Publications by authors named "Noemi Lois"

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Authors:
Noemi Lois

Ophthalmology 2021 Jun 24. Epub 2021 Jun 24.

The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK.

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http://dx.doi.org/10.1016/j.ophtha.2021.05.014DOI Listing
June 2021

New Classification for the Reporting of Complications in Retinal Detachment Surgical Trials.

JAMA Ophthalmol 2021 Jun 24. Epub 2021 Jun 24.

Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland.

Importance: Quantifying severity of complications in rhegmatogenous retinal detachment (RRD) surgical trials is needed. A consensus classification system will help surgeons to more effectively compare harms of different surgical techniques.

Objective: To develop a new consensus-based classification to quantify severity of complications of RRD surgery.

Design, Setting, And Participants: A comprehensive list of complications was developed followed by a Delphi consensus survey of international vitreoretinal surgeons. The survey was conducted in 17 countries in mainland Europe, the United Kingdom, the United States, Asia, South Africa, and Australia. Seventy vitreoretinal surgeons were invited to take part in the Delphi survey; 45 agreed to participate. Participants were selected through boards/members lists of retinal societies. Data were analyzed between April 2019 and August 2019.

Main Outcomes And Measures: Consensus-derived classification of complications of RRD surgery, according to their severity.

Results: Forty-three of 45 vitreoretinal surgeons who agreed to participate in the Delphi survey completed round 1 (96%); all but 1 (98%) completed round 2. Consensus was reached for 96% of the 84 complications assessed. Examples of complications classified as least severe (graded 1) included subconjunctival hemorrhage and chemosis while those classified as most severe included endophthalmitis and sympathetic ophthalmia (graded 9) and phthisis (graded 10).

Conclusions And Relevance: We propose a new classification for quantifying severity of surgical complications based on an international consensus of vitreoretinal surgeons to quantify harm and improve the reporting of complications of RRD surgery.
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http://dx.doi.org/10.1001/jamaophthalmol.2021.1078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227451PMC
June 2021

Reporting of Complications in Retinal Detachment Surgical Trials: A Systematic Review Using the CONSORT Extension for Harms.

JAMA Ophthalmol 2021 Jun 17. Epub 2021 Jun 17.

Wellcome-Wolfson Institute For Experimental Medicine, Queen's University, Belfast, United Kingdom.

Importance: Knowledge on the frequency and severity of complications in surgical trials for rhegmatogenous retinal detachment (RRD) is essential to determine whether surgical procedures are developed and compared adequately, taking into account not only efficacy but also harms.

Objective: To review standards of reporting of complications in recent randomized clinical trials of RRD surgery.

Evidence Review: This systematic review included randomized clinical trials on RRD surgery published between January 2008 and January 2021 in Embase, MEDLINE, and Web of Science Core Collection databases. Titles, abstracts, and full-text articles retrieved were reviewed for eligibility by 2 independent authors. Eligible studies were evaluated against checklist items from the Consolidated Standards of Reporting Trials Extension for Harms criteria by 2 independent authors, and discrepancies were resolved by discussion with a third author.

Findings: Fifty studies were included. The median number of checklist items fulfilled was 8 (range, 0-15), of a possible total of 18. Frequently reported items were discussions balanced with regard to efficacy and adverse events (42 studies [84%]) and inclusions of harm-associated timing of data collection (41 studies [82%]). The least frequently reported items were distinctions between expected and unexpected adverse events (1 study [2%]) and mentions of the use of a validated instrument to report adverse event severity (4 studies [8%]). Frequency of complications was commonly reported (29 studies [58%]) in contrast with complication severity (10 studies [20%]).

Conclusions And Relevance: This review suggests that severity of complications of RRD surgery has been infrequently quantified and reported in randomized clinical trials and potentially represents an important area of improvement in future RRD surgical trials.
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http://dx.doi.org/10.1001/jamaophthalmol.2021.1836DOI Listing
June 2021

Anatomic-Functional Correlates in Lesions of Retinal Vein Occlusion.

Invest Ophthalmol Vis Sci 2021 Jun;62(7):10

Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, United Kingdom.

Purpose: To evaluate anatomic-functional associations at sites of retinal lesions in retinal vein occlusion (RVO).

Methods: This pilot, prospective, observational study was conducted at the Northern Ireland Clinical Research Facility (NICRF) of Queen's University and the Belfast Health and Social Care Trust, Northern Ireland, between August 1, 2018, and September 30, 2019. The study included 10 treatment-naïve patients with RVO (10 RVO eyes and 10 fellow eyes). There were 81 points/sites assessed for each eye at baseline; six patients were re-assessed 6 months after anti-vascular endothelial growth factor therapy at the same locations. We investigated associations between retinal sensitivity and presence of structural RVO lesions, including retinal ischemia, hemorrhages, intraretinal fluid (IRF) and subretinal fluid outside the foveal/parafoveal regions. Comparisons were made between RVO eyes and fellow eyes at baseline, and between RVO eyes at baseline and at 6 months after treatment. Regression models were used to investigate anatomic-functional associations.

Results: At baseline, strong associations were found between reduced retinal sensitivity and presence of ischemia (estimate = -2.08 dB; P < 0.001), intraretinal fluid (estimate = -7.82 dB; P < 0.001), and subretinal fluid (estimate = -8.66 dB; P < 0.001). Resolution of subretinal fluid but not intraretinal fluid was associated with improved function (estimate = 2.40 dB [P = 0.022]; estimate = 1.16 dB [P = 0.228], respectively). However, reperfusion of ischemic retina, observed in 31 of 486 points (6%) 6 months after anti-vascular endothelial growth factor therapy, was associated with a further decrease in retinal sensitivity (estimate = -2.34 dB; P = 0.035).

Conclusions: Retinal sensitivity was decreased at sites of RVO lesions. Decreased function at sites of retinal ischemia did not recover after treatment, even when reperfusion occurred.
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http://dx.doi.org/10.1167/iovs.62.7.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196416PMC
June 2021

Surveillance of people with previously successfully treated diabetic macular oedema and proliferative diabetic retinopathy by trained ophthalmic graders: cost analysis from the EMERALD study.

Br J Ophthalmol 2021 Jun 3. Epub 2021 Jun 3.

Warwick Medical School, University of Warwick, Coventry, UK.

Background/aims: Surveillance of people with previously successfully treated diabetic macular oedema (DMO) and proliferative diabetic retinopathy (PDR) adds pressure on ophthalmology services. This study evaluated a new surveillance pathway entailing multimodal imaging reviewed by trained ophthalmic graders and compared it with the current standard care (face-to-face evaluation by an ophthalmologist).

Methods: Cost analysis of the new ophthalmic grader pathway, compared with the standard of care, from the perspective of the UK National Health Service, based on evidence from the Effectiveness of Multimodal imaging for the Evaluation of Retinal oedema And new vesseLs in Diabetic retinopathy study. Resource use data were prospectively obtained including times to undertake each procedure. Effectiveness was assessed in terms of sensitivity and specificity of referral decisions in the grader pathway. Costs (SDs) were analysed per 100 patients separately for DMO and PDR at 2018/2019 costs.

