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Abstract Oestradiol and progesterone levels are higher in menstruating women than men of the same age, and their receptors are present in their neurosensory retina and retinal pigment epithelium. However, the impact of this hormonal environment on retinal physiology in women remains unclear. Using self-reported menstrual cycle phases as a surrogate for fluctuating hormonal levels, we investigated associations with retinovascular indices on colour fundus photograph and retinal thickness in optical coherence tomography across regularly menstruating women in the UK Biobank. We found no differences in retinal thickness across the cycle; however, vessel density, arteriolar and venular, and fractal dimension were higher in the luteal phase than follicular. The calibre of the central retinal vessels did not differ. This study suggests that the menstrual cycle phase might be associated with retinal microvasculature density in non-invasive imaging. It raises awareness for this understudied area, providing insights into neuroscience fields and epidemiological studies.

Abstract Purpose To determine the association of gut microbiome diversity and sight-threatening diabetic retinopathy (STDR) amongst patients with pre-existing diabetes. Methods A cross-sectional study was performed, wherein 54 participants selected in total were placed into cases cohort if diagnosed with STDR and those without STDR but had a diagnosis of diabetes mellitus of at least 10-year duration were taken as controls. Statistical analysis comparing the gut microbial alpha diversity between cases and control groups as well as patients differentiated based on previously hypothesized Bacteroidetes/Firmicutes(B/F) ratio with an optimal cut-off 1.05 to identify patients with STDR were performed. Results Comparing gut microbial alpha diversity did not show any difference between cases and control groups. However, statistically significant difference was noted amongst patients with B/F ratio ≥1.05 when compared to B/F ratio 1.05:728.03 ± 227.37; p-0.016]; Chao1index [Cut-off 1.05:728.13 ± 227.58; p-0.016]; Simpson index [Cut-off 1.05:0.997 ± 0.001; p-0.006]; Shannon index [Cut-off 1.05:6.10 ± 0.43; p-0.003]. Sub-group analysis showed that cases with B/F ratio ≥ 1.05, divided into proliferative diabetic retinopathy (PDR) and clinically significant macular edema (CSME), showed decreased diversity compared to controls (B/F ratio

Abstract Introduction Advanced age-related macular degeneration (AMD) is a major cause of vision loss. Therefore, there is interest in precursor lesions that may predict or prevent the onset of advanced AMD. One such lesion is a shallow separation of the retinal pigment epithelium (RPE) and Bruch’s membrane (BM), which is described by various terms, including double-layer sign (DLS). Methods In this article, we aim to examine and clarify the different terms referring to shallow separation of the RPE and BM. We also review current evidence on the outcomes associated with DLS: firstly, whether DLS is predictive of exudative neovascular AMD; and secondly, whether DLS has potential protective properties against geographic atrophy. Results The range of terms used to describe a shallow separation of the RPE and BM reflects that DLS can present with different characteristics. While vascularised DLS appears to protect against atrophy but can progress to exudation, non-vascularised DLS is associated with an increased risk of atrophy. Optical coherence tomography (OCT) angiography (OCTA) is the principal method for identifying and differentiating various forms of DLS. If OCTA is unavailable or not practically possible, simplified classification of DLS as thick or thin, using OCT, enables the likelihood of vascularisation to be approximated. Research is ongoing to automate DLS detection by applying deep-learning algorithms to OCT scans. Conclusions The term DLS remains applicable for describing shallow separation of the RPE and BM. Detection and classification of this feature provides valuable information regarding the risk of progression to advanced AMD. However, the appearance of DLS and its value in predicting AMD progression can vary between patients. With further research, individualised risks can be confirmed to inform appropriate treatment.

Aims To identify baseline characteristics that best correlate to treatment interval for naive neovascular age-related macular degeneration patients treated with faricimab in the first year (Y1) of the TENAYA and LUCERNE phase 3 trials, and to further understand how these characteristics may impact treatment intervals.Methods This post-hoc analysis of Y1 data from the TENAYA and LUCERNE trials evaluated ocular baseline characteristics associated with Y1 treatment intervals. Patients were categorised into three subgroups based on their Y1 treatment interval: Q16W, Q12W or Q8W. Baseline characteristics (central subfield thickness (CST), best-corrected visual acuity, presence of subretinal fluid in centre 1 mm, presence of retinal fluid in centre 1 mm, macular neovascularisation (MNV) location and MNV type) were inputted into an R package ‘rpart’ to create a classification tree model. A data-driven tree model based on CST was fitted, producing CST subgroups of low, middle and high ranges. Within each CST subgroup, the model identified the most impactful variables and associated thresholds.Results After fitting the data to produce data-driven CST ranges, the model chose MNV location, followed by MNV lesion type as the most impactful baseline characteristics with these factors having a p value

The response of retinal pathology to interventions in diabetic retinopathy (DR) is often independent of the glycated hemoglobin (HbA1c) values at the point of care. This is despite glucose control being one of the strongest risk factors for the development and progression of DR. Previous preclinical and clinical research has indicated metabolic memory, whereby past cumulative glucose exposure may continue to impact DR for a prolonged period. Preclinical studies have evaluated punitive metabolic memory through poor initial control of DM, whereas clinical studies have evaluated protective metabolic memory through good initial control of DM. In this narrative review, we evaluate the preclinical and clinical evidence regarding metabolic memory and discuss how this may form the basis of preventive care for DR by inducing “metabolic amnesia” in people with a history of uncontrolled diabetes in the past. While our review suggested mitochondrial biology may be one such target, research is still far from a possible clinical trial. We discuss the challenges in such research.

Summary: The prevalence of type 2 diabetes (T2D), associated systemic disorders, diabetic retinopathy (DR) and current health policies in south Asian countries were analysed to assess country-specific preparedness to meet the 2030 Sustainable Development Goals. The south Asian countries were classified by human development index, socio-demographic index, multidimensional poverty indices, and eye health resources for epidemiological resource-level analysis. In south Asia, the prevalence of diagnosed and undiagnosed T2D in adults aged 40 years or above, was higher in Pakistan (26.3%) and Afghanistan (71.4%), respectively; India has the highest absolute number of people with DR, and Afghanistan has the highest prevalence of DR (50.6%). In this region, out-of-pocket spending is high (∼77%). This Health Policy is a situational analysis of data available on the prevalence of DR and common eye diseases in people with T2D in south Asia and available resources to suggest tailored health policies to local needs. The common issues in the region are insufficient human resources for eye health, unequal distribution of available workforce, and inadequate infrastructure. Addressing these challenges of individuals with T2D and DR, a 10-point strategy is suggested to improve infrastructure, augment human resources, reduce out-of-pocket spending, employ targeted screening, and encourage public-private partnerships.

