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Purpose: Serum lipids are modifiable, routinely collected blood test features associated with cardiovascular health. We examined the association of commonly collected serum lipid measures (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and triglycerides) with intraocular pressure (IOP). Design: Cross-sectional study in the UK Biobank and European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohorts. Participants: We included 94 323 participants from the UK Biobank (mean age, 57 years) and 6230 participants from the EPIC-Norfolk (mean age, 68 years) cohorts with data on TC, HDL-C, LDL-C, and triglycerides collected between 2006 and 2009. Methods: Multivariate linear regression adjusting for demographic, lifestyle, anthropometric, medical, and ophthalmic covariables was used to examine the associations of serum lipids with corneal-compensated IOP (IOPcc). Main Outcome Measures: Corneal-compensated IOP. Results: Higher levels of TC, HDL-C, and LDL-C were associated independently with higher IOPcc in both cohorts after adjustment for key demographic, medical, and lifestyle factors. For each 1-standard deviation increase in TC, HDL-C, and LDL-C, IOPcc was higher by 0.09 mmHg (95% confidence interval [CI], 0.06–0.11 mmHg; P < 0.001), 0.11 mmHg (95% CI, 0.08–0.13 mmHg; P < 0.001), and 0.07 mmHg (95% CI, 0.05–0.09 mmHg; P < 0.001), respectively, in the UK Biobank cohort. In the EPIC-Norfolk cohort, each 1-standard deviation increase in TC, HDL-C, and LDL-C was associated with a higher IOPcc by 0.19 mmHg (95% CI, 0.07–0.31 mmHg; P = 0.001), 0.14 mmHg (95% CI, 0.03–0.25 mmHg; P = 0.016), and 0.17 mmHg (95% CI, 0.06–0.29 mmHg; P = 0.003). An inverse association between triglyceride levels and IOP in the UK Biobank (–0.05 mmHg; 95% CI, –0.08 to –0.03; P < 0.001) was not replicated in the EPIC-Norfolk cohort (P = 0.30). Conclusions: Our findings suggest that serum TC, HDL-C, and LDL-C are associated positively with IOP in 2 United Kingdom cohorts and that triglyceride levels may be associated negatively. Future research is required to assess whether these associations are causal in nature.

Background Currently, no generally approved medical treatment can delay the onset of age-related macular degeneration (AMD) or slow the progression of degenerative changes. Repurposing drugs with beneficial effects on AMD pathophysiology offers a route to new treatments which is faster, cost-effective, and safer for patients. Recent studies indicate a potential role for metformin in delaying AMD development and progression. In this context, we conducted a systematic review and meta-analysis to look for beneficial associations between metformin and AMD. Methods We systematically searched Medline and Embase (via Ovid), Web of Science, and ClinicalTrials.gov databases for clinical studies in humans that examined the associations between metformin treatment and AMD published from inception to February 2021. We calculated pooled odds ratio (OR) with 95% confidence interval (CI) considering a random effect model in the meta-analysis. Results Five retrospective studies met the inclusion criteria. There are no prospective studies that have reported the effect of metformin in AMD. The meta-analysis showed that people taking metformin were less likely to have AMD although statistical significance was not met (pooled adjusted OR = 0.80, 95% CI 0.54–1.05, I2 = 98.8%). Subgroup analysis of the association between metformin and early and late AMD could not be performed since the data was not available from the included studies. Conclusions Analysis of retrospective data suggests a signal that metformin may be associated with decreased risk of any AMD. It should be interpreted with caution because of the failure to meet statistical significance, the small number of studies, and the limitation of routine record data. However prospective studies are warranted in generalizable populations without diabetes, of varied ethnicities, and AMD stages. Clinical trials are needed to determine if metformin has efficacy in treating early and late-stage AMD. Supplementary Information The online version contains supplementary material available at 10.1007/s40123-021-00344-3.

Purpose To describe and compare associations with macular retinal nerve fiber layer (mRNFL), ganglion cell complex (GCC), and ganglion cell–inner plexiform layer (GCIPL) thicknesses in a large cohort. Design Cross-sectional study. Participants We included 42 044 participants in the UK Biobank. The mean age was 56 years. Methods Spectral-domain OCT macular images were segmented and analyzed. Corneal-compensated intraocular pressure (IOPcc) was measured with the Ocular Response Analyzer (Reichert, Corp., Buffalo, NY). Multivariable linear regression was used to examine associations with mean mRNFL, GCC, and GCIPL thicknesses. Factors examined were age, sex, ethnicity, height, body mass index (BMI), smoking status, alcohol intake, Townsend deprivation index, education level, diabetes status, spherical equivalent, and IOPcc. Main Outcome Measures Thicknesses of mRNFL, GCC, and GCIPL. Results We identified several novel independent associations with thinner inner retinal thickness. Thinner inner retina was associated with alcohol intake (most significant for GCIPL: –0.46 μm for daily or almost daily intake compared with special occasion only or never [95% confidence interval (CI), 0.61–0.30]; P = 1.1×10–8), greater social deprivation (most significant for GCIPL: –0.28 μm for most deprived quartile compared with least deprived quartile [95% CI, –0.42 to –0.14]; P = 6.6×10–5), lower educational attainment (most significant for mRNFL: –0.36 μm for less than O level compared with degree level [95% CI, –0.45 to 0.26]; P = 2.3×10–14), and nonwhite ethnicity (most significant for mRNFL comparing blacks with whites: –1.65 μm [95% CI, –1.86 to –1.43]; P = 2.4×10–50). Corneal-compensated intraocular pressure was associated most significantly with GCIPL (–0.04 μm/mmHg [95% CI, –0.05 to –0.03]; P = 4.0×10–10) and was not associated significantly with mRNFL (0.00 μm/mmHg [95% CI, –0.01 to 0.01]; P = 0.77). The variables examined explained a greater proportion of the variance of GCIPL (11%) than GCC (6%) or mRNFL (7%). Conclusions The novel associations we identified may be important to consider when using inner retinal parameters as a diagnostic tool. Associations generally were strongest with GCIPL, particularly for IOP. This suggests that GCIPL may be the superior inner retinal biomarker for macular pathophysiologic processes and especially for glaucoma.

