Retinal photograph-based deep learning predicts biological age, and stratifies morbidity and mortality risk.

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.

Global Prevalence of Diabetic Retinopathy and Projection of Burden through 2045: Systematic Review and Meta-analysis.

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.

SURGICAL OUTCOMES OF 25-GAUGE PARS PLANA VITRECTOMY USING AIR AS AN INTERNAL TAMPONADE FOR PRIMARY RHEGMATOGENOUS RETINAL DETACHMENT.

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.

A novel model of persistent retinal neovascularization for the development of sustained anti-VEGF therapies.

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 Müller 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 (Müller) 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.

Sleep apnea and retinal signs in cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis.

PURPOSE: The aim of the study was to examine the relationship between sleep apnea, retinal vascular caliber and retinopathy, and their impact on cardiovascular disease (CVD) risk. METHODS: A multi-ethnic cohort of 5,803 participants was examined based on standardized grading of retinal vascular caliber and retinopathy from digital fundus photographs, self-reported physician-diagnosed sleep apnea (PDSA), and incident cardiovascular events. RESULTS: In women, PDSA was associated with narrower arterioles (regression coefficient [ß] -5.76; 95 % confidence Interval [CI] -8.51, -3.02) after adjusting for cardio-metabolic risk factors. The incident rate ratio (IRR) of CVD was also associated with narrower arterioles (IRR for highest versus lowest tertile 1.91; 95 % CI 1.08, 3.38). In men, PDSA was not associated with arteriolar caliber. However, incident CVD was associated with narrower arterioles (IRR 1.67; 95 % CI 1.10, 2.52), wider venules (IRR 1.71; 95 % CI 1.13, 2.59) and PDSA (IRR 2.03, 95 % CI 1.17, 3.51). The IRR of CVD in men with PDSA increased minimally to 2.06 (95 % CI 1.18, 3.56) after adjustment for retinal arteriolar and venular caliber. Combining women and men, the IRR of CVD was 3.41 (95 % CI 1.79, 6.50) in those with both PDSA and narrower retinal arterioles. CONCLUSIONS: Sleep apnea was associated with narrower retinal arterioles in women but not in men. However, sleep apnea was also associated with incident CVD in men. These suggest potential gender differences in susceptibility to microvascular disease in association with sleep apnea.

Quantifying silicone oil emulsification in patients: are we only seeing the tip of the iceberg?

PURPOSE: Emulsification of silicone oil in the eye is a difficult problem. In an effort to find an objective way to quantify emulsification, we used the Coulter principle to measure silicone oil emulsified droplets from the washings of a series of patients. METHODS: Aqueous washouts after silicone oil removal were obtained from nine patients (nine eyes). We used the Coulter counter Multisizer® 4 to obtain the size distribution of the oil droplets. RESULTS: Over 65 % of the emulsified silicone oil droplets in the clinical samples had a diameter smaller than is detectable by light microscopy (2 µm). The median size of the droplets was between 1.1 and 1.9 µm. Based on the Spearman's correlation coefficient (r), there was a strong correlation between the number of the droplets that cannot be seen (between 1 and 2 µm) and those that can be seen (7-30 µm) (r = 0.817, p = 0.007). CONCLUSION: Once emulsification was detected clinically in the anterior chamber, extensive emulsification would have already occurred in the posterior chamber, with most of the emulsified droplets that were too small in size to be seen on clinical examination. Ostwald ripening might explain why there were so many small droplets. The predominance of small droplets might account for some of the clinical complications associated with silicone oil use.

The relationship between changes in body mass index and retinal vascular caliber in children.

