Interobserver agreement in detecting spectral-domain optical coherence tomography features of diabetic macular edema

Purpose: To evaluate interobserver agreement for the detection of spectral-domain optical coherence tomography (SDOCT) features of diabetic macular edema (DME). Method: Cross-sectional study in which 2 retinal specialists evaluated SDOCT scans from eyes receiving treatment for DME. Scans from 50 eyes with DME of 39 patients were graded for features of DME including intra-retinal fluid (IRF), diffuse retinal oedema (DRE), hyper-reflective foci (HRF), subretinal fluid (SRF), macular fluid and vitreomacular traction (VMT). Features were graded as present or absent at zones involving the fovea, 1mm from the fovea and the whole scan of 49 line scans. Analysis was performed using cross-tabulations for percentage concordance and kappa values (κ). Results: In the 2950 line scans analysed, there was an increase in percentage concordance for DRE and HRF when moving from a foveal line scan, 1mm zone and then to a whole scan analysis (88% vs 94% vs 96%) and (88% vs 94% vs 94%) respectively with κ ranging from substantial to almost perfect. Percentage concordance for SRF was 96% at all 3 regions analysed, whilst IRF was 96% at fovea and 98% at higher number of line-scans analysed. Concordance for MF was 100% at fovea and 98% at 1mm zone and whole scan with almost perfect and substantial κ respectively. κ agreement was substantial for VMT at all regions analysed. Conclusion: We report a high level of interobserver agreement in the detection of SDOCT features of DME. This finding is important as detection of macular fluid is used to guide retreatment with anti-angiogenic agents

Mapping from visual acuity to EQ-5D, EQ-5D with vision bolt-on, and VFQ-UI in patients with macular edema in the LEAVO trial

Objectives Mappings to convert clinical measures to preference-based measures of health such as the EQ-5D-3L are sometimes required in cost-utility analyses. We developed mappings to convert best-corrected visual acuity (BCVA) to the EQ-5D-3L, the EQ-5D-3L with a vision bolt-on (EQ-5D V), and the Visual Functioning Questionnaire-Utility Index (VFQ-UI) in patients with macular edema caused by central retinal vein occlusion. Methods We used data from Lucentis, Eylea, Avastin in vein occlusion (LEAVO), which is a phase-3 randomized controlled trial comparing ranibizumab, aflibercept, and bevacizumab in 463 patients with observations at 6 time points. We estimated adjusted limited dependent variable mixture models consisting of 1 to 4 distributions (components) using BCVA in each eye, age, and sex to predict utility within the components and BCVA as a determinant of component membership. We compared model fit using mean error, mean absolute error, root mean square error, Akaike information criteria, Bayesian information criteria, and visual inspection of mean predicted and observed utilities and cumulative distribution functions. Results Mean utility scores were 0.82 for the EQ-5D-3L, 0.79 for the EQ-5D V, and 0.88 for the VFQ-UI. The best-fitting models for the EQ-5D and EQ-5D V had 2 components (with means of approximately 0.44 and 0.85), and the best-fitting model for VFQ-UI had 3 components (with means of approximately 0.95, 0.74, and 0.90). Conclusions Models with multiple components better predict utility than those with single components. This article provides a valuable addition to the literature, in which previous mappings in visual acuity have been limited to linear regressions, resulting in unfounded assumptions about the distribution of the dependent variable

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

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

Clinical efficacy and mechanistic evaluation of aflibercept for proliferative diabetic retinopathy (acronym CLARITY): a multicentre phase IIb randomised active-controlled clinical trial

