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    Research Update 571


    Proportion of people with diabetic retinopathy and macular oedema varies by ethnicity in a tertiary retinal clinic in Australia: findings from the Liverpool Eye and Diabetes Study (LEADS).

    BMJ Open. 2023 Feb 22;

    Liew G, Tsang T, Marshall B, Saw M, Khachigian LM, Ong S, Ho IV, Wong V.

    Objective: There are limited data on the influence of ethnicity on diabetic retinopathy (DR). We sought to determine the distribution of DR by ethnic group in Australia.

    Design: Clinic-based cross-sectional study.

    Setting: Participants with diabetes in a defined geographical region of Sydney, Australia, who attended a tertiary retina referral clinic.

    Participants: The study recruited 968 participants.

    Intervention: Participants underwent a medical interview and retinal photography and scanning.

    Primary Outcome Measures: DR was defined from two-field retinal photographs. Diabetic macular oedema (DMO) was defined from spectral domain optical coherence tomography (OCT-DMO). The main outcomes were any DR, proliferative DR (PDR), clinically significant macular oedema (CSME), OCT-DMO and sight-threatening DR (STDR).

    Results: There was high proportion of any DR (52.3%), PDR (6.3%), CSME (19.7%), OCT-DMO (28.9%) and STDR (31.5%) in people attending a tertiary retinal clinic. Participants of Oceanian ethnicity had the highest proportion of any DR and STDR (70.4% and 48.1%, respectively), while the lowest proportion was in participants of East Asian ethnicity (38.3% and 15.8%, respectively). Proportion of any DR and STDR in Europeans was 54.5% and 30.3%, respectively. Independent predictive factors for diabetic eye disease were ethnicity, longer duration of diabetes, higher glycated haemoglobin and higher blood pressure. Even after adjusting for risk factors, Oceanian ethnicity remained associated with twofold higher odds of any DR (adjusted OR 2.10, 95% CI 1.10 to 4.00) and all other forms of DR including STDR (adjusted OR 2.22, 95% CI 1.19 to 4.15).

    Conclusion: In people attending a tertiary retinal clinic, the proportion of people with DR varies among ethnic groups. The high proportion in persons of Oceanian ethnicity suggests a need for targeted screening of this at-risk group. In addition to traditional risks factors, ethnicity may be an additional independent predictor of DR.

    DOI: 10.1136/bmjopen-2021-055404


    Diabetic Macular Oedema Guidelines: An Australian Perspective.

    Journal of ophthalmology. 2023 Feb 14;

    Yuen YS, Gilhotra JS, Dalton M, Aujla JS, Mehta H, Wickremasinghe S, Uppal G, Arnold J, Chen F, Chang A, Fraser-Bell S, Lim L, Shah J, Bowditch E, Broadhead GK

    The number of people living with diabetes is expected to rise to 578 million by 2030 and to 700 million by 2045, exacting a severe socioeconomic burden on healthcare systems around the globe. This is also reflected in the increasing numbers of people with ocular complications of diabetes (namely, diabetic macular oedema (DMO) and diabetic retinopathy (DR)). In one study examining the global prevalence of DR, 35% of people with diabetes had some form of DR, 7% had PDR, 7% had DMO, and 10% were affected by these vision-threatening stages. In many regions of the world (Australia included), DR is one of the top three leading causes of vision loss amongst working age adults (20-74 years). In the management of DMO, the landmark ETDRS study demonstrated that moderate visual loss, defined as doubling of the visual angle, can be reduced by 50% or more by focal/grid laser photocoagulation. However, over the last 20 years, antivascular endothelial growth factor (VEGF) and corticosteroid therapies have emerged as alternative options for the management of DMO and provided patients with choices that have higher chances of improving vision than laser alone. In Australia, since the 2008 NHMRC guidelines, there have been significant developments in both the treatment options and treatment schedules for DMO. This working group was therefore assembled to review and address the current management options available in Australia.

    DOI: 10.1155/2023/6329819


    Imaging biomarkers and clinical factors associated with the rate of progressive inner and outer retinal thinning in patients with diabetic macular edema.

