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Age-related cataracts are the leading cause of visual impairment among older adults. Many significant cases remain undiagnosed or neglected in communities, due to limited availability or accessibility to cataract screening. In the present study, we report the development and validation of a retinal photograph-based, deep-learning algorithm for automated detection of visually significant cataracts, using more than 25,000 images from population-based studies. In the internal test set, the area under the receiver operating characteristic curve (AUROC) was 96.6%. External testing performed across three studies showed AUROCs of 91.6–96.5%. In a separate test set of 186 eyes, we further compared the algorithm’s performance with 4 ophthalmologists’ evaluations. The algorithm performed comparably, if not being slightly more superior (sensitivity of 93.3% versus 51.7–96.6% by ophthalmologists and specificity of 99.0% versus 90.7–97.9% by ophthalmologists). Our findings show the potential of a retinal photograph-based screening tool for visually significant cataracts among older adults, providing more appropriate referrals to tertiary eye centers.

Topic To provide updated estimates on the global prevalence and number of people with diabetic retinopathy (DR) through 2045. Clinical Relevance The International Diabetes Federation (IDF) estimated the global population with diabetes mellitus (DM) to be 463 million in 2019 and 700 million in 2045. Diabetic retinopathy remains a common complication of DM and a leading cause of preventable blindness in the adult working population. Methods We conducted a systematic review using PubMed, Medline, Web of Science, and Scopus for population-based studies published up to March 2020. Random effect meta-analysis with logit transformation was performed to estimate global and regional prevalence of DR, vision-threatening DR (VTDR), and clinically significant macular edema (CSME). Projections of DR, VTDR, and CSME burden were based on population data from the IDF Atlas 2019. Results We included 59 population-based studies. Among individuals with diabetes, global prevalence was 22.27% (95% confidence interval [CI], 19.73%–25.03%) for DR, 6.17% (95% CI, 5.43%–6.98%) for VTDR, and 4.07% (95% CI, 3.42%–4.82%) for CSME. In 2020, the number of adults worldwide with DR, VTDR, and CSME was estimated to be 103.12 million, 28.54 million, and 18.83 million, respectively; by 2045, the numbers are projected to increase to 160.50 million, 44.82 million, and 28.61 million, respectively. Diabetic retinopathy prevalence was highest in Africa (35.90%) and North American and the Caribbean (33.30%) and was lowest in South and Central America (13.37%). In meta-regression models adjusting for habitation type, response rate, study year, and DR diagnostic method, Hispanics (odds ratio [OR], 2.92; 95% CI, 1.22–6.98) and Middle Easterners (OR, 2.44; 95% CI, 1.51–3.94) with diabetes were more likely to have DR compared with Asians. Discussion The global DR burden is expected to remain high through 2045, disproportionately affecting countries in the Middle East and North Africa and the Western Pacific. These updated estimates may guide DR screening, treatment, and public health care strategies.

Background/aimsTo examine the relationship between macular perfusion, as assessed using optical coherence tomography angiography (OCTA), and long-term visual outcome after surgical repair of macula-off rhegmatogenous retinal detachment (RRD).MethodsA prospective study of 29 patients who had undergone successful surgical repair of macula-off RRD. OCTA imaging was performed at month 3 and repeated at months 6 and 12 after surgery. Associations between OCTA parameters including, foveal avascular zone (FAZ) area, vessel density (VD) in the superficial capillary plexus (SCP) and deep capillary plexus (DCP), choriocapillaris flow deficit features and logMAR best-corrected visual acuity (VA) were assessed using a random intercept hybrid linear mixed model.ResultsOver the 1-year follow-up, VA improved (0.025 logMAR/ month, 95% CI 0.015 to 0.035) and FAZ area decreased (−0.020 mm2/month, 95% CI −0.032 to −0.007). Better VA after surgery was significantly associated with denser superficial VD (β=0.079, 95% CI 0.026 to 0.131), lower number of choriocapillaris flow deficits (β=−0.087, 95% CI −0.154 to −0.021) and larger average size of choriocapillaris flow deficits (β=0.085, 95% CI 0.022 to 0.147), after adjusting for baseline VA, types of surgery and other factors.ConclusionsOCTA measures of vascular perfusion in the macula may provide new pathophysiological insights and prognostic information related to macula-off RRD.

Introduction Diabetes and bone health are closely related. We examined the incidence and risk factors of hip fractures in Chinese patients with type 2 diabetes (T2D). Materials and Methods In this prospective cohort, we consecutively enrolled 22,325 adults with T2D above the age of 40 years in the Hong Kong Diabetes Register between 1994 and 2015 with crude hip fracture incidence rate censored in 2017. Results At baseline, the mean age of this cohort was 60.9 ± 10.5 years (mean duration of diabetes 6 years, 52.4% male). During a mean ± standard deviation (SD) follow‐up period of 8.7 ± 5.2 years with 193,553 person‐years, 603 patients were hospitalized due to hip fractures with an incidence (95% confidence interval, CI) of 315.1 (290.4–341.3) per 100,000 person‐years. On multivariable analysis with competing death risk adjusted, the independent hazard ratios (95% CI) for hip fractures in T2D were 2.01 (1.61–2.51) for female sex, 1.08 (1.07–1.09) for age, 0.93 (0.90–0.95) for body mass index, 1.52 (1.25–1.85) for albuminuria and 1.12 (1.02–1.23) for low density lipoprotein‐cholesterol. In men, the 30‐day, 1‐year and 5‐year post‐hip fracture mortality rate (95% CI) were 5.8 (2.4–9.1) %, 29.2 (22.3–35.5) % and 65.9 (57.3–72.8) % respectively. The corresponding rates in women were 3.4 (1.6–5.1) %, 18.6 (14.7–22.4) %, and 46.8 (40.9–52.1) %. Conclusions Southern Chinese patients with T2D have a high risk of hip fracture associated with suboptimal cardiometabolic‐renal risk factors and a high post‐fracture mortality rate. The effects of improving modifiable risk factors on bone health warrants further evaluation., With prospective follow up of nearly 9 years, we identified several risk factors associated with increase hip fracture incidence in Southern Chinese patients with type 2 diabetes in the Hong Kong Diabetes Register. These include female sex, age, body mass index, albuminuria and low density lipoprotein.

