Glucose attenuates the long-term adverse neurodevelopment effect of neonate pain stimulus via CRF/GR in rats.

BACKGROUND: Neonates undergo numerous painful procedures throughout their hospitalization. Repeated procedural pain may cause adverse long-term effects. Glucose as a non-pharmacological analgesia, is used for neonate pain management. In this study, potential mechanism of attenuate pain induced by glucose in neurodevelopment effect of neonate pain stimulus was investigated. METHODS: Neonatal rats to perform a repetitive injury model and glucose intervention model in the postnatal day 0-7(P0-7). Pain thresholds were measured by von Frey test weekly. The puberty behavioral outcome, tissue loss and protein expression in hippocampus were analyzed. RESULTS: Oral administration of glucose after repeated pain stimulation can maintain the hippocampal structure in, and reduce the expressions of corticotropin releasing factor (CFR) and glucocorticoid receptor (GR), therefore, resulted in long-term threshold of pain and cognitive improvement. CONCLUSION: Exposure to neonatal repeated procedural pain causes persistent mechanical hypersensitivity and the dysfunction of spatial memory retention at puberty. In addition, glucose can relieve these adverse effects, possibly via decreasing CRF/GR levels to change the hypothalamus-pituitary-adrenal (HPA) axis.

A Deep Learning Model for Segmentation of Geographic Atrophy to Study Its Long-Term Natural History.

PURPOSE: To develop and validate a deep learning model for the automatic segmentation of geographic atrophy (GA) using color fundus images (CFIs) and its application to study the growth rate of GA. DESIGN: Prospective, multicenter, natural history study with up to 15 years of follow-up. PARTICIPANTS: Four hundred nine CFIs of 238 eyes with GA from the Rotterdam Study (RS) and Blue Mountain Eye Study (BMES) for model development, and 3589 CFIs of 376 eyes from the Age-Related Eye Disease Study (AREDS) for analysis of GA growth rate. METHODS: A deep learning model based on an ensemble of encoder-decoder architectures was implemented and optimized for the segmentation of GA in CFIs. Four experienced graders delineated, in consensus, GA in CFIs from the RS and BMES. These manual delineations were used to evaluate the segmentation model using 5-fold cross-validation. The model was applied further to CFIs from the AREDS to study the growth rate of GA. Linear regression analysis was used to study associations between structural biomarkers at baseline and the GA growth rate. A general estimate of the progression of GA area over time was made by combining growth rates of all eyes with GA from the AREDS set. MAIN OUTCOME MEASURES: Automatically segmented GA and GA growth rate. RESULTS: The model obtained an average Dice coefficient of 0.72±0.26 on the BMES and RS set while comparing the automatically segmented GA area with the graders' manual delineations. An intraclass correlation coefficient of 0.83 was reached between the automatically estimated GA area and the graders' consensus measures. Nine automatically calculated structural biomarkers (area, filled area, convex area, convex solidity, eccentricity, roundness, foveal involvement, perimeter, and circularity) were significantly associated with growth rate. Combining all growth rates indicated that GA area grows quadratically up to an area of approximately 12 mm2, after which growth rate stabilizes or decreases. CONCLUSIONS: The deep learning model allowed for fully automatic and robust segmentation of GA on CFIs. These segmentations can be used to extract structural characteristics of GA that predict its growth rate.

Wholegrain and legume consumption and the 5-year incidence of age-related cataract in the Blue Mountains Eye Study.

