Single-molecule epitranscriptomic analysis of full-length HIV-1 RNAs reveals functional roles of site-specific m6As.

Although the significance of chemical modifications on RNA is acknowledged, the evolutionary benefits and specific roles in human immunodeficiency virus (HIV-1) replication remain elusive. Most studies have provided only population-averaged values of modifications for fragmented RNAs at low resolution and have relied on indirect analyses of phenotypic effects by perturbing host effectors. Here we analysed chemical modifications on HIV-1 RNAs at the full-length, single RNA level and nucleotide resolution using direct RNA sequencing methods. Our data reveal an unexpectedly simple HIV-1 modification landscape, highlighting three predominant N6-methyladenosine (m6A) modifications near the 3' end. More densely installed in spliced viral messenger RNAs than in genomic RNAs, these m6As play a crucial role in maintaining normal levels of HIV-1 RNA splicing and translation. HIV-1 generates diverse RNA subspecies with distinct m6A ensembles, and maintaining multiple of these m6As on its RNAs provides additional stability and resilience to HIV-1 replication, suggesting an unexplored viral RNA-level evolutionary strategy.

Morphological Biomarkers Related to Visual Acuity in Patients With Radiation Retinopathy Treated With Intravitreal Ranibizumab.

BACKGROUND AND OBJECTIVE: Our objective was to monitor variables via spectral-domain optical coherence tomography (SD-OCT) and identify the most relevant biomarkers related to best-corrected visual acuity (BCVA) in radiation retinopathy (RR). PATIENTS AND METHODS: A post-hoc analysis of the two-year Ranibizumab for Radiation Retinopathy (RRR) trial analyzed vision and OCT parameters including intraretinal fluid, ellipsoid zone (EZ) disruption, retinal pigment epithelium atrophy, hard exudates, retinal hemorrhage, retinal neovascularization, and subfoveal fluid. BCVA and SD-OCT parameters were evaluated by univariate analysis and a mixed-effects model. RESULTS: Forty eyes from the RRR trial were included. Intraretinal cyst vertical size (week 24: P = 0.032; week 48: P = 0.021), neovascularization (week 48: P = 0.028; week 72: P = 0.025), and EZ disruption (week 72: P = 0.029; week 104: P = 0.019) were the clinical parameters most relevant to BCVA by univariate analysis in at least two time points. The mixed-effects model confirmed the relevance of intraretinal cyst vertical size (P = 0.001) and neovascularization (P = 0.001) but not EZ disruption (P = 0.119) over the course of the study. CONCLUSIONS: This study characterizes the course of visual loss in RR by identifying intraretinal cyst vertical size, neovascularization, and EZ disruption as biomarkers of poor BCVA over a span of two years. Larger multicenter studies are needed to confirm these findings. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Mapping m6A Sites on HIV-1 RNA Using Oligonucleotide LC-MS/MS.

The biological significance of chemical modifications to the ribonucleic acid (RNA) of human immunodeficiency virus type-1 (HIV-1) has been recognized. However, our understanding of the site-specific and context-dependent roles of these chemical modifications remains limited, primarily due to the absence of nucleotide-resolution mapping of modification sites. In this study, we present a method for achieving nucleotide-resolution mapping of chemical modification sites on HIV-1 RNA using liquid chromatography and tandem mass spectrometry (LC-MS/MS). LC-MS/MS, a powerful tool capable of directly analyzing native RNAs, has proven effective for mapping RNA modifications in small RNA molecules, including ribosomal RNA and transfer RNA. However, longer RNAs have posed challenges, such as the 9 Kb HIV-1 virion RNA, due to the complexity of and ambiguity in mass differences among RNase T1-cleaved RNA fragments in LC-MS/MS data. Here, we introduce a new target RNA enrichment method to isolate small local RNA fragments of HIV-1 RNA that potentially harbor site-specific N6-methyladenosine (m6A) modifications. In our initial trial, we used target-specific DNA probes only and encountered insufficient RNA fragmentation due to inefficient S1 digestion near the target site. Recognizing that inefficient S1 digestion by HIV-1 RNA is likely due to the formation of secondary structures in proximity to the target site, we designed multiple DNA probes annealing to various sites of HIV-1 RNA to better control the structures of RNA substrates for S1 digestion. The use of these non-target DNA probes significantly improved the isolation of more homogeneous target RNA fragments of approximately 50 bases in length. Oligonucleotide LC-MS/MS analysis of these isolated target RNA fragments successfully separated and detected both m6A-methylated and non-methylated oligomers at the two m6A-predicted sites. The principle of this new target enrichment strategy holds promise and should be broadly applicable to the analysis of any lengthy RNA that was previously deemed infeasible for investigation using oligonucleotide LC-MS/MS.

Impact of Prefilled Syringes and Masking on Postintravitreal Injection Endophthalmitis.

