Retinal Vascular Imaging Markers and Incident Chronic Kidney Disease: A Prospective Cohort Study.

Retinal microvascular changes indicating microvascular dysfunction have been shown to be associated with chronic kidney disease (CKD) in cross-sectional studies, but findings were mixed in prospective studies. We aimed to evaluate the relationship between retinal microvascular parameters and incident CKD in an Asian population. We examined 1256 Malay adults aged 40-80 years from the Singapore Malay Eye Study, who attended both the baseline (2004-07) and the follow-up (2011-13) examinations and were free of prevalent CKD. We measured quantitative retinal vascular parameters (arteriolar and venular calibre, tortuosity, fractal dimension and branching angle) using a computer-assisted program (Singapore I Vessel Assessment, SIVA) and retinopathy (qualitative parameter) using the modified Airlie house classification system from baseline retinal photographs. Incident CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 + 25% decrease in eGFR during follow-up. Over a median follow-up period of 6 years, 78 (6.21%) developed CKD (70.5% had diabetes). In multivariable models, smaller retinal arterioles (hazards ratio [95% confidence interval] = 1.34 [1.00-1.78]), larger retinal venules (2.35 [1.12-5.94] and presence of retinopathy (2.54 [1.48-4.36]) were associated with incident CKD. Our findings suggest that retinal microvascular abnormalities may reflect subclinical renal microvascular abnormalities involved in the development of CKD.

Dynamic Responses in Retinal Vessel Caliber With Flicker Light Stimulation and Risk of Diabetic Retinopathy and Its Progression.

Purpose: This study investigated the associations between the responses of retinal vessels to flickering light and the incidence and progression of diabetic retinopathy (DR). Methods: A prospective cohort study of adult subjects with diabetes mellitus. The dynamic vessel analyser (DVA) was used to measure retinal vascular dilatation in response to diffuse illuminance flicker. Diabetic retinopathy was graded from retinal photography at baseline and at 1 year. Incident DR and two-step change in DR were analyzed. Results: There were 276 subjects in total, with a mean age of 59.8 ± 8.9 years. The majority were male (73%) and the mean glycated hemoglobin A1c (HbA1c) level and mean duration of diabetes were 7.7 ± 1.4% and 14.0 ± 10.5 years, respectively. After adjustments for age, sex, smoking, duration of diabetes, HbA1c, hypertension, and hyperlipidemia, the responses of retinal arterioles to flicker stimulation were lower in subjects with incident DR (P = 0.048). Subjects with greater arteriolar dilatory responses were less likely to have DR progression (odds ratio [OR] 1.85, [95% confidence interval [CI] 1.33-2.56], P = 0.012, per SD decrease). Subjects with greater venular dilatory responses were also less likely to have DR progression (OR 1.89, [95% CI 1.35-2.63], P = 0.003, per SD decrease). There were no significant associations between arteriolar or venular dilation response and incident proliferative DR (PDR) and DR regression. Conclusions: Reduced retinal arteriolar and venular dilatory responses to flickering light are associated with risk of DR progression at 1 year in adult patients with diabetes.

Six-Year Incidence of Age-Related Macular Degeneration in Asian Malays: The Singapore Malay Eye Study.

PURPOSE: To determine the 6-year incidence of early and late age-related macular degeneration (AMD) in a Singaporean Malay population and to validate the Age-Related Eye Disease Study (AREDS) simplified severity scale in Asians. DESIGN: Prospective, population cohort study. PARTICIPANTS: The Singapore Malay Eye Study baseline participants (age, ≥40 years; 2006-2008) were followed up in 2011 through 2013, and 1901 of 3280 of eligible participants (72.1%) took part. METHODS: Fundus photographs were graded using the Wisconsin AMD grading system. MAIN OUTCOME MEASURES: Incidence of early and late AMD. RESULTS: Gradable fundus photographs were available for 1809 participants who attended both baseline and 6-year follow-up examinations. The age-standardized incidences of early and late AMD were 5.89% (95% confidence interval [CI], 4.81-7.16) and 0.76% (95% CI, 0.42-1.29), respectively. The 5-year age-standardized incidence of early AMD (calculated based on the 6-year incidence) was lower in our population (5.58%; 95% CI, 4.43-7.01) compared with the Beaver Dam Eye Study population (8.19%). The incidence of late AMD in our population was similar to that of the Beaver Dam Eye Study population (0.98% [95% CI, 0.49-1.86] vs. 0.91%), the Blue Mountains Eye Study population (1.10% [95% CI, 0.52-9.56] vs. 1.10%), and the Hisayama Study population (1.09% [95% CI, 0.54-4.25] vs. 0.84%). The incidence of late AMD increased markedly with increasing baseline AREDS score (step 0, 0.23%; step 4, 9.09%). CONCLUSIONS: This study documented the incidence of early and late AMD in a Malay population. The AREDS simplified severity scale is useful in predicting the risk of late AMD development in Asians.