Background Most neovascular age-related macular degeneration treatments involve long-term follow-up of disease activity. Home monitoring would reduce the burden on patients and those they depend on for transport, and release clinic appointments for other patients. The study aimed to evaluate three home-monitoring tests for patients to use to detect active neovascular age-related macular degeneration compared with diagnosing active neovascular age-related macular degeneration by hospital follow-up. Objectives There were five objectives: Estimate the accuracy of three home-monitoring tests to detect active neovascular age-related macular degeneration. Determine the acceptability of home monitoring to patients and carers and adherence to home monitoring. Explore whether inequalities exist in recruitment, participants’ ability to self-test and their adherence to weekly testing during follow-up. Provide pilot data about the accuracy of home monitoring to detect conversion to neovascular age-related macular degeneration in fellow eyes of patients with unilateral neovascular age-related macular degeneration. Describe challenges experienced when implementing home-monitoring tests. Design Diagnostic test accuracy cohort study, stratified by time since starting treatment. Setting Six United Kingdom Hospital Eye Service macular clinics (Belfast, Liverpool, Moorfields, James Paget, Southampton, Gloucester). Participants Patients with at least one study eye being monitored by hospital follow-up. Reference standard Detection of active neovascular age-related macular degeneration by an ophthalmologist at hospital follow-up. Index tests KeepSight Journal: paper-based near-vision tests presented as word puzzles. MyVisionTrack®: electronic test, viewed on a tablet device. MultiBit: electronic test, viewed on a tablet device. Participants provided test scores weekly. Raw scores between hospital follow-ups were summarised as averages. Results Two hundred and ninety-seven patients (mean age 74.9 years) took part. At least one hospital follow-up was available for 317 study eyes, including 9 second eyes that became eligible during follow-up, in 261 participants (1549 complete visits). Median testing frequency was three times/month. Estimated areas under receiver operating curves were < 0.6 for all index tests, and only KeepSight Journal summary score was significantly associated with the lesion activity (odds ratio = 3.48, 95% confidence interval 1.09 to 11.13, p = 0.036). Older age and worse deprivation for home address were associated with lower participation (χ2 = 50.5 and 24.3, respectively, p 6 and < 42 months earlier. We tried to recruit equal numbers by time since starting treatment in the first-treated study eye (6–17 months; 18–29 months; 30–41 months) to ensure test performance was estimated across this range of duration of nAMD. Patients were followed for at least 6 months. Reference standard The reference standard was the reviewing ophthalmologist’s decision about the activity status of a study eye at a HES monitoring visit, recorded as active, inactive or uncertain. There were no additional hospital visits for the study. Such decisions are usually based on clinical examination and the results of hospital-based retinal imaging investigations, for example, colour fundus photographs and ocular coherence tomograms (OCTs). The reference standard grouped uncertain with inactive judgements for analyses. Index tests Three home-monitoring (‘index’) tests were evaluated, spanning low to moderate cost and complexity. These were: KeepSight Journal (KSJ): a paper-based booklet of near-vision tests presented as word puzzles developed in the United States and adapted by the study team for use in the study. MyVisionTrack® (mVT®): electronic vision test, intended to be viewed on a tablet device. MultiBit (MBT): electronic vision test, intended to be viewed on a tablet device. Specific thresholds indicating a significant clinical change were not provided for any of index tests in advance by their developers. Outcomes The primary outcome was classification of a study eye at a monitoring visit as having active or inactive disease (active, inactive, uncertain), that is, the reviewing ophthalmologist’s decision. A secondary outcome (new reference standard) for Objective A was a change from inactive to active status from one management visit to the next. This was considered better to represent how home monitoring might be implemented. For Objective C, outcomes investigated were willingness in principle to participate; ability to carry out index tests; adherence to weekly testing. For Objective D, the outcome was conversion of a fellow eye to active nAMD as judged by an ophthalmologist, that is, same reference standard. For Objective E, the following outcomes were described as measures of the technical and logistical challenges identified during the study: Frequency and reason for incoming calls made to the helpline and outgoing calls made to participants. Frequency and duration of events leading to the digital tests being unavailable for testing. Other technical and logistical challenges. Objective B study recruitment and data collection Recruitment to the qualitative component began 3 months after the monitoring for neovascular age-related macular degeneration reactivation at home (MONARCH) study began recruiting. During the consent process for participation in the study, patients could consent to further contact from the qualitative research team to discuss participation in the qualitative study. Maximum variation sampling ensured a range of perspectives were captured in relation to: age (young-old 50–69 years and older-old > 70 years), gender, one or both eyes with nAMD, time since first treatment (defined as above) and adherence to home monitoring (test data from the two electronic tests were used to categorise participants into ‘regular’ testers and ‘irregular’ testers). Patients who declined to participate in MONARCH but provided consent to be contacted about the qualitative study, informal ‘carers’, supporters or significant others in the lives of patients and healthcare professionals who interacted with participants at study sites visits were also approached to gather their perspectives about the acceptability of home monitoring. Statistical analysis Objective A: The test accuracy of index tests was estimated by fitting a logistic regression model to predict the reference standard from summary test scores for the interval between monitoring visits, adjusting for participants’ baseline data. Accuracy was estimated for the primary outcome using all index test data, data only for the 4 weeks preceding the monitoring visit, the reference standard based on reading centre decisions made from OCT images and for the secondary outcome. Test scores were summarised as: means (MBT and mVT); median (KSJ reported near visual acuity (VA), ordinal six-point scale); proportions (KSJ reported VA, Amsler grid and household object appearance reported worse than baseline vs. same or better). All four scores were fitted in the KSJ model and a single area under the receiving operator curve (AUROC) was estimated. Separate models were fitted for each test for the primary outcome, the two sensitivity analyses and the secondary outcome. Model performance was quantified by the odds ratio (OR) for the index test summary score(s) and the estimate of the AUROC and their respective confidence intervals (CIs). AUROCs were based on predicted probabilities calculated using only the fixed effects in the models. Sensitivity, specificity, positive and negative predictive values and 95% CIs were calculated using cut-off thresholds corresponding to Youden’s index for each model, which minimises overall misclassifications. Average test scores above and below the thresholds were also calculated. Analyses took account of the structure within the data, that is, the nesting of visits and eyes within patients. Objective B: All interviews were audio-recorded and transcribed. A directed content analysis approach based on deductive and inductive coding was used. NVivo version 12 was used to manage data and facilitate the analysis process, which, in summary, included the following stages: (1) independent transcription, (2) data familiarisation, (3) independent coding, (4) development of an analytical framework, (5) indexing, (6) charting and (7) interpreting data. Objective C: Willingness in principle to participate was defined as an approached eligible patient agreeing to attend a research visit for training. Ability to perform an index test was defined as the proportion of monitoring visits for which some valid index test data were available. Adherence was defined as the proportion of weeks between monitoring visits for which some valid data for an index test were available. The ability and adherence models were performed for each test separately at the level of the patient. Regression models estimated associations of age, sex, Index of Multiple Deprivation (IMD), stratum of time since first diagnosis and baseline visual acuity at diagnosis on the outcomes of willingness to participate, ability to perform tests and adherence to weekly testing; models for the latter two outcomes were fitted for each index test. Associations were reported with 95% CIs. Analyses of adherence and ability took account of nesting of visits within participants. Objective D: The test accuracy of the index tests for the reference standard of an ophthalmologist’s classification of a fellow eye as having active disease at a monitoring visit, that is, conversion to active nAMD, was estimated by the same methods as described for Objective A. Two sensitivity analyses were carried out: (1) the same reference standard but using test data only for the 4 weeks preceding the management visit and (2) the alternative reference standard of classification of a fellow eye having active disease based on reading centre grading of OCTs carried out during the monitoring visits. Objective E: This objective used descriptive summary descriptive statistics only. Results The study recruited 297 patients (consented participants) between 21 August 2018 and 31 March 2020. Half of recruited participants were first treated for nAMD 6–17 months before consenting, 28% 18–29 months before consenting and 22% 30–41 months before consenting. At the end of the study, data for at least one monitoring visit after starting to use the index monitoring tests were available for 357 study eyes in 297 patients. Data were available for at least one complete monitoring visit after starting to use the index monitoring tests for 317 study eyes of 261 patients. More participants were women (58.6%). Participants’ mean age was 74.9 (6.6) years [standard deviation (SD)]. The mean visual acuity of study eyes (better seeing eyes if participants had two study eyes) was 0.2 (0.2) Logarithm of the minimum angle of resolution (LogMAR) (SD). Objective A: Median testing frequency was three times per month. In the primary analysis, estimated AUROCs were < 0.6 for all index tests, and only KSJ summary score was significantly associated with the lesion activity (OR = 3.48, 95% CI 1.09 to 11.13; p = 0.036). Estimated AUROCs were < 0.6 for all tests in both sensitivity analyses and for the secondary outcome of change from inactive to active status between adjacent management visits. Objective B: Two overarching meta-themes emerged from the qualitative studies related to acceptance or non-acceptance of home monitoring. Meta-theme 1 encompassed four main themes: (1) the role of home monitoring; (2) suitability of procedures and instruments; (3) experience of home monitoring; and (4) feasibility of home monitoring in usual practice. Meta-theme 2 consisted of one main theme covering key inhibitors to acceptability. The main factors influencing acceptability included a participant’s understanding about the purpose of home monitoring and their experience of using it. While home monitoring was generally seen as a relatively straightforward exercise to undertake and non-burdensome, training and ongoing support were regarded as essential to its success. Home monitoring was acceptable to patients and its potential to reduce clinic visits during non-active treatment phases was recognised. Objective C: A minority of patients who were approached were willing in principle to participate. Increasing age and worse deprivation index for home address were associated with being unwilling in principle to participate (χ2 = 50.5 and 24.3, respectively, both p ≤ 0.001). Recruiting site was also associated with willingness in principle to participate, believed to be due to sites adopting different strategies for approaching and recruiting patients. Increasing age and worse deprivation were not consistently associated with either being able to self-monitor with the index tests or adherence to weekly testing (χ2 for all tests 0.08 for ability and adherence, except for worse IMD being associated with better adherence for the KSJ, χ2 = 12.15, p = 0.016). Recruiting site was also associated with being able to test and adhering to weekly testing. Objective D: There were 132 fellow eyes with data from 544 monitoring visits, 17 of which (12.9%) had nAMD recorded at one or more management visits over about 100 participant-years. This rate of conversion was higher than expected based on epidemiological studies of conversion rates in unaffected fellow eyes, potentially due to study eyes having had nAMD longer ago. Some predictors could not be fitted in models and estimates of associations were imprecise. The no-test model predicted conversion better than for Objective A (AUROC = 0.73) and electronic tests did not increase this (AUROCs = 0.73 and 0.76 for MBT and mVT, respectively). The estimated AUROC for the KSJ was 0.85, due to a strong positive association of the household object summary score with conversion (OR 15.3, p = 0.036). Objective E: Despite two-thirds of the population having previously used a smartphone, there were still a variety of challenges experienced with the electronic devices while testing at home that contributed to both reduced adherence and ultimately withdrawals from the study. Strengths and limitations The study had several strengths. Estimates of the diagnostic test accuracy of index tests were at low risk of bias: the study population was appropriate for the intended use of the tests, and summary test scores were not available to ophthalmologists providing the reference standard, which was judged after the index test data were collected. Limitations A smaller-than-planned sample size (less than half the target number of monitoring visits); nonetheless, 95% CIs for AUROCs were narrow (± 0.04) and estimates were able to rule out tests providing adequate accuracy for diagnosing active nAMD to enable patients to be monitored without hospital review. Tests were sometimes not available for technical reasons that were beyond the control of the research team. The study had no control over monitoring visits and participants are likely to have reported their subjective visual experience to their consultants, which might have influenced the reference standard. We could not define test thresholds a priori, and instead estimated AUROCs. We did not compare AUROCs for tests due to their poor accuracy. The ways in which patients were approached and screened varied across sites, generating a site effect in analyses of potential inequalities; variations may have reflected the pre-conceptions of research staff regarding the capabilities of patients to use the electronic tests. Conclusions Based on the detection of lesion activity assessed by clinicians in the clinic, we have shown that none of the index tests provides acceptable test accuracy for home monitoring in this context. Associations of increasing age and deprivation index for home address with unwillingness in principle to participate despite provision of hardware highlight the potential for inequality with interventions of the kind evaluated. While a proportion of nAMD patients are willing and interested in the potential for home monitoring, substantial practical and technological issues are encountered in the implementation of such, requiring a significant support infrastructure, including a study helpline. Future work Future research should focus on the methodological challenge of efficiently evaluating mobile health technologies which deal with constantly emerging new technology. The clear evidence of inequalities in participation and retention should prompt future research on ways to encourage participant and adoption of mobile health technologies by underserved populations. Focus should also be placed on methods to improve adherence and retention in longitudinal studies involving electronic testing, particularly around the nature of feedback to participants. Trial registration This trial is registered as ISRCTN79058224. Funding This award was funded by the National Institute of Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/97/02) and is published in full in Health Technology Assessment; Vol. 28, No. 32. See the NIHR Funding and Awards website for further award information.