The present study aims to investigate the effect of wholegrain and legume consumption on the incidence of age-related cataract in an older Australian population-based cohort. The Blue Mountains Eye Study (BMES) is a population-based cohort study of eye diseases among older adults aged 49 years or older (1992-1994, n 3654). Of 2334 participants of the second examination of the BMES (BMES 2, 1997-2000), 1541 (78·3 % of survivors) were examined 5 years later (BMES 3) who had wholegrain and legume consumption estimated from the FFQ at BMES 2. Cataract was assessed using photographs taken during examinations following the Wisconsin cataract grading system. Multivariable-adjusted logistic regression models were used to assess associations with the 5-year incidence of cataract from BMES 2 (baseline) to BMES 3. The 5-year incidence of cortical, nuclear and posterior subcapsular (PSC) cataract was 18·2, 16·5 and 5·9 %, respectively. After adjustment for age, sex and other factors, total wholegrain consumption at baseline was not associated with incidence of any type of cataract. High consumption of legumes showed a protective association for incident PSC cataract (5th quintile: adjusted OR 0·37; 95 % CI 0·15, 0·92). There was no significant trend of this association across quintiles (P = 0·08). In this older Australian population, we found no associations between wholegrain intake at baseline and the 5-year incidence of three cataract types. However, intake of legumes in the highest quintile, compared with the lowest quintile, may protect against PSC formation, a finding needing replication in other studies.

Incidence, progression and risk factors of age-related cataract in Malays: The Singapore Malay Eye Study.

IMPORTANCE: Long-term data on age-related cataract, a leading cause of blindness and visual impairment, is scarce in Asian populations. BACKGROUND: We report the 6-year incidence and progression of age-related cataract and associated risk factors in Malay adults living in Singapore. DESIGN: Population-based cohort study. PARTICIPANTS: A total of 3280 Malays aged 40+ years participated in baseline examinations of the Singapore Malay Eye Study (2004-2006). Six years later, 1901 (72.1% of eligible) baseline participants were re-examined. METHODS: Cataract was assessed using lens photos, taken during eye examinations, following the Wisconsin Cataract Grading System. MAIN OUTCOMES AND MEASURES: Incidence and progression of cortical, nuclear and posterior subcapsular (PSC) cataract. Poisson regression models and generalized estimating equations models (with Poisson link) were used to assess factors associated with cataract incidence and progression, respectively, adjusting for age, sex and other risk factors. RESULTS: Age-adjusted 6-year incidence of cortical, nuclear and PSC cataract was 14.1%, 13.6% and 8.7%, respectively, and was strongly age-related (P for trend <.001 for all types). Diabetes (relative risk [RR], 1.97; 95% confidence intervals [CI], 1.46-2.67) was associated with incident cortical cataract, hypertension was associated with PSC cataract incidence (RR, 2.09; 95% CI, 1.22-3.61), after multivariable adjustment. Progression occurred in 20.4%, 5.9% and 40.6% of baseline cortical, nuclear and PSC cataract cases, respectively. CONCLUSIONS AND RELEVANCE: Similar to other elderly populations, incidence and progression of cataract were common in this Malay population. Diabetes and hypertension were important modifiable risk factors for cataract, highlighting the importance of systemic health on eye disease.

Receptor for advanced glycation end products reveals a mechanism regulating thyroid hormone secretion through the SIRT1/Nrf2 pathway.

Advanced glycation end products (AGEs) play a causative role in the complications involved with diabetes mellitus (DM). Nowadays, DM with hypothyroidism (DM-hypothyroidism) is indicative of an ascended tendency in the combined morbidity. In this study, we examine the role of the receptor (RAGE) played for AGEs in thyroid hormone (TH) secretion via the silent information regulator 1 (SIRT1)/nuclear factor erythroid-derived factor 2-related factor 2 (Nrf2) pathway. Blood samples were collected from patients with type 2 DM (T2DM)-hypothyroidism and from patients with T2DM, followed by detection of serum AGEs level. The underlying regulatory mechanisms of RAGE were analyzed in association with the treatment of high glucose, siRNA against RAGE, AGE, SIRT1, or Nrf2 vector in normal immortalized thyroid Nthy-ori 3-1 cells. Serum of patients with T2DM-hypothyroidism indicated promoted levels of AGEs vs those with just T2DM. Both AGEs and high glucose triggered cellular damage, increased oxidative stress, as well as displayed a decreased survival rate along with TH secretion in the Nthy-ori 3-1 cells. Moreover, AGEs and high glucose also led to RAGE upregulation, both SIRT1 and NRF2 downregulation, and the decreased expression of TH secretion-related proteins in Nthy-ori 3-1 cells. Notably, these alternations induced by the AGEs can be reserved by silencing RAGE or upregulating either SIRT1 or Nrf2, indicating a mechanism of regulating TH secretion through the SIRT1/Nrf2 pathway. Collectively, our data proposed that AGEs and high glucose exerted a potent effect on cellular damage and TH deficiency in Nthy-ori 3-1 cells through the RAGE upregulation as well as SIRT1/Nrf2 pathway inactivation. This mechanism may underlie the occurrence of DM-hypothyroidism.

