Impact of treat and extend criteria on proportions that can be extended after loading phase of 2 mg aflibercept therapy for neovascular age related macular degeneration: PRECISE Report 5.

OBJECTIVE: To study the impact of definitions of various treatment extension criteria on the proportion of patients who could be extended at their first visit after the loading phase of 2 mg aflibercept therapy for neovascular age related macular degeneration (nAMD). METHODS: Patients with nAMD initiated on the loading phase of three intravitreal doses of 2 mg aflibercept in routine clinical practice were recruited from December 2019 to August 2021. The response to the loading phase was assessed at approximately 8 weeks post-loading (up to 140 days from first injection) based on different definitions of response. The proportion of patients that qualify for interval extension based on different clinical trial criteria was also evaluated. RESULTS: A total of 722 patients with visual acuity (VA) and optical coherence tomography (OCT) scans done at all 4 visits were included. Of these 32.4% of eyes responded with complete macular fluid resolution after the first injection with no recurrence through the loading phase (super-responders) while 26.9% had persistent macular fluid in all 4 visits (true non-responders). The rest were considered suboptimal responders. Change in VA showed marked variations within each of these categories of fluid resolution. For extension of next treatment interval, if presence of any macular fluid at the post-loading visit is the only criteria considered, about 50% could be extended to 8 weeks. If both VA worsening by ≥5 letters and a > 25 µm increase in central sub-field thickness (CST) are considered, 90% will be eligible for interval extension. CONCLUSION: Clinical trial designs and pre-defined treatment extension/shortening criteria determine the proportion of patients requiring treatment in the post-loading visit. The short and long-term impact of interval extension immediate post-loading on visual outcome in clinical practice is unknown.

The Natural History of Retinal Sensitivity Loss in Diabetic Macular Ischemia over One Year Evaluated by Microperimetry.

Background/Objectives: This one-year prospective observational study, conducted at two centers, aimed to report the natural history of retinal sensitivity (RS) loss in diabetic macular ischemia (DMI). Methods: Patients with stable-treated proliferative diabetic retinopathy (PDR) were recruited if there was evidence of DMI on optical coherence tomography angiography, defined as a foveal avascular zone ≥ 0.5 mm2 or parafoveal capillary dropout ≥ 1 quadrant. The minimal visual acuity required for performing microperimetry (MP) was ≥54 Early Treatment Diabetic Retinopathy Study letters (Snellen equivalent 20/80). The overall RS (oRS) and pointwise sensitivity (PWS) within the 3 × 3 mm macula were assessed at baseline and twelve months. A value <25 decibels (dB) was defined as impaired RS, and a decrease of 2 and 7 dB was regarded as mild and severe loss, respectively. Results: A total of 88 patients (97 eyes) were included. No statistically significant MP changes were detected at one year. However, 10% of the cohort lost oRS ≥ 2 dB, and 73% lost ≥2 dB PWS in ≥5 loci, whereas 1% lost oRS ≥ 7 dB, and 4% lost ≥7 dB PWS in ≥5 loci. The foveola and temporal parafovea were the most vulnerable to severe RS loss. Compared to their counterpart, eyes with baseline oRS ≥ 25 dB had significantly more RS loss in the macula and superior parafovea (55% versus 32% and 53% versus 28%, both p = 0.01). Conclusions: Rather than oRS loss, ≥2 dB loss in PWS in ≥5 loci is a more feasible outcome measure for clinical trials in DMI.

National prevalence of vision impairment and blindness and associated risk factors in adults aged 40 years and older with known or undiagnosed diabetes: results from the SMART-India cross-sectional study.