Retinopathy Signs Improved Prediction and Reclassification of Cardiovascular Disease Risk in Diabetes: A prospective cohort study.

CVD risk prediction in diabetics is imperfect, as risk models are derived mainly from the general population. We investigate whether the addition of retinopathy and retinal vascular caliber improve CVD prediction beyond established risk factors in persons with diabetes. We recruited participants from the Singapore Malay Eye Study (SiMES, 2004-2006) and Singapore Prospective Study Program (SP2, 2004-2007), diagnosed with diabetes but no known history of CVD at baseline. Retinopathy and retinal vascular (arteriolar and venular) caliber measurements were added to risk prediction models derived from Cox regression model that included established CVD risk factors and serum biomarkers in SiMES, and validated this internally and externally in SP2. We found that the addition of retinal parameters improved discrimination compared to the addition of biochemical markers of estimated glomerular filtration rate (eGFR) and high-sensitivity C-reactive protein (hsCRP). This was even better when the retinal parameters and biomarkers were used in combination (C statistic 0.721 to 0.774, p = 0.013), showing improved discrimination, and overall reclassification (NRI = 17.0%, p = 0.004). External validation was consistent (C-statistics from 0.763 to 0.813, p = 0.045; NRI = 19.11%, p = 0.036). Our findings show that in persons with diabetes, retinopathy and retinal microvascular parameters add significant incremental value in reclassifying CVD risk, beyond established risk factors.

Vision impairment and major eye diseases reduce vision-specific emotional well-being in a Chinese population.

AIMS: To assess the relationship between vision impairment (VI) and major eye diseases, with vision-specific emotional well-being in a Chinese population. METHODS: In this population-based cross-sectional study, 3353 Chinese participants aged 40-80 years answered the emotional well-being scale of the Impact of Vision Impairment questionnaire, validated using Rasch analysis. Participants underwent visual acuity testing and collection of sociodemographic and medical data from standardised questionnaires. The relationships between presenting bilateral VI, presence of major eye diseases (cataract, undercorrected refractive error, glaucoma, age-related macular degeneration and diabetic retinopathy) and emotional well-being were assessed using linear regression models. Stratified analyses for age, gender, education and immigration status were conducted to determine if change in ß coefficients differed within each stratum. RESULTS: Approximately half of patients (n=1805) had normal vision, and 43% (n=1534) and 3.4% (n=114) had moderate and severe bilateral VI, respectively. Vision-specific emotional well-being systematically worsened as severity of bilateral VI increased (p<0.001). Compared with no VI and no eye diseases, respectively, severe bilateral VI (23%; ß -1.84; 95% CI -2.23 to -1.43) and glaucoma (ß -1.88; 95% CI -3.00 to -0.76) were associated with a clinically meaningful reduction in emotional well-being. The reduction in vision-related emotional well-being was substantially and significantly greater in men compared with women (p<0.05). CONCLUSIONS: Severe VI and glaucoma are associated with substantial decrements in vision-specific emotional well-being, highlighting the importance of preventing progression of vision loss. Evidence-based interventions to improve vision-related coping skills and emotional management for patients with severe VI and glaucoma are warranted.

The impact of typical neovascular age-related macular degeneration and polypoidal choroidal vasculopathy on vision-related quality of life in Asian patients.