Retracted: Advanced glycation end-products induce oxidative stress through the Sirt1/Nrf2 axis by interacting with the receptor of AGEs under diabetic conditions.

Despite the administration of exogenous insulin and other medications used to control many aspects of diabetes mellitus (DM), increased oxidative stress has been increasingly acknowledged in DM development and complications. Therefore, this study aims to investigate the role of advanced glycation end-products (AGEs) in oxidative stress (OS) of thyroid cells in patients with DM. Patients with DM with or without thyroid dysfunction (TD) were enrolled. Thyroid toxic damage was induced by adding AGE-modified bovine serum albumin (AGE-BSA) to normal human thyroid follicular epithelial cells. The cell viability, cell cycle, and cell apoptosis, as well as the content of reactive oxygen species (ROS), catalase (CAT), and malondialdehyde (MDA) in cells were measured. Thyroid hormones, T3, T4, FT3, and FT4 levels were measured by enzyme-linked immunosorbent assay. Receptor for advanced glycation end products (RAGE), sirtuin1 ( Sirt1), and NF-E2-related factor 2 ( Nrf2) expressions were detected, and the mitochondrial membrane potential was measured. We found increased AGEs in the serum of DM patients with TD. By increasing AGE-BSA concentration, cell viability; the thyroid hormones T3, T4, FT3, and FT4 levels; and mitochondrial membrane potential all significantly decreased. However, the increase in AGE-BSA concentration led to an increase in cell apoptosis, RAGE, and nuclear factor-κB expressions but produced the opposite effect on Sirt1, Nrf2, and heme oxygenase-1 expressions, as well as a decrease in antioxidant response element protein levels. The AGE-BSA increased ROS and MDA levels and reduced CAT level in normal human thyroid follicular epithelial cells on a dose independence basis. Our results demonstrated that AGEs-mediated direct increase of RAGE produced OS in thyroid cells of DM by inactivating the Sirt1/Nrf2 axis.

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

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.

The Combination of Healthy Diet and Healthy Body Weight Is Associated with Lower Risk of Nuclear Cataract in the Blue Mountains Eye Study.

BACKGROUND: Greater adherence to dietary guidelines has previously been found to be associated with decreased risk of visual impairment. However, whether or not this association extends to age-related cataract, 1 of the leading causes of visual impairment, is unknown. OBJECTIVES: The aim of this study was to assess the association between adherence to dietary guidelines, using total diet score, and incidence of age-related cataract. METHODS: Of 3654 baseline participants of the population-based Blue Mountains Eye Study cohort (1992-1994), 2334 (75.8% survivors) and 1952 (76.7% survivors) were examined after 5 and 10 y, respectively. Cataract was assessed from lens photographs using the Wisconsin Cataract Grading System. Baseline total diet score was calculated from FFQ data following a modified version of the Healthy Eating Index for Australians. OR with 95% CI were estimated using discrete logistic regression analyses, adjusting for age, sex, and other confounders. To test interaction, a cross-product term of 2 factors was included in regression models. RESULTS: Of 2173 participants (84.7% of those returned for 1 or both follow-ups) with total diet score estimated, 57% were women, mean baseline age was 63.9 ± 8.4y, and mean baseline BMI was 26.3 ± 4.3 kg/m2. After multivariable adjustment, baseline total diet score was not associated with incidence of any cataract. A multiplicative interaction was observed between total diet score and BMI for incident nuclear cataract (P-interaction = 0.04): increasing baseline total diet score was associated with decreased risk of nuclear cataract among participants with BMI <25 (per unit increased total diet score, OR: 0.90; 95% CI: 0.81, 0.99; P = 0.02), but not among participants with BMI ≥25 (OR: 1.00; 95% CI: 0.92, 1.10; P = 0.95). CONCLUSIONS: Adherence to dietary guidelines had no appreciable influence on cataract development overall in this older Australian population. However, adherence to dietary guidelines combined with healthy BMI is associated with decreased risk of nuclear cataract, an aging marker.