Background Falls are the second leading cause of accidental deaths worldwide mainly in older people. Older people have poor vision and published evidence suggests that it is a risk factor for falls. Less than half of falls clinics assess vision as part of the multi-factorial assessment of older adults at risk of falls despite vision being an essential input for postural stability. The aim of our study was to investigate the relationship between all clinically assessed visual functions and falls amongst older adults in a prospective observational individually age-matched case control study. Methods Visual acuity (VA), contrast sensitivity (CS), depth perception, binocular vision and binocular visual field were measured using routinely used clinical methods in falls participants (N = 83) and non-falls participants (N = 83). Data were also collected on socio-demographic factors, general health, number of medications, health quality, fear of falling and physical activity. Logistic regression analysis was carried out to determine key visual and non-visual risk factors for falls whilst adjusting for confounding covariates. Results Older adults have an increased risk of experiencing a fall if they have reduced visual function (odds ratio (OR): 3.49, 1.64-7.45, p = 0.001), specifically impaired stereoacuity worse than 85” of arc (OR: 3.4, 1.20-9.69, p = 0.02) and reduced (by 0.15 log unit) high spatial frequency CS (18 cpd) (OR:1.40, 1.12-1.80, p = 0.003). Older adults with a hearing impairment are also at higher risk of falls (OR: 3.18, 95% CI: 1.36-7.40, p = 0.007). The risk decreases with living in a less deprived area (OR: 0.74, 0.64-0.86, Conclusions The combination of social, behavioural and biological determinants are significant predictors of a fall. The non-visual risk factors include older adults, living in deprived neighbourhoods, socialising less outside of the home and those who have a hearing impairment. Impaired functional visual measures; depth perception and contrast are significant visual risk factors for falls above visual acuity.

To systematically review the epidemiology of early worsening of diabetic retinopathy (EWDR) after substantial improvements in glycaemic control and evaluate characteristics including risk factors. This systematic review was registered with PROSPERO (CRD42020158252). An electronic literature search was performed according to PRISMA guidelines using MEDLINE, EMBASE, PubMed, Web of Science, Scopus and Cochrane databases and manual reference for the articles published until 2020. Published full-text English language articles that report data on diabetic retinopathy in people with diabetes experiencing a rapid, substantial decrease in HbA1c after going through intensive therapy were included. All articles were screened, data were extracted and methodological quality was evaluated by two independent reviewers using a priori criteria. A total of 346 articles were identified after the removal of duplicates. Data were extracted from 19 full-text articles with a total of 15,588 participants. Included studies varied considerably in terms of patient selection, timing and method of assessing the eye and retinopathy classification. EWDR was reported to occur in a wide range of prevalences; 3.3-47% of participants within 3-84 months after intensification of glycaemic control. Risk factors for EWDR included long duration of diabetes, long-term uncontrolled hyperglycemia, amplitude of and baseline retinopathy severity in both type 1 and type 2 diabetes. The occurrence of EWDR and progression of retinopathy were found to have an association with the amplitude of HbA1c reduction. EWDR has been described in a proportion of people with intensification of glycaemic control. However, the prevalence remains unclear because of methodological differences in the identified studies. Future interventional studies should report retinopathy and visual outcomes using standardized protocols.

PurposeWe aimed to investigate structural retinal changes in malarial retinopathy (MR) using hand-held optical coherence tomography (HH-OCT) to investigate its diagnostic potential.MethodsChildren with MR (n=43) underwent ophthalmoscopy, fluorescein angiography and HH-OCT during admission, one month (n=31) and one year (n=8) post-discharge. Controls were comatose patients without malaria (n=6) and age/sex-matched healthy children (n=43). OCT changes and retinal layer thicknesses were compared.ResultsOn HH-OCT, hyper-reflective areas (HRAs) were seen in the inner retina of 81% of MR patients, corresponding to ischaemic retinal whiteningon fundus photography. Cotton wool spots were present in 37% and abnormal hyper-reflective dots, co-localized to capillary plexus, in 93%. Hyper-reflective vessel walls were present in 84%, and intra-retinal cysts in 9%. Vascular changes and cysts resolved within 48 hours. HRAs developed into retinal thinning at one month (p=0.027) whichwas more pronounced after one year (p=0.009).ConclusionsIschaemic retinal whitening is located within inner retinal layers, distinguishing it from cotton wool spots. Vascular hyper-reflectivity may represent the sequestration of parasitized erythrocytes in vessels, a key CM feature. The mechanisms of post-ischemic retinal atrophy and cerebral atrophy with cognitive impairment may be similar in CM survivors. HH-OCT has potential for monitoring patients, treatment response and predicting neurological deficits.

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.