OBJECTIVE: To examine the longitudinal relationship between changes in childhood body mass index (BMI) and retinal vascular caliber. STUDY DESIGN: A prospective study of 421 healthy children aged 7-9 years in 2001 who returned for follow-up in 2006. At both visits, retinal photographs and anthropometric measurements were taken following standardized protocols. Retinal arteriolar and venular calibers were measured using a computer-based program and summarized as central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE). RESULTS: At follow-up, mean weight, height, and BMI increased significantly (P < .001). Mean CRVE increased by 3.4 µm (P < .001) but mean CRAE did not alter significantly (P = .340). On multivariate analysis, greater BMI was cross-sectionally associated with narrower CRAE (P < .01) and wider CRVE (P < .01). On longitudinal analysis, increasing BMI was associated with increasing CRVE (P = .04) over the 5-year period. Baseline BMI was associated with increased venular caliber and decreased arteriolar caliber at follow-up, and vice versa (P < .05). CONCLUSIONS: Increasing BMI is associated with increasing retinal venular caliber over time in children, and baseline retinal vascular caliber changes increase the risk of higher BMI at follow-up. As both widened retinal venular caliber and greater BMI are associated with risk of cardiovascular events in adults, progressive retinal venular widening could be a manifestation of an adverse microvascular effect of obesity early in life.

Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo.

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n  =  6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p  =  1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p  =  2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

International incidence and temporal trends for rhegmatogenous retinal detachment: A systematic review and meta-analysis.

We set out to estimate the international incidence of rhegmatogenous retinal detachment (RRD) and to evaluate its temporal trend over time. There is a lack of robust estimates on the worldwide incidence and trend for RRD, a major cause of acute vision loss. We conducted a systematic review of RRD incidence. The electronic databases PubMed, Scopus, and Thomson Reuters' Web of Science were searched from inception through 2nd June 2022. Random-effects meta-analysis model with logit transformation was performed to obtain pooled annual incidence estimates of RRD. Pooled analysis was performed to evaluate the temporal trend of RRD incidence of the 20,958 records identified from the database searches; 33 studies from 21 countries were included for analysis (274,836 cases of RRD in 273,977 persons). Three of the 6 global regions as defined by WHO had studies that met the inclusion and exclusion criteria of the study. The annual international incidence of RRD was estimated to be 12.17 (95% confidence interval [CI] 10.51-14.09) per 100,000 population; with an increasing temporal trend of RRD at 5.4 per 100,000 per decade (p 0.001) from 1997 to 2019. Amongst world regions, the RRD incidence was highest in Europe (14.52 [95% CI 11.79 - 17.88] per 100,000 population), followed by Western Pacific (10.55 [95% CI 8.71-12.75] per 100,000 population) and Regions of Americas (8.95 [95% CI 6.73-11.92] per 100,000 population). About one in 10,000 persons develop RRD each year. There is evidence of increasing trend for RRD incidence over time, with possibly doubling of the current incidence rate within the next 2 decades.

Retinal microvascular signs and risk of stroke: the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND AND PURPOSE: Small-vessel disease contributes to the pathophysiology of stroke, and retinal microvascular signs have been linked to the risk of stroke. We examined the relationship of retinal signs with incident stroke in a multiethnic cohort. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective cohort study that enrolled participants without clinical cardiovascular diseases from 6 US communities between 2000 and 2002. Of the participants, 4849 (71.2%) had fundus photography performed in 2002 to 2004. Retinopathy and retinal vessel caliber were assessed from retinal images. Stroke risk factors including high-sensitivity C-reactive protein, carotid artery intima-media thickness, and coronary artery calcium were measured using standardized protocols. Incident stroke was confirmed from medical record review and death certificates. RESULTS: After 6 years of follow-up, there were 62 incident strokes. Narrower retinal arteriolar caliber was associated with increased risk of stroke after adjusting for conventional cardiovascular risk factors (adjusted incidence rate ratio, 2.83; 95% CI, 1.34-5.95; P=0.006; adjusted hazard ratio, 3.01; 95% CI, 1.29-6.99; P=0.011). Retinopathy in persons without diabetes was associated with increased risk of stroke (adjusted adjusted incidence rate ratio, 2.96; 95% CI, 1.50-5.84; P=0.002; adjusted hazard ratio, 3.07; 95% CI, 1.17-8.09; P=0.023). These associations remained significant after adjusting for high-sensitivity C-reactive protein, carotid intima-media thickness, or coronary artery calcium. CONCLUSIONS: Narrower retinal arteriolar caliber and retinopathy in nondiabetic persons were associated with increased risk of stroke in this relatively healthy multiethnic cohort independent of traditional risk factors and measures of atherosclerosis. The association between narrower retinal arteriolar caliber and stroke warrants further investigation.