Results: For DMO, where sensitivity was very high (97%), the cost difference (savings) for the grader's pathway would be £1390 per 100 patients. For PDR, the cost would be reduced by £461 for seven-field Early Treatment for Diabetic Retinopathy Study (ETDRS) images and by £1889 for ultrawide field images, per 100 patients. Ultrawide images required less time to be obtained and read than seven-field ETDRS. The real savings would be in ophthalmologist time, which could be then redirected to the evaluation of people at high risk of visual loss.

Conclusions: Surveillance of people with previously successfully treated DMO and PDR by trained ophthalmic graders can achieve satisfactory results and release ophthalmologist time.

Trial Registration Numbers: NCT03490318, ISRCTN10856638.
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http://dx.doi.org/10.1136/bjophthalmol-2021-318816DOI Listing
June 2021

Multimodal imaging interpreted by graders to detect re-activation of diabetic eye disease in previously treated patients: the EMERALD diagnostic accuracy study.

Health Technol Assess 2021 May;25(32):1-104

Warwick Medical School, University of Warwick, Coventry, UK.

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 Vol. 25, No. 32. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200933PMC
May 2021

Testing the performance of risk prediction models to determine progression to referable diabetic retinopathy in an Irish type 2 diabetes cohort.

Br J Ophthalmol 2021 Apr 26. Epub 2021 Apr 26.

Ophthalmology, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, UK

Background /aims: To evaluate the performance of existing prediction models to determine risk of progression to referable diabetic retinopathy (RDR) using data from a prospective Irish cohort of people with type 2 diabetes (T2D).

Methods: A cohort of 939 people with T2D followed prospectively was used to test the performance of risk prediction models developed in Gloucester, UK, and Iceland. Observed risk of progression to RDR in the Irish cohort was compared with that derived from each of the prediction models evaluated. Receiver operating characteristic curves assessed models' performance.

Results: The cohort was followed for a total of 2929 person years during which 2906 screening episodes occurred. Among 939 individuals followed, there were 40 referrals (4%) for diabetic maculopathy, pre-proliferative DR and proliferative DR. The original Gloucester model, which includes results of two consecutive retinal screenings; a model incorporating, in addition, systemic biomarkers (HbA1c and serum cholesterol); and a model including results of one retinopathy screening, HbA1c, total cholesterol and duration of diabetes, had acceptable discriminatory power (area under the curve (AUC) of 0.69, 0.76 and 0.77, respectively). The Icelandic model, which combined retinopathy grading, duration and type of diabetes, HbA1c and systolic blood pressure, performed very similarly (AUC of 0.74).

Conclusion: In an Irish cohort of people with T2D, the prediction models tested had an acceptable performance identifying those at risk of progression to RDR. These risk models would be useful in establishing more personalised screening intervals for people with T2D.
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http://dx.doi.org/10.1136/bjophthalmol-2020-318570DOI Listing
April 2021

Visual cycle modulators versus placebo or observation for the prevention and treatment of geographic atrophy due to age-related macular degeneration.

Cochrane Database Syst Rev 2020 12 17;12:CD013154. Epub 2020 Dec 17.

Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK.

Background: Age-related macular degeneration (AMD) is a highly prevalent condition in an ever-increasing elderly population. Although insidious in the early stages, advanced AMD (neovascular and atrophic forms) can cause significant visual disability and economic burden on health systems worldwide. The most common form, geographic atrophy, has no effective treatment to date, whereas neovascular AMD can be treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. Geographic atrophy has a slow disease progression and patients tend to have preserved central vision until the final stages. This tendency, coupled with the use of modern imaging modalities, provides a large window of opportunity to intervene with validated methods to assess treatment efficacy. As geographic atrophy is an increasingly common condition with no effective intervention, many treatments are under investigation, one of which is visual cycle modulators. These medications have been shown to reduce lipofuscin accumulation in pre-clinical studies that have led to several clinical trials, reviewed herein.

Objectives: To assess the efficacy and safety of visual cycle modulators for the prevention and treatment of geographic atrophy secondary to AMD.

Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); MEDLINE Ovid; Embase Ovid; Web of Science Core Collection; Scopus; Association for Research in Vision and Ophthalmology (ARVO) website; ClinicalTrials.gov and the WHO ICTRP to 11 January 2020 with no language restrictions. We also searched using the reference lists of reviews and existing studies and the Cited Reference Search function in Web of Science to identify further relevant studies.

Selection Criteria: We included randomised controlled trials (RCTs) and quasi-randomised clinical studies (if available) that compared visual cycle modulators to placebo or no treatment (observation) in people diagnosed with AMD (early, intermediate or geographic atrophy).

Data Collection And Analysis: Two authors independently assessed risk of bias in the included studies and extracted data. Both authors entered data into RevMan 5. We resolved discrepancies through discussion. We graded the certainty of the evidence using the GRADE approach.

Main Results: We included three RCTs from the USA; one of these had clinical sites in Germany. Two studies compared emixustat to placebo while the other compared fenretinide to placebo. All assigned one study eye per participant and, combined, have a total of 821 participants with a majority white ethnicity (97.6%). All participants were diagnosed with geographic atrophy due to AMD based on validated imaging modalities. All three studies have high risk of attrition bias mainly due to ocular adverse effects of emixustat and fenretinide. We considered only one study to be adequately conducted and reported with high risk of bias in only one domain (attrition bias). We considered the other two studies to be poorly reported and to have high risk of attrition bias and reporting bias. People with geographic atrophy treated with emixustat may not experience a clinically important change in best-corrected visual acuity (BCVA) between baseline and 24 months compared to people treated with placebo (mean difference (MD) 1.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% confidence interval (CI) -2.34 to 6.14, low-certainty evidence). Emixustat may also result in little or no difference in loss of 15 ETDRS letters or more of BCVA compared with placebo at 24 months (16.4% versus 18%) (risk ratio (RR) 0.91, 95% CI 0.59 to 1.4, low-certainty evidence). In terms of disease progression, emixustat may result in little or no difference in the annual growth rate of geographic atrophy compared with placebo (mean difference MD 0.09 mm/year (95% CI -0.26 to 0.44, low-certainty evidence). All three studies reported adverse events of both drugs (emixustat: moderate-certainty evidence; fenretinide: low-certainty evidence). The main adverse events were ocular in nature and associated with the mechanism of action of the drugs. Delayed dark adaptation (emixustat: 54.5%; fenretinide: 39.3%) and chromatopsia (emixustat: 22.6%; fenretinide: 25.2%) were the most common adverse events reported, and were the most prevalent reasons for study dropout in emixustat trials. These effects were dose-dependent and resolved after drug cessation. No specific systemic adverse events were considered related to emixustat; only pruritus and rash were considered to be due to fenretinide. One emixustat study reported six deaths, none deemed related to the drug. None of the included RCTs reported the other pre-specified outcomes, including proportion of participants losing 10 letters or more, and mean change in macular sensitivity. We planned to investigate progression to advanced AMD (geographic atrophy or neovascular AMD) in prevention studies, including participants with early or intermediate AMD, but we identified no such studies. Two of the included studies reported an additional outcome - incidence of choroidal neovascularisation (CNV) - that was not in our published protocol. CNV onset may be reduced in those treated with emixustat but the evidence was uncertain (risk ratio (RR) 0.67, 95% CI 0.27 to 1.65, low-certainty evidence), or fenretinide (RR 0.5, 95% CI 0.26 to 0.98, low-certainty evidence) compared to placebo. A dose-dependent relationship was observed with emixustat.

