Reattachment rate with pneumatic retinopexy versus pars plana vitrectomy for single break rhegmatogenous retinal detachment.

AIM: To assess the primary reattachment rate (PARR) in pneumatic retinopexy (PnR) versus pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment (RRD) meeting the Pneumatic Retinopexy versus Vitrectomy for the Management of Primary Rhegmatogenous Retinal Detachment Outcomes Randomised Trial (PIVOT) criteria with a single break in detached retina. METHODS: A post hoc analysis of two clinical trials. To be included, patients with primary RRD had to meet PIVOT criteria but could have only one break in the detached retina. Patients with additional pathology in the attached retina were included in a secondary analysis. The primary outcome was PARR following PnR versus PPV at 1-year postoperatively. RESULTS: 162 patients were included. 53% (86/162) underwent PnR and 47% (76/162) had a PPV. 99% (85/86) and 86.8% (66/76) completed the 1-year follow-up visits in the PnR and PPV groups, respectively. PARR was 88.2% (75/85) in the PnR group and 90.9% (60/66) in the PPV group (p=0.6) with a mean postoperative logMAR best-corrected visual acuity of 0.19±0.25 versus 0.34±0.37 (Snellen 20/30 vs 20/44) (p=0.01) each in the PnR and PPV groups, respectively.In an additional analysis of patients who were also allowed to have any pathology in the attached retina, the PARR was 85% (91/107) and 91.6% (66/72) in the PnR and PPV groups, respectively (p=0.18). CONCLUSIONS: PnR and PPV provide similar long-term PARR in a substantial proportion of patients meeting PIVOT criteria with only a single break in the detached retina. Therefore, in patients meeting these specific criteria, PnR is an appropriate first-line therapy as it offers superior functional outcomes without compromising PARR.

Facedown Positioning in Macular Hole Surgery: A Systematic Review and Individual Participant Data Meta-Analysis.

TOPIC: To assess the anatomical and visual effects of facedown positioning (FDP) advice in patients undergoing vitrectomy with gas tamponade for idiopathic full-thickness macular holes (FTMHs), and to explore differential treatment effects by macular hole size and FDP duration. CLINICAL RELEVANCE: The necessity and duration of FDP for FTMH closure remain contentious, with no consensus guidelines. METHODS: Prospectively registered systematic review and individual patient data (IPD) meta-analysis of randomised controlled trials comparing FDP to no FDP (nFDP) across the MEDLINE, Embase, and Cochrane Library databases and clinical trial registries from January 2000 to March 2023 (CRD42023395152). All adults with idiopathic FTMHs undergoing vitrectomy with gas tamponade were included. The main outcomes were primary macular hole closure and post-operative visual acuity at 6 months or nearest time point. RESULTS: Of 8 eligible trials, 5 contributed IPD for 379 eyes and were included in our analysis. The adjusted odds ratio (OR) for primary closure with FDP versus nFDP was 2.41 (95% CI 0.98 to 5.93, P = 0.06) [GRADE: Low], translating to a relative risk (RR) of 1.08 (1.00 to 1.11) and a number needed to treat (NNT) of 15. The FDP group exhibited a mean improvement in post-operative visual acuity of -0.08 logMAR (-0.13 to -0.02, P = 0.006) [GRADE: Low] compared to the nFDP group. Benefits were more certain in participants with larger holes of minimum linear diameter ≥ 400 µm: adjusted OR for closure ranged from 1.13 to 10.12 (P = 0.030) (NNT 12), with a mean visual acuity improvement of -0.18 to -0.01 logMAR (P = 0.022). Each additional day of FDP was associated with improved odds of anatomical success (adjusted OR 1.02 to 1.41, RR 1.00 to 1.02, P = 0.026) and visual acuity improvement (-0.02 logMAR, -0.03 to -0.01, P = 0.002), possibly plateauing at 3 days. CONCLUSION: This study provides low certainty evidence that FDP improves the anatomical and visual outcomes of macular hole surgery modestly and indicate that the effect may be more substantial for macular holes exceeding 400 µm. The findings support recommending FDP for patients with macular holes exceeding 400 µm pending further investigation.

Impact of COVID-19 on a real-world treat-and-extend regimen with aflibercept for neovascular age-related macular degeneration.

