Epidemiologic association and shared genetic architecture between cataract and hearing difficulties among middle-aged and older adults.

Age-related cataract and hearing difficulties are major sensory disorders that often co-exist in the global-wide elderly and have a tangible influence on the quality of life. However, the epidemiologic association between cataract and hearing difficulties remains unexplored, while little is known about whether the two share their genetic etiology. We first investigated the clinical association between cataract and hearing difficulties using the UK Biobank covering 502,543 individuals. Both unmatched analysis (adjusted for confounders) and a matched analysis (one control matched for each patient with cataract according to confounding factors) were undertaken and confirmed that cataract was associated with hearing difficulties (OR, 2.12; 95% CI, 1.98-2.27; OR, 2.03; 95% CI, 1.86-2.23, respectively). Furthermore, we explored and quantified the shared genetic architecture of these two complex sensory disorders at the common variant level using the bivariate causal mixture model (MiXeR) and conditional/conjunctional false discovery rate method based on the largest available genome-wide association studies of cataract (N = 585,243) and hearing difficulties (N = 323,978). Despite detecting only a negligible genetic correlation, we observe polygenic overlap between cataract and hearing difficulties and identify 6 shared loci with mixed directions of effects. Follow-up analysis of the shared loci implicates candidate genes QKI, STK17A, TYR, NSF, and TCF4 likely contribute to the pathophysiology of cataracts and hearing difficulties. In conclusion, this study demonstrates the presence of epidemiologic association between cataract and hearing difficulties and provides new insights into the shared genetic architecture of these two disorders at the common variant level.

EBD: an eye biomarker database.

MOTIVATION: Many ophthalmic disease biomarkers have been identified through comprehensive multiomics profiling, and hold significant potential in advancing the diagnosis, prognosis, and management of diseases. Meanwhile, the eye itself serves as a natural biomarker for several systemic diseases including neurological, renal, and cardiovascular systems. We aimed to collect and standardize this eye biomarkers information and construct the eye biomarker database (EBD) to provide ophthalmologists with a platform to search, analyze, and download these eye biomarker data. RESULTS: In this study, we present the EBD , a world-first online compilation comprising 889 biomarkers for 26 ocular diseases and 939 eye biomarkers for 181 systemic diseases. The EBD also includes the information of 78 "nonbiomarkers"-the objects that have been proven cannot be biomarkers. Biological function and network analysis were conducted for these ocular disease biomarkers, and several hub pathways and common network topology characteristics were newly identified, which may promote future ocular disease biomarker discovery and characterizes the landscape of biomarkers for eye diseases at the pathway and network level. The EBD is expected to yield broader utility among developmental biologists and clinical scientists in and outside of the eye field by assisting in the identification of biomarkers linked to eye disorders and related systemic diseases. AVAILABILITY AND IMPLEMENTATION: EBD is available at http://www.eyeseeworld.com/ebd/index.html.

Plasma Metabolomics Identifies Key Metabolites and Improves Prediction of Diabetic Retinopathy: Development and Validation across Multinational Cohorts.

PURPOSE: To identify longitudinal metabolomic fingerprints of diabetic retinopathy (DR) and to evaluate their usefulness in predicting DR development and progression. DESIGN: Multicenter, multiethnic cohort study. PARTICIPANTS: This study included 17 675 participants from the UK Biobank (UKB) who had baseline prediabetes or diabetes, identified in accordance with the 2021 American Diabetes Association guidelines, and were free of baseline DR and an additional 638 participants with type 2 diabetes mellitus from the Guangzhou Diabetic Eye Study (GDES) for external validation. Diabetic retinopathy was determined by ICD-10 codes in the UKB cohort and revised ETDRS grading criteria in the GDES cohort. METHODS: Longitudinal DR metabolomic fingerprints were identified through nuclear magnetic resonance (NMR) assay in UKB participants. The predictive value of these fingerprints for predicting DR development were assessed in a fully withheld test set. External validation and extrapolation analyses of DR progression and microvascular damage were conducted in the GDES cohort using NMR technology. Model assessments included the concordance (C) statistic, net classification improvement (NRI), integrated discrimination improvement (IDI), calibration, and clinical usefulness in both cohorts. MAIN OUTCOME MEASURES: DR development and progression and retinal microvascular damage. RESULTS: Of 168 metabolites, 118 were identified as candidate metabolomic fingerprints for future DR development. These fingerprints significantly improved the predictability for DR development beyond traditional indicators (C statistic, 0.802 [95% confidence interval (CI), 0.760-0.843] vs. 0.751 [95% CI, 0.706-0.796]; P = 5.56 × 10-4). Glucose, lactate, and citrate were among the fingerprints validated in the GDES cohort. Using these parsimonious and replicable fingerprints yielded similar improvements for predicting DR development (C statistic, 0.807 [95% CI, 0.711-0.903] vs. 0.617 [95% CI, 0.494-0.740]; P = 1.68 × 10-4) and progression (C statistic, 0.797 [95% CI, 0.712-0.882] vs. 0.665 [95% CI, 0.545-0.784]; P = 0.003) in the external GDES cohort. Improvements in NRIs, IDIs, and clinical usefulness also were evident in both cohorts (all P < 0.05). In addition, lactate and citrate were associated with microvascular damage across macular and optic nerve head regions among Chinese GDES (all P < 0.05). CONCLUSIONS: Metabolomic profiling may be effective in identifying robust fingerprints for predicting future DR development and progression, providing novel insights into the early and advanced stages of DR pathophysiology. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Myopia Control Effect of Repeated Low-Level Red-Light Therapy Combined with Orthokeratology: A Multicenter Randomized Controlled Trial.