Authors' Conclusions: There is limited evidence to support the use of visual cycle modulators (emixustat and fenretinide) for the treatment of established geographic atrophy due to AMD. The possible reduction in the incidence of CNV observed with fenretinide, and to a lesser extent, emixustat, requires formal assessment in focused studies.
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http://dx.doi.org/10.1002/14651858.CD013154.pub2DOI Listing
December 2020

Evaluation of a New Model of Care for People with Complications of Diabetic Retinopathy: The EMERALD Study.

Ophthalmology 2021 04 31;128(4):561-573. Epub 2020 Oct 31.

Warwick Medical School, University of Warwick, Coventry, United Kingdom.

Purpose: The increasing diabetes prevalence and advent of new treatments for its major visual-threatening complications (diabetic macular edema [DME] and proliferative diabetic retinopathy [PDR]), which require frequent life-long follow-up, have increased hospital demands markedly. Subsequent delays in patient's evaluation and treatment are causing sight loss. Strategies to increase capacity are needed urgently. The retinopathy (EMERALD) study tested diagnostic accuracy, acceptability, and costs of a new health care pathway for people with previously treated DME or PDR.

Design: Prospective, multicenter, case-referent, cross-sectional, diagnostic accuracy study undertaken in 13 hospitals in the United Kingdom.

Participants: Adults with type 1 or 2 diabetes previously successfully treated DME or PDR who, at the time of enrollment, had active or inactive disease.

Methods: A new health care pathway entailing multimodal imaging (spectral-domain OCT for DME, and 7-field Early Treatment Diabetic Retinopathy Study [ETDRS] and ultra-widefield [UWF] fundus images for PDR) interpreted by trained nonmedical staff (ophthalmic graders) to detect reactivation of disease was compared with the current standard care (face-to-face examination by ophthalmologists).

Main Outcome Measures: Primary outcome: sensitivity of the new pathway.

Secondary Outcomes: specificity; agreement between pathways; costs; acceptability; proportions requiring subsequent ophthalmologist assessment, unable to undergo imaging, and with inadequate images or indeterminate findings.

Results: The new pathway showed sensitivity of 97% (95% confidence interval [CI], 92%-99%) and specificity of 31% (95% CI, 23%-40%) to detect DME. For PDR, sensitivity and specificity using 7-field ETDRS images (85% [95% CI, 77%-91%] and 48% [95% CI, 41%-56%], respectively) or UWF images (83% [95% CI, 75%-89%] and 54% [95% CI, 46%-61%], respectively) were comparable. For detection of high-risk PDR, sensitivity and specificity were higher when using UWF images (87% [95% CI, 78%-93%] and 49% [95% CI, 42%-56%], respectively, for UWF versus 80% [95% CI, 69-88%] and 40% [95% CI, 34%-47%], respectively, for 7-field ETDRS images). Participants preferred ophthalmologists' assessments; in their absence, they preferred immediate feedback by graders, maintaining periodic ophthalmologist evaluations. When compared with the current standard of care, the new pathway could save £1390 per 100 DME visits and between £461 and £1189 per 100 PDR visits.

Conclusions: The new pathway has acceptable sensitivity and would release resources. Users' suggestions should guide implementation.
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http://dx.doi.org/10.1016/j.ophtha.2020.10.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980088PMC
April 2021

Author Correction: Targeting QKI-7 in vivo restores endothelial cell function in diabetes.

Nat Commun 2020 09 16;11(1):4770. Epub 2020 Sep 16.

The Wellcome-Wolfson Institute of Experimental Medicine, Belfast, BT9 7BL, UK.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-020-18712-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495446PMC
September 2020

Endothelial Cells Derived From Patients With Diabetic Macular Edema Recapitulate Clinical Evaluations of Anti-VEGF Responsiveness Through the Neuronal Pentraxin 2 Pathway.

Diabetes 2020 10 13;69(10):2170-2185. Epub 2020 Aug 13.

Wellcome-Wolfson Institute for Experimental Medicine, Belfast, U.K.

Diabetic macular edema (DME) remains a leading cause of vision loss worldwide. DME is commonly treated with intravitreal injections of vascular endothelial growth factor (VEGF)-neutralizing antibodies. VEGF inhibitors (anti-VEGFs) are effective, but not all patients fully respond to them. Given the potential side effects, inconvenience, and high cost of anti-VEGFs, identifying who may not respond appropriately to them and why is essential. Herein we determine first the response to anti-VEGFs, using spectral-domain optical coherence tomography scans obtained from a cohort of patients with DME throughout the 1st year of treatment. We found that fluid fully cleared at some time during the 1st year in 28% of eyes ("full responders"); fluid cleared only partly in 66% ("partial responders"); and fluid remained unchanged in 6% ("nonresponders"). To understand this differential response, we generated induced pluripotent stem cells (iPSCs) from full responders and nonresponders, from subjects with diabetes but no DME, and from age-matched volunteers without diabetes. We differentiated these iPSCs into endothelial cells (iPSC-ECs). Monolayers of iPSC-ECs derived from patients with diabetes showed a marked and prolonged increase in permeability upon exposure to VEGF; the response was significantly exaggerated in iPSC-ECs from nonresponders. Moreover, phosphorylation of key cellular proteins in response to VEGF, including VEGFR2, and gene expression profiles, such as that of neuronal pentraxin 2, differed between full responders and nonresponders. In this study, iPSCs were used in order to predict patients' responses to anti-VEGFs and to identify key mechanisms that underpin the differential outcomes observed in the clinic. This approach identified NPTX2 as playing a significant role in patient-linked responses and as having potential as a new therapeutic target for DME.
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http://dx.doi.org/10.2337/db19-1068DOI Listing
October 2020

Targeting QKI-7 in vivo restores endothelial cell function in diabetes.

Nat Commun 2020 07 30;11(1):3812. Epub 2020 Jul 30.

The Wellcome-Wolfson Institute of Experimental Medicine, Belfast, BT9 7BL, UK.

Vascular endothelial cell (EC) dysfunction plays a key role in diabetic complications. This study discovers significant upregulation of Quaking-7 (QKI-7) in iPS cell-derived ECs when exposed to hyperglycemia, and in human iPS-ECs from diabetic patients. QKI-7 is also highly expressed in human coronary arterial ECs from diabetic donors, and on blood vessels from diabetic critical limb ischemia patients undergoing a lower-limb amputation. QKI-7 expression is tightly controlled by RNA splicing factors CUG-BP and hnRNPM through direct binding. QKI-7 upregulation is correlated with disrupted cell barrier, compromised angiogenesis and enhanced monocyte adhesion. RNA immunoprecipitation (RIP) and mRNA-decay assays reveal that QKI-7 binds and promotes mRNA degradation of downstream targets CD144, Neuroligin 1 (NLGN1), and TNF-α-stimulated gene/protein 6 (TSG-6). When hindlimb ischemia is induced in diabetic mice and QKI-7 is knocked-down in vivo in ECs, reperfusion and blood flow recovery are markedly promoted. Manipulation of QKI-7 represents a promising strategy for the treatment of diabetic vascular complications.
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http://dx.doi.org/10.1038/s41467-020-17468-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393072PMC
July 2020

A Phase 2 Clinical Trial on the Use of Cibinetide for the Treatment of Diabetic Macular Edema.

J Clin Med 2020 Jul 14;9(7). Epub 2020 Jul 14.