PurposeWe described the 6-year incidence and changes of retinopathy, and their associated risk factors in a multi-ethnic Asian population without diabetes.MethodsWe included 4374 participants with non-diabetes from a population-based cohort, the Singapore Epidemiology of Eye Disease Study, with gradable retinal photographs at baseline and 6-year follow-up visit. Retinopathy was assessed according to the modified Airlie House classification system.ResultsOver the 6-year period, the cumulative rates were 2.5% (106/4279) for retinopathy incidence, 1.0% (1/95) for retinopathy progression and 68.4% (65/95) for retinopathy regression. In multivariable analysis, higher diastolic blood pressure (DBP) (risk ratio (RR)=1.02; 95% CI: 1.00 to 1.04; per 10 mm Hg increase in DBP) and wider retinal arteriolar calibre (RR=1.36; 95% CI: 1.13 to 1.63; per SD increase in central retinal artery equivalent) were associated with higher risk of incident retinopathy, while higher level of high-density lipoprotein (HDL) was associated with lower risk of incident retinopathy (RR=0.56; 95% CI: 0.32 to 0.99; per mmol/L increase in HDL). Compared with Chinese, Malays were more likely to have retinopathy regression (RR=1.63; 95% CI: 1.20 to 2.22), while overweight (RR=0.47; 95% CI: 0.26 to 0.84) and higher glycosylated haemoglobin (HbA1c) level (RR=0.58; 95% CI: 0.37 to 0.93; per per cent increase in HbA1c) were associated with lower likelihood of retinopathy regression.ConclusionRisk of developing retinopathy in Asians without diabetes is generally low. However, regression of retinopathy over time is common, suggesting that these retinopathy signs may reflect subclinical reversible microvascular dysfunction. Several metabolic risk factors are associated with incidence or regression of retinopathy, suggesting that good metabolic control may still be important in the management of non-diabetic retinopathy.

Background ageing is an important risk factor for a variety of human pathologies. Biological age (BA) may better capture ageing-related physiological changes compared with chronological age (CA). Objective we developed a deep learning (DL) algorithm to predict BA based on retinal photographs and evaluated the performance of our new ageing marker in the risk stratification of mortality and major morbidity in general populations. Methods we first trained a DL algorithm using 129,236 retinal photographs from 40,480 participants in the Korean Health Screening study to predict the probability of age being ≥65 years (‘RetiAGE’) and then evaluated the ability of RetiAGE to stratify the risk of mortality and major morbidity among 56,301 participants in the UK Biobank. Cox proportional hazards model was used to estimate the hazard ratios (HRs). Results in the UK Biobank, over a 10-year follow up, 2,236 (4.0%) died; of them, 636 (28.4%) were due to cardiovascular diseases (CVDs) and 1,276 (57.1%) due to cancers. Compared with the participants in the RetiAGE first quartile, those in the RetiAGE fourth quartile had a 67% higher risk of 10-year all-cause mortality (HR = 1.67 [1.42–1.95]), a 142% higher risk of CVD mortality (HR = 2.42 [1.69–3.48]) and a 60% higher risk of cancer mortality (HR = 1.60 [1.31–1.96]), independent of CA and established ageing phenotypic biomarkers. Likewise, compared with the first quartile group, the risk of CVD and cancer events in the fourth quartile group increased by 39% (HR = 1.39 [1.14–1.69]) and 18% (HR = 1.18 [1.10–1.26]), respectively. The best discrimination ability for RetiAGE alone was found for CVD mortality (c-index = 0.70, sensitivity = 0.76, specificity = 0.55). Furthermore, adding RetiAGE increased the discrimination ability of the model beyond CA and phenotypic biomarkers (increment in c-index between 1 and 2%). Conclusions the DL-derived RetiAGE provides a novel, alternative approach to measure ageing.

Context Contradictory findings were reported in observational studies on the association of thyroid function (thyrotropin [TSH] and free thyroxine [FT4] levels) with Alzheimer disease (AD). Objective This work aims to determine whether genetically determined TSH/FT4 levels within reference range are causally associated with AD. Methods A bidirectional, 2-sample mendelian randomization (MR) study was conducted. With summary statistics from the largest genome-wide association studies (GWAS)/GWAS meta-analysis of TSH level(n ≥ 54 288), FT4 level(n = 49 269), and AD (71 880 cases; 383 378 controls), we used an MR approach to evaluate the bidirectional causal relationship between TSH/FT4 levels and AD. The inverse-variance weighted method was adopted as the main analysis. Results One SD increase in genetically determined TSH level within reference range was causally associated with a reduced risk of AD (odds ratio: 0.988; 95% CI, 0.977-0.998). A similar inverse association was observed in sex-specific analysis. The causal association was attenuated after adjustment for atrial fibrillation and blood pressure, suggesting they may mediate the causal pathway. A positive causal effect of AD on TSH level was detected only in male participants. This male-specific feedback loop may explain why the largest cohort study to date (Rotterdam Study) demonstrated a null observational association in men. Null association was observed between FT4 level and AD in both directions. Conclusion Genetic predisposition to increased TSH level, even within reference range, may lower the risk of AD, with atrial fibrillation, systolic, and diastolic blood pressure as possible mediators. Given the higher magnitude of risk reduction observed in the Rotterdam Study, whether the causal estimates derived from this MR study are underestimated warrants further investigation.

Familial hCG syndrome is a rare and benign cause of elevated serum beta human chorionic gonadotropin (hCG). We present here a case of familial hCG syndrome diagnosed in a Hong Kong Chinese family, which we believe to be the first reported in Chinese. A 38-year-old woman presented with incidental finding of persistently elevated hCG, analytically confirmed both in urine and blood. Extensive radiological and biochemical work-up were performed but were negative for pregnancy and malignancy. Testing of another asymptomatic family member revealed unexplained elevation of serum hCG, confirming the diagnosis of familial hCG syndrome. Knowledge and awareness of this entity among clinicians are important to avoid unnecessary investigations and treatment in affected families.