PURPOSE: To investigate the efficacy and safety of repeated low-level red-light (RLRL) therapy combined with orthokeratology among children who, despite undergoing orthokeratology, exhibited an axial elongation of at least 0.50 mm over 1 year. DESIGN: Multicenter, randomized, parallel-group, single-blind clinical trial (ClinicaTrials.gov identifier, NCT04722874). PARTICIPANTS: Eligible children were 8-13 years of age with a cycloplegic spherical equivalent refraction of -1.00 to -5.00 diopters at the initial orthokeratology fitting examination and had annual axial length (AL) elongation of ≥0.50 mm despite undergoing orthokeratology. Forty-eight children were enrolled from March 2021 through January 2022, and the final follow-up was completed in March 2023. METHODS: Children were assigned randomly to the RLRL therapy combined with orthokeratology (RCO) group or to the orthokeratology group in a 2:1 ratio. The orthokeratology group wore orthokeratology lenses for at least 8 hours per night, whereas the RCO group received daily RLRL therapy twice daily for 3 minutes in addition to orthokeratology. MAIN OUTCOME MEASURES: The primary outcome was AL change measured at 12 months relative to baseline. The primary analysis was conducted in children who received the assigned intervention and completed at least 1 follow-up after randomization using the modified intention-to-treat principle. RESULTS: Forty-seven children (97.9%) were included in the analysis (30 in the RCO group and 17 in the orthokeratology group). The mean axial elongation rate before the trial was 0.60 mm/year and 0.61 mm/year in the RCO and orthokeratology groups, respectively. After 12 months, the adjusted mean AL changes were -0.02 mm (95% confidence interval [CI], -0.08 to +0.03 mm) in the RCO group and 0.27 mm (95% CI, 0.19-0.34 mm) in the orthokeratology group. The adjusted mean difference in AL change was -0.29 mm (95% CI, -0.44 to -0.14 mm) between the groups. The percentage of children achieving an uncorrected visual acuity of more than 20/25 was similar in the RCO (64.3%) and orthokeratology (65.5%) groups (P = 0.937). CONCLUSIONS: Combining RLRL therapy with orthokeratology may offer a promising approach to optimize axial elongation control among children with myopia. This approach also potentially allows children to achieve satisfactory visual acuity, reducing daytime dependence on corrective eyewear. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Leading determinants of incident dementia among individuals with and without the apolipoprotein E ε4 genotype: a retrospective cohort study.

BACKGROUND: Little is known regarding the leading risk factors for dementia/Alzheimer's disease (AD) in individuals with and without APOE4. The identification of key risk factors for dementia/Alzheimer's disease (AD) in individuals with and without the APOE4 gene is of significant importance in global health. METHODS: Our analysis included 110,354 APOE4 carriers and 220,708 age- and sex-matched controls aged 40-73 years at baseline (between 2006-2010) from UK Biobank. Incident dementia was ascertained using hospital inpatient, or death records until January 2021. Individuals of non-European ancestry were excluded. Furthermore, individuals without medical record linkage were excluded from the analysis. Moderation analysis was tested for 134 individual factors. RESULTS: During a median follow-up of 11.9 years, 4,764 cases of incident all-cause dementia and 2065 incident AD cases were documented. Hazard ratios (95% CIs) for all-cause dementia and AD associated with APOE4 were 2.70(2.55-2.85) and 3.72(3.40-4.07), respectively. In APOE4 carriers, the leading risk factors for all-cause dementia included low self-rated overall health, low household income, high multimorbidity risk score, long-term illness, high neutrophil percentage, and high nitrogen dioxide air pollution. In non-APOE4 carriers, the leading risk factors included high multimorbidity risk score, low overall self-rated health, low household income, long-term illness, high microalbumin in urine, high neutrophil count, and low greenspace percentage. Population attributable risk for these individual risk factors combined was 65.1%, and 85.8% in APOE4 and non-APOE4 carriers, respectively. For 20 risk factors including multimorbidity risk score, unhealthy lifestyle habits, and particulate matter air pollutants, their associations with incident dementia were stronger in non-APOE4 carriers. For only 2 risk factors (mother's history of dementia, low C-reactive protein), their associations with incident all-cause dementia were stronger in APOE4 carriers. CONCLUSIONS: Our findings provide evidence for personalized preventative approaches to dementia/AD in APOE4 and non-APOE4 carriers. A mother's history of dementia and low levels of C-reactive protein were more important risk factors of dementia in APOE4 carriers whereas leading risk factors including unhealthy lifestyle habits, multimorbidity risk score, inflammation and immune-related markers were more predictive of dementia in non-APOE4 carriers.