Prevalence and risk factors of diabetic retinopathy in migrant Indians in an urbanized society in Asia: the Singapore Indian eye study.

PURPOSE: To describe the prevalence of and risk factors for diabetic retinopathy (DR) in Indian persons living in a newly urbanized society in Asia. DESIGN: Population-based study. PARTICIPANTS: Ethnic Indians aged ≥40 years living in Singapore. METHODS: The Singapore Indian Eye Study was conducted between 2007 and 2009. All participants underwent an extensive ophthalmic examination, including retinal photographs obtained after pupil dilation. These images were graded for the presence and severity of DR using the modified Airlie House classification system. Diabetes was defined as hemoglobin A1c level of ≥6.5%, use of diabetic medication, or a physician diagnosis of diabetes. Risk factors were measured using questionnaires, clinical assessments, or laboratory tests. MAIN OUTCOME MEASURES: Any DR, diabetic macular edema (DME), or vision-threatening DR (VTDR). RESULTS: Among the 3400 participants, the age-standardized prevalence was 33.6% (95% confidence interval [CI], 31.4-35.8) for diabetes and 10.5% (95% CI, 9.3-11.8) for DR. Among those with diabetes only, the age-standardized prevalence was 30.4% (95% CI, 26.5-34.8) for any DR, 7.2% (95% CI, 5.3-9.7) for DME, and 7.1% (95% CI, 5.4-9.5) for VTDR. In multivariate analysis, independent risk factors for any DR were younger age (odds ratio [OR], 0.98; 95% CI, 0.96-1.00, per year increase), longer diabetes duration (OR, 1.09; 95% CI, 1.07-1.11 per year increase), higher hemoglobin A1c (OR, 1.23; 95% CI, 1.13-1.34 per percent increase), higher systolic blood pressure (OR, 1.01; 95% CI, 1.00-1.02 per 1-mmHg increase), lower diastolic blood pressure (OR, 0.97; 95% CI, 0.96-0.99 per 1-mmHg increase), history of previous stroke (OR, 2.16; 95% CI, 1.12-4.16), and insulin treatment (OR, 2.99; 95% CI, 1.84-4.87). Similar independent risk factors, except for blood pressure, were found for VTDR. Additionally, persons with lower income and living in smaller houses were associated with VTDR. CONCLUSIONS: One in 3 migrant Indians living in newly urbanized Asian societies have diabetes and 1 in 10 has DR. This is similar to rates reported in Western populations and significantly higher than those reported in India.

Six-year incidence and systemic associations of retinopathy in a multi-ethnic Asian population without diabetes.

PURPOSE: We described the 6-year incidence and changes of retinopathy, and their associated risk factors in a multi-ethnic Asian population without diabetes. METHODS: We 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. RESULTS: Over 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. CONCLUSION: Risk 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.

Incidence and progression of diabetic retinopathy in a multi-ethnic US cohort: the Multi-Ethnic Study of Atherosclerosis.

AIM: To provide contemporary longitudinal data on the incidence and progression of diabetic retinopathy (DR) in a multi-ethnic population of whites, African Americans, Chinese and Hispanics in the United States. METHODS: A prospective, multi-region, multi-ethnic population-based cohort study that included 498 participants with diabetes, aged 45-84 years at baseline, from the Multi-Ethnic Study of Atherosclerosis with retinal images obtained twice, on average 8 years apart. Presence and severity of DR were graded from these retinal images according to the modified Airlie House classification system. Main outcome measures were 8-year incidence, progression and improvement of DR, and their associated risk factors. RESULTS: Over the 8 years, the cumulative rates were 19.2% for incident DR, 17.3% for DR progression, 23.3% for DR improvement, 2.7% for incident vision-threatening DR, 1.8% for incident proliferative DR and 2.2% for incident macular oedema. In multivariate analysis, significant risk factors associated with incident DR were higher glycosylated haemoglobin (relative risk (RR) 1.28; 95% CI: 1.16 to 1.41) and higher systolic blood pressure (RR 1.14; 95% CI: 1.04 to 1.25). Significant factors associated with DR progression were higher glycosylated haemoglobin (RR 1.20; 95% CI: 1.00 to 1.43) and higher low-density lipoprotein cholesterol (RR 1.01; 95% CI: 1.00 to 1.03). CONCLUSION: Over an 8-year period, approximately one in five participants with diabetes developed DR, while almost a quarter of those with DR at baseline showed improvement, possibly reflecting the positive impact of clinical and public health efforts in improving diabetes care in the United States over the last two decades.