Araim Pharmaceuticals, 580 White Plains Road, Suite 210, Tarrytown, NY 10591, USA.

Purpose: Evaluating the effects of cibinetide in diabetic macular edema (DME).

Methods: Phase 2 trial. Naïve patients with >400 µm central retinal thickness (CRT) DME in one/both eyes were recruited (May 2016-April 2017) at the Belfast Health and Social Care Trust. The study eye was that with best vision and lowest CRT. Patients self-administered cibinetide 4 mg/day subcutaneously for 12 weeks. Primary and secondary outcomes: mean change from baseline to week 12 in best corrected visual acuity (BCVA), CRT, central retinal sensitivity, tear production, patient-reported outcomes, adverse events and antibodies to cibinetide. Descriptive statistics were used; exploratory analyses focused on non-study eyes, diabetic control, serum cytokines and albuminuria.

Results: Nine patients were recruited; eight completed the study. There was no improvement in mean change baseline-week 12 in BCVA (-2.9 + 5.0), CRT (10 + 94.6 microns), central retinal sensitivity (-0.53 + 1.9 dB) or tear production (-0.13 + 7.7 mm), but there was an improvement in National Eye Institute Visual Function Questionnaire (NEI VFQ-25) composite scores (2.7 + 3.1). Some participants experienced improvements in CRT, tear production, diabetic control and albuminuria. No serious adverse events/reactions or anti-cibinetide antibodies were seen.

Conclusions: The cibinetide 12-week course was safe. Improvements in NEI VFQ-25 scores, CRT, tear production, diabetic control and albuminuria, observed in some participants, warrant further investigation.

Trial Registration: EudraCT number: 2015-001940-12. ISRCTN16962255-registration date 25.06.15.
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http://dx.doi.org/10.3390/jcm9072225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408632PMC
July 2020

Reply.

Retina 2020 09;40(9):e48-e49

The Ophthalmology Department, Belfast Health and Social Care Trust, Belfast, Northern Ireland, United Kingdom.

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http://dx.doi.org/10.1097/IAE.0000000000002883DOI Listing
September 2020

Circulating Leukocyte Alterations and the Development/Progression of Diabetic Retinopathy in Type 1 Diabetic Patients - A Pilot Study.

Curr Eye Res 2020 09 30;45(9):1144-1154. Epub 2020 Jan 30.

Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast , Belfast, UK.

Background/aims: The aim of this study was to investigate the relationship between alterations in circulating leukocytes and the initiation and progression of DR in people with type 1 diabetes (T1D).

Methods: Forty-one patients with T1D [13 mild non-proliferative DR (mNPDR), 14 active proliferative DR (aPDR) and 14 inactive PDR (iPDR)], and 13 age- and gender-matched healthy controls were recruited prospectively. Circulating leukocytes, including CD4 and CD8 T-cells, CD14CD16, CD14CD16 and CD14CD16 monocytes; CD16HLA-DR neutrophils, CD19 B-cells and CD56 natural killer cells and their cell surface adhesion molecules and chemokine receptors (HLA-DR, CD62L, CCR2, CCR5, CD66a, CD157 and CD305) were examined by flow cytometry.

Results: In DR patients, compared to healthy controls, increased proportions of neutrophils ( = .0152); reduced proportions of lymphocytes ( = .0002), HLA-DR leukocytes ( = .0406) and non-classical monocytes ( = .0204); and reduced expression of CD66a ( = .0048) and CD157 ( = .0007) on CD4 T cells were observed. Compared to healthy controls, CD19 B cells were reduced at the mNPDR but not aPDR patients. Total lymphocytes, CD4 T cells and CD8 T cells progressively decreased whereas neutrophils, the neutrophil/lymphocyte ratio and the neutrophil/CD4 ratio progressively increased from early to late stages of DR, reaching statistical significance at the aPDR stage. Longer diabetes duration was associated with a reduced proportion of CD8 T cells ( = .002) and increased neutrophil/CD8 ratio ( = .033).

Conclusions: In this pilot study, DR is associated with increased innate cellular immunity especially neutrophils and reduced adaptive cellular immunity particularly lymphocytes. Impaired B-cell immunity may play a role in the initiation of DR; whereas impaired T-cell immunity with increased neutrophil response may contribute to progression of DR from non-proliferative to proliferative stages in T1D patients. Large multicenter studies are needed to further understand the immune dysregulation in DR initiation and progression.
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http://dx.doi.org/10.1080/02713683.2020.1718165DOI Listing
September 2020

FIRST FAILED MACULAR HOLE SURGERY OR REOPENING OF A PREVIOUSLY CLOSED HOLE: Do We Gain by Reoperating?-A Systematic Review and Meta-analysis.

Retina 2020 Jan;40(1):1-15

The Ophthalmology Department, Belfast Health and Social Care Trust, Belfast, Northern Ireland, United Kingdom.

Purpose: To evaluate repeated surgery for idiopathic full-thickness macular hole that failed to close (FTC) after first surgery or reopened (RO) once originally closed.

Methods: Systematic review and meta-analysis. Pubmed.gov and Cochrane Library were searched for studies in English presenting outcomes of idiopathic full-thickness macular hole that FTC or RO (case reports/series of <5 cases excluded).

Outcome Measures: Anatomical closure, postoperative best-corrected visual acuity, intraoperative/postoperative complications, and patient-reported outcomes. Meta-analysis was performed on aggregate and available individual participant data sets using the metafor package in R.

Results: Twenty-eight eligible studies were identified. After reoperation, pooled estimates for anatomical closure were 78% (95% confidence interval 71-84%) and 80% (95% confidence interval 66-89%) for FTC and RO groups, respectively. On average, best-corrected visual acuity improved in both groups. However, only 15% (28 of 189 eyes) of FTC eyes achieved best-corrected visual acuity of ≥6/12. The pooled estimated probability of ≥2-line best-corrected visual acuity improvement was 58% in the FTC group (95% confidence interval 45-71%); meta-analysis was not possible in the RO group. The most common complication was cataract.

Conclusion: Reoperation for FTC or RO idiopathic full-thickness macular hole achieved a clinically meaningful visual acuity improvement in more than half of patients; high levels of vision (≥6/12), however, were uncommon.
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http://dx.doi.org/10.1097/IAE.0000000000002564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924931PMC
January 2020

STAT3 activation in circulating myeloid-derived cells contributes to retinal microvascular dysfunction in diabetes.

J Neuroinflammation 2019 Jul 8;16(1):138. Epub 2019 Jul 8.

Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, UK.

Background: Leukostasis is a key patho-physiological event responsible for capillary occlusion in diabetic retinopathy. Circulating monocytes are the main cell type entrapped in retinal vessels in diabetes. In this study, we investigated the role of the signal transducer and activator of transcription 3 (STAT3) pathway in diabetes-induced immune cell activation and its contribution to retinal microvascular degeneration.

