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Introduction: Our study aimed to examine the relationship between cardiovascular diseases (CVD) with peripapillary retinal fiber layer (RNFL) and macular ganglion cell-inner plexiform layer (GCIPL) thickness profiles in a large multi-ethnic Asian population study., Methods: 6,024 Asian subjects were analyzed in this study. All participants underwent standardized examinations, including spectral domain OCT imaging (Cirrus HD-OCT; Carl Zeiss Meditec). In total, 9,188 eyes were included for peripapillary RNFL analysis (2,417 Malays; 3,240 Indians; 3,531 Chinese), and 9,270 eyes (2,449 Malays, 3,271 Indians, 3,550 Chinese) for GCIPL analysis. History of CVD was defined as a self-reported clinical history of stroke, myocardial infarction, or angina. Multivariable linear regression models with generalized estimating equations were performed, adjusting for age, gender, ethnicity, diabetes, hypertension, hyperlipidaemia, chronic kidney disease, body mass index, current smoking status, and intraocular pressure., Results: We observed a significant association between CVD history and thinner average RNFL (β = -1.63; 95% CI, -2.70 to -0.56; p  = 0.003). This association was consistent for superior (β = -1.79, 95% CI, -3.48 to -0.10; p  = 0.038) and inferior RNFL quadrant (β = -2.14, 95% CI, -3.96 to -0.32; p  = 0.021). Of the CVD types, myocardial infarction particularly showed significant association with average (β = -1.75, 95% CI, -3.08 to -0.42; p  = 0.010), superior (β = -2.22, 95% CI, -4.36 to -0.09; p  = 0.041) and inferior (β = -2.42, 95% CI, -4.64 to -0.20; p  = 0.033) RNFL thinning. Among ethnic groups, the association between CVD and average RNFL was particularly prominent in Indian eyes (β = -1.92, 95% CI, -3.52 to -0.33; p  = 0.018). CVD was not significantly associated with average GCIPL thickness, albeit a consistent negative direction of association was observed (β = -0.22, 95% CI, -1.15 to 0.71; p  = 0.641)., Discussion: In this large multi-ethnic Asian population study, we observed significant association between CVD history and RNFL thinning. This finding further validates the impact of impaired systemic circulation on RNFL thickness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Majithia, Quek, Chee, Lim, Nusinovici, Soh, Thakur, Rim, Sabanayagam, Cheng and Tham.)

Aims: To examine the relationship between vision impairment (VI) and employment outcomes in a multiethnic Asian population., Methods: We included 7608 Asian individuals aged ≥40 years (mean (SD) age: 58.4 (10.3) years; 64.8% male) from the Singapore Epidemiology Eye Disease Study (response rate: 78.8%), a population-based cohort study (mean follow-up period: 6.2 years). Presenting visual acuity (VA) was assessed using a logarithm of the minimum angle of resolution (logMAR) chart, with VI defined as mild (VA >0.3 to <0.6 logMAR) and moderate to severe (VA ≥0.6 logMAR). Self-reported employment statuses at both baseline and follow-up were used as outcomes. Underemployment was defined as a decline in occupational skill level, categorised by International Standard Classification of Occupations, at follow-up compared with baseline. Multinomial logistic regression models were used to determine independent associations between VI and various employment outcomes, adjusted for variables that were found to significantly differ across employment statuses., Results: Presenting VI was prevalent in 20.2% (N=1536) of participants. Compared with those without VI, participants with mild and moderate to severe VI were more likely to be unemployed at baseline (OR 1.47, 95% CI 1.15 to 1.87, p=0.002 and 2.74, 95% CI 1.94 to 3.89, p<0.001, respectively). At follow-up, participants with any VI at baseline were more likely to be underemployed (OR 1.46, 95% CI 1.03 to 2.05, p=0.033)., Conclusion: VI, even when mild, is associated with unemployment and underemployment. Future studies should investigate whether visual interventions could be used as part of a multipronged strategy to improve employment outcomes for the population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To characterise the association between visual field (VF) defects and myopic macular degeneration (MMD) in highly myopic adults without glaucoma., Methods: Participants (n=106; 181 eyes) with high myopia (HM; spherical equivalent ≤-5.0 D or axial length (AL) ≥26 mm), after excluding glaucoma and glaucoma suspects, from the Singapore Epidemiology of Eye Diseases-HM study were included in this cross-sectional study. Humphrey VF (central 24-2 threshold), cup-disc ratio (CDR) and intraocular pressure (IOP) measurements were performed. Mean deviation (MD) and pattern SD (PSD), VF defects (normal or abnormal; p<0.05 in ≥3 non-edge contiguous locations) and pattern (eg, generalised sensitivity loss) were analysed. MMD presence was diagnosed from fundus photographs. Generalised estimating equations were used for analysing factors (MD, PSD, VF defects, CDR and IOP) associated with MMD., Results: Mean age was 55.4±9.9 years and 51.9% were women (AL=26.7±1.1 mm). MMD eyes had lower MD (-3.8±2.9 dB vs -1.1±1.4 dB) and higher PSD (2.8±1.7 dB vs 1.7±0.6 dB). A higher percentage of MMD eyes (n=48) had abnormal VF (62.5% vs 28.6%; p<0.001) compared with no MMD (n=133 eyes). VF pattern in MMD eyes was significantly different from eyes without MMD (p=0.001) with greater generalised sensitivity loss (53.3% vs 10.5%) and arcuate defects (16.7% vs 10.5%). In multivariate analyses, MD (OR=1.52) and PSD (OR=1.67) were significantly (p=0.003) associated with MMD, but VF defects were not associated with MMD., Conclusion: Highly myopic adults with MMD may have VF loss when compared with highly myopic patients without MMD even in adults without glaucoma., Competing Interests: Competing interests: YLW is an employee of Essilor International, Singapore., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The relationship between baseline cognitive impairment (CI) and incident visual impairment (VI) in Asians is unclear., Objective: To determine the associations between baseline CI with incident VI and visual acuity (VA) at 6-year follow-up in multiethnic Asians., Design: Cohort., Setting: Population-based., Subjects: Two thousand three hundred and twenty-four adults aged ≥60 years from the Singapore Epidemiology of Eye Diseases Study (response rate 64%)., Methods: CI was defined using the validated Abbreviated Mental Test (AMT). VA was objectively measured using a LogMAR chart. Any incident VI was defined as having no VI (Snellen's VA better than or equal to 20/40) at baseline but present (VA worse than 20/40) at 6-year follow-up. VI severity was defined according to the International Classification of Diseases, 11th Revision. Associations were assessed using logistic and linear regression models., Results: Of the 2,324 participants, 248 had CI at baseline. Presence of baseline CI was associated with more than twice the odds of any incident VI, incident mild and moderate-severe VI (OR [95% confidence interval]: 2.48 [1.55-3.90], 2.07 [1.17-3.55], and 2.61 [1.36-4.93], respectively) and worse VA (β [95% confidence interval]: 0.026 [0.006-0.046]) at 6-year follow-up. The leading causes of incident VI were cataract and under-corrected refractive error., Conclusions: Older adults with CI had more than double the odds of VI development and poorer VA than their cognitively intact counterparts, and most causes of incident VI were correctable. Strategies such as targeted vision screening and early intervention for early detection and management of vision loss in patients with cognitive decline are warranted., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus, a metabolic disorder, but understanding of its pathophysiology remains incomplete. Meta-analysis of three population-based cross-sectional studies (2004-11) representing three major Asian ethnic groups (aged 40-80 years: Chinese, 592; Malays, 1052; Indians, 1320) was performed. A panel of 228 serum/plasma metabolites and 54 urinary metabolites were quantified using nuclear magnetic resonance (NMR) spectroscopy. Main outcomes were defined as any DR, moderate/above DR, and vision-threatening DR assessed from retinal photographs. The relationship between metabolites and DR outcomes was assessed using multivariate logistic regression models, and metabolites significant after Bonferroni correction were meta-analyzed. Among serum/plasma metabolites, lower levels of tyrosine and cholesterol esters to total lipids ratio in IDL and higher levels of creatinine were positively associated with all three outcomes of DR (all p < 0.005). Among urinary metabolites, lower levels of citrate, ethanolamine, formate, and hypoxanthine were positively associated with all three DR outcomes (all p < 0.005). Higher levels of serum/plasma 3-hydroxybutyrate and lower levels of urinary 3-hydroxyisobutyrate were associated with VTDR. Comprehensive metabolic profiling in three large Asian cohorts with DR demonstrated alterations in serum/plasma and urinary metabolites mostly related to amino acids, lipoprotein subclasses, kidney function, and glycolysis.