Ocular manifestations of obstructive sleep apnea: a systematic review and meta-analysis.

BACKGROUND: The association of obstructive sleep apnea (OSA) with development of eye diseases is unclear. This current systematic review and meta-analysis attempts to summarize and analyze associations between OSA and ocular disorders in the literature. METHODS: PubMed, EMBASE, Google Scholar, Web Of Science, and Scopus databases were searched from 1901 to July 2022 in accordance with the Preferred Reporting in Systematic Review & Meta-Analysis (PRISMA). Our primary outcome assessed the association between OSA and the odds of developing floppy eyelid syndrome (FES), glaucoma, non-arteritic anterior ischemic optic neuropathy (NAION), retinal vein occlusion (RVO), keratoconus (KC), idiopathic intracranial hypertension (IIH), age-related macular degeneration (AMD), and central serous chorioretinopathy (CSR) through odds ratio calculated at the 95% confidence interval. RESULTS: Forty-nine studies were included for systematic review and meta-analysis. The pooled OR estimate was highest for NAION [3.98 (95% CI 2.38, 6.66)], followed by FES [3.68 (95% CI 2.18, 6.20)], RVO [2.71(95% CI 1.83, 4.00)], CSR [2.28 (95% CI 0.65, 7.97)], KC [1.87 (95% CI 1.16, 2.99)], glaucoma [1.49 (95% CI 1.16, 1.91)], IIH [1.29 (95% CI 0.33, 5.01)], and AMD [0.92 [95% CI 0.24, 3.58] All observed associations were significant (p < 0.001) aside from IIH and AMD. CONCLUSION: OSA is significantly associated with NAION, FES, RVO, CSR, KC, and glaucoma. Clinicians should be informed of these associations so early recognition, diagnosis, and treatment of eye disorders can be addressed in at-risk groups, and early referral to ophthalmic services is made to prevent vision disturbances. Similarly, ophthalmologists seeing patients with any of these conditions should consider screening and referring patients for assessment of possible OSA.

Cutoff values of axial length/corneal radius ratio for determining myopia vary with age among 3-18 years old children and adolescents.

PURPOSE: To investigate the effectiveness and cutoffs of axial length/corneal radius (AL/CR) ratio for myopia detection in children by age. METHODS: Totally, 21 kindergartens and schools were enrolled. Non-cycloplegic autorefraction (NCAR), axial length (AL), horizontal and vertical meridian of corneal radius (CR1, CR2), and cycloplegic autorefraction were measured. Receiver operating characteristic (ROC) curve was used to obtain the effectiveness and cutoff for myopia detection. RESULTS: Finally, 7803 participants aged 3-18 years with mean AL/CR ratio of 2.99 ± 0.16 were included. Area under the ROC curve (AUC) of AL/CR ratio for myopia detection (0.958 for AL/CR1, 0.956 for AL/CR2, 0.961 for AL/CR) was significantly larger than that of AL (0.919, all P < 0.001), while AUCs of the three were similar with different cutoffs (> 2.98, > 3.05, and > 3.02). When divided by age, the ROC curves of AL/CR ratio in 3- to 5-year-olds showed no significance or low accuracy (AUCs ≤ 0.823) in both genders. In ≥ 6-year-olds, the accuracies were promising (AUCs ≥ 0.883, all P < 0.001), the cutoffs basically increased with age (from > 2.93 in 6-year-olds to > 3.07 in 18-year-olds among girls, and from > 2.96 in 6-year-olds to > 3.07 in 18-year-olds among boys). In addition, boys presented slightly larger cutoffs than girls in all ages except for 16 and 18 years old. For children aged 3-5 years, AL/CR ratio or AL combined with NCAR increased AUC to > 0.900. CONCLUSION: AL/CR ratio provided the best prediction of myopia with age-dependent cutoff values for all but preschool children, and the cutoffs of boys were slightly larger than those of girls. For preschool children, AL/CR ratio or AL combined with NCAR is recommended to achieve satisfactory accuracy. AL/CR ratio calculated by two meridians showed similar predictive power but with different cutoffs.

Retinal nerve fiber layer thinning as a novel fingerprint for cardiovascular events: results from the prospective cohorts in UK and China.

