-54·0) in central Europe, eastern Europe, and central Asia; 40·0% (31·7-48·2) in southeast Asia, east Asia, and Oceania; 34·5% (29·4-40·0) in Latin America and the Caribbean; 9·0% (6·5-12·0) in south Asia; and 5·7% (3·1-9·0) in sub-Saharan Africa. eREC was higher in men and reduced with increasing age. Global distance eREC increased from 2000 to 2021 by 19·0%. Global near vision eREC for 2021 was 20·5% (95% CI 17·8-24·4). INTERPRETATION: Over the past 20 years, distance eREC has increased in each super region yet the WHO target will require substantial improvements in quantity and quality of refractive services in particular for near vision impairment. FUNDING: WHO, Sightsavers, The Fred Hollows Foundation, Fondation Thea, Brien Holden Vision Institute, Lions Clubs International Foundation.

Acceptance and Perception of Artificial Intelligence Usability in Eye Care (APPRAISE) for Ophthalmologists: A Multinational Perspective.

Background: Many artificial intelligence (AI) studies have focused on development of AI models, novel techniques, and reporting guidelines. However, little is understood about clinicians' perspectives of AI applications in medical fields including ophthalmology, particularly in light of recent regulatory guidelines. The aim for this study was to evaluate the perspectives of ophthalmologists regarding AI in 4 major eye conditions: diabetic retinopathy (DR), glaucoma, age-related macular degeneration (AMD) and cataract. Methods: This was a multi-national survey of ophthalmologists between March 1st, 2020 to February 29th, 2021 disseminated via the major global ophthalmology societies. The survey was designed based on microsystem, mesosystem and macrosystem questions, and the software as a medical device (SaMD) regulatory framework chaired by the Food and Drug Administration (FDA). Factors associated with AI adoption for ophthalmology analyzed with multivariable logistic regression random forest machine learning. Results: One thousand one hundred seventy-six ophthalmologists from 70 countries participated with a response rate ranging from 78.8 to 85.8% per question. Ophthalmologists were more willing to use AI as clinical assistive tools (88.1%, n = 890/1,010) especially those with over 20 years' experience (OR 3.70, 95% CI: 1.10-12.5, p = 0.035), as compared to clinical decision support tools (78.8%, n = 796/1,010) or diagnostic tools (64.5%, n = 651). A majority of Ophthalmologists felt that AI is most relevant to DR (78.2%), followed by glaucoma (70.7%), AMD (66.8%), and cataract (51.4%) detection. Many participants were confident their roles will not be replaced (68.2%, n = 632/927), and felt COVID-19 catalyzed willingness to adopt AI (80.9%, n = 750/927). Common barriers to implementation include medical liability from errors (72.5%, n = 672/927) whereas enablers include improving access (94.5%, n = 876/927). Machine learning modeling predicted acceptance from participant demographics with moderate to high accuracy, and area under the receiver operating curves of 0.63-0.83. Conclusion: Ophthalmologists are receptive to adopting AI as assistive tools for DR, glaucoma, and AMD. Furthermore, ML is a useful method that can be applied to evaluate predictive factors on clinical qualitative questionnaires. This study outlines actionable insights for future research and facilitation interventions to drive adoption and operationalization of AI tools for Ophthalmology.

Associations between age-related macular degeneration and sleep dysfunction: A systematic review.

BACKGROUND: Age-related macular degeneration, a prevalent degenerative retinal disease, is associated with non-visual and psychosocial impairments that may affect sleep. In this systematic review, we evaluated associations between age-related macular degeneration (AMD) and sleep, highlighted knowledge gaps and provided evidence-based recommendations to clinicians to enable holistic management of AMD patients. METHODS: We searched PubMed, Embase and the Cochrane Central registries for papers published before May 2022. Non-English, qualitative studies and grey literature were excluded. Studies evaluating the association between AMD and sleep (including sleep disorders like insomnia and sleep apnea), and vice versa, were included. The quality of shortlisted studies was evaluated using the Newcastle Ottawa Scale. RESULTS: Six (two case-control studies, three longitudinal cohort studies and one cross-sectional study) of 551 studies were included in this review. Four studies found that AMD was associated with increased rates of sleep apnea and poorer reported sleep quality, while five studies showed that patients with sleep apnea or insomnia were at higher risk of developing AMD. Associations between self-reported sleep quantity and AMD were conflicting. No study evaluated the relationship between AMD and sleep using objective sleep assessment tools. CONCLUSION: Only a limited number of studies investigated associations between AMD and sleep. These studies suggest a bidirectional relationship between AMD and sleep dysfunction yet disagree on the relationship between sleep quantity and the likelihood of AMD. Additional studies, using objective characterisation of sleep in patients with AMD are required to confirm these findings.

The WHO-ITU MyopiaEd Programme: A Digital Message Programme Targeting Education on Myopia and Its Prevention.

The objective of this paper is to provide an overview of the World Health Organization - International Telecommunication Union MyopiaEd programme - a digital message programme targeting education on myopia and its prevention. The development of the MyopiaEd programme included 4 key steps: (1) Conceptualization and consultation with experts in the field of myopia, mHealth and health behavior change; (2) Creation of SMS message libraries and programme algorithm; (3) Review of the message libraries to ensure relevance to the target audience; and (4) Pre-testing amongst end-user groups to ensure that the design of the programme and the message content were understandable. After reviewing the available evidence and considering input of the experts, the aims, end users and key themes of the programme were finalized. Separate SMS-adapted message libraries were developed, reviewed and pre-tested for four target end-user groups; (1) general population involved in the care of children (2) parents or caregivers of children with myopia; (3) adolescents with myopia; and (4) adults with myopia. The message libraries are part of a comprehensive toolkit, developed through a consultative process with experts in digital health, to support implementation within countries. The development of the MyopiaEd programme aims to provide a basis for Member States and other stakeholders to develop, implement and monitor large-scale mHealth programmes. It is aimed at raising awareness of good eye care behaviors and addressing common reasons for non-compliance to spectacle wear. The next steps will involve adapting and evaluating the MyopiaEd programme in selected settings.

Concordance between SIVA, IVAN, and VAMPIRE Software Tools for Semi-Automated Analysis of Retinal Vessel Caliber.

We aimed to compare measurements from three of the most widely used software packages in the literature and to generate conversion algorithms for measurement of the central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) between SIVA and IVAN and between SIVA and VAMPIRE. We analyzed 223 retinal photographs from 133 human participants using both SIVA, VAMPIRE and IVAN independently for computing CRAE and CRVE. Agreement between measurements was assessed using Bland-Altman plots and intra-class correlation coefficients. A conversion algorithm between measurements was carried out using linear regression, and validated using bootstrapping and root-mean-square error. The agreement between VAMPIRE and IVAN was poor to moderate: The mean difference was 20.2 µm (95% limits of agreement, LOA, -12.2-52.6 µm) for CRAE and 21.0 µm (95% LOA, -17.5-59.5 µm) for CRVE. The agreement between VAMPIRE and SIVA was also poor to moderate: the mean difference was 36.6 µm (95% LOA, -12.8-60.4 µm) for CRAE, and 40.3 µm (95% LOA, 5.6-75.0 µm) for CRVE. The agreement between IVAN and SIVA was good to excellent: the mean difference was 16.4 µm (95% LOA, -4.25-37.0 µm) for CRAE, and 19.3 µm (95% LOA, 0.09-38.6 µm) for CRVE. We propose an algorithm converting IVAN and VAMPIRE measurements into SIVA-estimated measurements, which could be used to homogenize sets of vessel measurements obtained with different software packages.