Docosahexaenoic acid is an omega-3 fatty acid that is essential for neurological development and function, and it is supplied to the brain and eyes predominantly from dietary sources 1-6 . This nutrient is transported across the blood-brain and blood-retina barriers in the form of lysophosphatidylcholine by major facilitator superfamily domain containing 2A (MFSD2A) in a Na + -dependent manner 7,8 . Here we present the structure of MFSD2A determined using single-particle cryo-electron microscopy, which reveals twelve transmembrane helices that are separated into two pseudosymmetric domains. The transporter is in an inward-facing conformation and features a large amphipathic cavity that contains the Na + -binding site and a bound lysolipid substrate, which we confirmed using native mass spectrometry. Together with our functional analyses and molecular dynamics simulations, this structure reveals details of how MFSD2A interacts with substrates and how Na + -dependent conformational changes allow for the release of these substrates into the membrane through a lateral gate. Our work provides insights into the molecular mechanism by which this atypical major facility superfamily transporter mediates the uptake of lysolipids into the brain, and has the potential to aid in the delivery of neurotherapeutic agents.

The major facilitator superfamily domain-containing protein 2A (MFSD2A) is a constituent of the blood-brain barrier and functions to transport lysophosphatidylcholines (LPCs) into the central nervous system. LPCs such as that derived from docosahexanoic acid (DHA) are indispensable to neurogenesis and maintenance of neurons, yet cannot be synthesized within the brain and are dependent on MFSD2A for brain uptake. Recent studies have implicated MFSD2A mutations in lethal and non-lethal microcephaly syndromes, with the severity correlating to the residual activity of the transporter. We describe two siblings with shared parental ancestry, in whom we identified a homozygous missense mutation (c.1205C > A; p.Pro402His) in MFSD2A. Both affected individuals had microcephaly, hypotonia, appendicular spasticity, dystonia, strabismus, and global developmental delay. Neuroimaging revealed paucity of white matter with enlarged lateral ventricles. Plasma lysophosphatidylcholine (LPC) levels were elevated, reflecting reduced brain transport. Cell-based studies of the p.Pro402His mutant protein indicated complete loss of activity of the transporter despite the non-lethal, attenuated phenotype. The aggregate data of MFSD2A-associated genotypes and phenotypes suggest that additional factors, such as nutritional supplementation or modifying genetic factors, may modulate the severity of disease and call for consideration of treatment options for affected individuals.