BACKGROUND: Retinal structural abnormalities have been found to serve as biomarkers for cardiovascular disease (CVD). However, the association between retinal nerve fiber layer (RNFL) thickness and the incidence of CVD events remains inconclusive, and relevant longitudinal studies are lacking. Therefore, we aimed to examine this link in two prospective cohort studies. METHODS: A total of 25,563 participants from UK Biobank who were initially free of CVD were included in the current study. Another 635 participants without retinopathy at baseline from the Chinese Guangzhou Diabetes Eye Study (GDES) were adopted as the validation set. Measurements of RNFL thickness in the macular (UK Biobank) and peripapillary (GDES) regions were obtained from optical coherence tomography (OCT). Adjusted hazard ratios (HRs), odd ratios (ORs), and 95% confidence intervals (CI) were calculated to quantify CVD risk. RESULTS: Over a median follow-up period of 7.67 years, 1281 (5.01%) participants in UK Biobank developed CVD events. Each 5-µm decrease in macular RNFL thickness was associated with an 8% increase in incident CVD risk (HR = 1.08, 95% CI: 1.01-1.17, p = 0.033). Compared with participants in the highest tertile of RNFL thickness, the risk of incident CVD was significantly increased in participants in the lowest thickness tertile (HR = 1.18, 95% CI: 1.01-1.38, p = 0.036). In GDES, 29 (4.57%) patients developed CVD events within 3 years. Lower average peripapillary RNFL thickness was also associated with a higher CVD risk (OR = 1.35, 95% CI: 1.11-1.65, p = 0.003). The additive net reclassification improvement (NRI) was 21.8%, and the absolute NRI was 2.0% by addition of RNFL thickness over the Framingham risk score. Of 29 patients with incident CVD, 7 were correctly reclassified to a higher risk category while 1 was reclassified to a lower category, and 21 high risk patients were not reclassified. CONCLUSIONS: RNFL thinning was independently associated with increased incident cardiovascular risk and improved reclassification capability, indicating RNFL thickness derived from the non-invasive OCT as a potential retinal fingerprint for CVD event across ethnicities and health conditions. TRIAL REGISTRATION: ISRCTN 15853192.

Exploring multimorbidity profiles in middle-aged inpatients: a network-based comparative study of China and the United Kingdom.

BACKGROUND: Multimorbidity is better prevented in younger ages than in older ages. This study aims to identify the differences in comorbidity patterns in middle-aged inpatients from China and the United Kingdom (UK). METHODS: We utilized 184,133 and 180,497 baseline hospitalization records in middle-aged populations (40-59 years) from Shaanxi, China, and UK Biobank. Logistic regression was used to calculate odds ratios and P values for 43,110 unique comorbidity patterns in Chinese inpatients and 21,026 unique comorbidity patterns in UK inpatients. We included the statistically significant (P values adjusted by Bonferroni correction) and common comorbidity patterns (the pattern with prevalence > 1/10,000 in each dataset) and employed network analysis to construct multimorbidity networks and compare feature differences in multimorbidity networks for Chinese and UK inpatients, respectively. We defined hub diseases as diseases having the top 10 highest number of unique comorbidity patterns in the multimorbidity network. RESULTS: We reported that 57.12% of Chinese inpatients had multimorbidity, substantially higher than 30.39% of UK inpatients. The complete multimorbidity network for Chinese inpatients consisted of 1367 comorbidities of 341 diseases and was 2.93 × more complex than that of 467 comorbidities of 215 diseases in the UK. In males, the complexity of the multimorbidity network in China was 2.69 × more than their UK counterparts, while the ratio was 2.63 × in females. Comorbidities associated with hub diseases represented 68.26% of comorbidity frequencies in the complete multimorbidity network in Chinese inpatients and 55.61% in UK inpatients. Essential hypertension, dyslipidemia, type 2 diabetes mellitus, and gastritis and duodenitis were the hub diseases in both populations. The Chinese inpatients consistently demonstrated a higher frequency of comorbidities related to circulatory and endocrine/nutritional/metabolic diseases. In the UK, aside from these comorbidities, comorbidities related to digestive and genitourinary diseases were also prevalent, particularly the latter among female inpatients. CONCLUSIONS: Chinese inpatients exhibit higher multimorbidity prevalence and more complex networks compared to their UK counterparts. Multimorbidity with circulatory and endocrine/nutritional/metabolic diseases among both Chinese and UK inpatients necessitates tailored surveillance, prevention, and intervention approaches. Targeted interventions for digestive and genitourinary diseases are warranted for the UK.

Central obesity and its association with retinal age gap: insights from the UK Biobank study.

BACKGROUND: Conflicting evidence exists on the association between ageing and obesity. Retinal age derived from fundus images has been validated as a novel biomarker of ageing. In this study, we aim to investigate the association between different anthropometric phenotypes based on body mass index (BMI) and waist circumference (WC) and the retinal age gap (retinal age minus chronological age). METHODS: A total of 35,550 participants with BMI, WC and qualified retinal imaging data available were included to investigate the association between anthropometric groups and retinal ageing. Participants were stratified into 7 different body composition groups based on BMI and WC (Normal-weight/Normal WC, Overweight/Normal WC, Mild obesity/Normal WC, Normal-weight/High WC, Overweight/High WC, Mild obesity/High WC, and Severe obesity/High WC). Linear regression and logistic regression models were fitted to investigate the association between the seven anthropometric groups and retinal age gap as continuous and categorical outcomes, respectively. RESULTS: A total of 35,550 participants (55.6% females) with a mean age 56.8 ± 8.04 years were included in the study. Individuals in the Overweight/High WC, Mild obesity/High WC and Severe obesity/High WC groups were associated with an increase in the retinal age gap, compared with those in the Normal Weight/Normal WC group (ß = 0.264, 95% CI: 0.105-0.424, P =0.001; ß = 0.226, 95% CI: 0.082-0.371, P = 0.002; ß = 0.273, 95% CI: 0.081-0.465, P = 0.005; respectively) in fully adjusted models. Similar findings were noted in the association between the anthropometric groups and retinal ageing process as a categorical outcome. CONCLUSION: A significant positive association exists between central obesity and accelerated ageing indexed by retinal age gaps, highlighting the significance of maintaining a healthy body shape.