Objective Cerebral malaria (CM) is a complication of Plasmodium falciparum malaria, in which progressive brain swelling is associated with sequestration of parasites and impaired barrier function of the cerebral microvascular endothelium. To test the hypothesis that localised release of matrix metallopeptidase 8 (MMP8) within the retina is implicated in microvascular leak in CM, we examined its expression and association with extravascular fibrinogen leak in a case–control study of post‐mortem retinal samples from 13 Malawian children who met the clinical case definition of CM during life. Cases were seven children who were found on post‐mortem examination to have ‘true‐CM’ (parasite sequestration in brain blood vessels), whilst controls were six children who had alternative causes of death (‘faux‐CM’, no parasite sequestration in blood vessels). Methods We used immunofluorescence microscopy and independent scoring, by two assessors blinded to the CM status, to assess MMP8 expression, extravascular fibrinogen as an indicator of vascular leak and their co‐localisation in the retinal microvasculature. Results In ‘true‐CM’ subjects, MMP8 staining was invariably associated with sequestered parasites and a median of 88% (IQR = 74–91%) of capillaries showed MMP8 staining, compared with 14% (IQR = 3.8–24%) in ‘faux‐CM’ (P‐value = 0.001). 41% (IQR = 28–49%) of capillaries in ‘true‐CM’ subjects showed co‐localisation of extravascular fibrinogen leak and MMP8 staining, compared with 1.8% of capillaries in ‘faux‐CM’ (IQR = 0–3.9%, P‐value = 0.01). Vascular leak was rare in the absence of MMP8 staining. Conclusion Matrix metallopeptidase 8 was extensively expressed in retinal capillaries of Malawian children with malarial retinopathy and strongly associated with vascular leak. Our findings implicate MMP8 as a cause of the vascular endothelial barrier disruption in CM, which may precipitate fatal brain swelling., To test the hypothesis that localised release of matrix metallopeptidase 8 (MMP8) within the retina is implicated in microvascular leak in cerebral malaria (CM), we examined its expression and association with extravascular fibrinogen leak in a case‐control study of post‐mortem retinal samples from 13 Malawian children. MMP8 was extensively expressed in retinal capillaries of children with CM retinopathy and strongly associated with vascular leak. Our findings implicate MMP8 in the vascular endothelial barrier disruption in CM, which may precipitate fatal brain swelling.

ObjectiveTo develop a prognostic tool to predict the progression of age-related eye disease progression using longitudinal colour fundus imaging.Methods and analysisPrevious prognostic models using deep learning with imaging data require annotation during training or only use a single time point. We propose a novel deep learning method to predict the progression of diseases using longitudinal imaging data with uneven time intervals, which requires no prior feature extraction. Given previous images from a patient, our method aims to predict whether the patient will progress onto the next stage of the disease. The proposed method uses InceptionV3 to produce feature vectors for each image. In order to account for uneven intervals, a novel interval scaling is proposed. Finally, a recurrent neural network is used to prognosticate the disease. We demonstrate our method on a longitudinal dataset of colour fundus images from 4903 eyes with age-related macular degeneration (AMD), taken from the Age-Related Eye Disease Study, to predict progression to late AMD.ResultsOur method attains a testing sensitivity of 0.878, a specificity of 0.887 and an area under the receiver operating characteristic of 0.950. We compare our method to previous methods, displaying superior performance in our model. Class activation maps display how the network reaches the final decision.ConclusionThe proposed method can be used to predict progression to advanced AMD at some future visit. Using multiple images at different time points improves predictive performance.

Background In cerebral malaria, the retina can be used to understand disease pathogenesis. The mechanisms linking sequestration, brain swelling, and death remain poorly understood. We hypothesized that retinal vascular leakage would be associated with brain swelling. Methods We used retinal angiography to study blood-retinal barrier integrity. We analyzed retinal leakage, histopathology, brain magnatic resonance imaging (MRI), and associations with death and neurological disability in prospective cohorts of Malawian children with cerebral malaria. Results Three types of retinal leakage were seen: large focal leak (LFL), punctate leak (PL), and vessel leak. The LFL and PL were associated with death (odds ratio [OR] = 13.20, 95% confidence interval [CI] = 5.21–33.78 and OR = 8.58, 95% CI = 2.56–29.08, respectively) and brain swelling (P Conclusions Blood-retina barrier breakdown occurs in 3 patterns in cerebral malaria. Associations between LFL, brain swelling, and death suggest that the rapid accumulation of cerebral hemorrhages, with accompanying fluid egress, may cause fatal brain swelling. Vessel leak, from barrier dysfunction, and nonperfusion were not associated with severe brain swelling but with neurological deficits, suggesting hypoxic injury in survivors.

Optical Coherence Tomography (OCT) is commonly used to visualise tissue composition of the retina. Previously, deep learning has been used to analyse OCT images to automatically classify scans by the disease they display, however classification often requires downsampling to much lower dimensions. Downsampling often loses important features that may contain useful information. In this paper, a method is proposed which incorporates DAISY descriptors as ‘intelligent downsampling’. By avoiding random downsampling, we are able to keep more of the useful information to achieve more accurate results. The proposed method is tested on a publicly available dataset of OCT images, from patients with diabetic macula edema, drusen, and choroidal neovascularisation, as well as healthy patients. The method achieves an accuracy of 76.6% and an AUC of 0.935, this is an improvement to a previously used method which uses InceptionV3 with an accuracy of 67.8% and AUC of 0.912. This shows that DAISY descriptors do provide good representations of the image and can be used as an alternative to downsampling.

Cerebral Malaria (CM) as one of the most common and severe diseases in sub-Saharan Africa, claimed the lives of more than 435,000 people each year. Because Malarial Retinopathy (MR) is as one of the best clinical diagnostic indicators of CM, it may be essential to analysing MR in fundus images for assisting the CM diagnosis as an applicable solution in developing countries. Image segmentation is an essential topic in medical imaging analysis and is widely developed and improved for clinic study. In this paper, we aim to develop an automatic and fast approach to detect/segment MR haemorrhages in colour fundus images. We introduce a deep learning-based haemorrhages detection of MR inspired by Dense-Net based network called one-hundred-layers tiramisu for the segmentation tasks. We evaluate our approach on one MR dataset of 259 annotated colour fundus images. For keeping the originality of raw MR colour fundus images, 6,098 sub-images are extracted and split into a training set (70%), a validation set (10%) and a testing set (20%). After implementation, our experimental results testing on 1,669 annotated sub-images, show that the proposed method outperforms commonly mainstream network architecture U-Net.