    Scientific reports. 2023 Feb 24;

    Borrelli E, Barresi C, Feo A, Lari G, Grosso D, Querques L, Sacconi R, Bandello F, Querques G

    The aim of this study was to assess the relationship of clinical characteristics to the rate of retinal thinning in eyes with diabetic macular edema (DME) treated with anti-vascular endothelial growth factor (VEGF) therapy. We analyzed subjects with a long-term follow-up (≥ 3 years) and evidence of resolved DME after the initiation of anti-VEGF therapy (baseline visit). To measure the long-term rate of retinal thinning during treatment, a second visit (first visit with evidence of resolved DME after 3 years) was also considered. A longitudinal quantitative topographical assessment of the inner and outer retinal thicknesses was provided. Clinical characteristics were associated with the rate of longitudinal retinal thinning. We included 56 eyes (50 patients) in the analysis. A significant longitudinal thinning in the inner and outer retina was detected in all the analyzed regions (p values between 0.027 and < 0.0001). In the multivariable analysis, type of diabetes (type 2 vs. type 1) was associated with increased foveal inner retinal thinning (p = 0.019). A higher number of subfoveal neuroretinal detachment during follow-up (p = 0.006) was associated with faster rates of foveal outer retinal thinning. Type of diabetes (p < 0.0001), higher age (p = 0.033) and cystoid macular edema phenotype (p = 0.040) were associated with increased parafoveal inner retinal thinning. Gender (p = 0.003) and diabetic retinopathy stage (p = 0.013) were associated with faster rates of perifoveal inner retinal thinning, while diabetic retinopathy stage (p = 0.036) was associated with increased perifoveal outer retinal thinning. In conclusion, clinical factors, including DME phenotypes, were associated with the rates of retinal thinning in patients undergoing anti-VEGF treatment.

    DOI: 10.1038/s41598-023-30432-2

    Automated large-scale prediction of exudative AMD progression using machine-read OCT biomarkers.

    PLOS digital health. 2023 Feb 15;

    Rudas A, Chiang JN, Corradetti G, Rakocz N, Avram O, Halperin E, Sadda SR

    Age-related Macular Degeneration (AMD) is a major cause of irreversible vision loss in individuals over 55 years old in the United States. One of the late-stage manifestations of AMD, and a major cause of vision loss, is the development of exudative macular neovascularization (MNV). Optical Coherence Tomography (OCT) is the gold standard to identify fluid at different levels within the retina. The presence of fluid is considered the hallmark to define the presence of disease activity. Anti-vascular growth factor (anti-VEGF) injections can be used to treat exudative MNV. However, given the limitations of anti-VEGF treatment, as burdensome need for frequent visits and repeated injections to sustain efficacy, limited durability of the treatment, poor or no response, there is a great interest in detecting early biomarkers associated with a higher risk for AMD progression to exudative forms in order to optimize the design of early intervention clinical trials. The annotation of structural biomarkers on optical coherence tomography (OCT) B-scans is a laborious, complex and time-consuming process, and discrepancies between human graders can introduce variability into this assessment. To address this issue, a deep-learning model (SLIVER-net) was proposed, which could identify AMD biomarkers on structural OCT volumes with high precision and without human supervision. However, the validation was performed on a small dataset, and the true predictive power of these detected biomarkers in the context of a large cohort has not been evaluated. In this retrospective cohort study, we perform the largest-scale validation of these biomarkers to date. We also assess how these features combined with other EHR data (demographics, comorbidities, etc) affect and/or improve the prediction performance relative to known factors. Our hypothesis is that these biomarkers can be identified by a machine learning algorithm without human supervision, in a way that they preserve their predictive nature. The way we test this hypothesis is by building several machine learning models utilizing these machine-read biomarkers and assessing their added predictive power. We found that not only can we show that the machine-read OCT B-scan biomarkers are predictive of AMD progression, we also observe that our proposed combined OCT and EHR data-based algorithm outperforms the state-of-the-art solution in clinically relevant metrics and provides actionable information which has the potential to improve patient care. In addition, it provides a framework for automated large-scale processing of OCT volumes, making it possible to analyze vast archives without human supervision.

    DOI: 10.1371/journal.pdig.0000106


    Macular Edema in Central Retinal Vein Occlusion Correlates With Aqueous Fibrinogen Alpha Chain.