Association of macular and choroidal perfusion with long-term visual outcomes after macula-off rhegmatogenous retinal detachment.

BACKGROUND/AIMS: To 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). METHODS: A 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. RESULTS: Over 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 (ß=0.079, 95% CI 0.026 to 0.131), lower number of choriocapillaris flow deficits (ß=-0.087, 95% CI -0.154 to -0.021) and larger average size of choriocapillaris flow deficits (ß=0.085, 95% CI 0.022 to 0.147), after adjusting for baseline VA, types of surgery and other factors. CONCLUSIONS: OCTA measures of vascular perfusion in the macula may provide new pathophysiological insights and prognostic information related to macula-off RRD.

System-wide vitreous proteome dissection reveals impaired sheddase activity in diabetic retinopathy.

Rationale: Diabetic retinopathy (DR) is a major complication of diabetes mellitus causing significant vision loss. DR is a multifactorial disease involving changes in retinal microvasculature and neuronal layers, and aberrations in vascular endothelial growth factors (VEGF) and inflammatory pathways. Despite the success of anti-VEGF therapy, many DR patients do not respond well to the treatment, emphasizing the involvement of other molecular players in neuronal and vascular aberrations in DR. Methods: We employed advanced mass spectrometry-based proteome profiling to obtain a global snapshot of altered protein abundances in vitreous humor from patients with proliferative DR (PDR) in comparison to individuals with epiretinal membrane without active DR or other retinal vascular complications. Global proteome correlation map and protein-protein interaction networks were used to probe into the functional inclination of proteins and aberrated molecular networks in PDR vitreous. In addition, peptide-centric analysis of the proteome data was carried out to identify proteolytic processing, primarily ectodomain shedding events in PDR vitreous. Functional validation experiments were performed using preclinical models of ocular angiogenesis. Results: The vitreous proteome landscape revealed distinct dysregulations in several metabolic, signaling, and immune networks in PDR. Systematic analysis of altered proteins uncovered specific impairment in ectodomain shedding of several transmembrane proteins playing critical roles in neurodegeneration and angiogenesis, pointing to defects in their regulating sheddases, particularly ADAM10, which emerged as the predominant sheddase. We confirmed that ADAM10 protease activity was reduced in animal models of ocular angiogenesis and established that activation of ADAM10 can suppress endothelial cell activation and angiogenesis. Furthermore, we identified the impaired ADAM10-AXL axis as a driver of retinal angiogenesis. Conclusion: We demonstrate restoration of aberrant ectodomain shedding as an effective strategy for treating PDR and propose ADAM10 as an attractive therapeutic target. In all, our study uncovered impaired ectodomain shedding as a prominent feature of PDR, opening new possibilities for advancement in the DR therapeutic space.

Detecting visually significant cataract using retinal photograph-based deep learning.

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.

Diabetic retinopathy.