For the diagnosis and monitoring of retinal diseases, the spatial context of retinal thickness is highly relevant but often under-utilised. Despite the data being spatially collected, current approaches are not spatial: they involve analysing each location separately, or they analyse all image sectors together but they ignore the possible spatial correlations such as linear models, and multivariate analysis of variance (MANOVA). We propose spatial statistical inference framework for retinal images, which is based on a linear mixed effect model and which models the spatial topography via fixed effect and spatial error structures. We compare our method with MANOVA in analysis of spatial retinal thickness data from a prospective observational study, the Early Detection of Diabetic Macular Oedema (EDDMO) study involving 89 eyes with maculopathy and 168 eyes without maculopathy from 149 diabetic participants. Heidelberg Optical Coherence Tomography (OCT) is used to measure retinal thickness. MANOVA analysis suggests that the overall retinal thickness of eyes with maculopathy are not significantly different from the eyes with no maculopathy (p = 0.11), while our spatial framework can detect the difference between the two disease groups (p = 0.02). We also evaluated our spatial statistical model framework on simulated data whereby we illustrate how spatial correlations can affect the inferences about fixed effects. Our model addresses the need of correct adjustment for spatial correlations in ophthalmic images and to improve the precision of association in clinical studies. This model can be potentially extended into disease monitoring and prognosis in other diseases or imaging technologies.

Neutrophils are essential innate immune cells that extrude chromatin in the form of neutrophil extracellular traps (NETs) when they die. This form of cell death has potent immunostimulatory activity. We show that heme-induced NETs are essential for malaria pathogenesis. Using patient samples and a mouse model, we define two mechanisms of NET-mediated inflammation of the vasculature: activation of emergency granulopoiesis via granulocyte colony-stimulating factor production and induction of the endothelial cytoadhesion receptor intercellular adhesion molecule-1. Soluble NET components facilitate parasite sequestration and mediate tissue destruction. We demonstrate that neutrophils have a key role in malaria immunopathology and propose inhibition of NETs as a treatment strategy in vascular infections.

BackgroundIn chronic central serous chorioretinopathy (CSCR), fluid accumulates in the subretinal space. CSCR is a common visually disabling condition that develops in individuals up to 60 years of age, and there is no definitive treatment. Previous research suggests the mineralocorticoid receptor antagonist, eplerenone, is effective for treating CSCR; however, this drug is not licensed for the treatment of patients with CSCR. We aimed to evaluate whether eplerenone was superior to placebo in terms of improving visual acuity in patients with chronic CSCR.MethodsThis randomised, double-blind, parallel-group, multicentre placebo-controlled trial was done at 22 hospitals in the UK. Participants were eligible if they were aged 18–60 years and had had treatment-naive CSCR for 4 months or more. Patients were randomly assigned (1:1) to either the eplerenone or the placebo group by a trial statistician through a password-protected system online. Allocation was stratified by best-corrected visual acuity (BCVA) and hospital. Patients were given either oral eplerenone (25 mg/day for 1 week, increasing to 50 mg/day for up to 12 months) plus usual care or placebo plus usual care for up to 12 months. All participants, care teams, outcome assessors, pharmacists, and members of the trial management group were masked to the treatment allocation. The primary outcome was BCVA, measured as letters read, at 12 months. All outcomes apart from safety were analysed on a modified intention-to-treat basis (participants who withdrew consent without contributing a post-randomisation BCVA measurement were excluded from the primary analysis population and from most secondary analysis populations). The trial is registered with ISRCTN, ISRCTN92746680, and is completed.FindingsBetween Jan 11, 2017, and Feb 22, 2018, we enrolled and randomly assigned 114 patients to receive either eplerenone (n=57) or placebo (n=57). Three participants in the placebo group withdrew consent without contributing a post-randomisation BCVA measurement and were excluded from the primary outcome analysis population. All patients from the eplerenone group and 54 patients from the placebo group were included in the primary outcome. Modelled mean BCVA at 12 months was 79·5 letters (SD 4·5) in the placebo group and 80·4 letters (4·6) in the eplerenone group, with an adjusted estimated mean difference of 1·73 letters (95% CI −1·12 to 4·57; p=0·24) at 12 months. Hyperkalaemia occurred in eight (14%) patients in each group. No serious adverse events were reported in the eplerenone group and three unrelated serious adverse events were reported in the placebo group (myocardial infarction [anticipated], diverticulitis [unanticipated], and metabolic surgery [unanticipated]).InterpretationEplerenone was not superior to placebo for improving BCVA in people with chronic CSCR after 12 months of treatment. Ophthalmologists who currently prescribe eplerenone for CSCR should discontinue this practice.FundingEfficacy and Mechanism Evaluation Programme, and National Institute for Health Research and Social Care.

Background: Varying the intervals in retinopathy screening informed by personal risk offers reallocation of resources to better target high risk groups and address the increasing prevalence of diabetes. However, safety data especially on extended intervals is minimal. Aim: To evaluate the safety, efficacy and cost effectiveness (CE) of individualized variable-interval risk-based screening in a population setting compared to usual care. Methods: Masked 2 arm, parallel assignment, equivalence RCT (largest to date in screening) with independent trials unit monitoring in people with diabetes aged ≥12 years attending screening in a single English program. Randomization was 1:1 to individualized screening (active group; 6, 12 or 24 months for high, medium and low risk) determined by a risk calculation engine using real-time local demographic, retinal and clinical data, compared with annual screening (control). CE analysis measuring NHS and societal costs took a 2-year time horizon. Findings: 4534 participants entered the study - after withdrawals/loss to follow-up: active 2097; control 2224. Attendance rates at first follow-up visit (primary outcome, safety) were equivalent (per protocol analysis, 5% margin): active 83.6% control 84.7% (difference 1.0, 90% CI -0.8, 2.9). STDR detection rates were non-inferior (1.5% margin): active 1.43% control 1.71% (difference -0.28, CI -0.93, 0.36). Quality of life (EQ5D5L, HUI3) was not significantly different between the groups. Incremental cost saving per person was £18.75 (NHS cost) rising to £49.96 with societal costs. A 39.3% reduction in number of appointments was seen. Conclusions: All parties involved in diabetes care can be reassured that extended and personalized screening intervals can safely be introduced in established screening program. Scale-up with further validation outside a research setting is recommended. Views expressed are solely those of the authors. Disclosure D.M. Broadbent: None. A. Wang: None. C.P. Cheyne: None. J.G. Lathe: None. I.M. Stratton: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Bayer AG, Boehringer Ingelheim International GmbH. J. Vora: None. M. Garcia-Finana: None. M. James: None. S.P. Harding: None. Funding UK National Institute for Health Research