BACKGROUND: National estimates of the prevalence of vision impairment and blindness in people with diabetes are required to inform resource allocation. People with diabetes are more susceptible to conditions such as diabetic retinopathy that can impair vision; however, these are often missed in national studies. This study aims to determine the prevalence and risk factors of vision impairment and blindness in people with diabetes in India. METHODS: Data from the SMART-India study, a cross-sectional survey with national coverage of 42 147 Indian adults aged 40 years and older, collected using a complex sampling design, were used to obtain nationally representative estimates for the prevalence of vision impairment and blindness in people with diabetes in India. Vulnerable adults (primarily those who did not have capacity to provide consent); pregnant and breastfeeding women; anyone deemed too ill to be screened; those who did not provide consent; and people with type 1 diabetes, gestational diabetes, or secondary diabetes were excluded from the study. Vision impairment was defined as presenting visual acuity of 0·4 logMAR or higher and blindness as presenting a visual acuity of 1·0 logMAR or higher in the better-seeing eye. Demographic, anthropometric, and laboratory data along with geographic distribution were analysed in all participants with available data. Non-mydriatic retinal images were used to grade diabetic retinopathy, and risk factors were also assessed. FINDINGS: A total of 7910 people with diabetes were included in the analysis, of whom 5689 had known diabetes and 2221 were undiagnosed. 4387 (55·5%) of 7909 participants with available sex data were female and 3522 (44·5%) participants were male. The estimated national prevalence of vision impairment was 21·1% (95% CI 15·7-27·7) and blindness 2·4% (1·7-3·4). A higher prevalence of any vision impairment (29·2% vs 19·6%; p=0·016) and blindness (6·7% vs 1·6%; p<0·0001) was observed in those with ungradable images. In known diabetes, diabetic retinopathy (adjusted odds ratio [aOR] 3·06 [95% CI 1·25-7·51]), vision-threatening diabetic retinopathy (aOR 7·21 [3·52-14·75]), and diabetic macular oedema (aOR 5·41 [2·20-13·33]) were associated with blindness in adjusted analysis. Common sociodemographic risk factors for vision impairment and blindness include older age, lower educational attainment, and unemployment. INTERPRETATION: Based on the estimated 101 million people with diabetes in 2021 and the interpretation of the data from this study, approximately 21 million people with diabetes have vision impairment in India, of whom 2·4 million are blind. Higher prevalence is observed in those from lower socio-economic strata and policy makers should focus on these groups to reduce inequalities in health care. FUNDING: Global Challenge Research Fund of United Kingdom Research and Innovation through the Medical Research Council.

Associations of presenting visual acuity with morphological changes on OCT in neovascular age-related macular degeneration: PRECISE Study Report 2.

PURPOSE: To study associations of optical coherence tomography (OCT) features with presenting visual acuity (VA) in treatment naive neovascular age-related macular degeneration (nAMD). METHODS: Patients with nAMD initiated on aflibercept therapy were recruited from December 2019 to August 2021. Demographic and OCT (Spectralis, Heidelberg Engineering) features associated with good VA (VA ≥ 68 ETDRS letters, Snellen ≥ 6/12) and poor VA (VA < 54 letters, Snellen < 6/18) were analysed using Generalised Estimating Equations to account for inter-eye correlation. RESULTS: Of 2274 eyes of 2128 patients enrolled, 2039 eyes of 1901 patients with complete data were analysed. Mean age was 79.4 (SD 7.8) years, female:male 3:2 and mean VA 58.0 (SD 14.5) letters. On multivariable analysis VA < 54 letters was associated with increased central subfield thickness (CST) (OR 1.40 per 100 µm; P < 0.001), foveal intraretinal fluid (OR 2.14; P < 0.001), polypoidal vasculopathy (PCV) relative to Type 1 macular neovascularisation (MNV) (OR 1.66; P = 0.049), presence of foveal subretinal hyperreflective material (SHRM) (OR 1.73; P = 0.002), foveal fibrosis (OR 3.85; P < 0.001), foveal atrophy (OR 5.54; P < 0.001), loss of integrity of the foveal ellipsoid zone (EZ) or external limiting membrane (ELM) relative to their preservation (OR 3.83; P < 0.001) and absence of subretinal drusenoid deposits (SDD) (presence vs absence; OR 0.75; P = 0.04). These features were associated with reduced odds of VA ≥ 68 letters except MNV subtypes and SDD. CONCLUSION: Presence of baseline fovea-involving atrophy, fibrosis, intraretinal fluid, SHRM, PCV EZ/ELM loss and increased CST determine poor presenting VA. This highlights the need for early detection and treatment prior to structural changes that worsen baseline VA.

Baseline characteristics of eyes with early residual fluid post loading phase of aflibercept therapy in neovascular AMD: PRECISE study report 3.

PURPOSE: To compare the baseline characteristics in patients with and without early residual fluid (ERF) after aflibercept loading phase (LP) in patients with treatment naïve neovascular age related macular degeneration (nAMD). METHODS: Patients with nAMD initiated on LP of three intravitreal aflibercept doses were recruited from December 2019 to August 2021. Baseline demographic and OCT features associated with any ERF were analysed using Generalised Estimating Equations to account for inter-eye correlation. Receiver operating characteristic (ROC) curve was performed for selection of CST threshold. RESULTS: Of 2128 patients enrolled, 1999 eyes of 1862 patients with complete data were included. After LP, ERF was present in 1000 (50.0%), eSRF in 746(37.3%) and eIRF in 428 (21.4%) eyes. In multivariable analysis of baseline features, eyes with increased central subfield thickness (CST) (OR 1.31 per 100 microns increase [95% CI 1.22 to 1.41]; P < 0.001), eyes with IRF and SRF at baseline (1.62 [95% CI 1.17 to 2.22]; P = 0.003), and those with SRF only (OR 2.26 [95% CI 1.59 to 3.20]; P < 0.001) relative to IRF only were determinants of ERF. CST ≥ 418 microns had 57% sensitivity and 58% specificity to distinguish ERF from no ERF at visit 4. CONCLUSION: On average, 50% of eyes have ERF after aflibercept LP. Clinically relevant baseline determinants of ERF include CST ≥ 418 µ and presence of only SRF. These eyes may require further monthly treatment before extending treatment intervals.