Introduction Proliferative diabetic retinopathy (PDR) is the main cause of severe visual loss in people with diabetes mellitus. The standard treatment for this condition is panretinal photocoagulation (PRP). This laser treatment is inherently destructive, with predictable adverse effects on visual function, and a safer alternative is required. Intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors can induce short-term regression of retinal neovascularisation. The aim of this randomised controlled trial is to determine the efficacy, safety and cost-effectiveness of intravitreal aflibercept, an inhibitor of VEGF-A, VEGF-B and placental growth factor (PLGF), in PDR, and to investigate the impact on local oxygenation. Methods and analysis This is a phase IIb randomised controlled single-masked multicentre clinical trial to determine the impact of repeated intravitreal aflibercept injections in the treatment and prevention of PDR. 220 participants with treatment-naïve or treated but active retinal neovascularisation in at least one eye will be randomly allocated 1:1 to intravitreal aflibercept injections or PRP for a period of 52�weeks. The primary outcome is the change in best-corrected visual acuity in the study eye at 52�weeks. Secondary outcomes include changes from baseline in other visual functions, anatomical changes and cost-effectiveness. Ocular and non-ocular adverse events will also be reported over 52�weeks. Ethics and dissemination The study has been approved by the National Research Ethics Service (NRES) committee with respect to scientific content and compliance with applicable research and human subjects� regulations. Findings will be reported through scientific publications and research conferences. The results of this study will provide clinical evidence for the feasibility, efficacy safety and cost-effectiveness of intravitreal aflibercept for PDR

Cost effectiveness of ranibizumab vs aflibercept vs bevacizumab for the treatment of macular oedema due to central retinal vein occlusion: the LEAVO study

Background We aimed to assess the cost effectiveness of intravitreal ranibizumab (Lucentis), aflibercept (Eylea) and bevacizumab (Avastin) for the treatment of macular oedema due to central retinal vein occlusion. Methods We calculated costs and quality-adjusted life-years from the UK National Health Service and Personal Social Services perspective. We performed a within-trial analysis using the efficacy, safety, resource use and health utility data from a randomised controlled trial (LEAVO) over 100 weeks. We built a discrete event simulation to model long-term outcomes. We estimated utilities using the Visual-Functioning Questionnaire-Utility Index, EQ-5D and EQ-5D with an additional vision question. We used standard UK costs sources for 2018/19 and a cost of £28 per bevacizumab injection. We discounted costs and quality-adjusted life-years at 3.5% annually. Results Bevacizumab was the least costly intervention followed by ranibizumab and aflibercept in both the within-trial analysis (bevacizumab: £6292, ranibizumab: £13,014, aflibercept: £14,328) and long-term model (bevacizumab: £18,353, ranibizumab: £30,226, aflibercept: £35,026). Although LEAVO did not demonstrate bevacizumab to be non-inferior for the visual acuity primary outcome, the three interventions generated similar quality-adjusted life-years in both analyses. Bevacizumab was always the most cost-effective intervention at a threshold of £30,000 per quality-adjusted life-year, even using the list price of £243 per injection. Conclusions Wider adoption of bevacizumab for the treatment of macular oedema due to central retinal vein occlusion could result in substantial savings to healthcare systems and deliver similar health-related quality of life. However, patients, funders and ophthalmologists should be fully aware that LEAVO could not demonstrate that bevacizumab is non-inferior to the licensed agents

Clinical efficacy and safety of a light mask for prevention of dark adaptation in treating and preventing progression of early diabetic macular oedema at 24 months (CLEOPATRA): a multicentre, phase 3, randomised controlled trial

Background: We aimed to assess 24-month outcomes of wearing an organic light-emitting sleep mask as an intervention to treat and prevent progression of non-central diabetic macular oedema. Methods: CLEOPATRA was a phase 3, single-blind, parallel-group, randomised controlled trial undertaken at 15 ophthalmic centres in the UK. Adults with non-centre-involving diabetic macular oedema were randomly assigned (1:1) to wearing either a light mask during sleep (Noctura 400 Sleep Mask, PolyPhotonix Medical, Sedgefield, UK) or a sham (non-light) mask, for 24 months. Randomisation was by minimisation generated by a central web-based computer system. Outcome assessors were masked technicians and optometrists. The primary outcome was the change in maximum retinal thickness on optical coherence tomography (OCT) at 24 months, analysed using a linear mixed-effects model incorporating 4-monthly measurements and baseline adjustment. Analysis was done using the intention-to-treat principle in all randomised patients with OCT data. Safety was assessed in all patients. This trial is registered with Controlled-Trials.com, number ISRCTN85596558. Findings: Between April 10, 2014, and June 15, 2015, 308 patients were randomly assigned to wearing the light mask (n=155) or a sham mask (n=153). 277 patients (144 assigned the light mask and 133 the sham mask) contributed to the mixed-effects model over time, including 246 patients with OCT data at 24 months. The change in maximum retinal thickness at 24 months did not differ between treatment groups (mean change −9·2 μm [SE 2·5] for the light mask vs −12·9 μm [SE 2·9] for the sham mask; adjusted mean difference −0·65 μm, 95% CI −6·90 to 5·59; p=0·84). Median compliance with wearing the light mask at 24 months was 19·5% (IQR 1·9–51·6). No serious adverse events were related to either mask. The most frequent adverse events related to the assigned treatment were discomfort on the eyes (14 with the light mask vs seven with the sham mask), painful, sticky, or watery eyes (14 vs six), and sleep disturbance (seven vs one). Interpretation: The light mask as used in this study did not confer long-term therapeutic benefit on non-centre-involving diabetic macular oedema and the study does not support its use for this indication. Funding: The Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership

The combination of intravitreal triamcinolone and phacoemulsification surgery in patients with diabeticfoveal oedema and cataract

BACKGROUND: The management of diabetic patients with refractory macular oedema or patients with no adequate pre-operative view to administer laser treatment provide a challenge to the ophthalmologist. We wished to assess the use, safety and effect of intravitreal triamcinolone injection at the time of cataract surgery in patients with diabetic foveal oedema and sight limiting lens opacities. METHOD: This was a longitudinal non-randomised prospective pilot study in 18 eyes (12 patients). All patients had visually significant lens opacities and either persistent diabetic foveal oedema unresponsive to laser treatment-group A, or foveal oedema with no adequate pre-operative view for laser treatment- group B. The cataract surgery was carried out under full aseptic technique using a self-sealing temporal incision and a foldable acrylic lens. Intravitreal triamcinolone was given infratemporally pars plana at the completion of the cataract surgery. The patients were reviewed at day 5, 2 weeks, 2 months and then every 3 months as required. The Wilcoxin matched-pairs test was used to assess the significance of the improvement in visual acuity at 2 months. RESULTS: Twelve patients with a total of 18 eyes were included in the study. There were 10 patients (15 eyes) in group A and 3 patients (3 eyes) in group B. Preoperatively 16 of the 18 eyes had a visual acuity of 6/24 or worse. Postoperatively 83% of patients had completely dry foveae at 2 weeks. Best-corrected visual acuities at two months review ranged from 6/6 to CF with 9 eyes (50%) achieving 6/12 or better (7 eyes (47%) in group A and 2 eyes (67%) in group B). Three eyes had no recorded improvement in visual acuity, but no eyes had deterioration in acuity. The improvement in visual acuity was significant at p = 0.001. There were no significant sight threatening complications. CONCLUSION: Intravitreal triamcinolone has been shown to lead to an improvement in macular oedema and visual improvement in diabetic patients not undergoing cataract surgery but has not, to our knowledge, been previously used in a study like this one. We suggest that intravitreal injection at the time of cataract surgery could be carried out safely with encouraging visual outcomes in patients with diabetic foveal oedema and cataract

Intravitreal ranibizumab versus aflibercept versus bevacizumab for macular oedema due to central retinal vein occlusion: the LEAVO non-inferiority three-arm RCT

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

Successful application of ancient DNA extraction and library construction protocols to museum wet collection specimens

Millions of scientific specimens are housed in museum collections, a large part of which are fluid preserved. The use of formaldehyde as fixative and subsequent storage in ethanol is especially common in ichthyology and herpetology. This type of preservation damages DNA and reduces the chance of successful retrieval of genetic data. We applied ancient DNA extraction and single stranded library construction protocols to a variety of vertebrate samples obtained from wet collections and of different ages. Our results show that almost all samples tested yielded endogenous DNA. Archival DNA extraction was successful across different tissue types as well as using small amounts of tissue. Conversion of archival DNA fragments into single-stranded libraries resulted in usable data even for samples with initially undetectable DNA amounts. Subsequent target capture approaches for mitochondrial DNA using homemade baits on a subset of 30 samples resulted in almost complete mitochondrial genome sequences in several instances. Thus, application of ancient DNA methodology makes wet collection specimens, including type material as well as rare, old or extinct species, accessible for genetic and genomic analyses. Our results, accompanied by detailed step-by-step protocols, are a large step forward to open the DNA archive of museum wet collections for scientific studies