Methods: Forty-one patients with type 1 diabetes (T1D) [mild non-proliferative diabetic retinopathy (mNPDR) (n = 13), active proliferative DR (aPDR) (n = 14), inactive PDR (iPDR) (n = 14)] and 13 age- and gender-matched healthy controls were recruited to the study. C57BL/6 J WT mice, SOCS3 and LysMSOCS3 mice were rendered diabetic by Streptozotocin injection. The expression of the phosphorylated human and mouse STAT3 (pSTAT3), mouse LFA-1, CD62L, CD11b and MHC-II in circulating immune cells was evaluated by flow cytometry. The expression of suppressor of cytokine signalling 3 (SOCS3) was examined by real-time RT-PCR. Mouse plasma levels of cytokines were measured by Cytometric Beads Array assay. Retinal leukostasis was examined following FITC-Concanavalin A perfusion and acellular capillary was examined following Isolectin B4 and Collagen IV staining.

Results: Compared to healthy controls, the expression of pSTAT3 in circulating leukocytes was statistically significantly higher in mNPDR but not aPDR and was negatively correlated with diabetes duration. The expression of pSTAT3 and its inhibitor SOCS3 was also significantly increased in leukocytes from diabetic mice. Diabetic mice had higher plasma levels of IL6 and CCL2 compared with control mice. LysMSOCS3 mice and SOCS3 mice developed comparative levels of diabetes, but leukocyte activation, retinal leukostasis and number of acellular capillaries were statistically significantly increased in LysMSOCS3 diabetic mice.

Conclusion: STAT3 activation in circulating immune cells appears to contribute to retinal microvascular degeneration and may be involved in DR initiation in T1D.
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http://dx.doi.org/10.1186/s12974-019-1533-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615157PMC
July 2019

Effectiveness of Multimodal imaging for the Evaluation of Retinal oedema And new vesseLs in Diabetic retinopathy (EMERALD).

BMJ Open 2019 06 28;9(6):e027795. Epub 2019 Jun 28.

Centre for Public Health, Queen's University, Belfast, UK.

Introduction: Diabetic macular oedema (DMO) and proliferative diabetic retinopathy (PDR) are the major causes of sight loss in people with diabetes. Due to the increased prevalence of diabetes, the workload related to these complications is increasing making it difficult for Hospital Eye Services (HSE) to meet demands.

Methods And Analysis: Effectiveness of Multimodal imaging for the Evaluation of Retinal oedema And new vesseLs in Diabetic retinopathy (EMERALD) is a prospective, case-referent, cross-sectional diagnostic study. It aims at determining the diagnostic performance, cost-effectiveness and acceptability of a new form of surveillance for people with stable DMO and/or PDR, which entails multimodal imaging and image review by an ophthalmic grader, using the current standard of care (evaluation of patients in clinic by an ophthalmologist) as the reference standard. If safe, cost-effective and acceptable, this pathway could help HES by freeing ophthalmologist time. The primary outcome of EMERALD is sensitivity of the new surveillance pathway in detecting active DMO/PDR. Secondary outcomes include specificity, agreement between new and the standard care pathway, positive and negative likelihood ratios, cost-effectiveness, acceptability, proportion of patients requiring subsequent full clinical assessment, unable to undergo imaging, with inadequate quality images or indeterminate findings.

Ethics And Dissemination: Ethical approval was obtained for this study from the Office for Research Ethics Committees Northern Ireland (reference 17/NI/0124). Study results will be published as a Health Technology Assessment monograph, in peer-reviewed national and international journals and presented at national/international conferences and to patient groups.

Trial Registration Number: NCT03490318 and ISRCTN:10856638.
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http://dx.doi.org/10.1136/bmjopen-2018-027795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609061PMC
June 2019

IMPACT OF RETINAL ISCHEMIA ON FUNCTIONAL AND ANATOMICAL OUTCOMES AFTER ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY IN PATIENTS WITH RETINAL VEIN OCCLUSION.

Retina 2020 Jun;40(6):1098-1109

Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom.

Purpose: To compare the impact of the classification of retinal vein occlusion (RVO) into ischemic or nonischemic forms on outcomes after anti-vascular endothelial growth factor therapy.

Methods: Retrospective review of consecutive patients with RVO evaluated at the Belfast Health and Social Care Trust between July 1, 2014, and December 31, 2015. Outcomes, including gain of ≥10 and ≥15 letters at 12 months, mean change in best-corrected visual acuity from baseline to 12 months, resolution of macular edema at 12 months, and development of neovascular complications and epiretinal membrane after anti-vascular endothelial growth factor therapy, were compared between ischemic and nonischemic eyes using regression models.

Results: One hundred and seventeen eyes (115 patients), 58 with central RVO and 59 with branch RVO, were included. A greater proportion of eyes with ischemic branch RVO gained ≥10 and ≥15 letters at 12 months than those with nonischemic branch RVO (P = 0.005 and P = 0.016, respectively). No statistically significant differences in visual outcomes were observed between ischemic and nonischemic central RVO. Retinal vein occlusion classification was not associated with anatomical outcomes after treatment.

Conclusion: Findings support the use of anti-vascular endothelial growth factors in ischemic and nonischemic forms of RVO.
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http://dx.doi.org/10.1097/IAE.0000000000002571DOI Listing
June 2020

PRAGMATISM OF RANDOMIZED CLINICAL TRIALS ON RANIBIZUMAB FOR THE TREATMENT OF DIABETIC MACULAR EDEMA: Impact on Clinical Outcomes.

Retina 2020 May;40(5):919-927

Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, Northern Ireland, UK.

Purpose: To evaluate the pragmatism and generalizability of randomized clinical trials (RCTs) on ranibizumab for diabetic macular edema and determine whether clinical outcomes would differ based on whether or not patients fulfill the eligibility criteria of these RCTs.

Methods: Pragmatism and generalizability of three RCTs on ranibizumab for diabetic macular edema (DRCRnet Protocols I and T, and RESTORE) were rated using the PRECIS-2 tool. A cohort of consecutive patients with diabetic macular edema was assessed to determine whether clinical outcomes differed based on whether or not patients met the RCT eligibility criteria. Univariable and multivariable regression analyses, adjusted for baseline best-corrected visual acuity, central retinal thickness and number of injections received, were used.

Results: All RCTs were rated as being more pragmatic than explanatory, with DRCRnet trials being the most pragmatic. Of the 216 eyes (176 patients) included in the cohort, 63% would have met eligibility criteria for Protocol T, 61% for Protocol I, and 56% for RESTORE. When adjusted for best-corrected visual acuity, central retinal thickness, and number of ranibizumab injections received, there were no statistically significant differences in best-corrected visual acuity or central retinal thickness found between "eligible" and "ineligible" patients.

Conclusion: Randomized clinical trials evaluating ranibizumab for diabetic macular edema were more pragmatic than explanatory. "Ineligible" patients still benefited from ranibizumab therapy.
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http://dx.doi.org/10.1097/IAE.0000000000002476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176348PMC
May 2020

Diabetic macular oedema and diode subthreshold micropulse laser (DIAMONDS): study protocol for a randomised controlled trial.

Trials 2019 Feb 12;20(1):122. Epub 2019 Feb 12.

The Northern Ireland Clinical Trials Unit (NICTU), Belfast, UK.

Background: In the UK, macular laser is the treatment of choice for people with diabetic macular oedema with central retinal subfield thickness (CST) < 400 μm, as per National Institute for Health and Care Excellence guidelines. It remains unclear whether subthreshold micropulse laser is superior and should replace standard threshold laser for the treatment of eligible patients.