Topographic Correlation of Microperimetry With Structural Characteristics in Diabetic Macular Ischemia.

PURPOSE: This study aimed to determine the threshold for defining abnormal retinal sensitivity (RS) that correlates with structural changes in diabetic macular ischemia (DMI) patients with stable treated proliferative diabetic retinopathy (PDR). DESIGN: Prospective cross-sectional study. METHODS: In a single center, we recruited 85 eyes (67 patients) with stable treated PDR with best-corrected visual acuity (BCVA) ≥54 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (Snellen equivalent 20/80) and optical coherence tomography angiography evidence of DMI. The function-function and function-structure correlation were assessed. Two preselected thresholds in overall RS (oRS), 25 decibels (dB) and age-matched normative data (AMND), were tested on their ability to reflect abnormal anatomy in DMI. Finally, a multivariable regression model was established to depict the relationship between the oRS and various parameters. RESULTS: The oRS showed only a modest correlation with BCVA and low-luminance visual acuity (LLVA). The whole-image deep vessel density (wiDVD) was the most reliable vascular metric correlated with RS. For every 1% decline in the wiDVD, the oRS decreased by 0.37 dB (P < .001) after multivariable adjustment. Furthermore, both a reduction of oRS to <25 dB or below AMND could differentiate eyes with FAZ ≥0.5 mm2, whole image superficial vessel density (wiSVD) <37.7%, wiDVD <41.9%, and the presence of disorganization of the retinal inner layers (DRIL) from their counterparts. CONCLUSIONS: The absolute value of 25 dB in oRS is worth considering as a trial endpoint, because it does not require complex calculation and closely reflects the structural abnormalities in DMI.

Study protocol on prevalence of non-exudative macular neovascularisation and its contribution to prediction of exudation in fellow eyes with unilateral exudative AMD (EYE-NEON).

PURPOSE: Fellow eyes of patients with unilateral neovascular age-related macular degeneration (nAMD) are at risk of developing macular neovascularisation (MNV). These eyes may first develop subclinical non-exudative MNV (neMNV) before they leak to form exudative MNV (eMNV). The EYE NEON study is a 2-year study aimed at estimating the prevalence and incidence of neMNV and evaluating its role as a predictor for conversion to neovascular AMD. METHODS: EYE NEON is a multicentre study that will run in retinal clinics across 25 National Health Service with the aim to recruit 800 patients with new onset nAMD in the first eye. The fellow-eye with no evidence of nAMD at baseline will be the study eye. All study eyes will have OCT and OCTA done at first and second year following first anti-VEGF treatment to the first eye (non-study eye), with new onset nAMD. We will estimate the prevalence and incidence of neMNV over 2 years, rate of conversion from neMNV to eMNV and numbers initiated on treatment for neovascular AMD in the study eye will be reported. Predictive models of conversion including neMNV with other demographic and imaging parameters will be developed. CONCLUSION: The study design with proposed target sample size is sufficient to evaluate the retinal imaging characteristics of the study eyes with and without neMNV and develop predictive models to inform risk of conversion to nAMD.

Quantitative Autofluorescence in Non-Neovascular Age Related Macular Degeneration.

Quantitative autofluorescence (qAF8) level is a presumed surrogate marker of lipofuscin content in the retina. We investigated the changes in the qAF8 levels in non-neovascular AMD. In this prospective cohort study, Caucasians aged ≥50 years with varying severity of non-neovascular AMD in at least one eye and Snellen visual acuity ≥6/18 were recruited. The qAF8 levels were analysed in the middle eight segments of the Delori pattern (HEYEX software, Heidelberg, Germany). The AMD categories were graded using both the Beckman classification and multimodal imaging (MMI) to include the presence of subretinal drusenoid deposits (SDD). A total of 353 eyes from 231 participants were analyzed. Compared with the age-matched controls, the qAF8 values decreased in the eyes with AMD (adjusted % difference = -19.7% [95% CI -28.8%, -10.4%]; p < 0.001) and across the AMD categories, (adjusted % differences; Early, -13.1% (-24.4%, -1%), p = 0.04; intermediate AMD (iAMD), -22.9% (-32.3%, -13.1%), p < 0.001; geographic atrophy -25.2% (-38.1%, -10.4%), p = 0.002). On MMI, the qAF8 was reduced in the AMD subgroups relative to the controls, (adjusted % differences; Early, -5.8% (-18.9%, 8.3%); p = 0.40; iAMD, -26.7% (-36.2%, -15.6%); p < 0.001; SDD, -23.7% (-33.6%, -12.2%); p < 0.001; atrophy, -26.7% (-39.3%, -11.3%), p = 0.001). The qAF8 levels declined early in AMD and were not significantly different between the severity levels of non-neovascular AMD, suggesting the early and sustained loss of function of the retinal pigment epithelium in AMD.