OBJECTIVE: To assess the effect of the COVID-19 pandemic on injection intervals among patients treated for neovascular age-related macular degeneration. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients treated at a single practice using a treat-and-extend regimen with intravitreal aflibercept between December 2018 and April 2021. METHODS: The primary outcome was the change in injection intervals. Secondary outcomes included differences in best-recorded visual acuity (BRVA) and central subfield thickness (CST). Associations were evaluated with linear mixed-effects modelling. RESULTS: This study included 1839 injections from 185 eyes (141 patients). The median (interquartile range) injection intervals in the pre-COVID-19 and COVID-19 periods were 60 (42-70) and 70 (49-90) days, respectively. The pandemic was associated with a mean injection interval lengthening of 7.2 days (P < 0.001), a decrease in BRVA of 3.1 Early Treatment Diabetic Retinopathy Study letters (P < 0.001), and a reduction in CST of 14.7 µm (P = 0.003). The presence of exudative intraretinal fluid was associated with a reduction in treatment intervals of 11.1 days (P < 0.001), a reduction in BRVA of 1.9 Early Treatment Diabetic Retinopathy Study letters (P < 0.001), and an increase in CST of 52.4 µm (P < 0.001). The presence of subretinal fluid was associated with a reduction in treatment intervals of 8.5 days (P < 0.001) and an increase in CST of 21.6 µm (P < 0.001). CONCLUSIONS: This real-world study estimated that the severe acute respiratory syndrome coronavirus 2 pandemic resulted in an injection extension of 7.2 days with associated decreases in BRVA and CST that are unlikely clinically significant on a population basis. This builds on evidence suggesting that long-term vascular endothelial growth factor suppression can facilitate meaningful interval extensions while maintaining visual acuity.

Outcomes of Post-Cataract Surgery Endophthalmitis Managed Without Microbial Cultures.

PURPOSE: To evaluate outcomes of eyes with post-cataract surgery endophthalmitis that were managed without microbial cultures. DESIGN: This retrospective, single-center comparative cohort study identified all cases of endophthalmitis after cataract surgery presenting between February 1, 2014, and November 1, 2022. SUBJECTS: All eyes presenting with presumed endophthalmitis requiring in-office treatment with intravitreal antibiotics and either a vitreous or aqueous tap were included. METHODS: Endophthalmitis cases were divided into the "culture group" if the vitreous or aqueous specimens were sent for microbiologic sampling or into the "no culture group" if an aqueous or vitreous tap was performed but not sent for microbiologic sampling. MAIN OUTCOME MEASURES: Best corrected visual acuity (VA) 12 months following endophthalmitis presentation, incidence of retinal detachment, and need for subsequent procedures. RESULTS: Of the 232 endophthalmitis cases identified, 196 (85%) were in the "culture group" and 36 (15%) were in the "no culture group". At endophthalmitis presentation, eyes in the "culture group" had a mean (SD) logMAR VA [Snellen Equivalent] of 2.14 (0.8) [20/2760] and mean (SD) logMAR VA in the "no culture group" was 1.93 (0.8) [20/1702] (p=0.185). At 12-month follow up, mean (SD) logMAR VA for the "culture group" was 0.80 (1.0) [20/126] and 0.41 (0.5) [20/50] in the "no culture group" (adjusted difference = 0.41, 95% CI = -0.043 - 0.857, p=0.076). Twenty of 196 (10%) eyes in the "culture group" developed secondary retinal detachments within 12 months of presentation compared to 0 in the "no culture group" (p=0.045). CONCLUSIONS: Eyes with endophthalmitis following cataract surgery managed without microbiologic cultures have similar visual outcomes to eyes managed with microbiologic cultures and may be less likely to develop secondary retinal detachments. This may be an acceptable strategy to manage endophthalmitis after cataract surgery when prompt access to a microbiologic facility is unavailable.

Exploring the fragility of meta-analyses in ophthalmology: a systematic review.

OBJECTIVE: The fragility index (FI) of a meta-analysis evaluates the extent that the statistical significance can be changed by modifying the event status of individuals from included trials. Understanding the FI improves the interpretation of the results of meta-analyses and can help to inform changes to clinical practice. This review determined the fragility of ophthalmology-related meta-analyses. METHODS: Meta-analyses of randomized controlled trials with binary outcomes published in a journal classified as 'Ophthalmology' according to the Journal Citation Report or an Ophthalmology-related Cochrane Review were included. An iterative process determined the FI of each meta-analysis. Multivariable linear regression modeling evaluated the relationship between the FI and potential predictive factors in statistically significant and non-significant meta-analyses. RESULTS: 175 meta-analyses were included. The median FI was 6 (Q1-Q3: 3-12). This meant that moving 6 outcomes from one group to another would reverse the study's findings. The FI was 1 for 18 (10.2%) of the included meta-analyses and was ≤5 for 75 (42.4%) of the included meta-analyses. The number of events (p < 0.001) and the p-value (p < 0.001) were the best predictors of the FI in both significant and non-significant meta-analyses. CONCLUSION: The statistical significance of meta-analyses in ophthalmology often hinges on the outcome of a few patients. The number of events and the p-value are the most important factors in determining the fragility of the evidence. The FI is an easily interpretable measure that can supplement the reader's understanding of the strength of the evidence being presented. PROSPERO REGISTRATION: CRD42022377589.