Purpose: To analyze the outcome of intervention versus observation for vitreous cavity hemorrhage occurring after a 2-month period of blood-free cavity (late postoperative vitreous cavity hemorrhage—POVCH) in eyes operated by vitrectomy for complications of proliferative diabetic retinopathy (PDR). Methods: This study was a 10-year retrospective, observational, multi-center study involving eight major vitreoretinal surgical centers across India from January 2010 to December 2019. The primary objective of the study was to assess the visual and clinical outcomes of various management approaches for late POVCH. The key secondary objective was to determine the best management option that prevented recurrence. Patients with follow-up of less than 6 months of POVCH management were excluded. Results: The occurrence of late POVCH was studied in 261 eyes. The median time to occurrence was 7 months (range: 2–87) postvitrectomy/silicone oil removal. The majority (58%) experienced a single, nonrecurring POVCH event. Visual acuity outcome was independent of all management approaches (P = 0.179; mean follow-up 20.7 ± 14.1 months). With watchful observation, spontaneous resolution was noted in 83% (60/72 eyes) of eyes in 81.5 days (interquartile range, 169.75). Silicone oil injection was most effective in preventing recurrence (P < 0.001). Conclusion: The current treatment practice of late POVCH management in PDR suggests that watchful observation for at least 3 months could be as efficacious as any surgical intervention.

Purpose: The aim of the study was to describe imaging characteristics and detection rates of phenotypic features in macular telangiectasia type-2 (MacTel) on multicolor (MC), blue reflectance (BR), green reflectance (GR), infrared reflectance (IR), and fundus autofluorescence (FAF) and to evaluate sensitivity, specificity, and predictive values across modalities. Methods: In this monocentric observational study, 282 eyes of 148 patients with MacTel underwent color fundus photograph, MC, BR, GR, IR, FAF, spectral-domain optical coherence tomography (SD-OCT), OCT-angiography (OCT-A), and fundus fluorescein angiography (FFA). Grading was done by two graders qualitatively and quantitatively for the presence of the following prespecified MacTel findings [crystals, right-angle vessels (RAVs), plaques, subretinal neovascularization (SRNV), and MacTel area]. Across each imaging modality, the detection rate of RAVs and SRNV was compared with reference standard OCT-A (RAVs and SRNV) and FFA (SRNV), whereas that of plaques was compared with reference standard SD-OCT. Results: MC identified overall MacTel characteristics in 92.7% of eyes. Regarding the presence, number, and quadrants of RAVs and the presence and number of crystals, MC and GR had superior detection rates as well as the highest sensitivity and negative predictive value. Retinal plaques were better detected using FAF (97%), followed by MC (88%). In proliferative MacTel, SRNV was identified in 86% and 79% of eyes on MC and IR, respectively. While BR clearly delineated MacTel area in 100% eyes, FAF was able to ascertain a larger area of involvement in proliferative MacTel. Conclusion: The findings demonstrate the ability of MC, its component channels, and FAF to describe MacTel characteristics qualitatively and quantitatively.

Introduction The diagnosis of neovascular age-related macular degeneration (nAMD), the leading cause of visual impairment in the developed world, relies on the interpretation of various imaging tests of the retina. These include invasive angiographic methods, such as Fundus Fluorescein Angiography (FFA) and, on occasion, Indocyanine-Green Angiography (ICGA). Newer, non-invasive imaging modalities, predominately Optical Coherence Tomography (OCT) and Optical Coherence Tomography Angiography (OCTA), have drastically transformed the diagnostic approach to nAMD. The aim of this study is to undertake a comprehensive diagnostic accuracy assessment of the various imaging modalities used in clinical practice for the diagnosis of nAMD (OCT, OCTA, FFA and, when a variant of nAMD called Polypoidal Choroidal Vasculopathy is suspected, ICGA) both alone and in various combinations.Methods and analysis This is a non-inferiority, prospective, randomised diagnostic accuracy study of 1067 participants. Participants are patients with clinical features consistent with nAMD who present to a National Health Service secondary care ophthalmology unit in the UK. Patients will undergo OCT as per standard practice and those with suspicious features of nAMD on OCT will be approached for participation in the study. Patients who agree to take part will also undergo both OCTA and FFA (and ICGA if indicated). Interpretation of the imaging tests will be undertaken by clinicians at recruitment sites. A randomised design was selected to avoid bias from consecutive review of all imaging tests by the same clinician. The primary outcome of the study will be the difference in sensitivity and specificity between OCT+OCTA and OCT+FFA (±ICGA) for nAMD detection as interpreted by clinicians at recruitment sites.Ethics and dissemination The study has been approved by the South Central—Oxford B Research Ethics Committee with reference number 21/SC/0412.Dissemination of study results will involve peer-review publications, presentations at major national and international scientific conferences.Trial registration number ISRCTN18313457.

Abstract Real-world retinal optical coherence tomography (OCT) scans are available in abundance in primary and secondary eye care centres. They contain a wealth of information to be analyzed in retrospective studies. The associated electronic health records alone are often not enough to generate a high-quality dataset for clinical, statistical, and machine learning analysis. We have developed a deep learning-based age-related macular degeneration (AMD) stage classifier, to efficiently identify the first onset of early/intermediate (iAMD), atrophic (GA), and neovascular (nAMD) stage of AMD in retrospective data. We trained a two-stage convolutional neural network to classify macula-centered 3D volumes from Topcon OCT images into 4 classes: Normal, iAMD, GA and nAMD. In the first stage, a 2D ResNet50 is trained to identify the disease categories on the individual OCT B-scans while in the second stage, four smaller models (ResNets) use the concatenated B-scan-wise output from the first stage to classify the entire OCT volume. Classification uncertainty estimates are generated with Monte-Carlo dropout at inference time. The model was trained on a real-world OCT dataset, 3765 scans of 1849 eyes, and extensively evaluated, where it reached an average ROC-AUC of 0.94 in a real-world test set.

Introduction Diabetes is a major global public health burden. The objective of this study was to estimate the national and provincial-level prevalence of self-reported diabetes and establish the demographic risk factors of diabetes in Sri Lanka.Research design and methods A nationally representative sample of the population from all nine provinces in Sri Lanka was obtained from the cross-sectional Demographic and Health Survey 2016. Those aged 20 years and older were included in this study. Age, sex, ethnicity, religion, education level, marital status, sector of the resident (urban/rural/estate) and province of residence were included as potential exposures. The outcome was defined as self-reported diabetes.Results The age-adjusted national prevalence of self-reported diabetes was 10.60% (95% CI: 10.59% to 10.602%). Provinces with higher gross domestic product (GDP) per capita showed a higher prevalence of diabetes. The Western province with the highest GDP of 734 094 Sri Lankan rupee showed the highest prevalence of diabetes (13.3%; 95% CI: 13.32% to 13.34%) compared with 8.1% (95% CI: 8.54% to 8.58%) in the Northern province with lowest GDP (321 289 Sri Lankan rupee). Prevalence of diabetes was higher among residents living in urban areas (14.39%; 95% CI: 13.72% to 15.06%) compared with their counterpart. Other risk factors of self-reported diabetes included age, gender, ethnicity, education level and marital status with those aged 55–64 years, females, who belong to Moor ethnicity, had secondary or higher education, and divorced or widowed had higher risk of diabetes compared with their counterparts.Conclusions Sri Lanka has a high prevalence of self-reported diabetes and it differs by province, sector of residence, sex, education level, ethnicity, age and marital status. There is a need for risk stratifying adult Sri Lankan population to help target those at high risk of diabetes so that cost-effective approaches of screening, preventive and treatment options can be initiated.

Objective: To evaluate the appropriateness of responses generated by an online chat-based artificial intelligence (AI) model for diabetic retinopathy (DR) related questions. Design: Cross-sectional study. Methods: A set of 20 questions framed from the patient’s perspective addressing DR-related queries, such as the definition of disease, symptoms, prevention methods, treatment options, diagnostic methods, visual impact, and complications, were formulated for input into ChatGPT-4. Peer-reviewed, literature-based answers were collected from popular search engines for the selected questions and three retinal experts reviewed the responses. An inter-human agreement was analyzed for consensus expert responses and also between experts. The answers generated by the AI model were compared with those provided by the experts. The experts rated the response generated by ChatGPT-4 on a scale of 0–5 for appropriateness and completeness. Results: The answers provided by ChatGPT-4 were appropriate and complete for most of the DR-related questions. The response to questions on the adverse effects of laser photocoagulation therapy and compliance to treatment was not perfectly complete. The average rating given by the three retina expert evaluators was 4.84 for appropriateness and 4.38 for completeness of answers provided by the AI model. This corresponds to an overall 96.8% agreement among the experts for appropriateness and 87.6% for completeness regarding AI-generated answers. Conclusion: ChatGPT-4 exhibits a high level of accuracy in generating appropriate responses for a range of questions in DR. However, there is a need to improvise the model to generate complete answers for certain DR-related topics.

Objectives Remote monitoring of health has the potential to reduce the burden to patients of face-to-face appointments and make healthcare more efficient. Apps are available for patients to self-monitor vision at home, for example, to detect reactivation of age-related macular degeneration (AMD). Describing the challenges when implementing apps for self-monitoring of vision at home was an objective of the MONARCH study to evaluate two vision-monitoring apps on an iPod Touch (Multibit and MyVisionTrack).Design Diagnostic Test Accuracy study.Setting Six UK hospitals.Methods The study provides an example of the real-world implementation of such apps across health sectors in an older population. Challenges described include the following: (1) frequency and reason for incoming calls made to a helpline and outgoing calls made to participants; (2) frequency and duration of events responsible for the tests being unavailable; and (3) other technical and logistical challenges.Results Patients (n=297) in the study were familiar with technology; 252/296 (85%) had internet at home and 197/296 (67%) had used a smartphone. Nevertheless, 141 (46%) called the study helpline, more often than anticipated. Of 435 reasons for calling, all but 42 (10%) related to testing with the apps or hardware, which contributed to reduced adherence. The team made at least one call to 133 patients (44%) to investigate why data had not been transmitted. Multibit and MyVisionTrack apps were unavailable for 15 and 30 of 1318 testing days for reasons which were the responsibility of the app providers. Researchers also experienced technical challenges with a multiple device management system. Logistical challenges included regulations for transporting lithium-ion batteries and malfunctioning chargers.Conclusions Implementation of similar technologies should incorporate a well-resourced helpline and build in additional training time for participants and troubleshooting time for staff. There should also be robust evidence that chosen technologies are fit for the intended purpose.Trial registration number ISRCTN79058224.