Background: Varying diabetic retinopathy (DR) screening intervals, informed by personal risk-levels, empowers people with diabetes (PWD), and offers reallocation of resources to high risk groups, while addressing the increasing prevalence of diabetes. Safety data on extending intervals is minimal. We evaluated the safety, efficacy and cost effectiveness of individualised risk-based variable-interval population screening compared to usual care, with design input from PWD. Methods: Two-arm, parallel assignment, equivalence randomised controlled trial (minimum 2 year follow-up) in PWD aged ≥12 years registered with one English screening programme. Randomisation was 1:1 to individualised screening (6, 12 or 24 months for high, medium and low risk) determined by a risk calculation engine, using local demographic, screening and clinical data, or to annual screening (control). Primary outcome was attendance (safety). A secondary safety outcome was the development of sight threatening DR (STDR). Cost effectiveness was evaluated within a 2 year time horizon from NHS and societal perspectives. Findings: 4534 participants were randomised, 2265 to the individualised and 2269 to the control arm. Attendance rates at first follow-up were equivalent between individualised (1754/2097, 83·6%) and control (1883/2224, 84·7%) arms (difference -1·0, 95% CI -3·2 to 1·2). STDR detection rates were non-inferior: individualised 1·4%, control 1·7% (- 0·3, -1·1 to 0·5). Sensitivity analyses confirmed findings. Incremental QALYs/person were non-significant: EQ-5D-5L 0·035 (CI -0·04, 0·13), HUI3 0·009 (CI -0·09, 0·10). Incremental cost savings were £21·31 (CI 15·24, 26·79)/person for the NHS and £28·87 (CI 21·08, 35·78) including societal costs. 43·2% fewer screening appointments were required in the individualised arm. Interpretation: Stakeholders involved in diabetes care can be reassured by this largest ophthalmic RCT in DR screening to date that extended and individualised risk-based intervals can be safely and cost effectively introduced in established screening programmes. Trial Registration Number: ISRCTN 87561257. Funding Statement: This study was funded by the UK National Institute for Health Research (NIHR) (Programme Grants for Applied Research, RP-PG-1210-12016). Declaration of Interests: We declare no competing interests. Professor Mark Gabbay is part-funded by the NIHR Collaboration for Leadership in Applied Health Research and Care North West Coast. Ethics Approval Statement: A UK NHS Research Ethics Committee approved the trial (14/NW/0034).

The retinal pigment epithelium (RPE) plays a central role in neuroretinal homoeostasis throughout life. Altered proteolysis and inflammatory processes involving RPE contribute to the pathophysiology of age‐related macular degeneration (AMD), but the link between these remains elusive. We report for the first time the effect of advanced glycation end products (AGE)—known to accumulate on the ageing RPE's underlying Bruch's membrane in situ—on both key lysosomal cathepsins and NF‐κB signalling in RPE. Cathepsin L activity and NF‐κB effector levels decreased significantly following 2‐week AGE exposure. Chemical cathepsin L inhibition also decreased total p65 protein levels, indicating that AGE‐related change of NF‐κB effectors in RPE cells may be modulated by cathepsin L. However, upon TNFα stimulation, AGE‐exposed cells had significantly higher ratio of phospho‐p65(Ser536)/total p65 compared to non‐AGEd controls, with an even higher fold increase than in the presence of cathepsin L inhibition alone. Increased proportion of active p65 indicates an AGE‐related activation of NF‐κB signalling in a higher proportion of cells and/or an enhanced response to TNFα. Thus, NF‐κB signalling modulation in the AGEd environment, partially regulated via cathepsin L, is employed by RPE cells as a protective (para‐inflammatory) mechanism but renders them more responsive to pro‐inflammatory stimuli.

Medical images are often of very high resolutions, far greater than can be directly processed in deep learning networks. These images are usually downsampled to much lower resolutions, likely losing useful clinical information in the process. Although methods have been developed to make the image appear much the same to human observers, a lot of information that is valuable to deep learning algorithms is lost. Here, we present a novel dictionary learning method of reducing the image size, utilizing DAISY descriptors and Improved Fisher kernels to derive features to represent the image in a much smaller size, similar to traditional downsampling methods. Our proposed method works as a type of intelligent downsampling, reducing the size while keeping vital information in images. We demonstrate the proposed method in a classification problem on a publicly available dataset consisting of 108,309 training and 1,000 validation grayscale optical coherence tomography images. We used an Inception V3 network to classify the resulting representations and to compare with previously obtained results. The proposed method achieved a testing accuracy and area under the receiver operating curve of \(97.2\%\) and 0.984, respectively. Results show that the proposed method does provide an accurate representation of the image and can be used as a viable alternative to conventional downsampling.

Cerebral malaria (CM) is a life-threatening clinical syndrome associated with 5-10% of malarial infection cases, most prevalent in Africa. About 23% of cerebral malaria cases are misdiagnosed as false positives, leading to inappropriate treatment and loss of lives. Malarial retinopathy (MR) is a retinal manifestation of CM that presents with a highly specific set of lesions. The detection of MR can reduce the false positive diagnosis of CM and alert physicians to investigate for other possible causes of the clinical symptoms and apply a more appropriate clinical intervention of underlying diseases. In order to facilitate easily accessible and affordable means of MR detection, we have developed an automated software system that detects the retinal lesions specific to MR, whitening and hemorrhages, using retinal color fundus images. The individual lesion detection algorithms were combined into an MR detection model using partial least square classifier. The classifier model was trained and tested on retinal image dataset obtained from 64 patients presenting with clinical signs of CM (44 with MR, 20 without MR). The MR detection model yielded specificity of 92% and sensitivity of 68%, with an AUC of 0.82. The proposed MR detection system demonstrates potential for broad screening of MR and can be integrated with a low-cost and portable retinal camera, to provide a bed-side tool for confirming CM diagnosis.