Experimentally validated inverse design of multi-property Fe-Co-Ni alloys.

This study presents a machine learning (ML) framework aimed at accelerating the discovery of multi-property optimized Fe-Ni-Co alloys, addressing the time-consuming, expensive, and inefficient nature of traditional methods of material discovery, development, and deployment. We compiled a detailed heterogeneous database of the magnetic, electrical, and mechanical properties of Fe-Co-Ni alloys, employing a novel ML-based imputation strategy to address gaps in property data. Leveraging this comprehensive database, we developed predictive ML models using tree-based and neural network approaches for optimizing multiple properties simultaneously. An inverse design strategy, utilizing multi-objective Bayesian optimization (MOBO), enabled the identification of promising alloy compositions. This approach was experimentally validated using high-throughput methodology, highlighting alloys such as Fe66.8Co28Ni5.2 and Fe61.9Co22.8Ni15.3, which demonstrated superior properties. The predicted properties data closely matched experimental data within 14% accuracy. Our approach can be extended to a broad range of materials systems to predict novel materials with an optimized set of properties.

Understanding network meta-analysis methodology for the ophthalmologist.

PURPOSE OF REVIEW: Over the past decade, the number of studies published using network meta-analyses (NMAs) has rapidly increased, and there have been continued advancements to further advance this analysis approach. Due to the fast moving and changing landscape in the infancy of NMA methodology, there is a lack of consistency and standardization for this approach. This article aims to summarize the crucial components of an NMA for both future readers, and for potential NMA authors. RECENT FINDINGS: Key components of NMAs include, but are not limited to, reporting the proposed analysis methods, assessment of risk of bias within the included studies, reporting the overall quality of the available evidence, and defining the parameters in which the results will be presented. Although NMA allows for a comprehensive evaluation of all available treatment options for a given condition, we believe that there is importance in ensuring clear understanding and appropriate interpretation of results to inform clinical practice. SUMMARY: While many components of NMA mirror those of traditional pairwise meta-analysis, there are many novel methodologies that are specific to this approach. It is imperative that future NMAs follow guidance from key methodology groups, as these provide valuable tools for conducting and reporting NMAs.

Outcomes of Eyes Lost to Follow-up After Treatment With Intraocular or Periocular Steroid Injections.

Purpose: To evaluate the visual, intraocular pressure (IOP), and anatomic outcomes of eyes with loss to follow-up (LTFU) after intravitreal or periocular steroid injections. Methods: Patients receiving intraocular or periocular steroid injections and with LTFU for at least 180 days were included in this retrospective cohort study. Charts were reviewed for the visual acuity (VA), IOP, and central foveal thickness at the visit before LTFU, the first return visit, and 3, 6, and 12 months after return. Results: Fifty-three eyes of 47 patients were identified. The mean (±SD) age was 62.3 ± 14.9 years, the mean LTFU time was 295 ± 181.2 days (range, 182-1101), and the mean follow-up after return was 354 ± 339.3 days (range, 32-1141). The overall mean number of steroid injections was 5.2 ± 3.9 (range, 1-18). Compared with the mean logMAR VA at the visit before LTFU (0.59 [Snellen 20/77]), the mean VA remained stable at all timepoints after return as follows: return visit (0.62 [20/83]; P = .6), month 3 (0.55 [20/70]; P = .6), month 6 (0.55 [20/70]; P = .5), month 12 (0.64 [20/87]; P = .6), and final visit (0.69 [20/97]; P = .2). At the first return visit, 8 (15%) of 53 patients had an IOP of 21 mm Hg or higher (range, 21-31); 2 required treatment with a new antihypertensive medication (latanoprost and timolol, respectively). Conclusions: Patients with LTFU after receiving steroid injections maintained their VA. No patient required incisional glaucoma surgery. Compared with other etiologies, eyes with diabetic macular edema had a greater increase in IOP.

Maintenance of proteostasis by Drosophila Rer1 is essential for competitive cell survival and Myc-driven overgrowth.