Cardiovascular and microvascular outcomes according to vitamin D level and genetic variants among individuals with prediabetes: a prospective study.

BACKGROUND: Whether serum vitamin D mediate vascular diseases in prediabetic populations remains unclear. This study aimed to determine the associations between circulating 25-hydroxyvitamin D [25(OH)D] levels and vitamin D receptor (VDR) polymorphisms with the risk of macrovascular complications, including myocardial infarction and stroke, and microvascular complications such as diabetic nephropathy and retinopathy, among adults with prediabetes. METHODS: Participants with prediabetes in UK Biobank were included (N = 56,387). Multivariable dose-response and Cox proportion models were used to explore the relationship of serum 25(OH)D status and the risks of vascular complications. The interaction of VDR polymorphisms with serum 25(OH)D level on risks of vascular events was also assessed. RESULTS: During a median follow-up of 12 years, higher levels of 25(OH)D were significantly and nonlinearly associated with a lower risk of macrovascular diseases among prediabetic individuals. The adjusted hazard ratios (95% confidential interval) of serum 25(OH)D levels of ≥ 75.0 nmol/L versus < 25 nmol/L were 0.75 (0.63-0.88) for myocardial infarction, 0.74 (0.55-1.00) for stroke, 1.02 (0.60-1.74) for diabetic nephropathy, and 1.30 (0.92-1.84) for diabetic retinopathy, respectively. The rs2228570 (FokI) polymorphisms significantly interacted with 25(OH)D on incident myocardial infarction (P-interaction = 0.042) and stroke (P-interaction = 0.033). The individuals with serum 25(OH)D level of 50.0-74.9 nmol/L and rs2228570 (FokI) homozygotes had the lowest risks of vascular complications. CONCLUSIONS: Lower serum 25(OH)D levels are significantly and nonlinearly associated with an increased risk of cardiocerebrovascular diseases in prediabetic individuals, with VDR polymorphisms of rs2228570 (FokI) modify such associations. Monitoring a safe 25(OH)D concentration is suggested to prevent the vascular complications for prediabetes.

Metabolomic phenotyping of obesity for profiling cardiovascular and ocular diseases.

BACKGROUND: We aimed to evaluate the impacts of metabolomic body mass index (metBMI) phenotypes on the risks of cardiovascular and ocular diseases outcomes. METHODS: This study included cohorts in UK and Guangzhou, China. By leveraging the serum metabolome and BMI data from UK Biobank, this study developed and validated a metBMI prediction model using a ridge regression model among 89,830 participants based on 249 metabolites. Five obesity phenotypes were obtained by metBMI and actual BMI (actBMI): normal weight (NW, metBMI of 18.5-24.9 kg/m2), overweight (OW, metBMI of 25-29.9 kg/m2), obesity (OB, metBMI ≥ 30 kg/m2), overestimated (OE, metBMI-actBMI > 5 kg/m2), and underestimated (UE, metBMI-actBMI < - 5 kg/m2). Additional participants from the Guangzhou Diabetes Eye Study (GDES) were included for validating the hypothesis. Outcomes included all-cause and cardiovascular (CVD)-cause mortality, as well as incident CVD (coronary heart disease, heart failure, myocardial infarction [MI], and stroke) and age-related eye diseases (age-related macular degeneration [AMD], cataracts, glaucoma, and diabetic retinopathy [DR]). RESULTS: In the UKB, although OE group had lower actBMI than NW group, the OE group had a significantly higher risk of all-cause mortality than those in NW prediction group (HR, 1.68; 95% CI 1.16-2.43). Similarly, the OE group had a 1.7-3.6-fold higher risk than their NW counterparts for cardiovascular mortality, heart failure, myocardial infarction, and coronary heart disease (all P < 0.05). In addition, risk of age-related macular denegation (HR, 1.96; 95% CI 1.02-3.77) was significantly higher in OE group. In the contrast, UE and OB groups showed similar risks of mortality and of cardiovascular and age-related eye diseases (all P > 0.05), though the UE group had significantly higher actBMI than OB group. In the GDES cohort, we further confirmed the potential of metabolic BMI (metBMI) fingerprints for risk stratification of cardiovascular diseases using a different metabolomic approach. CONCLUSIONS: Gaps of metBMI and actBMI identified novel metabolic subtypes, which exhibit distinctive cardiovascular and ocular risk profiles. The groups carrying obesity-related metabolites were at higher risk of mortality and morbidity than those with normal health metabolites. Metabolomics allowed for leveraging the future of diagnosis and management of 'healthily obese' and 'unhealthily lean' individuals.