Characterization of the Structural and Functional Alteration in Eyes with Diabetic Macular Ischemia.

OBJECTIVE: To investigate the relative effect of disorganization of the retinal inner layers (DRIL) and ellipsoid zone (EZ) loss on visual function in diabetic macular ischemia (DMI). DESIGN: Prospective cross-sectional observational study. PARTICIPANTS: Patients with stable treated proliferative diabetic retinopathy (PDR) without center-involved diabetic macular edema were recruited at the Moorfields Eye Hospital from December 2019 to November 2021. The main inclusion criteria were best-corrected visual acuity (BCVA) of ≥ 40 ETDRS letters (Snellen equivalent 20/160) with OCT angiography (OCTA) evidence of DMI in ≥ 1 eye. METHODS: Each eligible eye of the recruited patients was assessed for BCVA, OCT, and OCTA metrics. The prespecified OCT parameters were DRIL and subfoveal EZ loss. Generalized estimating equations were used. MAIN OUTCOMES MEASURES: The frequency of DRIL and EZ loss, their relative contributions to vision loss, and their associations with microvascular alterations were evaluated. RESULTS: A total of 125 eyes of 86 patients with PDR were enrolled; 104 (83%) eyes had a BCVA of ≥ 70 letters. Disorganization of the retinal inner layers was more prevalent than EZ loss (46% [58 eyes] vs. 19% [24 eyes]). On average, the presence of DRIL had a more pronounced impact on vision, retinal thickness, and microvascular parameters than EZ loss. After multivariable adjustment, the odds of coexisting DRIL increased by 12% with every letter decrease in BCVA; however, there was no statistically significant association of subfoveal EZ loss with BCVA. In eyes with DRIL in the absence of EZ loss, the BCVA declined significantly by 6.67 letters compared with eyes with no DRIL nor EZ loss (95% confidence interval [CI], -9.92 to -3.41; P < 0.001). However, if DRIL and EZ loss coexisted, the resultant BCVA was 13.22 letters less than eyes without these structural abnormalities (95% CI, -18.85 to -7.59; P < 0.001). CONCLUSIONS: In patients with DMI with a Snellen visual acuity of 20/160 or better, eyes with DRIL were associated with more visual function loss and retinal blood circulation alterations than those with subfoveal EZ loss only.

Development and validation of predictive risk models for sight threatening diabetic retinopathy in patients with type 2 diabetes to be applied as triage tools in resource limited settings.

Background: Delayed diagnosis and treatment of sight threatening diabetic retinopathy (STDR) is a common cause of visual impairment in people with Type 2 diabetes. Therefore, systematic regular retinal screening is recommended, but global coverage of such services is challenging. We aimed to develop and validate predictive models for STDR to identify 'at-risk' population for retinal screening. Methods: Models were developed using datasets obtained from general practices in inner London, United Kingdom (UK) on adults with type 2 Diabetes during the period 2007-2017. Three models were developed using Cox regression and model performance was assessed using C statistic, calibration slope and observed to expected ratio measures. Models were externally validated in cohorts from Wales, UK and India. Findings: A total of 40,334 people were included in the model development phase of which 1427 (3·54%) people developed STDR. Age, gender, diabetes duration, antidiabetic medication history, glycated haemoglobin (HbA1c), and history of retinopathy were included as predictors in the Model 1, Model 2 excluded retinopathy status, and Model 3 further excluded HbA1c. All three models attained strong discrimination performance in the model development dataset with C statistics ranging from 0·778 to 0·832, and in the external validation datasets (C statistic 0·685 - 0·823) with calibration slopes closer to 1 following re-calibration of the baseline survival. Interpretation: We have developed new risk prediction equations to identify those at risk of STDR in people with type 2 diabetes in any resource-setting so that they can be screened and treated early. Future testing, and piloting is required before implementation. Funding: This study was funded by the GCRF UKRI (MR/P207881/1) and supported by the NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology.

Multicenter Evaluation of Diagnostic Circulating Biomarkers to Detect Sight-Threatening Diabetic Retinopathy.