AIMS: To determine the impact of neovascular age-related macular degeneration (nAMD) on vision-related quality of life (VRQoL) in an Asian population. METHODS: In this cross-sectional study, 162 subjects with nAMD from the Asian AMD Phenotyping Study and 105 randomly sampled age-matched and gender-matched controls from the population-based Singapore Chinese Eye Study were recruited. nAMD was categorised as either polypoidal choroidal vasculopathy (PCV) or 'typical' AMD (tAMD). The reading, mobility and emotional well-being subscales of the impact of vision impairment (IVI) scale were validated using Rasch analysis and used as the main outcome measures and collectively referred to as VRQoL. Multivariate linear regression analyses were performed to assess the impact of nAMD overall, and PCV and tAMD subtypes, on the three IVI domains. RESULTS: Of the 162 with nAMD, 103 (63.6%) had PCV and 59 (36.4%) had tAMD. In multivariate models, nAMD overall was independently associated with a 21% reduction in reading (ß=-1.08; CI -1.58 to -0.57); 16% reduction in mobility (ß=-0.74; -1.14 to -0.33) and 44% reduction in emotional well-being (ß=-2.15; -2.83 to -1.47) compared with controls. There were significant VRQoL deficits (p<0.05) associated with both PCV and tAMD; these deficits were similar and not statistically different between the two nAMD subtypes (p>0.05). CONCLUSIONS: Neovascular AMD, including both PCV and tAMD subtypes, has a detrimental impact on VRQoL in Asian subjects independent of level of vision impairment. Interventions to increase reading capacity, enhance mobility and independence and improve mental health outcomes for subjects with neovascular AMD further address the impact of the condition on VRQoL in addition to pharmacological therapies.

Association of Changes in Visual Acuity With Vision-Specific Functioning in the Singapore Malay Eye Study.

IMPORTANCE: Longitudinal population-based data on the effect of vision loss on vision-specific functioning (VSF) are scarce, particularly in Asian populations. OBJECTIVE: To examine the association between changes in presenting visual acuity (PVA) and VSF. DESIGN, SETTING, AND PARTICIPANTS: Vision-specific functioning of 1895 adults was assessed in the baseline (January 20, 2004-July 31, 2006) and follow-up (June 28, 2010-July 31, 2014) phases of the longitudinal population-based Singapore Malay Eye Study. Mean (SD) differences and effect sizes for results of the modified Visual Function Index were calculated for 3 categories of change in PVA in the eye with better vision during the follow-up period (PVA gain of ≥2 lines [+0.2 logMAR], no change [PVA between a loss of 2 lines and a gain of 2 lines], and PVA loss of ≥2 lines [-0.2 logMAR]). The group with PVA loss was further stratified into incident vision impairment (VI) (baseline PVA ≥6/12) and progression of VI (baseline PVA <6/12) that worsened by 2 or more lines at follow-up. Associations between PVA and VSF changes were assessed using multiple linear regression models. EXPOSURES: Presenting visual acuity was measured using a logMAR chart during an ophthalmic examination at baseline and follow-up. MAIN OUTCOMES AND MEASURES: Vision-specific functioning and associations between PVA and changes in VSF. RESULTS: Of the 1895 participants (mean [SD] age at baseline, 56.9 [10.1] years; 862 men and 1033 women), at follow-up, 319 (16.8%) had lost 2 or more lines of PVA (mean [SD] PVA loss, 0.34 [0.22] logMAR; P < .001), which was associated with a mean (SD) -0.87 [2.12] logit decrease in VSF (medium effect size, -0.61). Of these 319 participants, 153 (48%) had incident VI and 166 (52%) had progression of VI, which were associated with mean (SD) -1.08 (2.15) (effect size, -0.86) and -0.64 (2.06) (effect size, -0.41) logit reductions in VSF, respectively. In adjusted models, compared with participants with no change in PVA, those who lost 2 or more lines had a significant 117% reduction in VSF (ß, -0.39; 95% CI, -0.62 to -0.16). Older age (-0.55 logit decrease in VSF; 95% CI, -0.66 to -0.43) and female sex (-0.25 logit decrease in VSF; 95% CI, -0.45 to -0.06) were also independently associated with poorer VSF at follow-up (P < .01). CONCLUSIONS AND RELEVANCE: Approximately 1 in 6 Malay adults lost 2 or more lines of PVA during the 6 years of the study; this loss was associated with a sizable deterioration in VSF. Loss of VSF was greater in participants with new-onset VI compared with those whose existing VI worsened. In older adults, strategies to prevent the onset of new VI may have more relative effect than delaying further progression among those with existing VI.