Association of Retinal Age Gap and Risk of Kidney Failure: A UK Biobank Study.

RATIONALE & OBJECTIVE: The incidence of kidney failure is known to increase with age. We have previously developed and validated the use of retinal age based on fundus images as a biomarker of aging. However, the association of retinal age with kidney failure is not clear. We investigated the association of retinal age gap (the difference between retinal age and chronological age) with future risk of kidney failure. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 11,052 UK Biobank study participants without any reported disease for characterizing retinal age in a deep learning algorithm. 35,864 other participants with retinal images and no kidney failure were followed to assess the association between retinal age gap and the risk of kidney failure. EXPOSURE: Retinal age gap, defined as the difference between model-based retinal age and chronological age. OUTCOME: Incident kidney failure. ANALYTICAL APPROACH: A deep learning prediction model used to characterize retinal age based on retinal images and chronological age, and Cox proportional hazards regression models to investigate the association of retinal age gap with incident kidney failure. RESULTS: After a median follow-up period of 11 (IQR, 10.89-11.14) years, 115 (0.32%) participants were diagnosed with incident kidney failure. Each 1-year greater retinal age gap at baseline was independently associated with a 10% increase in the risk of incident kidney failure (HR, 1.10 [95% CI, 1.03-1.17]; P=0.003). Participants with retinal age gaps in the fourth (highest) quartile had a significantly higher risk of incident kidney failure compared with those in the first quartile (HR, 2.77 [95% CI, 1.29-5.93]; P=0.009). LIMITATIONS: Limited generalizability related to the composition of participants in the UK Biobank study. CONCLUSIONS: Retinal age gap was significantly associated with incident kidney failure and may be a promising noninvasive predictive biomarker for incident kidney failure.

Myopia Control Effect of Repeated Low-Level Red-Light Therapy in Chinese Children: A Randomized, Double-Blind, Controlled Clinical Trial.

PURPOSE: Repeated low-level red-light (RLRL) therapy is an emerging treatment for myopia control. Nevertheless, previous studies are limited by open-label design. Our study aimed to assess the efficacy and safety of RLRL therapy in controlling myopia progression compared to a sham device with only 10% of the original power. DESIGN: Randomized, double-blind, controlled clinical trial. PARTICIPANTS: A total of 112 Chinese children aged 7 to 12 years with myopia of at least -0.50 diopter (D), astigmatism of 1.50 D or less, and anisometropia of 1.50 D or less. METHODS: Participants were assigned randomly in a 1:1 ratio to the RLRL group or the sham device control group, following a schedule of 3 minutes per session, twice daily, with an interval between sessions of at least 4 hours. The RLRL therapy was provided by a desktop red-light therapy device and administered at home. The sham device was the same device but with only 10% of the original device's power. Cycloplegic refraction and axial length (AL) were measured at baseline and 6 months. MAIN OUTCOME MEASURES: Changes in cycloplegic spherical equivalence refraction (SER) and AL between 2 groups were compared using a generalized estimating equation (GEE). RESULTS: A total of 111 children were included in the analysis (n = 56 in the RLRL group and n = 55 in the sham device control group). The mean SER change over 6 months was 0.06 ± 0.30 D in the RLRL group and -0.11 ± 0.33 D in the sham device control group (P = 0.003), with respective mean increases in AL of 0.02 ± 0.11 mm and 0.13 ± 0.10 mm (P < 0.001). In the multivariate GEE models, children in the RLRL group showed less myopia progression and axial elongation than those in the sham device control group (SER: coefficient, 0.167 D; 95% confidence interval [CI], 0.050-0.283 D; P = 0.005; AL: coefficient, -0.101 mm; 95% CI, -0.139 to -0.062 mm; P < 0.001). No treatment-related adverse events were reported. CONCLUSIONS: In myopic children, RLRL therapy with 100% power significantly reduced myopia progression over 6 months compared with those treated with a sham device of 10% original power. The RLRL treatment was well tolerated without treatment-related adverse effects.

Longitudinal Changes and Predictive Value of Choroidal Thickness for Myopia Control after Repeated Low-Level Red-Light Therapy.