Methods: DIAMONDS is a pragmatic, multicentre, allocation-concealed, randomised, equivalence, double-masked clinical trial that aims to determine the clinical effectiveness and cost-effectiveness of subthreshold micropulse laser compared with standard threshold laser, for the treatment of diabetic macular oedema with CST < 400 μm. The primary outcome is the mean change in best-corrected visual acuity in the study eye from baseline to month 24 post treatment. Secondary outcomes (at 24 months) include change in binocular best corrected visual acuity; CST; mean deviation of the Humphrey 10-2 visual field; change in percentage of people meeting driving standards; European Quality of Life-5 Dimensions, National Eye Institute Visual Functioning Questionnaire-25 and VisQoL scores; incremental cost per quality-adjusted life year gained; side effects; number of laser treatments and use of additional therapies. The primary statistical analysis will be per protocol rather than intention-to-treat analysis because the latter increases type I error in non-inferiority or equivalence trials. The difference between lasers for change in best-corrected visual acuity (using 95% CI) will be compared to the permitted maximum difference of five Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Linear and logistic regression models will be used to compare outcomes between treatment groups. A Markov-model-based cost-utility analysis will extend beyond the trial period to estimate longer-term cost-effectiveness.

Discussion: This trial will determine the clinical effectiveness and cost-effectiveness of subthreshold micropulse laser, when compared with standard threshold laser, for the treatment of diabetic macular oedema, the main cause of sight loss in people with diabetes mellitus.

Trial Registration: International Standard Randomised Controlled Trials, ISRCTN17742985 . Registered on 19 May 2017 (retrospectively registered).
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http://dx.doi.org/10.1186/s13063-019-3199-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373040PMC
February 2019

Reply to Correspondence by Calugaru and Calugaru to the Article Entitled "Ischemic retinal vein occlusion: characterizing the more severe spectrum of retinal vein occlusion" by Khayat et al.

Surv Ophthalmol 2019 Jul - Aug;64(4):593-594. Epub 2019 Jan 23.

Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, Northern Ireland, UK. Electronic address:

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http://dx.doi.org/10.1016/j.survophthal.2019.01.004DOI Listing
November 2019

Enhanced Function of Induced Pluripotent Stem Cell-Derived Endothelial Cells Through ESM1 Signaling.

Stem Cells 2019 02 17;37(2):226-239. Epub 2018 Nov 17.

Centre for Experimental Medicine, Queen's University Belfast, Belfast, Co Antrim, United Kingdom.

The mortality rate for (cardio)-vascular disease is one of the highest in the world, so a healthy functional endothelium is of outmost importance against vascular disease. In this study, human induced pluripotent stem (iPS) cells were reprogrammed from 1 ml blood of healthy donors and subsequently differentiated into endothelial cells (iPS-ECs) with typical EC characteristics. This research combined iPS cell technologies and next-generation sequencing to acquire an insight into the transcriptional regulation of iPS-ECs. We identified endothelial cell-specific molecule 1 (ESM1) as one of the highest expressed genes during EC differentiation, playing a key role in EC enrichment and function by regulating connexin 40 (CX40) and eNOS. Importantly, ESM1 enhanced the iPS-ECs potential to improve angiogenesis and neovascularisation in in vivo models of angiogenesis and hind limb ischemia. These findings demonstrated for the first time that enriched functional ECs are derived through cell reprogramming and ESM1 signaling, opening the horizon for drug screening and cell-based therapies for vascular diseases. Therefore, this study showcases a new approach for enriching and enhancing the function of induced pluripotent stem (iPS) cell-derived ECs from a very small amount of blood through ESM1 signaling, which greatly enhances their functionality and increases their therapeutic potential. Stem Cells 2019;37:226-239.
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http://dx.doi.org/10.1002/stem.2936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392130PMC
February 2019

Polarized retinal pigment epithelium generates electrical signals that diminish with age and regulate retinal pathology.

J Cell Mol Med 2018 11 30;22(11):5552-5564. Epub 2018 Aug 30.

Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK.

The transepithelial potential difference (TEP) across the retinal pigment epithelial (RPE) is dependent on ionic pumps and tight junction "seals" between epithelial cells. RPE cells release neurotrophic growth factors such as pigment epithelial derived factor (PEDF), which is reduced in age-related macular degeneration (AMD). The mechanisms that control the secretion of PEDF from RPE cells are not well understood. Using the CCL2/CX3CR1 double knockout mouse model (DKO), which demonstrates RPE damage and retinal degeneration, we uncovered an interaction between PEDF and the TEP which is likely to play an important role in retinal ageing and in the pathogenesis of AMD. We found that: (a) the expression of ATP1B1 (the Na /K -ATPase β1 subunit) was reduced significantly in RPE from aged mice, in patients with CNV (Choroidal Neovascularization) and in DKO mice; (b) the expression of PEDF also was decreased in aged persons and in DKO mice; (c) the TEP across RPE was reduced markedly in RPE cells from DKO mice and (d) an applied electric field (EF) of 50-100 mV/mm, used to mimic the natural TEP, increased the expression and secretion of PEDF in primary RPE cells. In conclusion, the TEP across the RPE depends on the expression of ATP1B1 and this regulates the secretion of PEDF by RPE cells and so may regulate the onset of retinal disease. Increasing the expression of PEDF using an applied EF to replenish a disease or age-reduced TEP may offer a new way of preventing or reversing retinal dysfunction.
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http://dx.doi.org/10.1111/jcmm.13829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201363PMC
November 2018

Fenofibrate for Diabetic Retinopathy.

Asia Pac J Ophthalmol (Phila) 2018 Nov-Dec;7(6):422-426. Epub 2018 Jul 30.

Department of Ophthalmology, The Belfast Health and Social Care Trust, Belfast, Northern Ireland.

Fenofibrate is a safe and inexpensive orally administered fibric acid derivative conventionally used to treat dyslipidemia. Two large randomized clinical trials, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies, demonstrated the benefit of oral fenofibrate in the treatment of patients with type 2 diabetes and diabetic retinopathy (DR), including reduced disease progression and need for laser treatment for diabetic macular edema and proliferative diabetic retinopathy. These findings are supported by results of experimental studies, which have demonstrated beneficial effects of fenofibrate ameliorating retinal vascular leakage and leukostasis, downregulating vascular endothelial growth factor, and reducing endothelial cell and pericyte loss, among others; all of these are characteristic features of DR. In spite of this evidence, fenofibrate is not prescribed routinely for treating patients with diabetes and DR. In FIELD and ACCORD studies, retinopathy was not the primary outcome and this may explain, at least partly, its lack of use for this indication. New trials are now underway to specifically address the effects of fenofibrate in DR; these trials will provide additional and robust data that may support current evidence favoring the use of fenofibrate in this common microvascular complication of diabetes.
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http://dx.doi.org/10.22608/APO.2018288DOI Listing
December 2018

Treatments for dry age-related macular degeneration and Stargardt disease: a systematic review.

Health Technol Assess 2018 05;22(27):1-168

Ophthalmology, Royal Victoria Hospital, Belfast, UK.

Background: Age-related macular degeneration (AMD) is the leading cause of visual loss in older people. Advanced AMD takes two forms, neovascular (wet) and atrophic (dry). Stargardt disease (STGD) is the commonest form of inherited macular dystrophy.

Objective: To carry out a systematic review of treatments for dry AMD and STGD, and to identify emerging treatments where future NIHR research might be commissioned.

Design: Systematic review.