Topic: Several patient-reported outcome measures (PROMs) are available to measure health-related quality of life (HRQoL) in patients with late-stage clinical diabetic retinal diseases (DRDs). However, an understanding of the psychometric properties of PROMs is needed to assess how they could relate to severity levels of a revised DRD grading system. This narrative review assessed the available generic-, vision-, and DRD-related PROMs used in DRD research and highlights areas for improvement. Clinical Relevance: Diabetic retinal disease is a common complication of diabetes and can lead to sight-threatening complications with a devastating effect on HRQoL. Methods: The Quality of Life working group is one of 6 working groups organized for the DRD Staging System Update Effort, a project of the Juvenile Diabetes Research Foundation Mary Tyler Moore Vision Initiative. PubMed, Cochrane Library, Embase, and Google Scholar databases were searched using core keywords to retrieve ophthalmology-related review articles, randomized clinical trials, and prospective, observational, and cross-sectional studies in the English language. A detailed review of 12 PROMs (4 QoL questionnaires and 8 utilities) that met a minimum level of evidence (LOE) was conducted. The relevance of each PROM to DRD disease stage and Biomarker Qualification guidelines (Biomarkers, EndpointS, and other Tools) categories was also defined. Results: The National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25), Impact of vision impairment-computerized adaptive testing, and Diabetic Retinopathy and Macular Edema Computerized Adaptive Testing System had a LOE of II in detecting change due to late-stage DRD (diabetic macular edema), although several areas for improvement (e.g., psychometrics and generalizability) were identified. Other PROMs, particularly the utilities, had a LOE of III due to cross-sectional evidence in late-stage clinical DRD. Although the NEI VFQ-25 has been the most widely used PROM in late-stage DRD, more work is required to improve its multidimensional structure and other psychometric limitations. No PROM was deemed relevant for subclinical or early/mid-DRD. Conclusion: This narrative review found that the most commonly used PROM is NEI VFQ-25, but none meets the ideal psychometric, responsiveness, and clinical setting digital administration requirements that could be included in an updated DRD staging system for diagnosis and monitoring of DRD progression. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Abstract Background/objectives In healthcare research investigating complex interventions, gaps in understanding of processes can be filled by using qualitative methods alongside a quantitative approach. The aim of this mixed-methods pilot trial was to provide feasibility evidence comparing two treatment regimens for neovascular age-related macular degeneration (nAMD) to inform a future large-scale randomised controlled trial (RCT). Subjects/methods Forty-four treatment-naïve nAMD patients were followed over 24 months and randomised to one of two treatment regimens: standard care (SC) or treat and extend (T&E). The primary objective evaluated feasibility of the MATE trial via evaluations of screening logs for recruitment rates, nonparticipation and screen fails, whilst qualitative in-depth interviews with key study staff evaluated the recruitment phase and running of the trial. The secondary objective assessed changes in visual acuity and central retinal thickness (CRT) between the two treatment arms. Results The overall recruitment rate was 3.07 participants per month with a 40.8% non-participation rate, 18.51% screen-failure rate and 15% withdrawal/non-completion rate. Key themes in the recruitment phase included human factors, protocol-related issues, recruitment processes and challenges. Both treatment regimens showed a trend towards a visual acuity gain at month 12 which was not maintained at month 24, whilst CRT reduced similarly in both regimens over the same time period. These were achieved with one less treatment following a T&E regimen. Conclusion This mixed-methodology, pilot RCT achieved its pre-defined recruitment, nonparticipation and screen failure rates, thus deeming it a success. With some minor protocol amendments, progression to a large-scale RCT will be achievable.

Abstract The retina has the greatest metabolic demand in the body particularly in dark adaptation when its sensitivity is enhanced. This requires elevated level of perfusion to sustain mitochondrial activity. However, mitochondrial performance declines with age leading to reduced adaptive ability. We assessed human retina metabolism in vivo using broad band near-infrared spectroscopy (bNIRS), which records colour changes in mitochondria and blood as retinal metabolism shifts in response to changes in environmental luminance. We demonstrate a significant sustained rise in mitochondrial oxidative metabolism in the first 3 min of darkness in subjects under 50 years old. This was not seen in those over 50 years. Choroidal oxygenation declines in 50 s. Significant group differences in blood oxygenation are apparent in the first 6 min, consistent with mitochondrial demand leading hemodynamic changes. A greater coupling between mitochondrial oxidative metabolism with hemodynamics is revealed in subjects older than 50, possibly due to reduced capacity in the older retina. Rapid in vivo assessment of retinal metabolism with bNIRS provides a route to understanding fundamental physiology and early identification of retinal disease before pathology is established.

Objectives To estimate the economic costs, health-related quality-of-life outcomes and cost-effectiveness of subthreshold micropulse laser (SML) versus standard laser (SL) for the treatment of diabetic macular oedema (DMO) with central retinal thickness (CRT) of

Abstract Diabetic retinopathy (DR) at risk of vision loss (referable DR) needs to be identified by retinal screening and referred to an ophthalmologist. Existing automated algorithms have mostly been developed from images acquired with high cost mydriatic retinal cameras and cannot be applied in the settings used in most low- and middle-income countries. In this prospective multicentre study, we developed a deep learning system (DLS) that detects referable DR from retinal images acquired using handheld non-mydriatic fundus camera by non-technical field workers in 20 sites across India. Macula-centred and optic-disc-centred images from 16,247 eyes (9778 participants) were used to train and cross-validate the DLS and risk factor based logistic regression models. The DLS achieved an AUROC of 0.99 (1000 times bootstrapped 95% CI 0.98–0.99) using two-field retinal images, with 93.86 (91.34–96.08) sensitivity and 96.00 (94.68–98.09) specificity at the Youden’s index operational point. With single field inputs, the DLS reached AUROC of 0.98 (0.98–0.98) for the macula field and 0.96 (0.95–0.98) for the optic-disc field. Intergrader performance was 90.01 (88.95–91.01) sensitivity and 96.09 (95.72–96.42) specificity. The image based DLS outperformed all risk factor-based models. This DLS demonstrated a clinically acceptable performance for the identification of referable DR despite challenging image capture conditions.

Purpose: To study the individual course of retinal changes caused by healthy aging using deep learning. Design: Retrospective analysis of a large data set of retinal OCT images. Participants: A total of 85 709 adults between the age of 40 and 75 years of whom OCT images were acquired in the scope of the UK Biobank population study. Methods: We created a counterfactual generative adversarial network (GAN), a type of neural network that learns from cross-sectional, retrospective data. It then synthesizes high-resolution counterfactual OCT images and longitudinal time series. These counterfactuals allow visualization and analysis of hypothetical scenarios in which certain characteristics of the imaged subject, such as age or sex, are altered, whereas other attributes, crucially the subject’s identity and image acquisition settings, remain fixed. Main Outcome Measures: Using our counterfactual GAN, we investigated subject-specific changes in the retinal layer structure as a function of age and sex. In particular, we measured changes in the retinal nerve fiber layer (RNFL), combined ganglion cell layer plus inner plexiform layer (GCIPL), inner nuclear layer to the inner boundary of the retinal pigment epithelium (INL-RPE), and retinal pigment epithelium (RPE). Results: Our counterfactual GAN is able to smoothly visualize the individual course of retinal aging. Across all counterfactual images, the RNFL, GCIPL, INL-RPE, and RPE changed by −0.1 μm ± 0.1 μm, −0.5 μm ± 0.2 μm, −0.2 μm ± 0.1 μm, and 0.1 μm ± 0.1 μm, respectively, per decade of age. These results agree well with previous studies based on the same cohort from the UK Biobank population study. Beyond population-wide average measures, our counterfactual GAN allows us to explore whether the retinal layers of a given eye will increase in thickness, decrease in thickness, or stagnate as a subject ages. Conclusion: This study demonstrates how counterfactual GANs can aid research into retinal aging by generating high-resolution, high-fidelity OCT images, and longitudinal time series. Ultimately, we envision that they will enable clinical experts to derive and explore hypotheses for potential imaging biomarkers for healthy and pathologic aging that can be refined and tested in prospective clinical trials. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes mellitus, leading to visual impairment if left untreated. This review discusses the use of optical coherence tomography angiography (OCTA) as a diagnostic tool for the early detection and management of DR. OCTA is a fast, non-invasive, non-contact test that enables the detailed visualisation of the macular microvasculature in different plexuses. OCTA offers several advantages over fundus fluorescein angiography (FFA), notably offering quantitative data. OCTA is not without limitations, including the requirement for careful interpretation of artefacts and the limited region of interest that can be captured currently. We explore how OCTA has been instrumental in detecting early microvascular changes that precede clinical signs of DR. We also discuss the application of OCTA in the diagnosis and management of various stages of DR, including non-proliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), diabetic macular oedema (DMO), diabetic macular ischaemia (DMI), and pre-diabetes. Finally, we discuss the future role of OCTA and how it may be used to enhance the clinical outcomes of DR.