A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration.

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

Ethnic Differences in the Prevalence and Risk Factors of Diabetic Retinopathy: The Singapore Epidemiology of Eye Diseases Study.

PURPOSE: To evaluate the prevalence and risk factors for diabetic retinopathy (DR) in the Singapore Epidemiology of Eye Diseases (SEED) Study. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: Persons of Malay, Indian, and Chinese ethnicity aged 40+ years, living in Singapore. METHODS: Diabetes was defined as nonfasting plasma glucose ≥200 mg/dl (11.1 mmol/l), glycated hemoglobin A1c (HbA1c) >6.5%, self-reported physician-diagnosed diabetes, or the use of glucose-lowering medication. Retinal photographs, were graded for the presence and severity of DR using the modified Airlie House classification system. MAIN OUTCOME MEASURES: Diabetic retinopathy, diabetic macular edema (DME), vision-threatening diabetic retinopathy (VTDR), defined as the presence of severe nonproliferative or proliferative DR, or clinically significant macular edema (CSME). RESULTS: Of the 10 033 subjects, 2877 (28.7%) had diabetes and gradable photographs for analysis. The overall age-standardized prevalence (95% confidence interval [CI]) was 28.2% (25.9-30.6) for any DR, 7.6% (6.5-9.0) for DME, and 7.7% (6.6-9.0) for VTDR. Indians had a higher prevalence of any DR (30.7% vs. 26.2% in Chinese and 25.5% in Malays, P = 0.012); a similar trend was noted for any DME (P = 0.001) and CSME (P = 0.032). Independent risk factors for any DR were Indian ethnicity (odds ratio [OR], 1.41; 95% CI, 1.09-1.83, vs. Chinese), diabetes duration (OR, 1.10; 95% CI, 1.08-1.11, per year), HbA1c (OR, 1.25; 95% CI, 1.18-1.32, per %), serum glucose (OR, 1.03; 95% CI, 1.00-1.06, per mmol/l), and systolic blood pressure (OR, 1.14; 95% CI, 1.09-1.19, per 10 mmHg). Diastolic blood pressure (OR, 0.74; 95% CI, 0.65-0.84, per 10 mmHg increase), total cholesterol (OR, 0.87; 95% CI, 0.80-0.95, per mmol/l increase), and low-density lipoprotein (LDL) cholesterol (OR, 0.83; 95% CI, 0.74-0.92, per mmol/l increase) were associated with lower odds of any DR. Risk factors were largely similar across the 3 ethnic groups. CONCLUSIONS: Indian Singaporeans have a higher prevalence of DR and DME compared with Chinese and Malays. Major risk factors for DR in this study were similar across the 3 ethnic groups. Addressing these risk factors may reduce the impact of DR in Asia, regardless of ethnicity.

Six-Year Incidence of and Risk Factors for Cataract Surgery in a Multi-ethnic Asian Population: The Singapore Epidemiology of Eye Diseases Study.