Nephrogenic diabetes insipidus (NDI) is a rare disorder of the renal collecting tubules, characterized by an inability to concentrate urine due to an impaired response to arginine vasopressin (AVP), resulting in dilute urine and polyuria. Causes of NDI are heterogeneous and diagnosing congenital NDI (cNDI) in young infants is clinically challenging, as typical symptoms are often unappreciated or inconspicuous. Instead, young infants may present with non-specific signs such as vomiting, poor feeding, failure to thrive, unexplained fevers, irritability, constipation or diarrhea. We report a 37-day-old infant who presented with polyuria and severe hypernatremic dehydration that was unresponsive to vasopressin. The patient was treated with amiloride, indomethacin and hydrochlorothiazide. Genetic analysis revealed a novel contiguous deletion involving the entire AVPR2 gene and the last exon of the adjacent ARHGAP4 gene. A study of the family confirmed the carrier status in the mother. This case illustrates the importance of molecular testing in confirming the diagnosis in the index patient, as well as in identifying asymptomatic at-risk female carriers so that appropriate genetic counselling can be given for reproductive planning. All pediatric patients with suspected cNDI should undergo genetic analysis for a definitive diagnosis.

Metabolomics, the identification and quantitation of metabolites in a system, have been applied to identify new biomarkers or elucidate disease mechanism. In this review, we discussed the application of metabolomics in several ocular diseases and recent developments in metabolomics regarding tear fluids analysis, data acquisition and processing.

Background Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a rare inherited disorder characterised by hyponatraemia. To date, most reported cases are Caucasians with gain-of-function variants in AVPR2, an X-linked gene which encodes the vasopressin V2 receptor (V2R). Recently, germline gain-of-function variants in the stimulatory G protein α-subunit (Gsα) were reported to cause dominantly inherited NSIAD. Case report We report the first Chinese adult diagnosed with NSIAD. He was found to be hemizygous for R137C-V2R, the most prevalent pathogenic variant among Caucasians. After the genetic diagnosis and counselling on the importance of fluid restriction, he had no recurrence of hyponatraemia to date. Literature review Case reports of NSIAD published in the English literature in PubMed were reviewed to summarise the genetic and phenotypic heterogeneity of this disorder. Conclusion NSIAD is ethnically, genetically and phenotypically diverse. The diagnosis should especially be considered in young patients with otherwise unexplained hyponatraemia. Target analysis of R137C-V2R should make the diagnosis in most cases. Genetic testing could confirm the diagnosis, motivate adherence to treatment, offer the possibility of genotype-guided therapy, and allow cascade screening to prevent hyponatraemia.

To provide updated estimates on the global prevalence and number of people with diabetic retinopathy (DR) through 2045.The International Diabetes Federation (IDF) estimated the global population with diabetes mellitus (DM) to be 463 million in 2019 and 700 million in 2045. Diabetic retinopathy remains a common complication of DM and a leading cause of preventable blindness in the adult working population.We conducted a systematic review using PubMed, Medline, Web of Science, and Scopus for population-based studies published up to March 2020. Random effect meta-analysis with logit transformation was performed to estimate global and regional prevalence of DR, vision-threatening DR (VTDR), and clinically significant macular edema (CSME). Projections of DR, VTDR, and CSME burden were based on population data from the IDF Atlas 2019.We included 59 population-based studies. Among individuals with diabetes, global prevalence was 22.27% (95% confidence interval [CI], 19.73%-25.03%) for DR, 6.17% (95% CI, 5.43%-6.98%) for VTDR, and 4.07% (95% CI, 3.42%-4.82%) for CSME. In 2020, the number of adults worldwide with DR, VTDR, and CSME was estimated to be 103.12 million, 28.54 million, and 18.83 million, respectively; by 2045, the numbers are projected to increase to 160.50 million, 44.82 million, and 28.61 million, respectively. Diabetic retinopathy prevalence was highest in Africa (35.90%) and North American and the Caribbean (33.30%) and was lowest in South and Central America (13.37%). In meta-regression models adjusting for habitation type, response rate, study year, and DR diagnostic method, Hispanics (odds ratio [OR], 2.92; 95% CI, 1.22-6.98) and Middle Easterners (OR, 2.44; 95% CI, 1.51-3.94) with diabetes were more likely to have DR compared with Asians.The global DR burden is expected to remain high through 2045, disproportionately affecting countries in the Middle East and North Africa and the Western Pacific. These updated estimates may guide DR screening, treatment, and public health care strategies.