Importance: It is a global challenge to provide regular retinal screening for all people with diabetes to detect sight-threatening diabetic retinopathy (STDR). Objective: To determine if circulating biomarkers could be used to prioritize people with type 2 diabetes for retinal screening to detect STDR. Design, Setting, and Participants: This cross-sectional study collected data from October 22, 2018, to December 31, 2021. All laboratory staff were masked to the clinical diagnosis, assigned a study cohort, and provided with the database containing the clinical data. This was a multicenter study conducted in parallel in 3 outpatient ophthalmology clinics in the UK and 2 centers in India. Adults 40 years and older were categorized into 4 groups: (1) no history of diabetes, (2) type 2 diabetes of at least 5 years' duration with no evidence of DR, (3) nonproliferative DR with diabetic macular edema (DME), or (4) proliferative DR. STDR comprised groups 3 and 4. Exposures: Thirteen previously verified biomarkers were measured using enzyme-linked immunosorbent assay. Main Outcomes and Measures: Severity of DR and presence of DME were diagnosed using fundus photographs and optical coherence tomography. Weighted logistic regression and receiver operating characteristic curve analysis (ROC) were performed to identify biomarkers that discriminate STDR from no DR beyond the standard clinical parameters of age, disease duration, ethnicity (in the UK) and hemoglobin A1c. Results: A total of 538 participants (mean [SD] age, 60.8 [9.8] years; 319 men [59.3%]) were recruited into the study. A total of 264 participants (49.1%) were from India (group 1, 54 [20.5%]; group 2, 53 [20.1%]; group 3, 52 [19.7%]; group 4, 105 [39.8%]), and 274 participants (50.9%) were from the UK (group 1, 50 [18.2%]; group 2, 70 [25.5%]; group 3, 55 [20.1%]; group 4, 99 [36.1%]). ROC analysis (no DR vs STDR) showed that in addition to age, disease duration, ethnicity (in the UK) and hemoglobin A1c, inclusion of cystatin C had near-acceptable discrimination power in both countries (area under the receiver operating characteristic curve [AUC], 0.779; 95% CI, 0.700-0.857 in 215 patients in the UK with complete data; AUC, 0.696; 95% CI, 0.602-0.791 in 208 patients in India with complete data). Conclusions and Relevance: Results of this cross-sectional study suggest that serum cystatin C had good discrimination power in the UK and India. Circulating cystatin-C levels may be considered as a test to identify those who require prioritization for retinal screening for STDR.

Correlation of Optical Coherence Tomography Angiography Characteristics with Visual Function to Define Vision-Threatening Diabetic Macular Ischemia.

The thresholds of macular microvasculature parameters associated with mild visual impairment in diabetic macular ischemia (DMI) patients are unclear. Therefore, this prospective observational study is aimed at demonstrating the optical coherence tomography angiography parameters that best correlate with mild visual impairment (<70 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, Snellen equivalent 20/40) in DMI. The study was completed at the Moorfields Eye Hospital from December 2019 to August 2021. A total of 123 eyes of 87 patients with stable-treated proliferative diabetic retinopathy following panretinal photocoagulation were recruited. DMI was defined as an irregular foveal avascular zone (FAZ) area ≥ 0.5 mm2 or a smaller FAZ area with parafoveal capillary dropout in at least one quadrant. The analysis showed that the whole image deep vascular complex vessel density (DVC VD) in the 3 × 3 mm area had the best discriminatory ability to identify participants with mild visual impairment at 41.9% (area under the curve = 0.77, sensitivity 94%, specificity 54%, likelihood ratio [LR] = 2.04), and the FAZ area had the greatest post-test LR = 4.21 at 0.64 mm2. The 3 × 3 mm whole image DVC VD and FAZ area cutoffs are useful for screening vision-threatening DMI, but DVC VD has low specificity.

Visual Outcomes Associated With Patterns of Macular Edema Resolution in Central Retinal Vein Occlusion Treated With Anti-Vascular Endothelial Growth Factor Therapy: A Post Hoc Analysis of the Lucentis, Eylea, Avastin in Vein Occlusion (LEAVO) Trial.