Defects in protein homeostasis can induce proteotoxic stress, affecting cellular fitness and, consequently, overall tissue health. In various growing tissues, cell competition based mechanisms facilitate detection and elimination of these compromised, often referred to as 'loser', cells by the healthier neighbors. The precise connection between proteotoxic stress and competitive cell survival remains largely elusive. Here, we reveal the function of an endoplasmic reticulum (ER) and Golgi localized protein Rer1 in the regulation of protein homeostasis in the developing Drosophila wing epithelium. Our results show that loss of Rer1 leads to proteotoxic stress and PERK-mediated phosphorylation of eukaryotic initiation factor 2α. Clonal analysis showed that rer1 mutant cells are identified as losers and eliminated through cell competition. Interestingly, we find that Rer1 levels are upregulated upon Myc-overexpression that causes overgrowth, albeit under high proteotoxic stress. Our results suggest that increased levels of Rer1 provide cytoprotection to Myc-overexpressing cells by alleviating the proteotoxic stress and thereby supporting Myc-driven overgrowth. In summary, these observations demonstrate that Rer1 acts as a novel regulator of proteostasis in Drosophila and reveal its role in competitive cell survival.

Rationale and Design of VOYAGER: Long-term Outcomes of Faricimab and Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema in Clinical Practice.

Purpose: To describe the rationale and design of the VOYAGER (NCT05476926) study, which aims to investigate the safety and effectiveness of faricimab and the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) in clinical practice. VOYAGER also aims to understand drivers of clinical practice treatment outcomes by gaining novel insight into the intersection of treatment regimens, decisions, anatomic outcomes, and vision. Design: Primary data collection, noninterventional, prospective, multinational, multicenter clinical practice study. Participants: At least 5000 patients initiating/continuing faricimab or PDS for nAMD/DME (500 sites, 31 countries). Methods: Management will be per usual care, with no mandated scheduled visits/imaging protocol requirements. Using robust methodologies, relevant clinical and ophthalmic data, including visual acuity (VA), and data on treatment clinical setting/regimens/philosophies, presence of anatomic features, and safety events will be collected. Routinely collected fundus images will be uploaded to the proprietary Imaging Platform for analysis. An innovative investigator interface will graphically display the patient treatment journey with the aim of optimizing treatment decisions. Main Outcome Measures: Primary end point: VA change from baseline at 12 months per study cohort (faricimab in nAMD and in DME, PDS in nAMD). Secondary end points: VA change over time and per treatment regimens (fixed, treat-and-extend, pro re nata, and other) and number. Exploratory end points: VA change in relation to presence/location of anatomic features that impact vision (fluid, central subfield thickness, fibrosis, atrophy, subretinal hyperreflective material, diabetic retinopathy severity, and disorganization of retinal inner layers) and per treatment regimen/philosophies. The impact of regional and practice differences on outcomes will be assessed as will safety. Results: Recruitment commenced in November 2022 and will continue until late 2027, allowing for up to 5 years follow-up. Exploratory interim analyses are planned annually. Conclusions: VOYAGER is an innovative study of retinal diseases that will assess the effectiveness and safety of faricimab and PDS in nAMD and DME and identify clinician- and disease-related factors driving treatment outcomes in clinical practices globally to help optimize vision outcomes. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

XTEND: Two-Year Results from a Global Observational Study Investigating Proactive Dosing of Intravitreal Aflibercept in Neovascular Age-Related Macular Degeneration.

INTRODUCTION: XTEND (NCT03939767) is a multicenter, observational, prospective study of patients with treatment-naïve neovascular age-related macular degeneration (nAMD) in routine clinical practice. The study aims to examine treatment outcomes of proactive intravitreal aflibercept (IVT-AFL) treatment regimens (fixed dosing or treat-and-extend) according to local marketing labels. METHODS: Study eyes received IVT-AFL injections as per the local label. The mean changes in best-corrected visual acuity (BCVA) and central subfield thickness (CST) from baseline to month (M) 12 and M24 were measured and stratified by baseline factors. Treatment exposure and safety data were evaluated. Statistical analysis was descriptive. RESULTS: Overall, 1466 patients from 17 countries were treated. For the overall population, the mean ± standard deviation (SD) age was 78.7 ± 8.5 (range 50-100) years, and 891 patients (60.8%) were female. The mean ± SD baseline BCVA was 54.3 ± 20.3 letters and CST was 374 ± 126 µm. At M12 and M24, mean (95% confidence interval [CI]) BCVA change was + 4.3 (3.4, 5.3) and + 2.3 (1.3, 3.3) letters, respectively. Mean (95% CI) CST was - 106 (- 114, - 99) µm and - 109 (- 117, - 102) µm at M12 and M24, respectively. At M24, 41.5% of patients had a BCVA ≥ 70 letters. Patients received a mean ± SD of 7.7 ± 2.7 injections by M12 and 10.8 ± 5.0 injections by M24 (3.1 injections between M12 and M24). Adverse events were consistent with the known safety profile of IVT-AFL. CONCLUSION: The 24-month results indicate that, in routine clinical practice, a proactive IVT-AFL regimen achieves functional improvements in patients with treatment-naïve nAMD. The proportion of patients achieving ≥ 70 letters at M24 increased, and patients with baseline BCVA ≥ 70 letters maintained vision regardless of the followed IVT-AFL label. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03939767. A video abstract is available for this article. Supplementary file2 (MP4 364624 KB).