Summary Background Coronary artery calcium (CAC) score is a clinically validated marker of cardiovascular disease risk. We developed and validated a novel cardiovascular risk stratification system based on deep-learning-predicted CAC from retinal photographs. Methods We used 216 152 retinal photographs from five datasets from South Korea, Singapore, and the UK to train and validate the algorithms. First, using one dataset from a South Korean health-screening centre, we trained a deep-learning algorithm to predict the probability of the presence of CAC (ie, deep-learning retinal CAC score, RetiCAC). We stratified RetiCAC scores into tertiles and used Cox proportional hazards models to evaluate the ability of RetiCAC to predict cardiovascular events based on external test sets from South Korea, Singapore, and the UK Biobank. We evaluated the incremental values of RetiCAC when added to the Pooled Cohort Equation (PCE) for participants in the UK Biobank. Findings RetiCAC outperformed all single clinical parameter models in predicting the presence of CAC (area under the receiver operating characteristic curve of 0·742, 95% CI 0·732–0·753). Among the 527 participants in the South Korean clinical cohort, 33 (6·3%) had cardiovascular events during the 5-year follow-up. When compared with the current CAC risk stratification (0, >0–100, and >100), the three-strata RetiCAC showed comparable prognostic performance with a concordance index of 0·71. In the Singapore population-based cohort (n=8551), 310 (3·6%) participants had fatal cardiovascular events over 10 years, and the three-strata RetiCAC was significantly associated with increased risk of fatal cardiovascular events (hazard ratio [HR] trend 1·33, 95% CI 1·04–1·71). In the UK Biobank (n=47 679), 337 (0·7%) participants had fatal cardiovascular events over 10 years. When added to the PCE, the three-strata RetiCAC improved cardiovascular risk stratification in the intermediate-risk group (HR trend 1·28, 95% CI 1·07–1·54) and borderline-risk group (1·62, 1·04–2·54), and the continuous net reclassification index was 0·261 (95% CI 0·124–0·364). Interpretation A deep learning and retinal photograph-derived CAC score is comparable to CT scan-measured CAC in predicting cardiovascular events, and improves on current risk stratification approaches for cardiovascular disease events. These data suggest retinal photograph-based deep learning has the potential to be used as an alternative measure of CAC, especially in low-resource settings. Funding Yonsei University College of Medicine; Ministry of Health and Welfare, Korea Institute for Advancement of Technology, South Korea; Agency for Science, Technology, and Research; and National Medical Research Council, Singapore.

We evaluated the agreements in foveal avascular zone (FAZ) area and vessel density (VD) parameters (within the superficial capillary plexus region), between two widely used optical coherence tomography angiography machines. Participants who attended the Singapore Malay Eye Study III between 29th March and 6th August 2018, were enrolled in this study. Participants underwent fovea-centered 6×6-mm macular cube scan, using both AngioVue and Cirrus HDOCT machines. Scans were analyzed automatically using built-in review software of each machine. 177 eyes (95 participants) without retinal diseases were included for final analysis. Mean FAZ area was 0.38 ± 0.11 mm2 and 0.30 ± 0.10 mm2, based on AngioVue and Cirrus HDOCT, respectively. Mean parafoveal VD was 0.50 ± 0.04 in Angiovue, and 0.43 ± 0.04 in Cirrus HDOCT. Cirrus HDOCT measurements were consistently lower than those by AngioVue, with a mean difference of −0.08 (95% limits of agreement [LOA], −0.30–0.13) mm2 for FAZ area, and −0.07 (95% LOA, −0.17–0.03) for parafoveal VD. Intraclass correlation coefficients for FAZ area and parafoveal VD were 0.33 and 0.07, respectively. Our data suggest that agreements between AngioVue and Cirrus HDOCT machines were poor to fair, thus alternating use between these two machines may not be recommended especially for follow up evaluations.

With the rapidly aging population, the burden of visual impairment (VI) and cognitive decline is expected to increase. Previous cross-sectional studies suggest an association between these 2 health outcomes. However, few longitudinal reports have examined this association, and to our knowledge, no studies have been performed in Asian populations. Further investigation on this association may help to better identify individuals at risk of cognitive decline.To examine the longitudinal association between VI and decline in cognitive function in a multiethnic Asian population.In this longitudinal, population-based, prospective cohort study, Chinese, Indian, and Malay adults 60 years or older at baseline were recruited from the Singapore Epidemiology of Eye Diseases (SEED) study. At baseline, participants from the SEED study were recruited under 3 studies: the Singapore Malay Eye Study (SiMES; 2004-2006), the Singapore Indian Eye Study (SINDI; 2007-2009), and the Singapore Chinese Eye Study (SCES; 2009-2011). Eligible participants were reexamined after 6 years (2011-2013 for SiMES, 2013-2015 for SINDI, and 2015-2017 for SCES). Data analysis was performed from November 1 to 24, 2019.Visual impariment was defined as presenting visual acuity worse than 20/40 based on the better-seeing eye.Cognitive function was assessed using a locally validated Abbreviated Mental Test (AMT). The association between baseline VI and change in AMT score was determined using the multivariable linear regression model adjusting for baseline age; sex; race/ethnicity; presence of diabetes, hyperlipidemia, hypertension, and chronic kidney disease; history of cardiovascular disease; smoking status; alcohol intake; body mass index; educational status; and AMT score.A total of 2478 individuals (1256 [50.7%] male; 1073 Chinese, 768 Indian, and 637 Malay adults) with mean (SD) age of 67.6 (5.6) years were evaluated, of whom 489 (19.7%) had reduction in AMT scores over 6 years. Baseline VI was associated with a decrease in AMT score over 6 years (β = -0.27; 95% CI, -0.37 to -0.17; P .001). When change in vision over 6 years was evaluated, unchanged or deteriorated VI was associated with a decrease in AMT score over 6 years (β = -0.29; 95% CI, -0.40 to -0.18; P .001). Among individuals with baseline VI and a substantial decrease in AMT score of 3 units or more over 6 years, the leading causes of VI were undercorrected refractive error (14 [45.2%]) and cataract (11 [35.5%]).In this study, poor vision was independently associated with a decline in cognitive function. Causes of visual loss in these cases were mostly preventable, further suggesting that preserving good vision may be an important interventional strategy for mitigating cognitive decline.