Abstract To examine the retinal structure and function in relation to diabetes duration and glycemia in patients without diabetic retinopathy (DR). 85 adults with type 2 diabetes without DR or macular edema underwent dilated indirect ophthalmoscopy, optical coherence tomography (OCT), ultra-wide field fundus photography, multifocal electroretinography (mfERG) and HbA1C assessment. Patients were stratified as those with diabetes duration

Objectives This study provides an estimate of the annual cost of blindness and moderate to severe visual impairment (MSVI) among people with diabetes aged 40 years and above in India in the year 2019.Design A cost of illness study.Setting India.Participants People with diabetes aged 40 years and above in India in the year 2019.Primary and secondary outcome measures Estimates are provided for the total costs of screening for most common vision-threatening eye conditions, treatment of these conditions, economic activity lost by these people and their family carers whose ability to work is affected, and loss of quality of life experienced by people with diabetes and blindness or MSVI.Results It is estimated that for people with diabetes aged 40 years or above, annual screening followed by eye examination where required would cost around 42.3 billion Indian rupees (INR) (4230 crores) per year; treating sight problems around 2.87 billion INR (287 crores) per year if 20% of those needing treatment receive it; and lost economic activity around 472 billion INR (47 200 crores). Moreover, 2.86 million (0.286 crores) quality-adjusted life years (QALYs) are lost annually due to blindness and MSVI. The estimate of lost production is highly sensitive to the proportion of people with MSVI able to work and how their output compares with that of a person with no visual impairment.Conclusions This is the first study to estimate the cost of blindness and MSVI for people aged 40 years and over with diabetes in India. The annual cost to the Indian economy is substantial. This cost will be expected to fall if a successful screening and treatment plan is introduced in India. Further work is suggested using more robust data, when available, to estimate the loss of productivity and loss of QALYs, as this would be worthwhile.

Purpose: To determine the associations of predominant peripheral lesions (PPLs) with systemic comorbidities in individuals with diabetic retinopathy. Methods: This is a multicenter cross-sectional observational study conducted across three tertiary eye care centers in south India between January 2019 and July 2021. Ultra-widefield fundus images of consecutive patients with varying severity of diabetic retinopathy with data on systemic comorbidities were classified based on the presence or absence of PPL. Systemic comorbidities (hypertension, diabetic kidney disease, coronary artery disease, dyslipidemia, and anemia) were compared between the two groups. Results: A total of 879 participants (70.1% males) were included in the study, of which 443 (50.4%) patients had PPL. The mean age of the study participants was 56 ± 10 years, mean age of onset of diabetes was 41.24 ± 11.6 years, and mean duration of diabetes was 15.39 ± 7.6 years. The number of PPL increased with increasing severity of DR. Of all the systemic comorbidities analyzed, we found that coronary artery disease (CAD) had a significant association with PPL (Odds ratio [OR]-1.69; 95% confidence interval [CI], 1.12–2.55; P = 0.013) after adjusting for diabetic retinopathy severity, duration of diabetes, and age of onset of diabetes. Conclusion: The presence of PPL is a marker for coronary artery disease and early referral to cardiology is warranted.

A systematic review and meta-analysis were conducted to estimate the prevalence of diabetic retinopathy (DR) in India's urban and rural areas. Medline, Scopus, and ScienceDirect databases were searched for population-based studies published in English between January 1990 and April 2021, wherein the prevalence of DR among Indian residents with type 2 diabetes mellitus (DM) was reported. A random-effects model was used to estimate the overall, rural, and urban prevalence. Data from 10 eligible studies were aggregated for meta-analysis. The prevalence of DR was 17.44% (95% confidence interval [CI], 14.33–20.55) in urban and 14.00% (95% CI: 9.13–18.86) in rural population (P = 0.24). The overall DR prevalence was 16.10% (95% CI: 13.16–24.32), and the population prevalence was 1.63% [95% CI: 0.94–2.32]. Prevalence of DR in people with diabetes was lower in the age group of 40–49 years [13.57% (95% CI: 7.16–19.98)] than in the age group of 50–59 years [16.72% (95% CI: 12.80–20.64)] and the age group of 60 years and above [16.55% (95% CI: 12.09–21.00)]. Variability in studies was high: urban (I2 = 88.90%); rural (I2 = 92.14%). Pooled estimates indicate a narrow difference in DR prevalence among people with diabetes in rural and urban India. The fast urbanization and increasing diabetes prevalence in rural areas underscore the need for providing equitable eye care at the bottom of the health pyramid.

The classification of diabetic retinopathy has been based on 7-field photographs. With advances in retinal imaging, there is an unmet need to reclassify this condition as new predictive factors have been identified in the peripheral retina. In addition, we have transitioned from an era of laser treatment for vision-threatening complications to robust evidence that anti-VEGF therapy can modulate the diabetic retinopathy scores. In this review, the literature on both retinal imaging and role of anti-VEGF on diabetic retinopathy highlights both the merits and shortcomings of available evidence in this area.

Diabetic Retinopathy (DR) affects about 27% of patients with diabetes globally. According to the World Health Organization (WHO), DR is responsible for37 million cases of blindness worldwide. The SMART India study (October 2020-August 2021) documented the prevalence of diabetes, and DR in people40 years and above across ten Indian states and one Union Territory by conducting community screening. About 90% of people with sight threatening diabetic retinopathy (STDR) were referred from this screening study to eye hospitals for management, but failed to attend. This qualitative study, a component of the SMART India study, explored perceptions of referred patients regarding their susceptibility to eye related problems in diabetes and the benefits/barriers to seeking care. Perceived barriers from the viewpoint of ophthalmologists were also explored. Guided by the Health Beliefs Model (HBM), 20 semi structured interviews were carried out with consenting patients diagnosed with STDR. They included nine patients who had sought care recruited from eight eye hospitals across different states in India and eleven patients who did not seek care. Eleven ophthalmologists also participated. Four themes of analysis based on the HBM were, understanding of DR and its treatment, perceptions about susceptibility and severity, perceived barriers, perceived benefits and cues to action. Findings revealed poor understanding of the effects of diabetes on the eye contributing to low risk perception. Prohibitive costs of treatment, difficulties in accessing care services and poor social support were major barriers to seeking care. Ophthalmologists acknowledged that the absence of symptoms and the slow progressive nature of the disease deluded patients into thinking that they were fine. The study attests to the need for greater health literacy around diabetes, DR and STDR; for making treatment more affordable and accessible and for the development of effective patient education and communication strategies towards increasing compliance.

Background: The National Institute for Health and Care Excellence recommends macular laser to treat diabetic macular oedema with a central retinal subfield thickness of 24 Early Treatment Diabetic Retinopathy Study letters (Snellen equivalent > 20/320) in one/both eyes. Interventions: Participants were randomised 1 : 1 to receive 577 nm subthreshold micropulse laser or standard threshold macular laser (e.g. argon laser, frequency-doubled neodymium-doped yttrium aluminium garnet 532 nm laser); laser treatments could be repeated as needed. Rescue therapy with intravitreal anti-vascular endothelial growth factor therapies or steroids was allowed if a loss of ≥ 10 Early Treatment Diabetic Retinopathy Study letters between visits occurred and/or central retinal subfield thickness increased to > 400 µm. Main outcome measures: The primary outcome was the mean change in best-corrected visual acuity in the study eye at 24 months (non-inferiority margin 5 Early Treatment Diabetic Retinopathy Study letters). Secondary outcomes included the mean change from baseline to 24 months in the following: binocular best-corrected visual acuity; central retinal subfield thickness; the mean deviation of the Humphrey 10–2 visual field in the study eye; the percentage of people meeting driving standards; and the EuroQol-5 Dimensions, five-level version, National Eye Institute Visual Function Questionnaire – 25 and Vision and Quality of Life Index scores. Other secondary outcomes were the cost per quality-adjusted life-years gained, adverse effects, number of laser treatments and additional rescue treatments. Results: The DIAMONDS trial recruited fully (n = 266); 87% of participants in the subthreshold micropulse laser group and 86% of participants in the standard threshold macular laser group had primary outcome data. Groups were balanced regarding baseline characteristics. Mean best-corrected visual acuity change in the study eye from baseline to month 24 was –2.43 letters (standard deviation 8.20 letters) in the subthreshold micropulse laser group and –0.45 letters (standard deviation 6.72 letters) in the standard threshold macular laser group. Subthreshold micropulse laser was deemed to be not only non-inferior but also equivalent to standard threshold macular laser as the 95% confidence interval (–3.9 to –0.04 letters) lay wholly within both the upper and lower margins of the permitted maximum difference (5 Early Treatment Diabetic Retinopathy Study letters). There was no statistically significant difference between groups in any of the secondary outcomes investigated with the exception of the number of laser treatments performed, which was slightly higher in the subthreshold micropulse laser group (mean difference 0.48, 95% confidence interval 0.18 to 0.79; p = 0.002). Base-case analysis indicated no significant difference in the cost per quality-adjusted life-years between groups. Future work: A trial in people with ≥ 400 µm diabetic macular oedema comparing anti-vascular endothelial growth factor therapy alone with anti-vascular endothelial growth factor therapy and macular laser applied at the time when central retinal subfield thickness has decreased to

Abstract 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.

Summary: 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.

Background Recent clinical trials on proliferative diabetic retinopathy (PDR) show that presenting visual acuity can be stabilised with panretinal photocoagulation (PRP) within 2 years despite the need for supplementary PRP or anti-vascular endothelial growth factor therapy for concomitant diabetic macular oedema (DMO). It is unclear whether similar results can be obtained in daily clinical practice. Here, we query the probability of vision loss in patients with treatment-naïve PDR who have attained stability after PRP and its predictors.Methods Retrospective cohort study at a tertiary eye centre between 01 January 2015 and 31 December 2019, wherein 2336 eyes met study criteria with first record of stable PRP-treated PDR in at least one eye. Kaplan-Meier and Cox proportional hazards modelling were used to report the probability of vision loss of at least five Early Treatment Diabetic Retinopathy Study (ETDRS) letters.Results The probability of losing at least five ETDRS letters was 50% at 3.32 (95% CI, 2.94 to 3.78) years after achieving first stability post PRP in treatment-naïve PDR. The mean decrease at this event was 14.2 (SD 13.0) ETDRS letters irrespective of the presence of DMO. The strongest risk factor for vision loss was a history of DMO at baseline (HR 1.62 (95% CI, 1.34 to 1.95), p

Abstract Screening effectively identifies patients at risk of sight-threatening diabetic retinopathy (STDR) when retinal images are captured through dilated pupils. Pharmacological mydriasis is not logistically feasible in non-clinical, community DR screening, where acquiring gradable retinal images using handheld devices exhibits high technical failure rates, reducing STDR detection. Deep learning (DL) based gradability predictions at acquisition could prompt device operators to recapture insufficient quality images, increasing gradable image proportions and consequently STDR detection. Non-mydriatic retinal images were captured as part of SMART India, a cross-sectional, multi-site, community-based, house-to-house DR screening study between August 2018 and December 2019 using the Zeiss Visuscout 100 handheld camera. From 18,277 patient eyes (40,126 images), 16,170 patient eyes (35,319 images) were eligible and 3261 retinal images (1490 patient eyes) were sampled then labelled by two ophthalmologists. Compact DL model area under the receiver operator characteristic curve was 0.93 (0.01) following five-fold cross-validation. Compact DL model agreement (Kappa) were 0.58, 0.69 and 0.69 for high specificity, balanced sensitivity/specificity and high sensitivity operating points compared to an inter-grader agreement of 0.59. Compact DL gradability model performance was favourable compared to ophthalmologists. Compact DL models can effectively classify non-mydriatic, handheld retinal image gradability with potential applications within community-based DR screening.