Correction: The Impact of Macronutrients on Retinal Microvasculature among Singapore Pregnant Women during the Mid-Late Gestation.

[This corrects the article DOI: 10.1371/journal.pone.0160704.].

The Impact of Macronutrients on Retinal Microvasculature among Singapore Pregnant Women during the Mid-Late Gestation.

BACKGROUND: Imbalanced macronutrient intakes can induce impairment of endothelial and vascular function, and further lead to metabolic and cardiovascular disease. However, little is known about the influence of such diets on endothelial and vascular dysfunction in pregnant women, even though high-fat diet is a known risk for pregnancy complications such as gestational diabetes and pre-eclampsia. OBJECTIVE: We aimed to assess the association between maternal macronutrient intakes (protein, fat and carbohydrates), dietary quality and retinal microvascular changes in a multi-ethnic Asian mother-offspring cohort. METHODS: Pregnant women (n = 614) with singleton pregnancies were recruited during their first trimester from June 2009 to Sep 2010. Maternal diet quality and macronutrient intakes, expressed as a percentage of total energy during pregnancy, were ascertained using 24 hr recalls and 3 d food diaries at 26-28 weeks gestation. Retinal examination was completed at the same clinic visit. Dietary quality was assessed and scored using the Health Eating Index in Asian Pregnant women (HEI-AP), while macronutrients intakes ware expressed as percentages of total energy and further log transformed for analysis. Associations were examined cross-sectionally by substitution models with the use of multiple linear regression. RESULTS: In adjusted model, each 20 points decrease in HEI-AP score was associated with a significant increase of 1.70 µm (p<0.05) in retinal venular calibre. Each 0.1 log increase in percentage of total fat intake was associated with a significant increment of 1.84 µm (p<0.05) in retinal venular caliber. Additionally, each 0.1 log increase in percentage of mono-unsaturated fat intake was associated with an increment of 1.84 µm (p<0.01) in retinal venular caliber. CONCLUSIONS: In this cross-sectional study, we found that women with higher fat and lower protein intakes, and lower diet quality tended to have wider retinal venular caliber, which is suggestive of suboptimal microvasculature.

Association of Vision Impairment and Major Eye Diseases With Mobility and Independence in a Chinese Population.

IMPORTANCE: Mobility limitations arising from vision impairment (VI) can result in loss of independence and reduced quality of life. However, few data are available on the association between VI and mobility limitations at a population-based level, particularly in Asian populations. OBJECTIVE: To assess the association of VI and major eye diseases with mobility and independence (M&I) in a Chinese population. DESIGN, SETTING, AND PARTICIPANTS: The Singapore Chinese Eye Study (February 9, 2009, to December 19, 2011) was a population-based, cross-sectional study of 3353 persons aged 40 to 80 years of Chinese ethnicity. Patients underwent visual acuity testing, and sociodemographic and medical data were collected from standardized questionnaires. Data analysis for this study was performed October 2015 to April 2016. EXPOSURES: Presenting bilateral visual acuity (categorized as none, moderate, or severe VI) and major eye diseases (cataract, uncorrected refractive error, glaucoma, age-related macular degeneration, and diabetic retinopathy). MAIN OUTCOMES AND MEASURES: Patients answered questions on the M&I scale of the Impact of Vision Impairment questionnaire, validated using Rasch analysis. The composite M&I score (score range, -4.47 to 7.48 logits; higher scores indicate better M&I) and 11 individual item scores were the main outcomes. The association between bilateral VI and eye conditions and the composite and individual M&I item scores was assessed using linear regression models. RESULTS: Of the 3353 patients, the mean (SD) age was 59.7 (9.9) years, and 1662 (49.6%) were male. The mean (SD) presenting visual acuity values in the better and worse eyes were 0.20 (0.21) and 0.39 (0.42) logMAR, respectively. A total of 1432 patients (42.7%) and 114 patients (3.4%) had moderate and severe bilateral VI, respectively. Mobility and independence systematically worsened as the severity of bilateral VI increased. There was a clinically meaningful reduction in M&I (20%; ß, -1.44; 95% CI, -1.75 to -1.13) and all 11 M&I tasks in patients with severe bilateral VI compared with no VI. Glaucoma (13%; ß, -0.94; 95% CI, -1.82 to -0.06) and cataract (6%; ß, -0.43; 95% CI, -0.65 to -0.22) were independently associated with worse M&I, with patients with glaucoma particularly concerned about avoiding falling or tripping. CONCLUSIONS AND RELEVANCE: Bilateral VI in this population was associated with substantial decrements in M&I, with glaucoma and cataract independently associated with worse M&I. Although these associations do not prove that preventing bilateral VI will improve M&I in this population, the results suggest that such interventions could be of tremendous value from this perspective.