Background Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder that is rare in adults, with a reported incidence of 1-2 cases per million per year. Cranial diabetes insipidus (CDI) is the most common and often the first endocrine manifestation of LCH, when histiocytes infiltrate the pituitary. Anterior pituitary dysfunction, when present, usually develops after onset of CDI. Unlike most other etiologies of CDI, multisystem involvement is frequent in LCH, especially the bones, skin, and lungs. Case A 23-year-old man of good past health presented with 3 months of polyuria and polydipsia in 2015. CDI was confirmed by water deprivation test, and his symptoms resolved with DDAVP treatment. There were no anterior pituitary hormone deficiencies on presentation. Pituitary MRI showed loss of the posterior bright spot and a contrast enhancing pituitary stalk thickening (PST) of 5 mm, with no compression on the optic chiasm. Lumbar puncture showed no evidence of CNS infection or neoplastic cells. Beta HCG, AFP, IgG4, ANA, and chest Xray were unremarkable. Three months later he developed central hypogonadism, and was treated with testosterone after sperm banking. A repeat MRI showed persistent PST of 5 mm, and biopsy of the pituitary suggested lymphocytic infundibulo-hypophysitis (LIH). Unfortunately the biopsy was complicated with irreversible focal visual field defect. It was then noted that a bone scan had been arranged earlier for intermittent left hip pain, which revealed a 3.5 cm osteolytic lesion over the left ilium. The concomitant pituitary and bone lesions thus make LCH the more likely diagnosis. However bone biopsy showed nonspecific fibrosis only. The pathologist was then contacted for further immunohistochemical analysis. This identifies clusters of Langerhans cells with positive stain for S100, CD1a, and Langerin (LCH cell markers) in the pituitary tissue, and BRAF V600E mutation was detected by PCR, compatible with the diagnosis of LCH. Systemic chemotherapy was proposed due to multisystemic disease, but was declined by patient. At 4 years of follow-up, the PST spontaneously regressed to 2 mm but the CDI and central hypogonadism persisted. Conclusion Our case illustrates the diagnostic challenge in a patient presenting with CDI, given a pituitary biopsy with histological features mimicking LIH and an inconclusive bone biopsy. However, a diagnosis of LIH would not explain for the unusual bone lesion in a young man, and bone biopsies can be prone to crush artifacts limiting analysis. The importance of actively looking for and biopsying extracranial lesions before biopsying the pituitary cannot be understated as the latter entails risks of hypopituitarism and visual defect, as had happened to our patient. When clinical and pathologic findings do not match, communication with the pathologist for histological review had been essential in establishing the diagnosis of LCH.

Purpose To report surgical outcomes of 25-gauge pars plana vitrectomy using air as an internal tamponade for patients with primary rhegmatogenous retinal detachment (RRD). Methods A retrospective clinical study of 59 eyes of 59 consecutive patients presented with primary RRD at the Beijing Tongren Eye Center in China. From August 2016 to May 2018, medical records of the patients who underwent 25-gauge pars plana vitrectomy with air tamponade for RRD were reviewed. The main outcome measures were primary and final anatomical success (retinal re-attachment) rates, and postoperative complications. Results Of the 59 patients, aged 54.47 ± 11.81 years, 31 (52.5%) were men. Vitrectomy was performed 3 to 40 (averaged 16.98 ± 10.17) days after the onset of symptoms, and the mean follow-up period was 12.90 ± 5.92 months (ranging 6.07-26.10 months). Forty-two eyes (71.2%) had RRD with retinal breaks in the superior half of the retina, and the mean number of retinal breaks was 1.75 ± 0.94. Three eyes (5.1%) had RRD with giant retinal tears. Of the 59 eyes, 35 (59.3%) had RRD with inferior quadrants involved. Proliferative vitreoretinopathy (PVR) gradings were C1 in 2 (3.4%) eyes and B or below in 57 (96.6%) eyes. The primary and final anatomical success rates were 94.9% (56/59) and 98.3% (58/59), respectively. Of the three eyes which developed re-detachment of the retina, one eye had postoperative progression of PVR and two eyes were RRD associated with macular hole in high myopia. Postoperative complications included 5 eyes (8.5%) with serous choroidal detachment within 3 days after surgery and 4 eyes (6.8%) with macular epiretinal membrane formation 1 to 8 months after surgery. Secondary cataract surgery was performed in 13 of the 53 phakic eyes (24.5%) during follow-up. Conclusion Small-gauge pars plana vitrectomy with air tamponade may be effective in treating selected cases of relatively simple primary RRD. Additional studies are needed to verify the efficacy of this surgical approach for more complicated cases such as those with giant retinal tears.

Aim The intrathecal baclofen pump is an effective treatment for spasticity. However, long-term results have reported patients' dissatisfaction and perception of disability. Potential causes include a frequent need for baclofen pump refill and risks of complications. The aim of the present study was to evaluate the long-term maintenance, complications and clinical outcome of intrathecal baclofen pumps. Patients and methods We conducted a 16-year retrospective cohort study of patients with spasticity treated with an intrathecal baclofen pump at a university hospital from 2000 to 2016. The primary outcome was the rate of infection per puncture for baclofen pump refill. Secondary outcomes included the incidence of other complications, such as running out of baclofen causing symptomatic withdrawal symptoms, pump mechanical failure, pump battery end of life and the need for pump replacement. The clinical outcome was assessed by the Modified Ashworth Scale (mAS). Results In total, 340 follow-up episodes with pump refill procedures were recorded. The average interval between each pump refill was 57.3 days (±15.4 days). The average duration of admission for each pump refill was 4 h and 49 min (from 2 h 23 min to 10 h). There were two events with established infection after puncture for the refill, giving rise to an infection rate per puncture of 0.6 percent (2/340).For the long-term clinical outcome, at an average follow-up period of 7.6 years, the postoperative mAS for spasticity was 2.0 ± 0.756, which was significantly better than the preoperative mAS at 3.75 ± 0.462 (P = 0.001). Conclusion Long-term aftercare with baclofen pump refill was safe, with an infection rate of 0.6 per cent per puncture for each refill. Long-term intrathecal baclofen pump was effective in the treatment of spasticity with persistent significant improvement in the spasticity scale.