Abstract To evaluate the effect of aging, intra- and intersession repeatability and regional scotopic sensitivities in healthy and age-related macular degeneration (AMD) eyes. Intra- and intersession agreement and effect of age was measured in healthy individuals. The mean sensitivity (MS) and pointwise retinal sensitivities (PWS) within the central 24° with 505 nm (cyan) and 625 nm (red) stimuli were evaluated in 50 individuals (11 healthy and 39 AMD eyes). The overall intra- and intersession had excellent reliability (intraclass correlation coefficient, ICC > 0.90) and tests were highly correlated (Spearman rs = 0.75–0.86). Eyes with subretinal drusenoid deposit (SDD) had reduced PWS centrally, particularly at inferior and nasal retinal locations compared with controls and intermediate AMD (iAMD) without SDD. There was no difference in MS or PWS at any retinal location between iAMD without SDD and healthy individuals nor between iAMD with SDD and non-foveal atrophic AMD groups. Eyes with SDD have reduced rod function compared to iAMD without SDD and healthy eyes, but similar to eyes with non-foveal atrophy. Our results highlight rod dysfunction is not directly correlated with drusen load and SDD location.

Abstract Background The associations between England’s incentivised primary care-based diabetes prevention activities and hard clinical endpoints remain unclear. We aimed to examine the associations between attainment of primary care indicators and incident diabetic retinopathy (DR) among people with type 2 diabetes. Methods A historical cohort (n = 60,094) of people aged ≥ 18 years with type 2 diabetes and no DR at baseline was obtained from the UK Clinical Practice Research Datalink (CPRD). Exposures included attainment of the Quality and Outcomes Framework (QOF) HbA1c (≤ 7.5% or 59 mmol/mol), blood pressure (≤ 140/80 mmHg), and cholesterol (≤ 5 mmol/L) indicators, and number of National Diabetes Audit (NDA) care processes completed (categorised as 0–3, 4–6, or 7–9), in 2010–2011. Outcomes were time to development of DR and sight-threatening diabetic retinopathy (STDR). Nearest neighbour propensity score matching was undertaken and Cox proportional hazards models then fitted using the matched samples. Concordance statistics were calculated for each model. Results 8263 DR and 832 STDR diagnoses were observed over mean follow-up periods of 3.5 (SD 2.1) and 3.8 (SD 2.0) years, respectively. HbA1c and blood pressure (BP) indicator attainment were associated with lower rates of DR (adjusted hazard ratios (aHRs) 0.94 (95% CI 0.89–0.99) and 0.87 (0.83–0.92), respectively), whereas cholesterol indicator attainment was not (aHR 1.03 (0.97–1.10)). All QOF indicators were associated with lower rates of STDR (aHRs 0.74 (0.62–0.87) for HbA1c, 0.78 (0.67–0.91) for BP, and 0.82 (0.67–0.99) for cholesterol). Completion of 7–9 vs. 0–3 NDA processes was associated with fewer STDR diagnoses (aHR 0.72 (0.55–0.94)). Conclusions Attainment of key primary care indicators is associated with lower incidence of DR and STDR among patients with type 2 diabetes in England.

Abstract Mitochondrial function declines with age and in some diseases, but we have been unable to analyze this in vivo. Here, we optically examine retinal mitochondrial function as well as choroidal oxygenation and hemodynamics in aging C57 and complement factor H (CFH−/−) mice, proposed models of macular degeneration which suffer early retinal mitochondrial decline. In young C57s mitochondrial populations respire in coupled oscillatory behavior in cycles of ~ 8 min, which is phase linked to choroidal oscillatory hemodynamics. In aging C57s, the oscillations are less regular being ~ 14 min and more dissociated from choroidal hemodynamics. The mitochondrial oscillatory cycles are extended in CFH−/− mice being ~ 16 min and are further dissociated from choroidal hemodynamics. Mitochondrial decline occurs before age-related changes to choroidal vasculature, hence, is the likely origin of oscillatory disruption in hemodynamics. This technology offers a non-invasive technique to detect early retinal disease and its relationship to blood oxygenation in vivo and in real time.

Diabetic retinopathy (DR) is an emerging preventable cause of blindness in India. All India Ophthalmology Society (AIOS) and Vitreo-Retinal Society of India (VRSI) have initiated several measures to improve of DR screening in India. This article is a consensus statement of the AIOS DR task force and VRSI on practical guidelines of DR screening in India. Although there are regional variations in the prevalence of diabetes in India at present, all the States in India should screen their population for diabetes and its complications. The purpose of DR screening is to identify people with sight-threatening DR (STDR) so that they are treated promptly to prevent blindness. This statement provides strategies for the identification of people with diabetes for DR screening, recommends screening intervals in people with diabetes with and without DR, and describes screening models that are feasible in India. The logistics of DR screening emphasizes the need for dynamic referral pathways with feedback mechanisms. It provides the clinical standards required for DR screening and treatment of STDR and addresses the governance and quality assurance (QA) standards for DR screening in Indian settings. Other aspects incorporate education and training, recommendations on Information technology (IT) infrastructure, potential use of artificial intelligence for grading, data capture, and requirements for maintenance of a DR registry. Finally, the recommendations include public awareness and the need to work with diabetologists to control the risk factors so as to have a long-term impact on prevention of diabetes blindness in India.

Purpose: The aim of this study was to report visual and anatomical outcomes following treatment for diabetic macular edema (DME) in clinical practice in India. Methods: Retrospective chart review of patients with DME who were initiated on treatment and followed up for at least 1 year at 9 tertiary eye care centers during 2016–2017 was performed. Data on demographics, systemic illnesses, visual acuity and anatomical characteristics of DME, treatment history were collated and analyzed for change in visual acuity level and central macular thickness at 1 year. Results: A total 1853 patients were diagnosed with treatable DME during study period, 1315 patients were treated and 556 patients (1019 eyes) followed up at one year. Although patients achieved significantly better anatomical outcome (central macular thickness of

Summary: Background: We undertook a Grand Challenges in Global Eye Health prioritisation exercise to identify the key issues that must be addressed to improve eye health in the context of an ageing population, to eliminate persistent inequities in health-care access, and to mitigate widespread resource limitations. Methods: Drawing on methods used in previous Grand Challenges studies, we used a multi-step recruitment strategy to assemble a diverse panel of individuals from a range of disciplines relevant to global eye health from all regions globally to participate in a three-round, online, Delphi-like, prioritisation process to nominate and rank challenges in global eye health. Through this process, we developed both global and regional priority lists. Findings: Between Sept 1 and Dec 12, 2019, 470 individuals complete round 1 of the process, of whom 336 completed all three rounds (round 2 between Feb 26 and March 18, 2020, and round 3 between April 2 and April 25, 2020) 156 (46%) of 336 were women, 180 (54%) were men. The proportion of participants who worked in each region ranged from 104 (31%) in sub-Saharan Africa to 21 (6%) in central Europe, eastern Europe, and in central Asia. Of 85 unique challenges identified after round 1, 16 challenges were prioritised at the global level; six focused on detection and treatment of conditions (cataract, refractive error, glaucoma, diabetic retinopathy, services for children and screening for early detection), two focused on addressing shortages in human resource capacity, five on other health service and policy factors (including strengthening policies, integration, health information systems, and budget allocation), and three on improving access to care and promoting equity. Interpretation: This list of Grand Challenges serves as a starting point for immediate action by funders to guide investment in research and innovation in eye health. It challenges researchers, clinicians, and policy makers to build collaborations to address specific challenges. Funding: The Queen Elizabeth Diamond Jubilee Trust, Moorfields Eye Charity, National Institute for Health Research Moorfields Biomedical Research Centre, Wellcome Trust, Sightsavers, The Fred Hollows Foundation, The Seva Foundation, British Council for the Prevention of Blindness, and Christian Blind Mission. Translations: For the French, Spanish, Chinese, Portuguese, Arabic and Persian translations of the abstract see Supplementary Materials section.