IMPORTANCE: It is unclear how visual outcomes vary between patterns of macular edema (ME) resolution in eyes with central retinal vein occlusion (CRVO). OBJECTIVE: To assess best-corrected visual acuity (BCVA) outcomes at 100 weeks based on macular fluid resolution patterns by 52 and 100 weeks among patients receiving anti-vascular endothelial growth factor therapy for CRVO-related ME. DESIGN, SETTING, AND PARTICIPANTS: Post hoc analysis of the prospective, 3-arm, double-masked, randomized noninferiority trial Lucentis, Eylea, Avastin in Vein Occlusion (LEAVO), which evaluated intravitreal aflibercept (2.0 mg/0.05 mL), bevacizumab (1.25-mg/0.05 mL), or ranibizumab (0.5 mg/0.05 mL) over 100 weeks in adult patients (18 years and older) with CRVO-related ME with BCVA Early Treatment Diabetic Retinopathy Study (ETDRS) letter score of 19 to 78 in the study eye (approximate Snellen equivalent, 20/400 to 20/32, respectively) from December 2014 to December 2016 at 44 UK National Health Service ophthalmology departments. A total of 140 of 154 eyes were randomized to aflibercept, 144 of 154 randomized to bevacizumab, and 141 of 155 randomized to ranibizumab. Data were analyzed from January 2019 to March 2019. EXPOSURES: Persistent ME included eyes with central subfield thickness (CST) 320 µm or greater, and persistently dry macula (no ME) included eyes with CST less than 320 µm at 52 and 100 weeks. Recurrent ME included eyes that did not meet the criteria for persistently dry or wet. If CST was missing, the closest intervening visit was carried forward. MAIN OUTCOMES AND MEASURES: Adjusted mean BCVA at 100 weeks. RESULTS: The mean (SD) age of the 425 included participants was 69.2 (12.7) years, and 243 participants (57.2%) were men. A total of 425 eyes from 425 participants were included. By 100 weeks, 117 eyes (28.5%) were persistently dry, 44 (10.7%) were persistently wet (with ME), and 250 (60.8%) had recurrent ME. Persistent ME at 100 weeks was associated with worse VA compared with dry macula (adjusted difference, -10.98 ETDRS letters; 95% CI, -16.19 to -5.76; P < .001) and recurrent ME (adjusted difference, -5.39 letters; 95% CI, -10.15 to -0.64; P = .03). By 52 weeks, individuals with persistent ME also had poorer 100-week BCVA compared with individuals with dry macula (adjusted difference, -7.39; 95% CI, -11.72 to -3.05; P < .001) and recurrent ME (adjusted difference, -3.92; 95% CI, -8.05 to 0.20; P = .06). By 100 weeks, more eyes treated with bevacizumab had persistently wet macula than those treated with aflibercept (26 of 140 [18.6%] vs 7 of 134 [5.2%]; difference, 13.3%; 95% CI, 5.9 to 20.8; P < .001) or ranibizumab (11 of 137 [8%]; difference, 10.5%; 95% CI, 2.7 to 18.4; P = .01). CONCLUSIONS AND RELEVANCE: These findings suggest that attempts should be made to maintain persistently fluid-free macula for optimal visual acuity outcomes.

Survival analysis following enucleation for uveal melanoma.

OBJECTIVES: To determine survival outcomes following enucleation for uveal melanoma. To compare these outcomes with the 8th edition AJCC classification and determine the influence of cytogenetics, using Fluorescent in situ Hybridisation (FISH), on survival. To determine whether failure to gain sufficient sample for cytogenetics using Fine Needle Aspiration Biopsy (FNAB) correlates with survival. SUBJECTS/METHODS: All patients undergoing primary enucleation for uveal melanoma at Moorfields Eye Hospital between 2012 and 2015 were included. Clinical, pathological, cytological and survival data were analysed for all patients. RESULTS: In total, 155 subjects were included. Mean age at enucleation was 65.9 years (SD 14.13). 88 (56.8%) patients died at a mean of three (SD 1.9) years following enucleation. Of these, 52 (33.5%) died from metastatic melanoma, 16 (10.3%) from other causes and 20 (12.9%) causes of death were unknown. Cumulative incidence analysis demonstrated AJCC grade, chromosome 8q gain and monosomy three all predict metastatic mortality. The greatest 5-year mortality rate (62%, SD10.1%) was in those with both chromosome abnormalities and AJCC stage III (Stage IV patients excluded due to low numbers). Largest basal diameter and chromosome status, both independently (p = 0.02 and p < 0.001) predicted metastatic mortality on multivariable regression analysis. Those who had an insufficient sample of cells gained during FNAB (n = 16) had no different prognosis. CONCLUSIONS: This study confirms, in this population, the poor survival of patients enucleated for uveal melanomas. It confirms the prognostic utility of adding AJCC grade to cytogenetic information. It demonstrates that the lack of sample in patients undergoing FNAB is not related to prognosis.

Incidence and Risk Factors for Macular Atrophy in Acquired Vitelliform Lesions.