    Investigative ophthalmology visual science. 2023 Feb 1;

    Cehofski LJ, Kojima K, Kusada N, Rasmussen M, Muttuvelu DV, Grauslund J, Vorum H, Honoré B.

    Purpose: The global protein profile of the aqueous humor has been found to correlate with the severity of retinal vascular disease. Studying the aqueous humor in central retinal vein occlusion (CRVO) with proteomic techniques may bring insights to the molecular mechanisms underlying the condition.

    Methods: Aqueous humor samples from treatment naïve patients with CRVO complicated by macular edema (n = 28) and age-matched controls (n = 20) were analyzed by label-free quantification liquid chromatography – tandem mass spectrometry. Best corrected visual acuity (BCVA) was measured as logMAR, and the severity of macular edema was evaluated as central retinal thickness (CRT) with optical coherence tomography. Control samples were obtained prior to cataract surgery. Significantly changed proteins were identified by a permutation-based calculation with a false discovery rate of 0.05.

    Results: A total of 177 proteins were differentially expressed in CRVO. Regulated proteins were involved in complement activation, innate immune response, blood coagulation, and cell adhesion. Upregulated proteins that correlated with BCVA and CRT included fibrinogen alpha, beta, and gamma chains, fibronectin, Ig lambda-6 chain C region, Ig alpha-1 chain C region, and complement C7. Downregulated proteins that correlated negatively with BCVA, and CRT, included procollagen C-endopeptidase enhancer 1, clusterin, opticin, reelin, fibrillin-1, and cadherin-2. Monocyte differentiation antigen CD14 and lipopolysaccharide-binding protein were increased in CRVO.

    Conclusions: Fibrinogen chains, fibronectin, and immunoglobulin components correlated with BCVA and CRT, suggesting a multifactorial response. Protective anti-angiogenic proteins, including procollagen C-endopeptidase enhancer 1, clusterin, and opticin, were downregulated in CRVO and correlated negatively with BCVA and CRT.

    DOI: 10.1167/iovs.64.2.23


    The effect of a brief, unplanned treatment delay on neovascular age-related macular degeneration patients: a retrospective cohort study.

    Scietific reports. 2023 Feb 23;13(1):3156. doi: 10.1038/s41598-023-29819-y.

    Zehden JA, Ghosh A, Soundararajan S, Tsujimoto THM, Jiang H, Lin FC, Blahnik T, Fleischman D, Zhang AY.

    Non-compliance to intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy can result in increased disease activity in neovascular age-related macular degeneration (nAMD). Our study aims to determine effects of unplanned delay in anti-VEGF injection treatment for nAMD. This retrospective observational study included patients with delays in receiving intravitreal injections for nAMD treatment from March to May 2020 by at least 21 days. Baseline demographic and clinical characteristics, visual acuity (VA), central macular thickness (CMT) measured on optical coherence tomography (OCT), and duration of delayed treatment were analyzed for 3 time points, the pre-delay visit (v1) and post-delay visits (v2 and v3). Data were compared to age-matched controls treated for nAMD in 2019 without delay. Demographic characteristics were compared using two-sample t-tests for continuous variables and Pearson’s chi-square tests for categorical variables. For the two primary outcomes of interest, VA and CMT, means and standard deviations were reported for each combination of group and time. Each outcome was modeled using a linear mixed model with the group, time and group-time interaction as fixed effects. A total of 69 patients (99 eyes) in the treatment delay group and 44 patients (69 eyes) in the control group were identified. Statistically significant differences between control and delayed groups were detected for VA (difference in mean logMAR = 0.16; 95% CI 0.06, 0.27; p = 0.002) and CMT (difference in mean CMT = 29; 95% CI 12, 47; p = 0.001) at v2. No differences were detected for v1 and v3 time points for both outcomes. An unplanned delay in intravitreal injection treatment for nAMD resulted in an increase in CMT and worsening of VA compared to controls observed at v2. At v3, CMT and VA recovered to near v1 levels. This study demonstrates that a one-time, brief interruption in treatment for nAMD results in reversible, temporary worsening.

    DOI: 10.1038/s41598-023-29819-y


    Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis.