Methods: We searched MEDLINE, EMBASE, Web of Science and The Cochrane Library from 2005 to 13 July 2017 for reviews, journal articles and meeting abstracts. We looked for studies of interventions that aim to preserve or restore vision in people with dry AMD or STGD. The most important outcomes are those that matter to patients: visual acuity (VA), contrast sensitivity, reading speed, ability to drive, adverse effects of treatment, quality of life, progression of disease and patient preference. However, visual loss is a late event and intermediate predictors of future decline were accepted if there was good evidence that they are strong predictors of subsequent visual outcomes. These include changes detectable by investigation, but not necessarily noticed by people with AMD or STGD. ClinicalTrials.gov, the World Health Organization search portal and the UK Clinical Trials gateway were searched for ongoing and recently completed clinical trials.

Results: The titles and abstracts of 7948 articles were screened for inclusion. The full text of 398 articles were obtained for further screening and checking of references and 112 articles were included in the final report. Overall, there were disappointingly few good-quality studies (including of sufficient size and duration) reporting useful outcomes, particularly in STGD. However we did identify a number of promising research topics, including drug treatments, stem cells, new forms of laser treatment, and implantable intraocular lens telescopes. In many cases, research is already under way, funded by industry or governments.

Limitations: In AMD, the main limitation came from the poor quality of much of the evidence. Many studies used VA as their main outcome despite not having sufficient duration to observe changes. The evidence on treatments for STGD is sparse. Most studies tested interventions with no comparison group, were far too short term, and the quality of some studies was poor.

Future Work: We think that the topics on which the Health Technology Assessment (HTA) and Efficacy Mechanism and Evaluation (EME) programmes might consider commissioning primary research are in STGD, a HTA trial of fenretinide (ReVision Therapeutics, San Diego, CA, USA), a visual cycle inhibitor, and EME research into the value of lutein and zeaxanthin supplements, using short-term measures of retinal function. In AMD, we suggest trials of fenretinide and of a potent statin. There is epidemiological evidence from the USA that the drug, levodopa, used for treating Parkinson's disease, may reduce the incidence of AMD. We suggest that similar research should be carried out using the large general practice databases in the UK. Ideally, future research should be at earlier stages in both diseases, before vision is impaired, using sensitive measures of macular function. This may require early detection of AMD by screening.

Study Registration: This study is registered as PROSPERO CRD42016038708.

Funding: The National Institute for Health Research HTA programme.
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http://dx.doi.org/10.3310/hta22270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994642PMC
May 2018

Vitreomacular interface abnormalities in patients with diabetic macular oedema and their implications on the response to anti-VEGF therapy.

Graefes Arch Clin Exp Ophthalmol 2018 Aug 19;256(8):1411-1418. Epub 2018 May 19.

Department of Ophthalmology, Belfast Health and Social Care Trust, Belfast, UK.

Purpose: To determine whether the presence of vitreomacular interface abnormalities (VMIA) in patients with diabetic macular oedema (DMO) modifies the response to ranibizumab.

Methods: Medical records and spectral-domain optical coherence tomography (SD-OCT) scans of consecutive patients with centre-involving DMO initiating therapy with ranibizumab between December 2013 and March 2014 at the Belfast Health and Social Care Trust were reviewed. Patients were identified through an electronic database. Demographics; systemic baseline characteristics; history of previous ocular surgery/laser; best-corrected visual acuity (BCVA), central retinal thickness (CRT) and stage of retinopathy at presentation; and BCVA, CRT and presence/absence of fluid at the last follow-up were recorded. OCT scans were reviewed by a masked investigator who graded them for the presence/absence of VMIA at baseline and during follow-up and for the change in the posterior hyaloid face during follow-up. The association between (1) VMIA at baseline and (2) the change in the posterior hyaloid face during the follow-up and functional/anatomical outcomes was evaluated.

Results: One hundred forty-six eyes of 100 patients (mean age 63.5 years) followed for a mean of 9 months (range 2-14 months; only 9/146 dropped to follow-up before month 6) were included. Statistically significant differences were observed at baseline in BCVA (p = 0.007), previous macular laser and panretinal photocoagulation (PRP) (p = 0.006) and previous cataract surgery (p = 0.01) between eyes with and without VMIA, with better levels of vision, higher frequency of macular laser and lower frequency of PRP in eyes where no VMIA was present. Multivariable regression analysis did not disclose any statistically significant associations between VMIA at baseline or change in the posterior hyaloid face during the follow-up and functional and anatomical outcomes following treatment.

Conclusion: VMIA are associated with worse presenting vision in patients with DMO; VMIA or change in the posterior hyaloid face during the follow-up did not modify the response to ranibizumab in this study.
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http://dx.doi.org/10.1007/s00417-018-4009-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060772PMC
August 2018

Ischemic retinal vein occlusion: characterizing the more severe spectrum of retinal vein occlusion.

Surv Ophthalmol 2018 Nov - Dec;63(6):816-850. Epub 2018 Apr 27.

Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom. Electronic address:

Retinal vein occlusion (RVO)-including central RVO, branch RVO, and hemicentral and hemispheric RVO-is the second most common vascular cause of visual loss, surpassed only by diabetic retinopathy. The presence and extent of retinal ischemia in RVO is associated with a worse prognosis. On this basis, most previously conducted studies considered ischemic retinal vein occlusion (iRVO) and non-iRVO as separate entities based on set thresholds of existing retinal ischemia as determined by fundus fluorescein angiography. Other diagnostic technologies have been used specifically in the differentiation of ischemic central retinal vein occlusion and nonischemic central retinal vein occlusion. To date, there is no fully accepted definition for iRVO. Some clinicians and researchers may favor establishing a clear differentiation between these forms of RVO; others may prefer not to consider iRVO as a separate entity. Whatever the case, retinal ischemia in RVO confers a higher risk of visual loss and neovascular complications; thus, it should be determined as accurately as possible in patients with this disease and be considered in clinical and experimental studies. Most recently conducted clinical trials evaluating new treatments for macular edema secondary to RVO included none or only few patients with iRVO based on previous definitions (i.e., few patients with sizeable areas of retinal ischemia were recruited in these trials), and thus it is unclear whether the results observed in recruited patients could be extrapolated to those with retinal ischemia. There has been scant research aiming at developing and/or testing treatments for retinal ischemia, as well as to prevent new vessel formation as a result of RVO. We provide a detailed review of the knowledge gathered over the years on iRVO, from controversies on its definition and diagnosis to the understanding of its epidemiology, risk factors and pathogenesis, the structural and functional effects of this disease in the eye and its complications, natural history, and outcomes after treatment. In each section, the definition of iRVO used is given so, independently of whether iRVO is considered a separate clinical entity or a more severe end of the spectrum of RVO, the information will be useful to clinicians to determine patient's risk, guide therapeutic decisions, and counsel patients and for researchers to design future studies.
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http://dx.doi.org/10.1016/j.survophthal.2018.04.005DOI Listing
November 2018

Different lasers and techniques for proliferative diabetic retinopathy.

Cochrane Database Syst Rev 2018 03 15;3:CD012314. Epub 2018 Mar 15.

Ophthalmology Department, Royal Victoria Hospital, Grosvenor Road, Belfast, UK, BT12 6BA.