Aims To evaluate our proposed multivariate approach to identify patients who will develop sight‐threatening diabetic retinopathy (STDR) within a 1‐year screen interval, and explore the impact of simple stratification rules on prediction. Materials and methods A 7‐year dataset (2009‐2016) from people with diabetes (PWD) was analysed using a novel multivariate longitudinal discriminant approach. Level of diabetic retinopathy, assessed from routine digital screening photographs of both eyes, was jointly modelled using clinical data collected over time. Simple stratification rules based on retinopathy level were also applied and compared with the multivariate discriminant approach. Results Data from 13 103 PWD (49 520 screening episodes) were analysed. The multivariate approach accurately predicted whether patients developed STDR or not within 1 year from the time of prediction in 84.0% of patients (95% confidence interval [CI] 80.4‐89.7), compared with 56.7% (95% CI 55.5‐58.0) and 79.7% (95% CI 78.8‐80.6) achieved by the two stratification rules. While the stratification rules detected up to 95.2% (95% CI 92.2‐97.6) of the STDR cases (sensitivity) only 55.6% (95% CI 54.5‐56.7) of patients who did not develop STDR were correctly identified (specificity), compared with 85.4% (95% CI 80.4‐89.7%) and 84.0% (95% CI 80.7‐87.6%), respectively, achieved by the multivariate risk model. Conclusions Accurate prediction of progression to STDR in PWD can be achieved using a multivariate risk model whilst also maintaining desirable specificity. While simple stratification rules can achieve good levels of sensitivity, the present study indicates that their lower specificity (high false‐positive rate) would therefore necessitate a greater frequency of eye examinations.

Purpose To report on the development and progression of macular atrophy (MA) and its relationship with morphologic and functional measures in study and fellow eyes in the Inhibition of vascular endothelial growth factor (VEGF) in Age-related Choroidal Neovascularisation trial. Design Reading center analysis of data from a randomized controlled trial. Participants Participants with previously untreated neovascular age-related macular degeneration (nAMD) in the study eye. Methods Color, fluorescein angiography (FA) and OCT images acquired at baseline and during the 2-year follow-up were graded systematically for presence of MA. Regression models were constructed to explore relationships between MA and lesion morphology and vision measures (best-corrected distance and near acuity, reading speed and index, contrast sensitivity). Main Outcome Measures Primary outcome was development of intralesional MA (≥175 μm greatest linear dimension of choroidal vessels seen on FA and/or color, aided by OCT) lying within the maximum footprint of the neovascular lesion. Results Study eye data were available for 594 of 610 participants; 57 (9.6%) showed intralesional MA at baseline. Incident intralesional MA occurred in 24.4% by the final visit and extralesional MA in only 1.54%. In fellow eyes, an established nAMD lesion was present at baseline in 248 of whom 42 (16.9%) showed intralesional MA at baseline and 32 (12.9%) developed incident intralesional MA. The odds of incident intralesional MA by final visit were lower in study eyes that had ≥50% classic CNV at baseline (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.19–0.80; P = 0.010), subretinal fluid at final visit (OR, 0.41; 95% CI, 0.25–0.76; P = 0.004), or pigment epithelial detachment at final visit (OR, 0.40; 95% CI, 0.21–0.74; P = 0.004). Secondary analyses of incident or progressed intralesional MA in study eyes supported these findings, with odds increasing if the fellow eye had baseline intralesional MA (OR, 2.43; 95% CI, 1.09–5.44; P = 0.030). No significant associations were observed between development of intralesional MA and any other morphologic or visual function measure. Conclusions Macular atrophy frequently develops within an nAMD lesion in eyes receiving anti–VEGF therapy over 2 years. No associations between incident MA and drug or treatment frequency or visual function were detected, providing some reassurance to clinicians; however, the longer-term effects remain unknown.

Objective:\ud \ud To investigate the economic impact of introducing targeted screening and laser photocoagulation treatment for sight-threatening diabetic retinopathy and macular edema in a setting with no previous screening or laser treatment for diabetic retinopathy in sub-Saharan Africa.\ud \ud Materials and methods:\ud \ud A cohort Markov model was built to compare combined targeted screening and laser treatment for patients with sight-threatening diabetic retinopathy and macular edema against no intervention. Primary outcomes were incremental cost per quality-adjusted life year (QALY) gained and per disability-adjusted life year (DALY) averted. Primary data were collected on 357 participants from the Malawi Diabetic Retinopathy Study, a prospective, observational cohort study. Multiple scenarios were explored and a probabilistic sensitivity analysis was performed.\ud \ud Results:\ud \ud In the base case (age: 50 years, service utilization rate: 80%), the cost of the intervention and the years of severe visual impairment averted per patient screened were $209 and 2.2 years respectively. Applying the World Health Organization threshold of cost-effectiveness for Malawi ($679), the base case was cost-effective when QALYs were used ($400 per QALY gained) but not when DALYs were used ($766 per DALY averted). The intervention was more cost-effective when it targeted younger patients (age: 30 years) and less cost-effective when the utilization rate was lowered to 50%.\ud \ud Conclusions:\ud \ud Annual photographic screening of diabetic patients attending medical diabetes clinics in Malawi, with the provision of laser treatment for those with sight-threatening diabetic retinopathy and macular edema, appears to be cost-effective in terms of QALYs gained, in our base case scenario. Cost-effectiveness improves if services are utilized more intensively and extended to younger patients.