BackgroundTo evaluate retinal thickness profiles in eyes with and without diabetic retinopathy (DR) using spectral-domain optical coherence tomography (SD-OCT) among individuals with diabetes.MethodsParticipants were recruited from the Singapore Epidemiology of Eye Diseases Study, a population-based study among Chinese, Malays and Indians aged 40 years or older residing in Singapore. All participants underwent standardised systemic and ophthalmic examinations. Average thickness of the macula, ganglion cell-inner plexiform layer and outer retina layer (from the outer plexiform layer to the retinal pigment epithelium layer) were measured using SD-OCT. DR status and severity were graded based on fundus photographs using the modified Airlie House classification system. Participants with macular oedema were excluded.Results2240 eyes from 1280 participants were included. Of these, 1764 (78.7%) eyes had no DR, 351 (15.7%) eyes had minimal or mild DR and 125 (5.6%) eyes had moderate or worse DR. After adjusting for age, gender, ethnicity, axial length, hypertension, glycated haemoglobin, body mass index, total cholesterol and diabetes duration, eyes with DR had thicker macula (245.44 µm vs 243.04 µm, P=0.03) and outer retina (124.26 µm vs 123.08 µm, P=0.01) than eyes without DR. When stratified by DR severity, thicker macula (250.24 µm vs 242.88 µm, P=0.011) and outer retina (126.4 µm vs 123.0 μm, P=0.006) were observed in eyes with moderate or worse, but not minimal or mild DR, compared with eyes without DR.ConclusionsEven in the absence of macular oedema, eyes with DR, particularly those with more severe DR, had thicker macular and outer retinal layers than eyes without DR.

Summary Diabetic macular oedema, characterised by exudative fluid accumulation in the macula, is the most common form of sight-threatening retinopathy in people with diabetes. It affects one in 15 people with diabetes resulting in more than 20 million cases worldwide. Few epidemiological studies have been done to specifically investigate risk factors for diabetic macular oedema, although poor glycaemic and blood pressure control are associated with the presence and development of the disorder. The pathophysiological processes begin with chronic hyperglycaemia, and interplay between vascular endothelial growth factor (VEGF) and inflammatory mediators. Non-invasive imaging using optical coherence tomography has allowed clinicians to detect mild levels of diabetic macular oedema in order to monitor progress and guide treatment. Although focal or grid laser photocoagulation was the traditional mode of treatment, intraocular pharmacotherapy with anti-VEGF agents is now the standard of care. However, these therapies are expensive and resource intensive. Emerging therapeutic strategies include improving efficacy and duration of VEGF suppression, targeting alternative pathways such as inflammation, the kallikrein–kinin system, the angiopoietin–Tie2 system, and neurodegeneration, and using subthreshold and targeted laser therapy. Ongoing research should lead to improvements in screening, diagnosis, and management of diabetic macular oedema.

Isolated 17,20-lyase deficiency may be caused by mutations in the CYP17A1 (coding for cytochrome P450c17), POR (coding for cytochrome P450 oxidoreductase) and CYB5A (coding for microsomal cytochrome b5) genes. Of these, mutations in the CYB5A gene have thus far only been described in genetic males who presented with methemoglobinemia and 46,XY disorders of sex development (DSD) due to 17,20-lyase deficiency. A 24-year-old Chinese woman presented to the hematology outpatient clinic with purplish discoloration of fingers, toes, and lips since childhood. Investigations confirmed methemoglobinemia. A homozygous c.105C>G (p.Tyr35Ter) nonsense mutation was detected in the CYB5A gene. Hormonal studies showed isolated 17,20-lyase deficiency. Interestingly, she had a completely normal female phenotype with no DSD, normal pubertal development, and spontaneous pregnancy giving birth uneventfully to a healthy female infant. The sex hormone-related features of genetic females with 17,20-lyase deficiency due to cytochrome b5 gene mutation appear to differ from that of females with 17,20-lyase deficiency caused by other genetic defects who presented with hypergonadotropic hypogonadism and infertility and differ from genetic males with the same mutation.

To elucidate the molecular processes associated with the development of myopic macular degeneration (MMD), we measured the intraocular concentrations of molecular factors in emmetropic and myopic eyes. This is a retrospective clinic-based case-control study that included eyes undergoing routine cataract surgery whereby aqueous humour samples were obtained. We measured the concentrations of pigment epithelium derived factor(PEDF), matrix metalloproteinase 2(MMP-2), tissue inhibitor of metalloproteinase(TIMP-2), vascular endothelial growth factor isoform A(VEGF-A), interleukin 8(IL-8), interleukin 6(IL-6), C-reactive protein(CRP), angiopoietin 2(Ang2), and amphiregulin. 38 eyes (axial length (AL): 22.4–32.4 mm), including 12 highly myopic (HM) eyes (AL ≥ 26.5 mm) without MMD and 12 HM eyes with MMD but without neovascularization were included. Eyes with MMD were found to have significantly lower VEGF-A levels (p = 0.007) and higher MMP-2 levels (p = 0.02) than control eyes after adjusting for age and gender. MMP-2 levels correlated positively (r = 0.58, p = 0.002), while VEGF-A levels correlated negatively with longer axial length (r = −0.75, p P = 0.25) and MMP-2 (P = 0.69) were not significantly associated with MMD after adjusting for AL. These findings suggest that the predominant mechanism underlying the development of non-neovascular MMD may be axial elongation, driven in part by MMP-2 related mechanisms.

Background: Exogenous steroid use is the most common cause of central adrenal insufficiency. Depending on the duration and strength used, it may take months to years for the hypothalamic-pituitary-adrenal (HPA) axis to recover after the steroid is stopped. We report a case of iatrogenic hypoadrenalism with persistent suppression of the HPA axis for 13 years, discovered later to be due to a second pathology. Case: A 48 year old lady presented in 2005 with weight gain of 20 kg over 1 year and florid Cushingoid features. 9AM cortisol was undetectable ( 329 (30 min) -> 408 nmol/L (60 min) [N peak>500 nmol/L]), and she was back to her usual body weight. However, subsequent monitoring revealed declining trend of 9AM cortisol from 135 nmol/L (2013) -> 99 nmol/L (2014) -> 57 nmol/L (2015) -> 64 nmol/L (2016) -> 18 nmol/L (2017) [N 166–507 nmol/L]. Hydrocortisone compliance and abstinence from exogenous steroids was confirmed with the patient. The ongoing hypofunction of the HPA axis was continually attributed by multiple physicians to her history of prolonged use of dexamethasone. In 2018, at the age of 60, the lady presented with new onset headaches, blurred vision, and bitemporal hemianopia for 3 months. MRI showed a 1.8x1.8x3.5 cm (WxAPxH) pituitary mass with suprasellar extension compressing the optic chiasm. Blood tests revealed panhypopituitarism: SST cortisol 17 -> 59 -> 49 nmol/L, ACTH 2.7 pmol/L [N Discussion: This case presents the uncommon course of a patient who had almost recovered from iatrogenic hypoadrenalism, only to lapse back into worsened central adrenal insufficiency, as part of panhypopituitarism related to an undiagnosed pituitary mass. In retrospect, the unusually protracted state of hypocortisolemia and the atypical waxing and waning HPA axis should have alerted one to consider alternative etiologies at work. As LH-FSH and GH deficiencies commonly develop before ACTH and TSH deficiencies in most pituitary macroadenomas, a lower threshold for testing the other anterior pituitary hormones followed by imaging of the pituitary could have picked up the tumor earlier in this patient.