PURPOSE: To study the time course to macular atrophy (MA) and associated risk factors in eyes with acquired vitelliform lesions (AVLs) as they vary between patients and between eyes of an individual. DESIGN: Single-center, retrospective, observational cohort study. PARTICIPANTS: Consecutive patients registered between January 2009 and January 2014 with first diagnosis of AVL confirmed by multimodal imaging were included. Eyes with baseline MA or choroidal neovascularization were excluded. METHODS: Patient demographics were collected. Serial OCT scans and fundus autofluorescence (FAF) scans were graded and analyzed. Turnbull's estimator was used, and time was censored at 5 years. Multivariable Weibull parametric proportional hazard models were used to assess the association of risk factors with MA after adjustment for age and gender. Hazard ratios (HRs) are reported with 95% confidence interval (CI). MAIN OUTCOME MEASURES: Time to the first OCT evidence of MA stratified by presenting visual acuity (VA) and AVL lesion subtypes. Secondary outcome included risk factors for incident MA. RESULTS: A total of 237 eyes (132 patients) met the inclusion criteria. Incident MA was detected in 52 of 237 eyes (21.9%) by 5 years. Stratified by baseline VA, 40.3% of eyes with VA ≤70 letters developed atrophy within 5 years of first diagnosis in contrast to 10.3% eyes with VA >70 letters (P < 0.001). Based on lesion type only, 12.9% of eyes with vitelliform lesion at baseline developed MA versus 39.8% and 44.2% of eyes with pseudohypopyon or vitelliruptive lesion type, respectively. In adjusted analysis, baseline factors associated with increased risk of MA included VA ≤70 letters (hazard ratio [HR], 5.54; 95% confidence interval [CI], 2.30-13.34), base width (HR, 1.22; 95% CI, 1.16-1.28), maximum height (HR, 2.61; 95% CI, 1.82-3.74), presence of subretinal drusenoid deposits (SDDs) (HR, 2.83; 95% CI, 1.34-5.96), and disrupted external limiting membrane (ELM) (HR, 2.81; 95% CI, 1.34-5.86). CONCLUSIONS: Baseline VA of ≤70 letters (Snellen ≤20/40) and pseudohypopyon or vitelliruptive lesion type attribute the highest risk for MA. Other prognostic indicators for MA include baseline presence of SDD, disrupted ELM, and larger lesion area.

Functional clinical endpoints and their correlations in eyes with AMD with and without subretinal drusenoid deposits-a pilot study.

PURPOSE: To evaluate functional clinical endpoints and their structural correlations in AMD, with a focus on subretinal drusenoid deposits (SDD). METHODS: This prospective study enroled 50 participants (11 controls, 17 intermediate AMD (iAMD) with no SDD, 11 iAMD with SDD and 11 non-foveal atrophic AMD). Participants underwent best-corrected visual acuity (BCVA), low luminance visual acuity (LLVA), low luminance questionnaire (LLQ), scotopic thresholds, rod-intercept time (RIT), photopic flicker electroretinograms and multimodal imaging. Functional and structural relationships were assessed. RESULTS: Compared with healthy participants, BCVA, LLVA, scotopic thresholds were depressed, and RIT prolonged in iAMD patients with SDD (p = 0.028, p = 0.045, p = 0.014 and p < 0.0001 respectively). Patients with SDD also had reduced scotopic function and delayed RIT compared to iAMD without SDD (p = 0.005 and p < 0.0001). Eyes with SDD and non-foveal atrophy did not differ functionally. Nor did healthy subjects compared with iAMD without SDD. Functional parameters were significantly associated with scotopic thresholds (r = 0.39-0.64). BCVA, LLVA and scotopic thresholds correlated well with ONL volume, ONL thickness and choroidal thickness (r = 0.34-0.61). CONCLUSION: Eyes with SDD are surrogate markers of photoreceptor abnormalities comparable with non-central atrophy and should be sub-analysed in clinical trials evaluating potential prophylactic agents to decrease the progression of AMD and may even require different therapeutic interventions.

Ethnic Disparities in the Development of Sight-Threatening Diabetic Retinopathy in a UK Multi-Ethnic Population with Diabetes: An Observational Cohort Study.

There is little data on ethnic differences in incidence of DR and sight threatening DR (STDR) in the United Kingdom. We aimed to determine ethnic differences in the development of DR and STDR and to identify risk factors of DR and STDR in people with incident or prevalent type II diabetes (T2DM). We used electronic primary care medical records of people registered with 134 general practices in East London during the period from January 2007-January 2017. There were 58,216 people with T2DM eligible to be included in the study. Among people with newly diagnosed T2DM, Indian, Pakistani and African ethnic groups showed an increased risk of DR with Africans having highest risk of STDR compared to White ethnic groups (HR: 1.36 95% CI 1.02-1.83). Among those with prevalent T2DM, Indian, Pakistani, Bangladeshi and Caribbean ethnic groups showed increased risk of DR and STDR with Indian having the highest risk of any DR (HR: 1.24 95% CI 1.16-1.32) and STDR (HR: 1.38 95% CI 1.17-1.63) compared with Whites after adjusting for all covariates considered. It is important to optimise prevention, screening and treatment options in these ethnic minority groups to avoid health inequalities in diabetes eye care.

Development and validation of resource-driven risk prediction models for incident chronic kidney disease in type 2 diabetes.