Background: Diabetic retinopathy (DR) is a chronic progressive disease of the retinal microvasculature associated with prolonged hyperglycaemia. Proliferative DR (PDR) is a sight-threatening complication of DR and is characterised by the development of abnormal new vessels in the retina, optic nerve head or anterior segment of the eye. Argon laser photocoagulation has been the gold standard for the treatment of PDR for many years, using regimens evaluated by the Early Treatment of Diabetic Retinopathy Study (ETDRS). Over the years, there have been modifications of the technique and introduction of new laser technologies.

Objectives: To assess the effects of different types of laser, other than argon laser, and different laser protocols, other than those established by the ETDRS, for the treatment of PDR. We compared different wavelengths; power and pulse duration; pattern, number and location of burns versus standard argon laser undertaken as specified by the ETDRS.

Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2017, Issue 5); Ovid MEDLINE; Ovid Embase; LILACS; the ISRCTN registry; ClinicalTrials.gov and the ICTRP. The date of the search was 8 June 2017.

Selection Criteria: We included randomised controlled trials (RCTs) of pan-retinal photocoagulation (PRP) using standard argon laser for treatment of PDR compared with any other laser modality. We excluded studies of lasers that are not in common use, such as the xenon arc, ruby or Krypton laser.

Data Collection And Analysis: We followed Cochrane guidelines and graded the certainty of evidence using the GRADE approach.

Main Results: We identified 11 studies from Europe (6), the USA (2), the Middle East (1) and Asia (2). Five studies compared different types of laser to argon: Nd:YAG (2 studies) or diode (3 studies). Other studies compared modifications to the standard argon laser PRP technique. The studies were poorly reported and we judged all to be at high risk of bias in at least one domain. The sample size varied from 20 to 270 eyes but the majority included 50 participants or fewer.Nd:YAG versus argon laser (2 studies): very low-certainty evidence on vision loss, vision gain, progression and regression of PDR, pain during laser treatment and adverse effects.Diode versus argon laser (3 studies): very-low certainty evidence on vision loss, vision gain, progression and regression of PDR and adverse effects; moderate-certainty evidence that diode laser was more painful (risk ratio (RR) troublesome pain during laser treatment (RR 3.12, 95% CI 2.16 to 4.51; eyes = 202; studies = 3; I = 0%).0.5 second versus 0.1 second exposure (1 study): low-certainty evidence of lower chance of vision loss with 0.5 second compared with 0.1 second exposure but estimates were imprecise and compatible with no difference or an increased chance of vision loss (RR 0.42, 95% CI 0.08 to 2.04, 44 eyes, 1 RCT); low-certainty evidence that people treated with 0.5 second exposure were more likely to gain vision (RR 2.22, 95% CI 0.68 to 7.28, 44 eyes, 1 RCT) but again the estimates were imprecise . People given 0.5 second exposure were more likely to have regression of PDR compared with 0.1 second laser PRP again with imprecise estimate (RR 1.17, 95% CI 0.92 to 1.48, 32 eyes, 1 RCT). There was very low-certainty evidence on progression of PDR and adverse effects.'Light intensity' PRP versus classic PRP (1 study): vision loss or gain was not reported but the mean difference in logMAR acuity at 1 year was -0.09 logMAR (95% CI -0.22 to 0.04, 65 eyes, 1 RCT); and low-certainty evidence that fewer patients had pain during light PRP compared with classic PRP with an imprecise estimate compatible with increased or decreased pain (RR 0.23, 95% CI 0.03 to 1.93, 65 eyes, 1 RCT).'Mild scatter' (laser pattern limited to 400 to 600 laser burns in one sitting) PRP versus standard 'full' scatter PRP (1 study): very low-certainty evidence on vision and visual field loss. No information on adverse effects.'Central' (a more central PRP in addition to mid-peripheral PRP) versus 'peripheral' standard PRP (1 study): low-certainty evidence that people treated with central PRP were more likely to lose 15 or more letters of BCVA compared with peripheral laser PRP (RR 3.00, 95% CI 0.67 to 13.46, 50 eyes, 1 RCT); and less likely to gain 15 or more letters (RR 0.25, 95% CI 0.03 to 2.08) with imprecise estimates compatible with increased or decreased risk.'Centre sparing' PRP (argon laser distribution limited to 3 disc diameters from the upper temporal and lower margin of the fovea) versus standard 'full scatter' PRP (1 study): low-certainty evidence that people treated with 'centre sparing' PRP were less likely to lose 15 or more ETDRS letters of BCVA compared with 'full scatter' PRP (RR 0.67, 95% CI 0.30 to 1.50, 53 eyes). Low-certainty evidence of similar risk of regression of PDR between groups (RR 0.96, 95% CI 0.73 to 1.27, 53 eyes). Adverse events were not reported.'Extended targeted' PRP (to include the equator and any capillary non-perfusion areas between the vascular arcades) versus standard PRP (1 study): low-certainty evidence that people in the extended group had similar or slightly reduced chance of loss of 15 or more letters of BCVA compared with the standard PRP group (RR 0.94, 95% CI 0.70 to 1.28, 270 eyes). Low-certainty evidence that people in the extended group had a similar or slightly increased chance of regression of PDR compared with the standard PRP group (RR 1.11, 95% CI 0.95 to 1.31, 270 eyes). Very low-certainty information on adverse effects.

Authors' Conclusions: Modern laser techniques and modalities have been developed to treat PDR. However there is limited evidence available with respect to the efficacy and safety of alternative laser systems or strategies compared with the standard argon laser as described in ETDRS.
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http://dx.doi.org/10.1002/14651858.CD012314.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494342PMC
March 2018

Diabetic retinopathy and the use of laser photocoagulation: is it cost-effective to treat early?

BMJ Open Ophthalmol 2017 25;2(1):e000021. Epub 2017 Sep 25.

Warwick Medical School, University of Warwick, Coventry, UK.

Background/aims: The aim of the study was to explore whether it would be cost-effective to apply panretinal photocoagulation (PRP) at the severe non-proliferative diabetic retinopathy (NPDR) (early treatment) stage, compared with waiting until high-risk proliferative diabetic retinopathy (HR-PDR) characteristics (deferred treatment) developed.

Methods: A Markov model with a 30-year time horizon was developed, in which patients presenting with moderate NPDR could progress through all stages of DR (severe NPDR>early PDR>HR-PDR>severe PDR) to severe vision loss and blindness (and to death). A National Health Service and personal social services perspective was adopted. Transition probabilities were mainly derived from the Early Treatment Diabetic Retinopathy Study. Health state utilities, costs and complications were based on information from the literature, supplemented by expert opinion. Costs and outcomes were discounted at 3.5%. Both deterministic and probabilistic sensitivity analyses were conducted.

Results: Administering PRP at the severe NPDR stage could be more effective and less costly than waiting until HR-PDR developed. Sensitivity analyses gave similar results, with early treatment continuing to dominate deferred treatment. The probabilistic sensitivity analysis suggests that at willingness-to-pay threshold of £20-£30 000 per quality-adjusted life year, the probability of early treatment being cost-effective is 60%.

Conclusion: PRP administered at the severe NPDR stage is likely to be cost-effective compared with delaying photocoagulation until HR-PDR develops. However, given the limitations of the evidence, these results need to be interpreted with caution. A trial of early versus deferred laser therapy is needed to provide better data based on modern treatments.
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http://dx.doi.org/10.1136/bmjophth-2016-000021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721644PMC
September 2017