Joint Effect of Early Microvascular Damage in the Eye &Kidney on Risk of Cardiovascular Events.

Microalbuminuria is associated with an increased risk of cardiovascular disease (CVD), but not all individuals require treatment. Retinal microvascular abnormalities and microalbuminuria reflect early systemic microvascular changes. We examined the joint effect of retinal abnormalities and microalbuminuria on CVD risk in an Asian cohort. We conducted a prospective, population-based study. Retinal abnormalities were defined as presence of retinopathy and/or retinal venular widening. Microalbuminuria was defined as urinary albumin: creatinine ratio between 30-300 mg/g. Incident CVD was defined as newly diagnosed clinical stroke, acute myocardial infarction or CVD death. Cox regression models were performed to determine the associations between retinal abnormalities and microalbuminuria with risk of CVD, while controlling for established risk factors. 3,496 participants (aged ≥ 40) were free of prevalent CVD. During the follow-up (5.8 years), 126 (3.60%) participants developed CVD. Persons presenting with both retinal abnormalities and microalbuminuria were 6.71 times (95% CI, 2.68, 16.79) as likely to have incident CVD compared with those without either abnormalities. There was a significant interaction effect between retinal abnormalities and microalbuminuria on incident CVD. Assessment of retinal abnormalities in patients with microalbuminuria may provide additional value in identifying persons at risk of developing CVD.

Assessment of the psychometric properties of the Chinese Impact of Vision Impairment questionnaire in a population-based study: findings from the Singapore Chinese Eye Study.

PURPOSE: We investigated whether the Chinese impact of vision impairment (IVI) questionnaire is valid to generate reliable person estimates in a population-based sample. METHODS: VRQoL was measured using the 32-item Chinese version of the IVI questionnaire in the Singapore Chinese Eye Study (2009-2011), a population-based study of the prevalence and risk factors for VI and eye diseases in Chinese Singaporeans. Rasch analysis was used to assess the Chinese IVI's response category functioning, precision, unidimensionality, targeting and differential item functioning. The ability of the Chinese IVI to discriminate participants along the spectrum of VI demonstrated criterion validity. RESULTS: Of the 3353 participants, 27.2 % (n = 912) had VI (presenting visual acuity <6/12, better eye). Response categories were collapsed from six to four to resolve disordered thresholds. The Chinese IVI initially demonstrated multidimensionality and was split into three scales: 'Reading and Accessing Information'; 'Mobility and Independence'; and 'Emotional Well-being'. All three scales were unidimensional and demonstrated excellent range-based precision (all reliability coefficients 0.97), following removal of three misfitting items. Mean person measures decreased with worsening VI (e.g. Reading: none (7.50 logits); mild (6.99 logits); moderate (6.44 logits); and severe (3.01 logits) VI; p < 0.001). CONCLUSIONS: A three-dimensional 29-item Chinese IVI is a valid tool to assess the impact of VI on VRQoL in a large population-based sample, comprising over a quarter of participants with VI. The 28-item English IVI is also likely to be valid for use in population-based studies; however, this must be demonstrated empirically in future studies.

Impact of Visual Impairment and Eye diseases on Mortality: the Singapore Malay Eye Study (SiMES).