Subthreshold Compared with Threshold Macular Photocoagulation for Diabetic Macular Edema: A Systematic Review and Meta-Analysis.

TOPIC: To compare the efficacy and safety of subthreshold macular laser to conventional focal laser photocoagulation for the treatment of vision loss secondary to diabetic macular edema (DME). CLINICAL RELEVANCE: Macular laser remains an important and cost effective treatment option for vision loss secondary to DME. Although anti-VEGF therapy is often first-line, macular laser is of utility in low-resource or remote settings, for patients at risk of loss to follow-up, and for DME not meeting country-specific reimbursement criteria for anti-VEGF therapy. Subthreshold laser is a modality that does not produce clinical or histologic evidence of thermal damage, thereby potentially limiting the common complications of conventional laser. METHODS: Ovid MEDLINE, EMBASE, and CENTRAL databases were searched for randomized controlled trials (RCTs) from inception to September 28, 2022. Meta-analyses were performed using random-effects modeling. Data were collected at 12 and 24 months for best-corrected visual acuity (BCVA), central retinal thickness, diabetic retinopathy severity scale, rate of adverse events, rate of enrolled patients not completing treatment, rate of patients receiving retreatment, and quality-of-life measures. The risk of bias and certainty of evidence were assessed using Cochrane's Risk-of-Bias version 2 and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) frameworks, respectively. Subgroup analysis was performed between subthreshold laser modalities and evaluated with Instrument to assess the Credibility of Effect Modification Analyses tool. RESULTS: Fourteen RCTs comprising 514 eyes receiving conventional laser and 574 eyes receiving subthreshold laser were included. Subthreshold laser likely results in no difference to BCVA (moderate GRADE certainty) compared with conventional laser. Conventional laser demonstrated a small, statistically significant improvement in central retinal thickness (low GRADE certainty); however, the magnitude of this improvement is unlikely to be clinically important. There may not be a difference in the rate of adverse events (low GRADE certainty) at 12 months when comparing subthreshold laser to conventional laser for DME. CONCLUSION: Randomized controlled trial literature to date suggests subthreshold laser to be as effective as conventional laser in the treatment of DME. Increased follow-up duration is needed to observe any long-term safety benefit from reduced retinal damage. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Treatment of geographic atrophy: an update on data related to pegcetacoplan.

PURPOSE OF REVIEW: Geographic atrophy is an advanced and currently untreatable form of age-related macular degeneration (AMD), which leads to significant compromise of visual function and quality of life. Dysregulation of the complement cascade has been directly implicated in AMD pathogenesis. Pegcetacoplan is a pegylated highly selective bicyclic peptide that inhibits the cleavage of complement component 3 (C3), which represents a key step in propagation of the complement cascade. The phase 2 FILLY trial as well as the phase 3 OAKS and DERBY trials have evaluated the safety and efficacy of pegcetacoplan for the treatment of GA. RECENT FINDINGS: The FILLY, OAKS and DERBY trials have demonstrated that local inhibition of C3 cleavage with pegcetacoplan can reduce geographic atrophy lesion growth compared with sham with an effect size of approximately 11-35% depending on the specific trial and specific geographic atrophy phenotype considered. Overall pegcetacoplan has appeared to be well tolerated with the notable side effect of a dose-dependent increase in the rate of exudative AMD development in treated eyes. SUMMARY: The FILLY, OAKS and DERBY trials have demonstrated that pegcetacoplan is a potentially viable treatment for geographic atrophy. Additional data from the 2-year outcomes of DERBY and OAKS as well as data from the ongoing 3-year GALE extension study will provide additional insights into the potential therapeutic benefit of pegcetacoplan. Future studies assessing complement inhibition at earlier stages of AMD, with the goal of preventing geographic atrophy formation, are warranted.