PURPOSE: To report the 6-year incidence of cataract surgery in an Asian population-based cohort of Malay, Indian, and Chinese persons living in Singapore and factors associated with undergoing cataract surgery over the follow-up period. DESIGN: Population-based prospective cohort study. PARTICIPANTS: From 2004 through 2011, 10 033 participants (3280 Malays, 3400 Indians, and 3353 Chinese) 40 years of age or older participated in the Singapore Epidemiology of Eye Diseases Study. Six years later, 6762 participants (78.7% of those eligible, including 1901 Malays [72.1% of eligible], 2200 Indians [75.5% of eligible], and 2661 Chinese [87.7% of eligible]) were re-examined. METHODS: Detailed eye examinations including slit-lamp biomicroscopy were conducted at both visits. Logistic regression models were used to assess factors associated with cataract surgery after adjusting for age, gender, socioeconomic status, and other risk factors. MAIN OUTCOME MEASURE: Incident cataract surgery. RESULTS: The age-adjusted 6-year incidence of cataract surgery was 11.0% (9.5%, 12.6%, and 11.1% for Malays, Indians, and Chinese, respectively) and was strongly age related (P < 0.001 for trend). After adjustment, baseline factors associated with incident cataract surgery included older age (odds ratio [OR], 1.13 per 1-year increase; 95% confidence interval [CI], 1.11-1.14), diabetes (OR, 1.90; 95% CI, 1.54-2.33), myopia (OR, 1.78; 95% CI, 1.44-2.20), and baseline presence of any cataract, including nuclear cataract (OR, 3.78; 95% CI, 2.91-4.89), cortical cataract (OR, 3.01; 95% CI, 2.45-3.71), and posterior subcapsular cataract (OR, 5.00; 95% CI, 3.91-6.41). The population attributable risks of cataract surgery related to diabetes and myopia were 17.6% and 19.1%, respectively. CONCLUSIONS: One in 10 Malay, Indian, and Chinese Singaporeans 40 years of age or older underwent cataract surgery in at least 1 eye over 6 years. In Asian populations, diabetes and myopia, 2 well-known factors associated with cataract prevalence, are significant and potentially modifiable factors associated with the need for cataract surgery.

Severe Acute Type B Aortic Dissection Complicated by Acute Pancreatitis: A Case Report.

A 52-year-old man presented with sudden abdominal pain and intermittent vomiting. The patient underwent contrast-enhanced computed tomography scan and was diagnosed with an acute type B aortic dissection involving the celiac trunk superior mesenteric artery and extending to the renal artery. The patient was treated with thoracic endovascular aortic repair. After the procedure, the patient still complained of left upper abdomen abdominal pain, and an abdominal mass was detected on physical examination. Imaging revealed a 15-cm cystic lesion involving the pancreatic tail and serum amylase measured at 556 U/L. A definitive diagnosis of severe acute pancreatitis was made. The patient was treated with injection of somatostatin, ultrasound-guided puncture drainage, and jejunal nutrition tube placement. The patient was discharged with symptom free after 30 days and well recovered in subsequent follow-up 12 months later.

Gestational retinal microvasculature and the risk of 5 year postpartum abnormal glucose metabolism.