    Frontiers in cell developmental biology. 2023 Feb 3;

     Panneman DM, Hitti-Malin RJ, Holtes LK, de Bruijn SE, Reurink J, Boonen EGM, Khan MI, Ali M, Andréasson S, De Baere E, Banfi S, Bauwens M, Ben-Yosef T, Bocquet B, De Bruyne M, de la Cerda B, Coppieters F, Farinelli P, Guignard T, Inglehearn CF, Karali M, Kjellström U, Koenekoop , de Koning B, Leroy BP, McKibbin M, Meunier I, Nikopoulos K, Nishiguchi KM, Poulter JA, Rivolta C, Rodríguez de la Rúa E, Saunders P, Simonelli F, Tatour Y, Testa F, Thiadens AAHJ, Toomes C, Tracewska AM, Tran HV, Ushida H, Vaclavik V, Verhoeven VJM, van de Vorst M, Gilissen C, Hoischen A, Cremers FPM, Roosing S

    Introduction: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are two groups of inherited retinal diseases (IRDs) where the rod photoreceptors degenerate followed by the cone photoreceptors of the retina. A genetic diagnosis for IRDs is challenging since >280 genes are associated with these conditions. While whole exome sequencing (WES) is commonly used by diagnostic facilities, the costs and required infrastructure prevent its global applicability. Previous studies have shown the cost-effectiveness of sequence analysis using single molecule Molecular Inversion Probes (smMIPs) in a cohort of patients diagnosed with Stargardt disease and other maculopathies.

    Methods: Here, we introduce a smMIPs panel that targets the exons and splice sites of all currently known genes associated with RP and LCA, the entire RPE65 gene, known causative deep-intronic variants leading to pseudo-exons, and part of the RP17 region associated with autosomal dominant RP, by using a total of 16,812 smMIPs. The RP-LCA smMIPs panel was used to screen 1,192 probands from an international cohort of predominantly RP and LCA cases.

    Results And Discussion: After genetic analysis, a diagnostic yield of 56% was obtained which is on par with results from WES analysis. The effectiveness and the reduced costs compared to WES renders the RP-LCA smMIPs panel a competitive approach to provide IRD patients with a genetic diagnosis, especially in countries with restricted access to genetic testing.

    DOI: 10.3389/fcell.2023.1112270


    Prognostic factors for the development and progression of proliferative diabetic retinopathy in people with diabetic retinopathy.

    The Cochrane database of systematic reviews. 2023 Feb 22;

    Perais J, Agarwal R, Evans JR, Loveman E, Colquitt JL, Owens D, Hogg RE, Lawrenson JG, Takwoingi Y, Lois N.

    Background: Diabetic retinopathy (DR) is characterised by neurovascular degeneration as a result of chronic hyperglycaemia. Proliferative diabetic retinopathy (PDR) is the most serious complication of DR and can lead to total (central and peripheral) visual loss. PDR is characterised by the presence of abnormal new blood vessels, so-called “new vessels,” at the optic disc (NVD) or elsewhere in the retina (NVE). PDR can progress to high-risk characteristics (HRC) PDR (HRC-PDR), which is defined by the presence of NVD more than one-fourth to one-third disc area in size plus vitreous haemorrhage or pre-retinal haemorrhage, or vitreous haemorrhage or pre-retinal haemorrhage obscuring more than one disc area. In severe cases, fibrovascular membranes grow over the retinal surface and tractional retinal detachment with sight loss can occur, despite treatment. Although most, if not all, individuals with diabetes will develop DR if they live long enough, only some progress to the sight-threatening PDR stage. 

    Objectives: To determine risk factors for the development of PDR and HRC-PDR in people with diabetes and DR. SEARCH

    Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2022, Issue 5), Ovid MEDLINE, and Ovid Embase. The date of the search was 27 May 2022. Additionally, the search was supplemented by screening reference lists of eligible articles. There were no restrictions to language or year of publication. 