Diabetic retinopathy is a common and specific microvascular complication of diabetes, and remains the leading cause of preventable blindness in working-aged people. It is identified in a third of people with diabetes and associated with increased risk of life-threatening systemic vascular complications, including stroke, coronary heart disease, and heart failure. Optimum control of blood glucose, blood pressure, and possibly blood lipids remains the foundation for reduction of risk of retinopathy development and progression. Timely laser therapy is effective for preservation of sight in proliferative retinopathy and macular oedema, but its ability to reverse visual loss is poor. Vitrectomy surgery might occasionally be needed for advanced retinopathy. New therapies, such as intraocular injection of steroids and antivascular endothelial growth-factor agents, are less destructive to the retina than are older therapies, and could be useful in patients who respond poorly to conventional therapy. The outlook for future treatment modalities, such as inhibition of other angiogenic factors, regenerative therapy, and topical therapy, is promising.

Prevalence and risk factors for epiretinal membranes in a multi-ethnic United States population.

PURPOSE: To describe the prevalence of and risk factors for epiretinal membrane (ERM) in a multi-ethnic population and to evaluate possible racial or ethnic differences. DESIGN: Cross-sectional study. PARTICIPANTS: Participants of the Multi-Ethnic Study of Atherosclerosis (MESA), examined at the second visit of the MESA when retinal photography was performed. METHODS: Data on 5960 participants aged 45 to 84 years from MESA, including white, black, Hispanic, and Chinese persons from 6 United States communities, were analyzed. Epiretinal membrane was assessed from digital nonstereoscopic fundus photographs and was defined as cellophane macular reflex (CMR) without retinal folds or preretinal macular fibrosis (PMF) with retinal folds. Risk factors were assessed from standardized interviews, clinical examinations, and laboratory investigations. MAIN OUTCOME MEASURES: Epiretinal membrane prevalence by ethnic or racial group and risk factors associated with ERM. RESULTS: The prevalence of any ERM was 28.9%, of which 25.1% were CMR cases and 3.8% were PMF cases. The prevalence of ERM was significantly higher in Chinese persons (39.0%), compared with Hispanic (29.3%), white (27.5%), or black (26.2%; P<0.001) persons. In multivariate models, increasing age (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.06-1.34, per year increase in age), diabetes (OR, 1.92; 95% CI, 1.39-2.65), and hypercholesterolemia (OR, 1.33; 95% CI, 1.04-1.69) were significantly associated with CMR. CONCLUSIONS: This study showed that ERM was significantly more common in Chinese persons compared with whites, blacks, and Hispanics. Risk factors for ERM were increasing age, presence of diabetes, and hypercholesterolemia.

Prevalence and causes of visual impairment and blindness in an urban Indian population: the Singapore Indian Eye Study.

PURPOSE: To describe the prevalence and causes of visual impairment and blindness in an urban Indian population. DESIGN: Population-based study. PARTICIPANTS: Ethnic Indians aged more than 40 years living in Singapore. METHODS: Participants underwent standardized ophthalmic assessments for visual impairment and blindness, defined using best-corrected visual acuity (BCVA) and presenting visual acuity (PVA), according to US and modified World Health Organization (WHO) definitions. MAIN OUTCOME MEASURES: Unilateral visual impairment or blindness was defined on the basis of the worse eye, and bilateral visual impairment or blindness was defined on the basis of the better eye. Primary causes of visual impairment were determined. RESULTS: A total of 3400 eligible individuals (75.6% response rate) participated. On the basis of US definitions, the age-standardized prevalence was 0.4% for bilateral blindness (≤20/200, better eye) and 3.4% for bilateral visual impairment (<20/40 to >20/200, better eye). Another 0.3% of bilateral blindness and 13.4% of bilateral visual impairment were correctable with refraction. Cataract was the principal cause of best-corrected bilateral blindness (60.0%) and bilateral visual impairment (65.7%). Other major causes of blindness and visual impairment included diabetic retinopathy, age-related macular degeneration, glaucoma, corneal opacity, and myopic maculopathy. CONCLUSIONS: The prevalence of bilateral blindness and visual impairment in Indians living in Singapore is lower than estimates from populations living in India, but similar to estimates obtained from Singapore Malay and Chinese populations. Cataract is the leading cause of blindness and visual impairment. One in 20 cases of bilateral blindness and 1 in 10 cases of bilateral visual impairment are attributable to diabetic retinopathy. These data may have relevance to many ethnic Indian persons living outside India.