Manual grading of lesions in retinal images is relevant to clinical management and clinical trials, but it is time-consuming and expensive. Furthermore, it collects only limited information - such as lesion size or frequency. The spatial distribution of lesions is ignored, even though it may contribute to the overall clinical assessment of disease severity, and correspond to microvascular and physiological topography. Capillary non-perfusion (CNP) lesions are central to the pathogenesis of major causes of vision loss. Here we propose a novel method to analyse CNP using spatial statistical modelling. This quantifies the percentage of CNP-pixels in each of 48 sectors and then characterises the spatial distribution with goniometric functions. We applied our spatial approach to a set of images from patients with malarial retinopathy, and found it compares favourably with the raw percentage of CNP-pixels and also with manual grading. Furthermore, we were able to quantify a biological characteristic of macular CNP in malaria that had previously only been described subjectively: clustering at the temporal raphe. Microvascular location is likely to be biologically relevant to many diseases, and so our spatial approach may be applicable to a diverse range of pathological features in the retina and other organs.

Introduction Standard treatment for neovascular age-related macular degeneration (nAMD) is intravitreal injections of anti-VEGF drugs. Following multiple injections, nAMD lesions often become quiescent but there is a high risk of reactivation, and regular review by hospital ophthalmologists is the norm. The present trial examines the feasibility of community optometrists making lesion reactivation decisions.Methods The Effectiveness of Community vs Hospital Eye Service (ECHoES) trial is a virtual trial; lesion reactivation decisions were made about vignettes that comprised clinical data, colour fundus photographs, and optical coherence tomograms displayed on a web-based platform. Participants were either hospital ophthalmologists or community optometrists. All participants were provided with webinar training on the disease, its management, and assessment of the retinal imaging outputs. In a balanced design, 96 participants each assessed 42 vignettes; a total of 288 vignettes were assessed seven times by each professional group.The primary outcome is a participant’s judgement of lesion reactivation compared with a reference standard. Secondary outcomes are the frequency of sight threatening errors; judgements about specific lesion components; participant-rated confidence in their decisions about the primary outcome; cost effectiveness of follow-up by optometrists rather than ophthalmologists.Discussion This trial addresses an important question for the NHS, namely whether, with appropriate training, community optometrists can make retreatment decisions for patients with nAMD to the same standard as hospital ophthalmologists. The trial employed a novel approach as participation was entirely through a web-based application; the trial required very few resources compared with those that would have been needed for a conventional randomised controlled clinical trial.

We aimed to investigate the visual evoked potential (VEP) in children unconscious with Plasmodium falciparum malaria, a common cause of death in Africa. Flash VEPs were carried out in Malawi during one peak malaria season. Children were included in the study if they had P. falciparum malaria and reduced consciousness – Blantyre Coma Score (BCS) 4 or less out of 5. Initial VEPs were performed after stabilising the patient and commencing treatment. To investigate optimal VEP protocols, varying stimulus parameters were tested. Where possible, VEPs were repeated daily until the child recovered full consciousness (BCS 5). The initial traces of 40 children were included in the study and serial traces were obtained in 30 of these. Mean VEP latency was greater on admission than either on day 1 or at BCS 5 (paired t-test, P P P. falciparum malaria have delayed VEP responses and recovery occurs in parallel with return to normal consciousness. VEP recordings are quick and reproducible and may find a place in assessing levels of coma and cerebral function in severe malaria.

The inverse problem of image restoration to remove noise and blur in an observed image was extensively studied in the last two decades. For the case of a known blurring kernel (or a known blurring type such as out of focus or Gaussian blur), many effective models and efficient solvers exist. However when the underlying blur is unknown, there have been fewer developments for modelling the so-called blind deblurring since the early works of You and Kaveh (1996) and Chan and Wong (1998). A major challenge is how to impose the extra constraints to ensure quality of restoration. This paper proposes a new transform based method to impose the positivity constraints automatically and then two numerical solution algorithms. Test results demonstrate the effectiveness and robustness of the proposed method in restoring blurred images.

Aims/hypothesis Individualised variable-interval risk-based screening offers better targeting and improved cost-effectiveness in screening for diabetic retinopathy. We developed a generalisable risk calculation engine (RCE) to assign personalised intervals linked to local population characteristics, and explored differences in assignment compared with current practice. Methods Data from 5 years of photographic screening and primary care for people with diabetes, screen negative at the first of > 1 episode, were combined in a purpose-built near-real-time warehouse. Covariates were selected from a dataset created using mixed qualitative/quantitative methods. Markov modelling predicted progression to screen-positive (referable diabetic retinopathy) against the local cohort history. Retinopathy grade informed baseline risk and multiple imputation dealt with missing data. Acceptable intervals (6, 12, 24 months) and risk threshold (2.5%) were established with patients and professional end users. Results Data were from 11,806 people with diabetes (46,525 episodes, 388 screen-positive). Covariates with sufficient predictive value were: duration of known disease, HbA1c, age, systolic BP and total cholesterol. Corrected AUC (95% CIs) were: 6 months 0.88 (0.83, 0.93), 12 months 0.90 (0.87, 0.93) and 24 months 0.91 (0.87, 0.94). Sensitivities/specificities for a 2.5% risk were: 6 months 0.61, 0.93, 12 months 0.67, 0.90 and 24 months 0.82, 0.81. Implementing individualised RCE-based intervals would reduce the proportion of people becoming screen-positive before the allocated screening date by > 50% and the number of episodes by 30%. Conclusions/interpretation The Liverpool RCE shows sufficient performance for a local introduction into practice before wider implementation, subject to external validation. This approach offers potential enhancements of screening in improved local applicability, targeting and cost-effectiveness. Electronic supplementary material The online version of this article (doi:10.1007/s00125-017-4386-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

s will be available online on 25 May 2017.