AIMS/HYPOTHESIS: Changes in retinal microvasculature may reflect insulin resistance. We examined the association of changes in retinal microvasculature during pregnancy and risk of subsequent abnormal glucose metabolism in a cohort of mothers at baseline and 5 years postpartum. METHODS: Of the participants from the Singapore birth cohort (Growing Up in Singapore Towards Healthy Outcomes [GUSTO]), 276 mothers attended both baseline (at 26-28 weeks of gestation) and follow-up (5 year postpartum) visits. At baseline we performed retinal photography and assessed retinal microvascular variables using a validated grading system. At follow-up, we assessed glucose tolerance using a 75 g OGTT. We defined abnormal glucose metabolism if participants: (1) had onset of gestational diabetes mellitus (GDM) in subsequent pregnancies within a 5 year follow-up period (n = 103) or (2) had prediabetes (impaired fasting glucose, impaired glucose tolerance or HbA1c 5.7-6.4% [39-46 mmol/mol]) and diabetes diagnosed at the 5 year follow-up visit (n = 84), according to WHO guidelines. RESULTS: The incidence of GDM in subsequent pregnancy and abnormal glucose metabolism 5 years postpartum was 25.2% and 30.4%, respectively. Each 10 µm widening in retinal venular calibre was associated with a significant risk of postpartum abnormal glucose metabolism (RR 1.2 [95% CI 1.0, 1.5]), independent of maternal age, college education, ethnicity, pre-pregnancy BMI and GDM at baseline. Narrower retinal arteriolar calibre and venular branching angle at baseline was associated with a higher insulin resistance index (1.4 [95% CI 1.1, 1.7] and 1.3 [95% CI 1.1, 1.6], respectively) at follow-up. CONCLUSIONS/INTERPRETATION: Retinal microvasculature in pregnant women was associated with abnormal glucose metabolism 5 years postpartum. Alteration of microvascular structure during pregnancy may signal subclinical changes that underlie the development of prediabetes and diabetes.

Assessing the Genetic Predisposition of Education on Myopia: A Mendelian Randomization Study.

Myopia is the largest cause of uncorrected visual impairments globally and its recent dramatic increase in the population has made it a major public health problem. In observational studies, educational attainment has been consistently reported to be correlated to myopia. Nonetheless, correlation does not imply causation. Observational studies do not tell us if education causes myopia or if instead there are confounding factors underlying the association. In this work, we use a two-step least squares instrumental-variable (IV) approach to estimate the causal effect of education on refractive error, specifically myopia. We used the results from the educational attainment GWAS from the Social Science Genetic Association Consortium to define a polygenic risk score (PGRS) in three cohorts of late middle age and elderly Caucasian individuals (N = 5,649). In a meta-analysis of the three cohorts, using the PGRS as an IV, we estimated that each z-score increase in education (approximately 2 years of education) results in a reduction of 0.92 ± 0.29 diopters (P = 1.04 × 10(-3) ). Our estimate of the effect of education on myopia was higher (P = 0.01) than the observed estimate (0.25 ± 0.03 diopters reduction per education z-score [∼2 years] increase). This suggests that observational studies may actually underestimate the true effect. Our Mendelian Randomization (MR) analysis provides new evidence for a causal role of educational attainment on refractive error.

ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure.

Primary open-angle glaucoma (POAG) is a blinding disease. Two important risk factors for this disease are a positive family history and elevated intraocular pressure (IOP), which is also highly heritable. Genes found to date associated with IOP and POAG are ABCA1, CAV1/CAV2, GAS7 and TMCO1. However, these genes explain only a small part of the heritability of IOP and POAG. We performed a genome-wide association study of IOP in the population-based Rotterdam Study I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n = 8105), we identified a new locus associated with IOP. The most significantly associated SNP was rs58073046 (ß = 0.44, P-value = 1.87 × 10(-8), minor allele frequency = 0.12), within the gene ARHGEF12. Independent replication in five population-based studies (n = 7471) resulted in an effect size in the same direction that was significantly associated (ß = 0.16, P-value = 0.04). The SNP was also significantly associated with POAG in two independent case-control studies [n = 1225 cases and n = 4117 controls; odds ratio (OR) = 1.53, P-value = 1.99 × 10(-8)], especially with high-tension glaucoma (OR = 1.66, P-value = 2.81 × 10(-9); for normal-tension glaucoma OR = 1.29, P-value = 4.23 × 10(-2)). ARHGEF12 plays an important role in the RhoA/RhoA kinase pathway, which has been implicated in IOP regulation. Furthermore, it binds to ABCA1 and links the ABCA1, CAV1/CAV2 and GAS7 pathway to Mendelian POAG genes (MYOC, OPTN, WDR36). In conclusion, this study identified a novel association between IOP and ARHGEF12.