PURPOSE: To evaluate longitudinal changes in macular choroidal thickness (mCT) in myopic children treated for 1 year with repeated low-level red-light (RLRL) therapy and their predictive value for treatment efficacy on myopia control. DESIGN: A secondary analysis of data from a multicenter, randomized controlled trial (RCT; NCT04073238). PARTICIPANTS: Myopic children aged 8-13 years who participated in the RCT at 2 of 5 sites where mCT measurements were available. METHODS: Repeated low-level red-light therapy was delivered using a home-use desktop light device that emitted red-light at 650 nm. Choroidal thickness was measured by SS-OCT at baseline and 1-, 3-, 6-, and 12-month follow-ups. Visual acuity, axial length (AL), cycloplegic spherical equivalent refraction (SER), and treatment compliance were measured. MAIN OUTCOME MEASURES: Changes in mCT at 1, 3, 6, and 12 months relative to baseline, and their associations with myopia control. RESULTS: A total of 120 children were included in the analysis (RLRL group: n = 60; single-vision spectacle [SVS] group: n = 60). Baseline characteristics were well balanced between the 2 groups. In the RLRL group, changes in mCT from baseline remained positive over 1 year, with a maximal increase of 14.755 µm at 1 month and gradually decreasing from 5.286 µm at 3 months to 1.543 µm at 6 months, finally reaching 9.089 µm at 12 months. In the SVS group, mCT thinning was observed, with changes from baseline of -1.111, -8.212, -10.190, and -10.407 µm at 1, 3, 6, and 12 months, respectively. Satisfactory myopia control was defined as annual progression rates of less than 0, 0.05, or 0.10 mm for AL and less than 0, 0.25, or 0.50 diopters for SER. Models that included mCT changes at 3 months alone had acceptable predictive discrimination of satisfactory myopia control over 12 months, with areas under the curve of 0.710-0.786. The predictive performance of the models did not significantly improve after adding age, gender, and baseline AL or SER. CONCLUSIONS: This analysis from a multicenter RCT found RLRL induced sustained choroidal thickening over the full course of treatment. Macular choroidal thickness changes at 3 months alone can predict 12-month myopia control efficacy with reasonable accuracy. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Normal-weight central obesity and risk of cardiovascular and microvascular events in adults with prediabetes or diabetes: Chinese and British cohorts.

OBJECTIVE: To investigate the relationship between body fat distribution and risk of cardiometabolic and microvascular events among individuals with prediabetes or diabetes with normal body mass index (BMI). METHODS: A total of 17,232 participants with prediabetes or diabetes from UK Biobank (UKB) with 12-year follow-up and 499 diabetic participants from China with 2-year follow-up with normal BMI were included. Anthropometric measurements of waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR), and body fat composition assessment of trunk-to-leg fat ratio (TLFR) were obtained. Outcomes included incident all-cause and cardiovascular mortality and macrovascular and microvascular diseases. RESULTS: In British cohort, participants with central obesity defined by WHR had 27%-54% higher risk of incident all-cause mortality (hazard ratio (HR) 1.42, 95% confidence interval (CI): 1.23-1.64), cardiovascular mortality (HR 1.54 [1.15-2.07]), myocardial infarction (HR = 1.43 [1.15, 1.78]), stroke (HR 1.26 [0.90, 1.75]), heart failure (HR = 1.27 [1.00, 1.61]), diabetic nephropathy (HR 1.33 [1.07, 1.65]), and diabetic retinopathy (DR) (HR = 1.48 [1.12, 1.96]) than those without obesity. Central obesity defined by WC and WHtR was associated with 40%-44% and 23%-98% higher risks of developing diabetic events, respectively. In the Chinese cohort, individuals with abdominal obesity, defined by WC (HR 1.44) or WHtR (HR 1.43) but not by WHR, carried more than 40% higher risk of developing DR than those without it. Higher TLFR carried 1.30-2.85 times higher risk of CVD and microvascular diseases among the dysglycemic population. CONCLUSIONS: Body fat distribution diseases among individuals with prediabetes or diabetes are associated with an increased risk of cardiometabolic and microvascular diseases independent of BMI.

Association of type 1 diabetes and age at diagnosis of type 2 diabetes with brain volume and risk of dementia in the UK Biobank: A prospective cohort study of community-dwelling participants.

AIMS: To investigate the association of type 1 diabetes (T1D) and age at diagnosis of type 2 diabetes (T2D) with brain structure and incident dementia. METHODS: Our analysis was based on the UK Biobank. We included 1376 participants with diabetes and 2752 randomly selected controls for brain volume analysis, and 25,141 participants with diabetes and 50,282 randomly selected controls for dementia analysis. Brain volume was measured using magnetic resonance imaging. Dementia was identified using hospital inpatient records and mortality register data until January 2021. RESULTS: T2D diagnosed at a younger age was associated with larger reductions in brain volume. After adjustment for glycated haemoglobin (HbA1c) and other covariates, only T2D diagnosed <50 years was associated with smaller total brain volume (ß (95% CI): -14.56 (-24.67, -4.44) ml), and grey (-6.47[-12.75, -0.20] ml) and white matter volumes (-8.08[-14.66, -1.51] ml). Corresponding numbers for total brain, grey matter and white matter volumes associated with T1D were -62.86 (-93.71,-32.01), -34.27 (-53.72, -14.83), and -28.59 (-47.65, -9.52) ml, respectively. During a median follow-up of 11.9 years, 2035 new dementia cases were identified. Younger age at diagnosis of T2D was associated with larger excessive risk of dementia, whereas T2D diagnosed <50 years was associated with the largest hazard ratio (HR) (95% CI: 2.03[1.53-2.69]) in the multivariable analysis. The HR (95% CI) for dementia associated with T1D was 2.08 (1.40-3.09). CONCLUSION: Individuals with T1D or T2D diagnosed at younger age are at larger excessive risk of brain volume reduction and dementia.