Objective To investigate the economic impact of introducing targeted screening and laser photocoagulation treatment for sight-threatening diabetic retinopathy and macular edema in a setting with no previous screening or laser treatment for diabetic retinopathy in sub-Saharan Africa. Materials and methods A cohort Markov model was built to compare combined targeted screening and laser treatment for patients with sight-threatening diabetic retinopathy and macular edema against no intervention. Primary outcomes were incremental cost per quality-adjusted life year (QALY) gained and per disability-adjusted life year (DALY) averted. Primary data were collected on 357 participants from the Malawi Diabetic Retinopathy Study, a prospective, observational cohort study. Multiple scenarios were explored and a probabilistic sensitivity analysis was performed. Results In the base case (age: 50 years, service utilization rate: 80%), the cost of the intervention and the years of severe visual impairment averted per patient screened were $209 and 2.2 years respectively. Applying the World Health Organization threshold of cost-effectiveness for Malawi ($679), the base case was cost-effective when QALYs were used ($400 per QALY gained) but not when DALYs were used ($766 per DALY averted). The intervention was more cost-effective when it targeted younger patients (age: 30 years) and less cost-effective when the utilization rate was lowered to 50%. Conclusions Annual photographic screening of diabetic patients attending medical diabetes clinics in Malawi, with the provision of laser treatment for those with sight-threatening diabetic retinopathy and macular edema, appears to be cost-effective in terms of QALYs gained, in our base case scenario. Cost-effectiveness improves if services are utilized more intensively and extended to younger patients.

Purpose The purpose of the study was to study the effect of an organic light-emitting diode sleep mask on daytime alertness, wellbeing, and retinal structure/function in healthy volunteers and in diabetic macular oedema (DMO). Patients and methods Healthy volunteers in two groups, 18–30 yrs (A), 50–70 yrs (B) and people with DMO (C) wore masks (504 nm wavelength; 80 cd/m2 luminance; ≤8 h) nightly for 3 months followed by a 1-month recovery period. Changes from baseline were measured for (means): psychomotor vigilance task (PVT) (number of lapses (NL), response time (RT)), sleep, depression, psychological wellbeing (PW), visual acuity, contrast sensitivity, colour, electrophysiology, microperimetry, and retinal thickness on OCT. Results Of 60 participants, 16 (27%) withdrew, 8 (13%) before month 1, due to sleep disturbances and mask intolerance. About 36/55 (65%) who continued beyond month 1 reported ≥1 adverse event. At month 3 mean PVT worsened in Group A (RT (7.65%, P

BackgroundPatients with neovascular age-related macular degeneration (nAMD) usually attend regular reviews, even when the disease is quiescent. Reviews are burdensome to health services, patients and carers.ObjectivesTo compare the proportion of correct lesion classifications made by community-based optometrists and ophthalmologists from vignettes of patients; to estimate the cost-effectiveness of community follow-up by optometrists compared with follow-up by ophthalmologists in the Hospital Eye Service (HES); to ascertain views of patients, their representatives, optometrists, ophthalmologists and clinical commissioners on the proposed shared care model.DesignCommunity-based optometrists and ophthalmologists in the HES classified lesions from vignettes comprising clinical information, colour fundus photographs and optical coherence tomography images. Participants’ classifications were validated against experts’ classifications (reference standard).SettingInternet-based application.ParticipantsOphthalmologists had to have ≥ 3 years post-registration experience in ophthalmology, have passed part 1 of the Royal College of Ophthalmologists, Diploma in Ophthalmology or equivalent examination, and have experience in the age-related macular degeneration service. Optometrists had to be fully qualified, be registered with the General Optical Council for ≥ 3 years and not be participating in nAMD shared care.InterventionsThe trial sought to emulate a conventional trial in comparing optometrists’ and ophthalmologists’ decision-making, but vignettes, not patients, were assessed; therefore, there were no interventions. Participants received training prior to assessing vignettes.Main outcome measuresPrimary outcome – correct classification of the activity status of a lesion based on a vignette, compared with a reference standard. Secondary outcomes – frequencies of potentially sight-threatening errors, participants’ judgements about specific lesion components, participant-rated confidence in their decisions and cost-effectiveness of follow-up by community-based optometrists compared with HES ophthalmologists.ResultsIn total, 155 participants registered for the trial; 96 (48 in each professional group) completed training and main assessments and formed the analysis population. Optometrists and ophthalmologists achieved 1702 out of 2016 (84.4%) and 1722 out of 2016 (85.4%) correct classifications, respectively [odds ratio (OR) 0.91, 95% confidence interval (CI) 0.66 to 1.25;p = 0.543]. Optometrists’ decision-making was non-inferior to ophthalmologists’ with respect to the pre-specified limit of 10% absolute difference (0.298 on the odds scale). Frequencies of sight-threatening errors were similar for optometrists and ophthalmologists [57/994 (5.7%) vs. 62/994 (6.2%), OR 0.93, 95% CI 0.55 to 1.57;p = 0.789]. Ophthalmologists assessed lesion components as present less often than optometrists and were more confident about their lesion classifications than optometrists. The mean care-pathway cost for assessment was very similar by group, namely £397.33 for ophthalmologists and £410.78 for optometrists. The optometrist-led monitoring reviews were slightly more costly and less effective than ophthalmologist-led reviews, although the differences were extremely small. There was consensus that optometrist-led monitoring has the potential to reduce clinical workload and be more patient-centred. However, potential barriers are ophthalmologists’ perceptions of optometrists’ competence, the need for clinical training, the ability of the professions to work collaboratively and the financial feasibility of shared care for Clinical Commissioning Groups.ConclusionsThe ability of optometrists to make nAMD retreatment decisions from vignettes is non-inferior to that of ophthalmologists. Various barriers to implementing shared cared for nAMD were identified.Future work recommendationsThe Effectiveness, cost-effectiveness and acceptability of Community versus Hospital Eye Service follow-up for patients with neovascular age-related macular degeneration with quiescent disease (ECHoES) study web application was robust and could be used for future training or research. The benefit of reducing HES workload was not considered in the economic evaluation. A framework of programme budgeting and marginal analysis could explicitly explore the resource implications of shifting resources within a given health service area, as the benefit of reducing HES workload was not considered in the economic evaluation. Future qualitative research could investigate professional differences of opinion that were identified in multidisciplinary focus groups.Trial registrationCurrent Controlled Trials ISRCTN07479761.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 80. See the NIHR Journals Library website for further project information.