We investigated the relationship of visual impairment (VI) and age-related eye diseases with mortality in a prospective, population-based cohort study of 3,280 Malay adults aged 40-80 years between 2004-2006. Participants underwent a full ophthalmic examination and standardized lens and fundus photographic grading. Visual acuity was measured using logMAR chart. VI was defined as presenting (PVA) and best-corrected (BCVA) visual acuity worse than 0.30 logMAR in the better-seeing eye. Participants were linked with mortality records until 2012. During follow-up (median 7.24 years), 398 (12.2%) persons died. In Cox proportional-hazards models adjusting for relevant factors, participants with VI (PVA) had higher all-cause mortality (hazard ratio[HR], 1.57; 95% confidence interval[CI], 1.25-1.96) and cardiovascular (CVD) mortality (HR 1.75; 95% CI, 1.24-2.49) than participants without. Diabetic retinopathy (DR) was associated with increased all-cause (HR 1.70; 95% CI, 1.25-2.36) and CVD mortality (HR 1.57; 95% CI, 1.05-2.43). Retinal vein occlusion (RVO) was associated with increased CVD mortality (HR 3.14; 95% CI, 1.26-7.73). No significant associations were observed between cataract, glaucoma and age-related macular degeneration with mortality. We conclude that persons with VI were more likely to die than persons without. DR and RVO are markers of CVD mortality.

Prevalence, Risk Factors, and Visual Features of Undiagnosed Glaucoma: The Singapore Epidemiology of Eye Diseases Study.

IMPORTANCE: Glaucoma can remain asymptomatic until a severe stage, resulting in a high prevalence of undiagnosed glaucoma worldwide. Asia accounts for 60% of the world's total glaucoma cases. To our knowledge, no epidemiological studies have assessed ethnic differences in undiagnosed glaucoma among various Asian subgroups. OBJECTIVE: To determine the prevalence of, risk factors for, and visual features of undiagnosed primary glaucoma in a multiethnic Asian population. DESIGN, SETTING, AND PARTICIPANTS: The Singapore Epidemiology of Eye Diseases Study is a population-based trial in which 3353 Chinese (2009-2011), 3280 Malays (2004-2006), and 3400 Indians (2007-2009) aged 40 to 80 years were invited for an eye examination, including visual field assessment, to establish glaucoma diagnosis. Participants with undiagnosed glaucoma (ie, answering no to whether they previously had been told by a physician that they had glaucoma, not using glaucoma medication, or not having undergone glaucoma surgery) were identified. MAIN OUTCOMES AND MEASURES: Prevalence of, risk factors for, and visual features of undiagnosed glaucoma. RESULTS: Of 272 participants with primary glaucoma, 196 (72.1%) were previously undiagnosed. The overall prevalence of undiagnosed primary glaucoma was highest among Malays (2.65%; 95% CI, 2.10%-3.31%), followed by Chinese (1.51%; 95% CI, 1.13%-2.01%) and Indians (0.97%; 95% CI, 0.64%-1.43%). In multivariable analysis, variables associated with higher risk of undiagnosed glaucoma were younger age (odds ratio [OR], 1.04; 95% CI, 1.00-1.09; P = .04), Malay ethnicity (OR, 3.65; 95% CI, 1.31-10.13; P = .01), presence of primary open-angle glaucoma (OR, 3.82; 95% CI, 1.60-9.14; P = .003), absence of yearly eyeglass checks (OR, 9.29; 95% CI, 3.43-25.21; P < .001), and lack of cataract surgery (OR, 4.19; 95% CI, 1.68-10.48; P < .001). No patients were blind in both eyes. A mean (SD) of 4.1% (2.8%) (n = 8) of the newly diagnosed patients were blind in 1 eye, and a mean (SD) of 56.0% (7.2%) (n = 102) had noteworthy visual field damage (mean deviation worse than -6 dB) in at least 1 eye. CONCLUSIONS AND RELEVANCE: The prevalence of undiagnosed primary glaucoma varied among ethnic populations in whom a mean (SD) of 49.0% (14.0%) (n = 24) of affected individuals 50 to 59 years old already had clinically significant visual field loss. Such data may assist policymakers in implementing cost-effective public health interventions to reduce the effect of blindness associated with undiagnosed glaucoma.

Prevalence and determinants of undiagnosed diabetic retinopathy and vision-threatening retinopathy in a multiethnic Asian cohort: the Singapore Epidemiology of Eye Diseases (SEED) study.