IMPORTANCE: The incidence of rhegmatogenous retinal detachment (RRD) is partly determined by its risk factors, such as age, sex, cataract surgery, and myopia. Changes in the prevalence of these risk factors could change RRD incidence in the population. OBJECTIVE: To determine whether the incidence of RRD in the Netherlands has changed over recent years and whether this change is associated with an altered prevalence of RRD risk factors. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included data from all 14 vitreoretinal clinics in the Netherlands, as well as a large Dutch population-based cohort study. All patients who underwent surgical repair for a primary RRD in the Netherlands from January 1 to December 31, 2009, and January 1 to December 31, 2016, were analyzed, in addition to all participants in the population-based Rotterdam Study who were examined during these years. Analysis began February 2018 and ended November 2019. EXPOSURES: RRD risk factors, including age, male sex, cataract extraction, and myopia. MAIN OUTCOMES AND MEASURES: Age-specific RRD incidence rate in the Dutch population, as well as change in RRD incidence and risk factor prevalence between 2009 and 2016. RESULTS: In 2016, 4447 persons (median [range] age, 61 [3-96] years) underwent surgery for a primary RRD within the Netherlands, resulting in an RRD incidence rate of 26.2 per 100 000 person-years (95% CI, 25.4-27.0). The overall RRD incidence rate had increased by 44% compared with similar data from 2009. The increase was observed in both phakic (1994 in 2009 to 2778 in 2016 [increase, 39%]) and pseudophakic eyes (1004 in 2009 to 1666 in 2016 [increase, 66%]), suggesting that cataract extraction could not solely account for the overall rise. Over the same period, the prevalence of mild, moderate, and severe myopia among persons aged 55 to 75 years had increased by 15.6% (881 of 4561 [19.3%] vs 826 of 3698 [22.3%]), 20.3% (440 of 4561 [9.6%] vs 429 of 3698 [11.6%]), and 26.9% (104 of 4561 [2.3%] vs 107 of 3698 [2.9%]), respectively, within the population-based Rotterdam Study. CONCLUSIONS AND RELEVANCE: In this study, an increase was observed in primary RRD incidence in the Netherlands over a 7-year period, which could not be explained by a different age distribution or cataract surgical rate. A simultaneous myopic shift in the Dutch population may be associated, warranting further population-based studies on RRD incidence and myopia prevalence.

Purpose Emulsification is related to complications arising from silicone oil (SO) tamponade. Currently, there is no widely accepted method for testing the propensity of SO to emulsify that are physiologically realistic and quantitative. Methods We compared different ways of inducing emulsification namely vortex mixing, sonication and homogenization. Silicone oil (SO) emulsification was quantitatively assessed using the Coulter counter and laser light scattering. The in vitro results are compared with the droplet size distribution profile of vitreous clinical washout. Conventional SO was compared with two novel SO blends with high-molecular-weight (HMW) additives (SOHMW2000 and SOHMW5000). Results Of the three methods for inducing emulsification, homogenization generated the most consistent emulsion samples with the smallest variance. The results from the Coulter counter measurement correlated strongly with the laser light scattering measurement within the range of 1 to 30 µm. The droplet size distribution profiles from human eyes were similar to that of emulsions generated in vitro by homogenization. The human size distribution profile was within the range of values obtained by the in vitro experiment. Compared to the conventional SO, the emulsion droplet counts for the new SO blends were significantly lower (SOHMW2000 and SOHMW5000 were 79% (±17%) and 49% (±18%) of the SO2000 and SO5000, respectively; p = 0.03 and p = 0.002). Conclusion Emulsion generated in vitro by homogenization has similar droplet size profile as human eyes filled with SO. Using this method to induce emulsion, SO blends with HMW additives demonstrated less propensity to emulsification with lower droplet counts compared to conventional SO with similar shear viscosity.

AimsDiabetes is a major public health problem in migrants and ethnic minorities worldwide. We determined the incidence and risk factors of diabetic retinopathy (DR) in migrant Indians living in Singapore.MethodsWe included data from 759 Indian adults with diabetes, who participated in the baseline (aged 40–80 years, 2007–2009) and 6-year follow-up 2012–2015 of the Singapore Indian Eye Study. Retinal photographs were graded for the presence and severity of DR using modified Airlie House Classification. Incidence was assessed in participants who were free of DR at baseline visit (n=501), while progression in those with DR but free of proliferative DR at baseline visit (n=189). Risk factors included demographic, lifestyle, socioeconomic, family history, genes, duration of diabetes, glycaemic control, insulin use, ocular and clinical factors.ResultsThe 6-year age-standardised DR incidence and progression were 21.89% and 33.45%, respectively. HbA1c (risk ratio (RR) 1.41, 95% CI 1.28 to 1.55 per unit increase), current smoking (RR 1.63, 95% CI 1.02 to 2.62) and insulin use (RR 2.63, 95% CI 1.44 to 4.82) were associated with higher incidence, whereas estimated cerebrospinal fluid pressure (RR 0.90, 95% CI 0.82 to 0.98) and body mass index (BMI) (RR 0.74, 95% CI 0.60 to 0.93) were associated with lower incidence of DR. Higher HbA1c (RR 1.26, 95% CI 1.13 to 1.42), BMI (RR 1.26, 95% CI 1.02 to 1.56) and estimated cerebrospinal fluid pressure (RR 1.11, 95% CI 1.02 to 1.21) were associated with DR progression. The population attributable risk of HbA1c >8% was 41.29% and 49.63% for DR incidence and progression.ConclusionDR incidence and progression in migrant Indians living in Singapore was more than double that reported in Indians living in urban India. Consistent with past studies, poor glycaemic control was an important predictor for incidence and progression of DR.