Background: Neovascular age-related macular degeneration is a leading cause of sight loss, and early detection and treatment is important. For patients with neovascular age-related macular degeneration in one eye, it is usual practice to monitor the unaffected eye. The test used to diagnose neovascular age-related macular degeneration, fundus fluorescein angiography, is an invasive test. Non-invasive tests are available, but their diagnostic accuracy is unclear. Objectives: The primary objective was to determine the diagnostic monitoring performance of tests for neovascular age-related macular degeneration in the second eye of patients with unilateral neovascular age-related macular degeneration. The secondary objectives were the cost-effectiveness of tests and to identify predictive factors of developing neovascular age-related macular degeneration. Design: This was a multicentre, prospective, cohort, comparative diagnostic accuracy study in a monitoring setting for up to 3 years. A Cox regression risk prediction model and a Markov microsimulation model comparing cost-effectiveness of the index tests over 25 years were used. Setting: This took place in hospital eye services. Participants: Participants were adults (aged 50–95 years) with newly diagnosed (within the previous 6 weeks) neovascular age-related macular degeneration in one eye and an unaffected second (study) eye who were attending for treatment injections in the first eye and who had a study eye baseline visual acuity of ≥ 68 Early Treatment Diabetic Retinopathy Study letters. Interventions: The index tests were Amsler chart (completed by participants), fundus clinical examination, optical coherence tomography, self-reported vision assessment (completed by participants) and visual acuity. The reference standard was fundus fluorescein angiography. Main outcome measures: The main outcome measures were sensitivity and specificity; the performance of the risk predictor model; and costs and quality-adjusted life-years. Results: In total, 552 out of 578 patients who consented from 24 NHS hospitals (n = 16 ineligible; n = 10 withdrew consent) took part. The mean age of the patients was 77.4 years (standard deviation 7.7 years) and 57.2% were female. For the primary analysis, 464 patients underwent follow-up fundus fluorescein angiography and 120 developed neovascular age-related macular degeneration on fundus fluorescein angiography. The diagnostic accuracy [sensitivity (%) (95% confidence interval); specificity (%) (95% confidence interval)] was as follows: optical coherence tomography 91.7 (85.2 to 95.6); 87.8 (83.8 to 90.9)], fundus clinical examination [53.8 (44.8 to 62.5); 97.6 (95.3 to 98.9)], Amsler [33.7 (25.1 to 43.5); 81.4 (76.4 to 85.5)], visual acuity [30.0 (22.5 to 38.7); 66.3 (61.0 to 71.1)] and self-reported vision [4.2 (1.6 to 9.8); 97.0 (94.6 to 98.5)]. Optical coherence tomography had the highest sensitivity across all secondary analyses. The final prediction model for neovascular age-related macular degeneration in the non-affected eye included smoking status, family history of neovascular age-related macular degeneration, the presence of nodular drusen with or without reticular pseudodrusen, and the presence of pigmentary abnormalities [c-statistic 0.66 (95% confidence interval 0.62 to 0.71)]. Optical coherence tomography monitoring generated the greatest quality-adjusted life-years gained per patient (optical coherence tomography, 5.830; fundus clinical examination, 5.787; Amsler chart, 5.736, self-reported vision, 5.630; and visual acuity, 5.600) for the lowest health-care and social care costs (optical coherence tomography, £19,406; fundus clinical examination, £19,649; Amsler chart, £19,751; self-reported vision, £20,198; and visual acuity, £20,444) over the lifetime of the simulated cohort. Optical coherence tomography dominated the other tests or had an incremental cost-effectiveness ratio below the accepted cost-effectiveness thresholds (£20,000) across the scenarios explored. Limitations: The diagnostic performance may be different in an unselected population without any history of neovascular age-related macular degeneration; the prediction model did not include genetic profile data, which might have improved the discriminatory performance. Conclusions: Optical coherence tomography was the most accurate in diagnosing conversion to neovascular age-related macular degeneration in the fellow eye of patients with unilateral neovascular age-related macular degeneration. Economic modelling suggests that optical coherence tomography monitoring is cost-effective and leads to earlier diagnosis of and treatment for neovascular age-related macular degeneration in the second eye of patients being treated for neovascular age-related macular degeneration in their first eye. Future work: Future works should investigate the role of home monitoring, improved risk prediction models and impact on long-term visual outcomes. Study registration: This study was registered as ISRCTN48855678. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 8. See the NIHR Journals Library website for further project information.

Diabetic Retinopathy (DR) is a leading cause of preventable visual impairment in the working age population. Despite the increasing prevalence of DR, there remain gaps in our understanding of its pathophysiology. This is a prospective case-control study comparing the genetic profiles of patients with no DR vs. non-proliferative DR (NPDR) focusing on intraretinal microvascular abnormalities (IRMA) and venous beading (VB) in Caucasians. A total of 596 participants were recruited to the study; 199 with moderate/severe NPDR and 397 with diabetes for at least 5 years without DR. Sixty-four patients were excluded due to technical issues. In total, 532 were analysed; 181 and 351 were in the NPDR group and no DR group, respectively. Those with severe IRMA and VB had distinctly different genetic profiles from each other and from the no DR group, which further supports the theory that these two features of DR might have different etiologies. This also suggests that IRMA and VB are independent risk factors for the development of PDR and may have different pathophysiologies. If these findings are confirmed in larger studies, this could pave the way for personalised treatment options for those more at risk of developing different features of NPDR.

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.

Purpose: This study aims to explore the correlations of arteriosclerosis-associated plasma indices with various severity levels of diabetic retinopathy (DR) and to test the hypothesis that elevated circulating level of known angiogenic cytokines induced by hyperglycemia is associated with dyslipidemia on DR.Methods: This cross-sectional study consists of 131 patients with type 2 diabetes. The patients were categorized based on their DR status into those with no DR (diabetes mellitus, DM), non-proliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR) groups. The biochemical profile including fasting glucose, glycated hemoglobin (HbA1c), lipid profile were estimated, plasma angiogenic cytokines (vascular endothelial growth factor, VEGF-A, -C, -D) and placental growth factor (PlGF) were analyzed by protein microarrays. The atherogenic plasma index (API) was defined as low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C); atherogenic index (AI) was calculated as (TC-(HDL-C))/HDL-C and atherogenic index of plasma (AIP) was defined as log (TG/HDL-C).Results: No significant differences were detected in the duration of hypertension, age, and gender between the three groups. Serum TC and LDL-C, AI, and API in the NPDR group and PDR group were significantly higher than those in the DM group. The circulating level of PlGF, VEGF-A, and VEGF-C were significantly correlated with the severity of DR. VEGF-D is a risk factor independent of API (Z = −2.61, P = 0.009) and AI (Z = −2.40, P = 0.016). Multivariate logistic regression showed that AI and API are strong risk factors for the occurrence and severity of DR. Associated with AI and API, VEGF-D and PlGF contribute to DR: VEGF-D [AI: P = 0.038, odd ratio (OR) = 1.38; VEGF-D: P = 0.002, OR = 1.00. API: P = 0.027, OR = 1.56, VEGF-D:P = 0.002, OR = 1.00] and PlGF [AI: P = 0.021, OR = 1.43; VEGF-D: P = 0.004, OR = 1.50. API: P = 0.011, OR = 1.66; VEGF-D: P = 0.005, OR = 1.49].Conclusions: Total cholesterol (TC) and LDL-C are risk factors for presence of any DR. Atherogenic index and API are novel and better predictive indicators for the occurrence and severity of DR in comparion with the traditional lipid profiles. Abnormal lipid metabolism are associated with the upregulation of circulating cytokines that are linked to the severity of DR.

Objective There is contrasting evidence on the relationship between socioeconomic status (SES) and age-related macular degeneration (AMD), the most common cause of visual impairment (VI) in developed countries. This study examines the relationship between SES, cardiovascular risk factors and self-reported AMD.Methods and analysis Over 500000 people participated in the UK Biobank study from 2006 to 2019, with sociodemographic data and clinical measurements collected using standardised procedures. Visual acuity was measured in 117907 participants with VI defined as LogMAR ≤0.3. We used logistic regression to examine the cross-sectional associations between SES and self-reported AMD.Results Self-reported AMD was available for 133339 participants aged 50 and older. People reporting AMD had higher academic qualifications, lower income, were unable to work due to disability, have higher BMI, diabetes and vascular heart disease after adjusting for age and sex. In a multivariable analysis, higher income was protective of AMD and economic inactivity due to disability increased the odds of AMD (2.02, 95% CI 1.13 to 3.61). Both associations were independent of cardiovascular factors, but was no longer significant after adjusting for VI.Conclusions The association between education, employment and household income with AMD was independent of cardiovascular risk factors.

Abstract Background In the UK, macular laser is the treatment of choice for people with diabetic macular oedema with central retinal subfield thickness (CST)

Abstract Introduction The specific impact from the patient’s perspective of geographic atrophy (GA), an advanced form of age-related macular degeneration (AMD), is not well understood. Methods An ethnographic study was conducted to understand the impact of bilateral GA secondary to AMD on daily functioning by observing regular activities performed at home and through semi-structured interviews. Eligible subjects had a definitive GA diagnosis, including presence of drusen, GA lesion size of at least one disc area in the better-seeing eye, and no other confounding ophthalmologic diagnosis. Data were collected via video recordings and field notes, and analyzed by coding video transcripts. Results Functional impact domains affecting more than two of the 16 subjects from the United Kingdom, United States, or Germany were activities of daily living (difficulty reading, n = 16; driving, n = 12; and watching movies, television, or theater, n = 11), emotional (frustration, and fear of blindness, n = 7 each), social/leisure (interference with hobbies, n = 8, and diminished social activities, n = 4), physical (n = 4), and financial (n = 10). Subjects with a best-corrected visual acuity (BCVA) of 20/100 or better in the better-seeing eye (n = 10) reported similar functional impacts to those with a BCVA of worse than 20/100 in their better-seeing eye (n = 5). Conclusion This study helps address gaps in patient-focused research into GA, which negatively impacts the day-to-day functioning of patients. Larger qualitative and quantitative studies are needed to quantify patient experiences and assess the correlation between BCVA score and impact of GA. Funding F. Hoffmann-La Roche Ltd.