Type 2 Diabetes Genetic Variants and Risk of Diabetic Retinopathy.

PURPOSE: Genetic association studies to date have not identified any robust risk loci for diabetic retinopathy (DR). We hypothesized that individuals with more diabetes genetic risk alleles have a higher risk of developing DR. DESIGN: Case-control genetic association study. PARTICIPANTS: We evaluated the aggregate effects of multiple type 2 diabetes-associated genetic variants on the risk of DR among 1528 participants with diabetes from the Singapore Epidemiology of Eye Diseases Study, of whom 547 (35.8%) had DR. METHODS: Participants underwent a comprehensive ocular examination, including dilated fundus photography. Retinal photographs were graded using the modified Airlie House classification system to assess the presence and severity of DR following a standardized protocol. We identified 76 previously discovered type 2 diabetes-associated single nucleotide polymorphisms (SNPs) and constructed multilocus genetic risk scores (GRSs) for each individual by summing the number of risk alleles for each SNP weighted by the respective effect estimates on DR. Two GRSs were generated: an overall GRS that included all 76 discovered type 2 diabetes-associated SNPs, and an Asian-specific GRS that included a subset of 55 SNPs previously found to be associated with type 2 diabetes in East and/or South Asian ancestry populations. Associations between the GRSs with DR were determined using logistic regression analyses. Discriminating ability of the GRSs was determined by the area under the receiver operating characteristic curve (AUC). MAIN OUTCOME MEASURES: Odds ratios on DR. RESULTS: Participants in the top tertile of the overall GRS were 2.56-fold more likely to have DR compared with participants in the lowest tertile. Participants in the top tertile of the Asian-specific GRS were 2.00-fold more likely to have DR compared with participants in the bottom tertile. Both GRSs were associated with higher DR severity levels. However, addition of the GRSs to traditional risk factors improved the AUC only modestly by 3% to 4%. CONCLUSIONS: Type 2 diabetes-associated genetic loci were significantly associated with higher risks of DR, independent of traditional risk factors. Our findings may provide new insights to further our understanding of the genetic pathogenesis of DR.

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.

Screening, Education, and Rehabilitation Services for Hearing Loss Provided to Clients with Low Vision: Measured and Perceived Value Among Participants of the Vision-Hearing Project.

OBJECTIVES: Combined vision and hearing impairment, termed dual sensory impairment (DSI), is associated with poorer health outcomes compared with a single sensory loss alone. Separate systems of care exist for visual and hearing impairment which potentially limit the effectiveness of managing DSI. To address this, a Hearing Screening Education Model (HSEM) was offered to older adults attending a low-vision clinic in Australia within this pilot study. The present study aimed to evaluate the benefits of seeking help on hearing handicap, self-perceived health, and use of community services among those identified with unmet hearing needs after participation in the HSEM. DESIGN: Of 210 older adults (>55 years of age) who completed the HSEM and were referred for follow-up, 169 returned for a follow-up interview at least 12 months later. Of these, 68 (40.2%) sought help, and the majority were seen by a hearing healthcare provider (89.7%). Changes in hearing handicap, quality of life, and reliance on community services between the baseline and 12-month follow-up were compared between those who sought help and those who did not. In addition, the perceived value of the HSEM was assessed. RESULTS: Results showed that there was no significant difference in hearing handicap between those who sought help (mean change -1.02 SD = 7.97, p = 0.3) and those who did not (mean change 0.94 SD = 7.68, p = 0.3), p = 0.18. The mental component of the SF-36 worsened significantly between baseline and follow-up measures across the whole group (mean change -2.49 SD = 9.98, p = 0.002). This was largely driven by those not seeking help, rather than those seeking help, but was not significantly different between the two groups. Those who sought help showed a significant reduction in the use of community services compared with those who did not. Further, all participants positively viewed the HSEM's underlying principle of greater integration between vision and hearing services. CONCLUSIONS: These findings suggest a need to further develop and evaluate integrated models of healthcare for older adults with DSI. It also highlights the importance of using broader measures of benefit, other than use of hearing aids to evaluate outcomes of hearing healthcare programs.