Background/aimsTo evaluate the distribution and determinants of outer retinal thickness in eyes without retinal diseases, using spectral-domain optical coherence tomography (SD-OCT).MethodsParticipants were recruited from the Singapore Epidemiology of Eye Diseases Study, a population-based study among Chinese, Malays and Indians in Singapore. A total of 5333 participants underwent SD-OCT imaging in which a 6×6 mm2 measurement area centred at the fovea. Outer retinal thickness was defined as the distance from the outer plexiform layer to the retinal pigment epithelium layer boundary.Results7444 eyes from 4454 participants were included in final analysis. Of them, mean age was 58.4 years (SD 8.3), and 2294 (51.5%) were women. Women (121.0±8.1 µm) had thinner average outer retinal thickness than men (125.6±8.2 µm) (pConclusionIn this large sample of Asian population, we provided normative SD-OCT data on outer retinal thickness in eyes without retinal diseases. Women had thinner outer retina than men. For the first time, these findings provide fundamental knowledge on normative profile of outer retinal thickness in Asians.

Anti-vascular endothelial growth factor (VEGF) therapies lead to a major breakthrough in treatment of neovascular retinal diseases such as age-related macular degeneration or diabetic retinopathy. Current management of these conditions require regular and frequent intravitreal injections to prevent disease recurrence once the effect of the injected drug wears off. This has led to a pressing clinical need of developing sustained release formulations or therapies with longer duration. A major drawback in developing such therapies is that the currently available animal models show spontaneous regression of vascular leakage. They therefore not only fail to recapitulate retinal vascular disease in humans, but also prevent to discern if regression is due to prolonged therapeutic effect or simply reflects spontaneous healing. Here, we described the development of a novel rabbit model of persistent retinal neovascularization (PRNV). Retinal Muller glial are essential for maintaining the integrity of the blood-retinal barrier. Intravitreal injection of DL-alpha-aminoadipic acid (DL-AAA), a selective retinal glial (Muller) cell toxin, results in persistent vascular leakage for up to 48 weeks. We demonstrated that VEGF concentrations were significantly increased in vitreous suggesting VEGF plays a significant role in mediating the leakage observed. Intravitreal administration of anti-VEGF drugs (e.g. bevacizumab, ranibizumab and aflibercept) suppresses vascular leakage for 8-10 weeks, before recurrence of leakage to pre-treatment levels. All three anti-VEGF drugs are very effective in re-ducing angiographic leakage in PRNV model, and aflibercept demonstrated a longer duration of action compared with the others, reminiscent of what is observed with these drugs in human in the clinical setting. Therefore, this model provides a unique tool to evaluate novel anti-VEGF formulations and therapies with respect to their duration of action in comparison to the currently used drugs.

Importance To our knowledge, population-based data on retinal emboli are limited in Asia. Besides its associations with traditional cardiovascular risk factors and stroke, associations between retinal emboli and renal disease and function remain unclear. Objective To examine the prevalence of and risk factors for retinal emboli in a large, contemporary, multiethnic Asian population. Design, Setting, and Participants This population-based cross-sectional study was conducted from 2004 to 2011 and included a total of 10 033 Chinese, Malay, and Indian persons aged 40 to 80 years residing in the general communities of Singapore. Analyses were performed from November 2016 to February 2017. Interventions or Exposures Retinal emboli were ascertained from retinal photographs obtained from both eyes of all participants according to a standardized protocol. Age-standardized prevalence of retinal emboli was calculated using the 2010 Singapore adult population. Risk factors were assessed from comprehensive systemic and ophthalmic examinations, interviews, and laboratory investigations. Main Outcomes and Measures Retinal emboli. Results Of the 10 033 participants, 9978 (99.5%) had gradable retinal photographs. Of these, 5057 (50.7%) were female, and 3375 (33.8%) were Indian. We identified 88 individuals (0.9%) with retinal emboli; the overall person-specific, age-standardized prevalence of retinal emboli was 0.75% (95% CI, 0.60-0.95), with the highest prevalence seen in the Indian cohort (0.98%), followed by the Chinese (0.73%) and Malay (0.44%) cohorts ( P = .03). In multivariable-adjusted analysis, factors associated with prevalent retinal emboli included older age (per 5-year increase; odds ratio [OR], 1.22; 95% CI, 1.05-1.41), Indian ethnicity (compared with Malay ethnicity; OR, 3.58; 95% CI, 1.95-6.60), hypertension (OR, 1.95; 95% CI, 1.03-3.70), chronic kidney disease (OR, 2.05; 95% CI, 1.15-3.64), creatinine level (per SD increase; OR, 1.13; 95% CI, 1.05-1.21), glomerular filtration rate (per SD increase; OR, 0.67; 95% CI, 0.51-0.86), and history of stroke (OR, 3.45; 95% CI, 1.70-6.99). Conclusions and Relevance Based on 88 individuals among 9978 participants of 3 major Asian ethnic populations, retinal emboli were most commonly seen in Indian persons and associated with conventional cardiovascular risk factors, stroke, and chronic kidney disease. Therefore, its presence may signal vascular embolic event and damage not only in the brain but also in the kidneys. If these data are confirmed in longitudinal studies, they would suggest that persons with retinal emboli may require both general cardiovascular and renal assessment.