    Selection Criteria: We included prospective or retrospective cohort studies and case-control longitudinal studies evaluating prognostic factors for the development and progression of PDR, in people who have not had previous treatment for DR. The target population consisted of adults (≥18 years of age) of any gender, sexual orientation, ethnicity, socioeconomic status, and geographical location, with non-proliferative diabetic retinopathy (NPDR) or PDR with less than HRC-PDR, diagnosed as per standard clinical practice. Two review authors independently screened titles and abstracts, and full-text articles, to determine eligibility; discrepancies were resolved through discussion. We considered prognostic factors measured at baseline and any other time points during the study and in any clinical setting. Outcomes were evaluated at three and eight years (± two years) or lifelong. 

    Data Collection and Analysis: Two review authors independently extracted data from included studies using a data extraction form that we developed and piloted prior to the data collection stage. We resolved any discrepancies through discussion. We used the Quality in Prognosis Studies (QUIPS) tool to assess risk of bias. We conducted meta-analyses in clinically relevant groups using a random-effects approach. We reported hazard ratios (HR), odds ratios (OR), and risk ratios (RR) separately for each available prognostic factor and outcome, stratified by different time points. Where possible, we meta-analysed adjusted prognostic factors. We evaluated the certainty of the evidence with an adapted version of the GRADE framework.  

    Main Results: We screened 6391 records. From these, we identified 59 studies (87 articles) as eligible for inclusion. Thirty-five were prospective cohort studies, 22 were retrospective studies, 18 of which were cohort and six were based on data from electronic registers, and two were retrospective case-control studies. Twenty-three studies evaluated participants with type 1 diabetes (T1D), 19 with type 2 diabetes (T2D), and 17 included mixed populations (T1D and T2D). Studies on T1D included between 39 and 3250 participants at baseline, followed up for one to 45 years. Studies on T2D included between 100 and 71,817 participants at baseline, followed up for one to 20 years. The studies on mixed populations of T1D and T2D ranged from 76 to 32,553 participants at baseline, followed up for four to 25 years.  We found evidence indicating that higher glycated haemoglobin (haemoglobin A1c (HbA1c)) levels (adjusted OR ranged from 1.11 (95% confidence interval (CI) 0.93 to 1.32) to 2.10 (95% CI 1.64 to 2.69) and more advanced stages of retinopathy (adjusted OR ranged from 1.38 (95% CI 1.29 to 1.48) to 12.40 (95% CI 5.31 to 28.98) are independent risk factors for the development of PDR in people with T1D and T2D. We rated the evidence for these factors as of moderate certainty because of moderate to high risk of bias in the studies.  There was also some evidence suggesting several markers for renal disease (for example, nephropathy (adjusted OR ranged from 1.58 (95% CI not reported) to 2.68 (2.09 to 3.42), and creatinine (adjusted meta-analysis HR 1.61 (95% CI 0.77 to 3.36)), and, in people with T1D, age at diagnosis of diabetes (< 12 years of age) (standardised regression estimate 1.62, 95% CI 1.06 to 2.48), increased triglyceride levels (adjusted RR 1.55, 95% CI 1.06 to 1.95), and larger retinal venular diameters (RR 4.28, 95% CI 1.50 to 12.19) may increase the risk of progression to PDR. The certainty of evidence for these factors, however, was low to very low, due to risk of bias in the included studies, inconsistency (lack of studies preventing the grading of consistency or variable outcomes), and imprecision (wide CIs). There was no substantial and consistent evidence to support duration of diabetes, systolic or diastolic blood pressure, total cholesterol, low- (LDL) and high- (HDL) density lipoproteins, gender, ethnicity, body mass index (BMI), socioeconomic status, or tobacco and alcohol consumption as being associated with incidence of PDR. There was insufficient evidence to evaluate prognostic factors associated with progression of PDR to HRC-PDR. 

    Authors’ Conclusions: Increased HbA1c is likely to be associated with progression to PDR; therefore, maintaining adequate glucose control throughout life, irrespective of stage of DR severity, may help to prevent progression to PDR and risk of its sight-threatening complications. Renal impairment in people with T1D or T2D, as well as younger age at diagnosis of diabetes mellitus (DM), increased triglyceride levels, and increased retinal venular diameters in people with T1D may also be associated with increased risk of progression to PDR. Given that more advanced DR severity is associated with higher risk of progression to PDR, the earlier the disease is identified, and the above systemic risk factors are controlled, the greater the chance of reducing the risk of PDR and saving sight.

    DOI: 10.1002/14651858.CD013775.