GUNN'S DOTS IN RETINAL IMAGES OF 2,286 ADOLESCENTS: Prevalence, Retinal Distribution and Associations.

PURPOSE: To investigate the epidemiology of Gunn's dots and their associations in a population-based cohort of children. METHODS: Red-free fundus photographs from 2,286 children aged 11 years to 14 years from the Sydney Myopia Study were graded. Gunn's dots were manually marked and counted within a 6 mm grid centered on the optic disc. RESULTS: One or more Gunn's dots were seen in at least one eye in 82.6% of children. The median number of Gunn's dots per eye was 46 (range 0-482). Most Gunn's dots were found inferior and superior of the optic disc (49.3% and 45.8%, respectively, of the total number of Gunn's dots in the population). The odds for having 1 or more Gunn's dots were 3-fold greater in children with dark brown irides compared with children with blue irides (odds ratio 2.99, 95% CI 1.81 to 4.94, P < 0.0001 adjusted for age, sex, retinal nerve fiber layer thickness, refraction, ethnicity, and axial length). In the same analysis, the presence of 1 or more Gunn's dots was less frequent in children with thin retinal nerve fiber layers (first quartile) compared with children with thick retinal nerve fiber layers (fourth quartile) (odds ratio 0.68, 95% CI 0.49-0.93, P = 0.016). No disease or disease-marker associations were identified. CONCLUSION: Gunn's dots were visible on fundus photographs in most of the school children, most of the dots being located inferiorly and superiorly to the optic disc. Fundus photographically visible Gunn's dots were associated with darker irides and thicker retinal nerve fiber layers. Gunn's dots are a common and apparently harmless finding in children. Assessment of their clinical significance will require long-term follow-up.

Singapore Indian Eye Study-2: methodology and impact of migration on systemic and eye outcomes.

IMPORTANCE: Asian Indians are the fastest growing migration groups in the world. Studies evaluating the impact of migration on disease outcomes in this population are rare. BACKGROUND: We describe the methodology of the Singapore Indian Eye Study-2 (SINDI-2) aimed to evaluate the impact of migration status on diabetic retinopathy and other major age-related eye diseases in Asian Indians living in an urban environment. DESIGN: Population-based cohort study. PARTICIPANTS: A total of 2200 adults had participated in baseline SINDI (2007-2009, mean age [range] = 57.8 [42.7-84.1] years) and SINDI-2 (2013-2015, 56.5 [48.4-90.2] years). METHODS: Participants were classified as 'first generation' if they were Indian residents born outside of Singapore and as 'second-generation' immigrants (59.7% in SINDI vs. 63.6% in SINDI-2) if they were born in Singapore. MAIN OUTCOME MEASURES: Response rate, participant characteristics and prevalence of systemic diseases were stratified by migration status. RESULTS: Of the 2914 eligible SINDI participants invited to participate, 2200 participated in SINDI-2 (response rate of 75.2%). In both SINDI and SINDI-2, compared with first-generation immigrants, second-generation immigrants were younger, less likely to have income <1000 SGD, had lower levels of pulse pressure, higher levels of high-density lipoprotein cholesterol, had lower prevalence of hypertension and chronic kidney disease and had higher prevalence of current smoking and obesity (all P < 0.05). CONCLUSIONS AND RELEVANCE: In both SINDI and SINDI-2, second-generation immigrants had lower prevalence of cardiovascular risk factors except smoking and obesity compared with first-generation immigrants. The final report will confirm if these differences between generations are evident with regard to eye diseases.