Background: Licensed ranibizumab (0.5 mg/0.05 ml Lucentis®; Novartis International AG, Basel, Switzerland) and aflibercept (2 mg/0.05 ml Eylea®; Bayer AG, Leverkusen, Germany) and unlicensed bevacizumab (1.25 mg/0.05 ml Avastin®; F. Hoffmann-La Roche AG, Basel, Switzerland) are used to treat macula oedema due to central retinal vein occlusion, but their relative clinical effectiveness, cost-effectiveness and impact on the UK NHS and Personal Social Services have never been directly compared over the typical disease treatment period. Objective: The objective was to compare the clinical effectiveness and cost-effectiveness of three intravitreal antivascular endothelial growth factor agents for the management of macula oedema due to central retinal vein occlusion. Design: This was a three-arm, double-masked, randomised controlled non-inferiority trial. Setting: The trial was set in 44 UK NHS ophthalmology departments, between 2014 and 2018. Participants: A total of 463 patients with visual impairment due to macula oedema secondary to central retinal vein occlusion were included in the trial. Interventions: The participants were treated with repeated intravitreal injections of ranibizumab (n = 155), aflibercept (n = 154) or bevacizumab (n = 154). Main outcome measures: The primary outcome was an increase in the best corrected visual acuity letter score from baseline to 100 weeks in the trial eye. The null hypothesis that aflibercept and bevacizumab are each inferior to ranibizumab was tested with a non-inferiority margin of –5 visual acuity letters over 100 weeks. Secondary outcomes included additional visual acuity, and imaging outcomes, Visual Function Questionnaire-25, EuroQol-5 Dimensions with and without a vision bolt-on, and drug side effects. Cost-effectiveness was estimated using treatment costs and Visual Function Questionnaire-Utility Index to measure quality-adjusted life-years. Results: The adjusted mean changes at 100 weeks in the best corrected visual acuity letter scores were as follows – ranibizumab, 12.5 letters (standard deviation 21.1 letters); aflibercept, 15.1 letters (standard deviation 18.7 letters); and bevacizumab, 9.8 letters (standard deviation 21.4 letters). Aflibercept was non-inferior to ranibizumab in the intention-to-treat population (adjusted mean best corrected visual acuity difference 2.23 letters, 95% confidence interval –2.17 to 6.63 letters; p = 0.0006), but not superior. The study was unable to demonstrate that bevacizumab was non-inferior to ranibizumab in the intention-to-treat population (adjusted mean best corrected visual acuity difference –1.73 letters, 95% confidence interval –6.12 to 2.67 letters; p = 0.071). A post hoc analysis was unable to demonstrate that bevacizumab was non-inferior to aflibercept in the intention-to-treat population (adjusted mean best corrected visual acuity difference was –3.96 letters, 95% confidence interval –8.34 to 0.42 letters; p = 0.32). All per-protocol population results were the same. Fewer injections were required with aflibercept (10.0) than with ranibizumab (11.8) (difference in means –1.8, 95% confidence interval –2.9 to –0.8). A post hoc analysis showed that more bevacizumab than aflibercept injections were required (difference in means 1.6, 95% confidence interval 0.5 to 2.7). There were no new safety concerns. The model- and trial-based cost-effectiveness analyses estimated that bevacizumab was the most cost-effective treatment at a threshold of £20,000–30,000 per quality-adjusted life-year. Limitations: The comparison of aflibercept and bevacizumab was a post hoc analysis. Conclusion: The study showed aflibercept to be non-inferior to ranibizumab. However, the possibility that bevacizumab is worse than ranibizumab and aflibercept by 5 visual acuity letters cannot be ruled out. Bevacizumab is an economically attractive treatment alternative and would lead to substantial cost savings to the NHS and other health-care systems. However, uncertainty about its relative effectiveness should be discussed comprehensively with patients, their representatives and funders before treatment is considered. Future work: To obtain extensive patient feedback and discuss with all stakeholders future bevacizumab NHS use. Trial registration: Current Controlled Trials ISRCTN13623634. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 38. See the NIHR Journals Library website for further project information.

Introduction Using a type 2 hybrid effectiveness-implementation design, we aim to pilot a diabetic retinopathy (DR) care pathway in the public health system in Kerala to understand how it can be scaled up to and sustained in the whole state.Methods and analysis Currently, there is no systematic DR screening programme in Kerala. Our intervention is a teleophthalmology pathway for people with diabetes in the non-communicable disease registers in 16 family health centres. The planned implementation strategy of the pathway will be developed based on the discrete Expert Recommendations for Implementing Change taxonomy. We will use both quantitative data from a cross-sectional study and qualitative data obtained from structured interviews, surveys and group discussions with stakeholders to report the effectiveness of the DR care pathway and evaluation of the implementation strategy.We will use logistic regression models to assess crude associations DR and sight-threatening diabetic retinopathy and fractional polynomials to account for the form of continuous covariates to predict uptake of DR screening. The primary effectiveness outcome is the proportion of patients in the non-communicable disease register with diabetes screened for DR over 12 months. Other outcomes include cost-effectiveness, safety, efficiency, patient satisfaction, timeliness and equity. The outcomes of evaluation of the implementation strategies include acceptability, feasibility, adoption, appropriateness, fidelity, penetration, costs and sustainability. Addition of more family health centres during the staggered initial phase of the programme will be considered as a sign of acceptability and feasibility. In the long term, the state-wide adoption of the DR care pathway will be considered as a successful outcome of the Nayanamritham study.Ethics and dissemination The study was approved by Indian Medical Research Council (2018-0551) dated 13 March 2019. Study findings will be disseminated through scientific publications and the report will inform adoption of the DR care pathway by Kerala state in future.Trial registration number ISRCTN28942696.

Diseases of the retina are major causes of visual impairment and blindness in developed countries and, due to an ageing population, their prevalence is continually rising. The lack of effective therapies and the limitations of those currently in use highlight the importance of continued research into the pathogenesis of these diseases. Vascular endothelial growth factor (VEGF) plays a major role in driving vascular dysfunction in retinal disease and has therefore become a key therapeutic target. Recent evidence also points to a potentially similarly important role of galectins, a family of β-galactoside-binding proteins. Indeed, they have been implicated in regulating fundamental processes, including vascular hyperpermeability, angiogenesis, neuroinflammation, and oxidative stress, all of which also play a prominent role in retinopathies. Here, we review direct evidence for pathological roles of galectins in retinal disease. In addition, we extrapolate potential roles of galectins in the retina from evidence in cancer, immune and neuro-biology. We conclude that there is value in increasing understanding of galectin function in retinal biology, in particular in the context of the retinal vasculature and microglia. With greater insight, recent clinical developments of galectin-targeting drugs could potentially also be of benefit to the clinical management of many blinding diseases.

Background: Owing to the increasing prevalence of diabetes, the workload related to diabetic macular oedema and proliferative diabetic retinopathy is rising, making it difficult for hospital eye services to meet demands. Objective: The objective was to evaluate the diagnostic performance, cost-effectiveness and acceptability of a new pathway using multimodal imaging interpreted by ophthalmic graders to detect reactivation of diabetic macular oedema/proliferative diabetic retinopathy in previously treated patients. Design: This was a prospective, case-referent, cross-sectional diagnostic study. Setting: The setting was ophthalmic clinics in 13 NHS hospitals. Participants: Adults with type 1 or type 2 diabetes with previously successfully treated diabetic macular oedema/proliferative diabetic retinopathy in one/both eyes in whom, at the time of enrolment, diabetic macular oedema/proliferative diabetic retinopathy could be active or inactive. Methods: For the ophthalmic grader pathway, review of the spectral domain optical coherence tomography scans to detect diabetic macular oedema, and seven-field Early Treatment Diabetic Retinopathy Study/ultra-wide field fundus images to detect proliferative diabetic retinopathy, by trained ophthalmic graders. For the current standard care pathway (reference standard), ophthalmologists examined patients face to face by slit-lamp biomicroscopy for proliferative diabetic retinopathy and, in addition, spectral domain optical coherence tomography imaging for diabetic macular oedema. Outcome measures: The primary outcome measure was sensitivity of the ophthalmic grader pathway to detect active diabetic macular oedema/proliferative diabetic retinopathy. The secondary outcomes were specificity, agreement between pathways, cost–consequences, acceptability and the proportion of patients requiring subsequent ophthalmologist assessment, unable to undergo imaging and with inadequate quality images/indeterminate findings. It was assumed for the main analysis that all patients in whom graders diagnosed active disease or were ‘unsure’ or images were ‘ungradable’ required examination by an ophthalmologist. Results: Eligible participants with active and inactive diabetic macular oedema (152 and 120 participants, respectively) and active and inactive proliferative diabetic retinopathy (111 and 170 participants, respectively) were recruited. Under the main analysis, graders had a sensitivity of 97% (142/147) (95% confidence interval 92% to 99%) and specificity of 31% (35/113) (95% confidence interval 23% to 40%) to detect diabetic macular oedema. For proliferative diabetic retinopathy, graders had a similar sensitivity and specificity using seven-field Early Treatment Diabetic Retinopathy Study [sensitivity 85% (87/102), 95% confidence interval 77% to 91%; specificity 48% (77/160), 95% confidence interval 41% to 56%] or ultra-wide field imaging [sensitivity 83% (87/105), 95% confidence interval 75% to 89%; specificity 54% (86/160), 95% confidence interval 46% to 61%]. Participants attending focus groups expressed preference for face-to-face evaluations by ophthalmologists. In the ophthalmologists’ absence, patients voiced the need for immediate feedback following grader’s assessments, maintaining periodic evaluations by ophthalmologists. Graders and ophthalmologists were supportive of the new pathway. When compared with the reference standard (current standard pathway), the new grader pathway could save £1390 per 100 patients in the review of people with diabetic macular oedema and, depending on the imaging modality used, between £461 and £1189 per 100 patients in the review of people with proliferative diabetic retinopathy. Conclusions: For people with diabetic macular oedema, the ophthalmic grader pathway appears safe and cost saving. The sensitivity of the new pathway to detect active proliferative diabetic retinopathy was lower, but may still be considered acceptable for patients with proliferative diabetic retinopathy previously treated with laser. Suggestions from focus group discussions should be taken into consideration if the new pathway is introduced to ensure its acceptability to users. Limitations: Lack of fundus fluorescein angiography to confirm diagnosis of active proliferative diabetic retinopathy. Future work: Could refinement of the new pathway increase its sensitivity to detect proliferative diabetic retinopathy? Could artificial intelligence be used for automated reading of images in this previously treated population? Trial registration: Current Controlled Trials ISRCTN10856638 and ClinicalTrials.gov NCT03490318. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment Vol. 25, No. 32. See the NIHR Journals Library website for further project information.