Prediction models for population-based screening need, for global usage, to be resource-driven, involving predictors that are affordably resourced. Here, we report the development and validation of three resource-driven risk models to identify people with type 2 diabetes (T2DM) at risk of stage 3 CKD defined by a decline in estimated glomerular filtration rate (eGFR) to below 60 mL/min/1.73m2. The observational study cohort used for model development consisted of data from a primary care dataset of 20,510 multi-ethnic individuals with T2DM from London, UK (2007-2018). Discrimination and calibration of the resulting prediction models developed using cox regression were assessed using the c-statistic and calibration slope, respectively. Models were internally validated using tenfold cross-validation and externally validated on 13,346 primary care individuals from Wales, UK. The simplest model was simplified into a risk score to enable implementation in community-based medicine. The derived full model included demographic, laboratory parameters, medication-use, cardiovascular disease history (CVD) and sight threatening retinopathy status (STDR). Two less resource-intense models were developed by excluding CVD and STDR in the second model and HbA1c and HDL in the third model. All three 5-year risk models had good internal discrimination and calibration (optimism adjusted C-statistics were each 0.85 and calibration slopes 0.999-1.002). In Wales, models achieved excellent discrimination(c-statistics ranged 0.82-0.83). Calibration slopes at 5-years suggested models over-predicted risks, however were successfully updated to accommodate reduced incidence of stage 3 CKD in Wales, which improved their alignment with the observed rates in Wales (E/O ratios near to 1). The risk score demonstrated similar model performance compared to direct evaluation of the cox model. These resource-driven risk prediction models may enable universal screening for Stage 3 CKD to enable targeted early optimisation of risk factors for CKD.

Predictors of Visual Acuity Outcomes after Anti-Vascular Endothelial Growth Factor Treatment for Macular Edema Secondary to Central Retinal Vein Occlusion.

PURPOSE: To evaluate whether baseline demographic, clinical, and OCT characteristics predict visual acuity (VA) outcomes in patients receiving anti-vascular endothelial growth factor (VEGF) therapy for macular edema (ME) due to central retinal vein occlusion (CRVO). DESIGN: Post hoc analysis of the randomized noninferiority trial (Lucentis, Eylea, Avastin in CRVO) LEAVO Study from December 12, 2014, to December 16, 2016, carried out across 44 UK National Health Service ophthalmology departments. PARTICIPANTS: Data on 267 participants with a baseline best-corrected mean visual acuity (BCVA) range of 19 to 78 Early Treatment Diabetic Retinopathy Study letter score (approximate Snellen equivalent, 20/32 to 20/320) who had central subfield thickness (CST) ≥ 320 µm on Spectralis OCT (Heidelberg Engineering) were analyzed. METHODS: Study participants were randomized to receive repeated intravitreal injections of ranibizumab (0.5 mg/50 µl), aflibercept (2.0 mg/50 µl), or bevacizumab (1.25 mg/50 µl), and a protocol-driven pro re nata re-treatment regimen at 4 to 8 weekly visits was followed up to week 100 after 4 mandated 4-weekly loading injections. MAIN OUTCOME MEASURES: Change in BCVA and percentage of patients gaining ≥ 10 letters and achieving BCVA letter score > 70 letters at 52 and 100 weeks. RESULTS: The analysis was adjusted for treatment effects and confirmed by sensitivity analysis. Age ≥ 75 years is a poor predictor for all 3 visual outcomes. Lower baseline BCVA predicted 10-letter gainers and higher gains in BCVA, although it is a poor predictor of achieving > 70 Early Treatment Diabetic Retinopathy Study letters. None of the baseline OCT morphologic characteristics except ellipsoid zone (EZ) integrity influenced any visual outcomes. Both baseline CST and total macular volume showed a nonlinear relation to 10-letter gainers, with CST > 900 µm being a poor prognostic indicator. Baseline CST and macular volume did not predict mean change in BCVA or BCVA > 70 letters at 52 and 100 weeks. The sensitivity analysis conclusions after removing iCRVO were similar. CONCLUSIONS: At presentation, younger age, higher baseline BCVA, and a definitely intact subfoveal EZ are predictors of BCVA score > 70 letters at 100 weeks.

Low Luminance Visual Acuity and Low Luminance Deficit in Proliferative Diabetic Retinopathy.

This study aimed to determine the relation of best corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) in proliferative diabetic retinopathy (PDR) following treatment with either aflibercept or pan-retinal photocoagulation (PRP). The study was conducted as a post-hoc analysis of the CLARITY trial in which naïve and PRP treated PDR patients were randomised to receive either aflibercept or PRP. BCVA and LLVA were assessed at baseline and at week 52. Our analyses showed that the BCVA and LLVA correlate well in treatment naïve PDR with an average low luminance deficit of 11.79 Early Treatment Diabetic Retinopathy Score (ETDRS) letters. However, LLVA at lower levels of BCVA showed more variance. Post aflibercept therapy, the mean change in BCVA and LLVA at 52 weeks after aflibercept was +2.1 (SD 6.05) letters and +0.39 (SD 5.6) letters, respectively. Similarly, after PRP, it was -2.5 (SD 4.9) letters and -1.9 (SD 8.7) letters, respectively. When comparing treatment arms, BCVA change was found to be statistically significant (p < 0.001) whereas LLVA was not (p = 0.11). These findings show that LLVA does not respond as well as BCVA following any treatment for PDR, even though BCVA and LLVA both test foveal function.