OBJECTIVE: To determine the prevalence and risk factors of undiagnosed diabetic retinopathy (DR), in particular vision-threatening DR (VTDR) in a multiethnic Asian cohort. DESIGN: A population-based survey of 3353 Chinese, 3280 Malays and 3400 Indians (73.6% response) aged 40-80 years residing in Singapore. Diabetes mellitus (DM) was defined as random glucose ≥11.1 mmol/L, use of diabetic medication or a previous physician diagnosis. DR severity was graded from retinal photographs following the modified Airlie House classification. VTDR was defined as the presence of severe non-proliferative DR (NPDR), proliferative DR (PDR) or clinically significant macular oedema (CSMO), using the Eye Diseases Prevalence Research Group definition. Participants were deemed 'undiagnosed' if they reported no prior physician diagnosis in structured interviews, in those with the condition. RESULTS: Of 10 033 participants, 2376 had DM (23.7%), of which 805 (33.9%) had DR. Among 2376 with DM, 11.1% (n=263) were undiagnosed. Among 805 with DR, 671 (83.3%) were undiagnosed. Among 212 with VTDR, 59 (27.3%) were undiagnosed. In multivariate models, factors associated with undiagnosed VTDR were higher low-density lipoprotein (LDL) cholesterol (OR=1.53, 95% CI 0.99 to 2.35, p=0.05) and absence of visual impairment or blindness in any eye in terms of best-corrected vision OR=3.00, 95% CI 1.47 to 6.11, p=0.003). CONCLUSIONS: In this community, a quarter with VTDR is undiagnosed, and 8 in 10 with any DR are undiagnosed, compared with only 1 in 10 with DM undiagnosed. These findings suggest that screening for diabetes is successful, while screening for DR is currently inadequate in our population. Public health strategies to aid early diagnosis of DR in Singapore are urgently warranted to reduce blindness due to diabetes.

Relationship of systemic endothelial function and peripheral arterial stiffness with diabetic retinopathy.

BACKGROUND: To investigate possible associations between diabetic retinopathy (DR) and systemic vascular endothelial function and arterial stiffness measured using reactive hyperaemia peripheral arterial tonometry. METHODS: This was a cross-sectional observational clinical study. Subjects with diabetes were recruited and DR was graded from retinal photographs. Systemic endothelial function was measured using reactive hyperaemia peripheral arterial tonometry (EndoPAT) and expressed as the reactive hyperaemia index (RHI). Peripheral arterial stiffness was measured using the same device and expressed as the augmentation index (AI). RESULTS: In total, 164 eyes of 95 Chinese patients were evaluated. The mean age of the subject eyes was 60.1±8.2 years and 76.8% were men. The mean duration of diabetes was 15.5±9.8 years, and the mean HbA1c was 8.1±1.4%. In age-gender-adjusted models, increasing severity of DR was associated with increasing mean RHI (p=0.001) and increasing mean AI (p<0.001). In multivariate models, adjusting additionally for smoking, mean duration of diabetes, HbA1c and hypertension, the associations with RHI and AI persisted (p=0.011 and 0.001, respectively). In analyses of the dichotomous outcomes clinically significant macular oedema (CSME), moderate DR and vision-threatening DR, AI was a significant predictor of CSME and vision-threatening DR. In multivariate-adjusted models, for every SD increase in AI, the odds of having CSME was 1.78 times higher (95% CI 1.05 to 2.99; p=0.029). For every SD increase in AI, the odds of having vision-threatening DR was 1.73 times higher (95% CI 1.17 to 2.56; p=0.003). CONCLUSIONS: Subjects with more severe DR have larger peripheral reactive hyperaemic responses and greater peripheral vascular stiffness. These findings support the link between the microvascular changes of diabetes and macrovascular disease.

Incidence of myocardial infarction, stroke, and death in patients with age-related macular degeneration treated with intravitreal anti-vascular endothelial growth factor therapy.