Brain and Cognition Signature Fingerprinting Vascular Health in Diabetic Individuals: An International Multi-Cohort Study.

OBJECTIVE: To evaluate the correlation between cognitive signatures and the risk of diabetic vascular complications and mortality, based on a multicountry prospective study. METHODS: The participants comprised 27,773 diabetics from the UK Biobank (UKB) and 1307 diabetics from the Guangzhou Diabetic Eye Study (GDES) cohort. The exposures were brain volume and cognitive screening tests for UKB participants, whilst the global cognitive score (GCS) measuring orientation to time and attention, episodic memory, and visuospatial abilities were determined for GDES participants. The outcomes for the UKB group were mortality, as well as macrovascular (myocardial infarction [MI] and stroke), microvascular (end-stage renal disease [ESRD], and diabetic retinopathy [DR]) events. The outcomes for the GDES group were retinal and renal microvascular damage. RESULTS: In the UKB group, a 1-SD reduction in brain gray matter volume was associated with 34%-77% higher risks of incident MI, ESRD, and DR. The presence of impaired memory was associated with 18%-73% higher risk of mortality and ESRD; impaired reaction was associated with 1.2-1.7-fold higher risks of mortality, stroke, ESRD, and DR. In the GDES group, the lowest GCS tertile exhibited 1.4-2.2-fold higher risk of developing referable DR and a twofold faster decline in renal function and retinal capillary density compared with the highest tertile. Restricting data analysis to individuals aged less than 65 years produced consistent results. CONCLUSION: Cognitive decline significantly elevates the risk of diabetic vascular complications and is correlated with retinal and renal microcirculation damage. Cognitive screening tests are strongly recommended as routine tools for management of diabetes.

Axial length changes in progressive and non-progressive myopic children in China.

PURPOSE: Due to pubertal development and crystalline lens compensation, axial length (AL) continues to increase among non-progressive myopic children (absolute annual spherical equivalent (SE) progression less than 0.25 diopter), but the amount is unknown. This study was to investigate the cutoff of AL change to accurately differentiate between progressive and non-progressive myopes. METHODS: A total of 8,546 myopic and treatment-naive children aged 6-10 years were enrolled from two cohort studies. AL with optical biometer and cycloplegic SE with auto refraction were evaluated at baseline and annually. Annual AL change was calculated, and the percentiles of annual axial elongation among progressive and non-progressive myopes were estimated by quantile regression with restricted cubic spline. Area under receiver-operating characteristic (ROC) curve (AUROC), positive predictive value (PPV), and negative predictive value (NPV) were applied to evaluate the accuracy of predicting progressive and non-progressive myopes. RESULTS: Among 8,546 myopic children, 603 (7.06%) were non-progressive myopes. Annual AL changes among non-progressive myopes remained stable with the median annual change being 0.25 mm, while the median for progressive myopes decreased with age from 0.58 to 0.42 mm. AUROC for distinguishing between non-progressive and progressive myopes was 0.88 and was > 0.85 for each age group. Annual AL change, the cutoff of 0.20 mm/year, had significantly high PPV and NPV in predicting progressive myopes with high proportion of progressive myopes and non-progressive myopes with low proportions of progressive myopes. CONCLUSION: Myopic children with non-progressive status had markedly less axial elongation than progressive ones. AL changes with cutoff of 0.20 mm/year could differentiate between non-progressive and progressive status and may be an alternative for evaluating progressive status.

Association of Retinal Age Gap With Arterial Stiffness and Incident Cardiovascular Disease.

BACKGROUND: Retinal parameters could reflect systemic vascular changes. With the advances of deep learning technology, we have recently developed an algorithm to predict retinal age based on fundus images, which could be a novel biomarker for aging and mortality. Therefore, we aim to investigate associations of retinal age gap with arterial stiffness index and incident cardiovascular disease (CVD). METHODS: A deep learning model was trained based on 19 200 fundus images of 11 052 participants without any medical history at baseline to predict the retinal age. Retinal age gap (retinal age predicted minus chronological age) was generated for the remaining 35 917 participants. Regression models were used to assess the association between retinal age gap and arterial stiffness index. Cox proportional hazards regression models and restricted cubic splines were used to explore the association between retinal age gap and incident CVD. RESULTS: We found each 1-year increase in retinal age gap was associated with increased arterial stiffness index (ß=0.002 [95% CI, 0.001-0.003]; P<0.001). After a median follow-up of 5.83 years (interquartile range: 5.73-5.97), 675 (2.00%) developed CVD. In the fully adjusted model, each 1-year increase in retinal age gap was associated with a 3% increase in the risk of incident CVD (hazard ratio=1.03 [95% CI, 1.01-1.06]; P=0.014). In the restricted cubic splines analysis, the risk of incident CVD increased significantly when retinal age gap reached 1.21 (hazard ratio=1.05 [95% CI, 1.00-1.10]; P-overall <0.0001; P-nonlinear=0.0681). CONCLUSIONS: We found that retinal age gap was significantly associated with arterial stiffness index and incident CVD events, supporting the potential of this novel biomarker in identifying individuals at high risk of future CVD events.