PURPOSE: To describe the rates of myocardial infarction (MI), stroke, and mortality in patients who have treatment with intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections for age-related macular degeneration (AMD). DESIGN: A retrospective population linkage study. METHOD: We identified patients aged 40 years and above who received treatment with intravitreal anti-VEGF injections for AMD from January 1, 2008 to December 31, 2011 at the Singapore National Eye Centre. We used a national record linkage database to identify patients who developed MI, stroke, and all-cause mortality after the first injection, excluding those with previous MI or stroke at baseline from the respective analysis. We compared rates of MI, stroke, and mortality to that of the total Singapore population. RESULTS: A total of 1182 individuals had an intravitreal anti-VEGF injection included in this analysis, with the majority receiving bevacizumab (n = 1011). Overall, 19 patients developed MI, 16 developed stroke, and there were 43 mortalities, giving an age-adjusted incidence rate of 350.2 per 100 000 person-years for MI, 299.3 per 100 000 person-years for stroke, and 778.9 per 100 000 person-years for mortality. This is comparable to the weighted incidence rates of the Singapore population (427.1 per 100 000 person-years for MI, 340.4 per 100 000 person-years for stroke, and 921.3 per 100 000 person-years for mortality). CONCLUSION: The incidence rate of MI, stroke, and death in this cohort of AMD patients treated with anti-VEGF was low, and was not significantly higher than the age-adjusted incidence rate of these events in the Singapore population.

Chronic kidney disease, cardiovascular disease and mortality: A prospective cohort study in a multi-ethnic Asian population.

BACKGROUND: Few studies have examined the impact of chronic kidney disease (CKD) on adverse cardiovascular outcomes and deaths in Asian populations. We evaluated the associations of CKD with cardiovascular disease (CVD) and all-cause mortality in a multi-ethnic Asian population. DESIGN: Prospective cohort study of 7098 individuals who participated in two independent population-based studies involving Malay adults (n = 3148) and a multi-ethnic cohort of Chinese, Malay and Indian adults (n = 3950). METHODS: CKD was assessed from CKD-EPI estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). Incident CVD (myocardial infarction, stroke and CVD mortality) and all-cause mortality were identified by linkage with national disease/death registries. RESULTS: Over a median follow-up of 4.3 years, 4.6% developed CVD and 6.1% died. Risks of both CVD and all-cause mortality increased with decreasing eGFR and increasing albuminuria (all p-trend <0.05). Adjusted hazard ratios (HR (95% confidence interval)) of CVD and all-cause mortality were: 1.54 (1.05-2.27) and 2.21 (1.67-2.92) comparing eGFR <45 vs ≥60; 2.81 (1.49-5.29) and 2.34 (1.28-4.28) comparing UACR ≥300 vs <30. The association between eGFR <60 and all-cause mortality was stronger among those with diabetes (p-interaction = 0.02). PAR of incident CVD was greater among those with UACR ≥300 (12.9%) and that of all-cause mortality greater among those with eGFR <45 (16.5%). CONCLUSIONS: In multi-ethnic Asian adults, lower eGFR and higher albuminuria were independently associated with incident CVD and all-cause mortality. These findings extend previously reported similar associations in Western populations to Asians and emphasize the need for early detection of CKD and intervention to prevent adverse outcomes.

Dynamic responses in retinal vessel caliber with flicker light stimulation in eyes with diabetic retinopathy.

PURPOSE: This study investigated the responses of retinal vessels to flickering light in diabetic patients with various stages of diabetic retinopathy (DR). METHODS: This cross-sectional observational study evaluated adult subjects with diabetes mellitus. The Dynamic Vessel Analyzer (DVA) was used to measure retinal vascular dilatation in response to diffuse illuminance flicker. Diabetic retinopathy was graded from retinal photography. RESULTS: There were 279 subjects in total, with a mean age of 59.9 ± 9.2 years. The majority were male (73%) and the mean HbA1c level and mean duration of diabetes were 7.7% ± 1.4% and 13.9 ± 10.4 years, respectively. After adjustments for age, sex, smoking, duration of diabetes, HbA1c, hypertension, and hyperlipidemia, the responses of both retinal arterioles and venules to flicker stimulation decreased continuously with increasing stages of diabetic retinopathy (P = 0.008 and <0.001, respectively). Subjects with reduced arteriolar dilation responses were more likely to have any DR (odds ratio, OR, 1.20, [95% confidence interval (CI), 1.01-1.45], P = 0.045, per SD decrease). Subjects with reduced venular dilation responses were more likely to have any DR, moderate DR, or vision-threatening DR (OR: 1.27 [1.04-1.53], P = 0.02; OR: 1.27 (1.06-1.49), P = 0.007; and OR: 1.51 (1.14-1.50), P = 0.002; per SD decrease, respectively). CONCLUSIONS: The responses of retinal arterioles and venules to flickering light are reduced in subjects with DR, and decrease progressively with more severe stages of DR.