Purpose: To compare rates of endophthalmitis (1) following intravitreal injection of antivascular endothelial growth factor therapies with glass-vial preparation (GVP) vs prefilled syringes (PFS) and (2) before and after masking protocols were implemented. Methods: Medical records within a multicenter retina practice in Houston, Texas, from January 2015 to August 2021 were retrospectively reviewed. The primary outcome was rate of endophthalmitis after intravitreal injection. Results: A total of 307 349 injections were performed during the study period and 101 cases of endophthalmitis were identified (0.033%). PFS use was associated with a decreased risk of endophthalmitis (relative risk [RR], 0.320; 95% CI, 0.198-0.518, P < .001); 54 cases of endophthalmitis occurred in the GVP group of aflibercept and ranibizumab (0.052%) compared with 24 in the PFS group (0.017%). There was no difference in the endophthalmitis rates with or without universal masking (RR, 0.953; 95% CI 0.616-1.473, P = .91). Discussion: PFS use was associated with a significant reduction in the rate of endophthalmitis while the use of surgical face masks did not appear to significantly impact the rate of endophthalmitis.

Assessment of Visual Acuity Outcomes in Ocular Syphilis Treated With Adjunctive Topical or Oral Steroids.

PURPOSE: There is no consensus surrounding adjunctive steroid use in the treatment of ocular syphilis. We evaluated clinical outcomes of patients with ocular syphilis who were treated with penicillin plus either topical or oral steroids. METHODS: Nine male patients aged 26 to 72 years with a diagnosis of ocular syphilis were retrospectively identified (18 eyes). All patients were treated with penicillin and adjunctive topical or oral steroids. Visual acuity reported as the logarithm of the minimum angle of resolution (logMAR) and slit lamp findings were documented at presentation, short-term follow-up (<7 days after initiating therapy), and long-term follow-up (day 7+). Visual acuity outcomes were compared between eyes treated with topical versus oral steroids as well as eyes treated simultaneously with adjunctive steroids and penicillin versus patients treated with steroids after penicillin. RESULTS: At short-term follow-up, the mean logMAR (SD, Snellen fraction) visual acuity for eyes treated with topical steroids 0.93 (0.53, 20/170) was significantly lower than that for the oral steroid group 0.23 (0.09, 20/110; p=0.0075). Similarly, at long-term follow-up, the topical steroid group had a significantly lower visual acuity of 0.75 (20/112) compared to a visual acuity of 0.07 (20/25) for the oral steroid group (p=0.0022). Moreover, the oral steroid group displayed significant improvement in visual acuity at long-term follow-up compared to baseline while the topical steroid group did not demonstrate the same effect (p=0.0406 and p=0.5945, respectively). Initiation of steroid treatment simultaneously with penicillin did not result in better visual acuity than delayed steroid treatment (p>0.05). CONCLUSIONS: Steroids are an effective adjunctive treatment for patients with ocular syphilis. Oral steroids may be superior to topical steroids for improving visual function, especially in patients with a severe inflammatory component. Patients treated with oral or topical steroids and penicillin simultaneously did not demonstrate better visual acuity outcomes than patients treated with oral or topical steroids after penicillin was initiated.

Risk Factors for the Development of Fellow Eye Horseshoe Retinal Tears Following Horseshoe Retinal Tear in the Presenting Eye.

BACKGROUND: This study investigated factors associated with fellow eye horseshoe retinal tear (HST) development in consecutive patients with a presenting eye HST. MATERIALS AND METHODS: Medical records were reviewed for patients with initial HSTs between 2015 and 2017 and 24 factors were analyzed. Logistic regression was used to assess factors associated with fellow eye HST development. RESULTS: In total, 242 patients with an HST were identified with mean follow-up of 68.3 months. Four associations with fellow eye HST development were identified: (1) presence of fellow eye lattice degeneration, (2) subsequent presenting eye HSTs, (3) fellow eye vitreous hemorrhage at presenting eye HST occurrence, (4) OCT-determined stage 3 fellow eye posterior vitreous detachment at presenting eye HST occurrence. CONCLUSION: Four clinical findings associated with fellow eye HST development following presenting eye HST were identified. These factors may be important considerations during management patients with HST. [Ophthalmic Surg Lasers Imaging Retina 2023;54:338-345.].

Social group membership, burnout, and subjective well-being in new nurses in the life transition period: A cross-sectional study.

AIM: To assess differences in social group memberships and burnout levels by work tenure among new nurses and identify factors associated with their subjective well-being. DESIGN: A cross-sectional study. METHODS: Participants were 356 registered nurses who had fewer than 3 years of work tenure. Data were collected from February-March 2021. Participants' social identity, burnout, and subjective well-being were assessed using validated questionnaires. STROBE checklist was applied. RESULTS: Multiple group membership was positively associated with life satisfaction and positive affect and negatively with burnout. Burnout influenced new nurses' negative effect in their life transition period. To improve new nurses' subjective well-being, it is essential to focus on their social group membership, encourage participation in group activities, and improve access to sociopsychological resources that can help them take their first steps as professional staff and develop as healthy members of society, which will foster sustainable healthcare systems.

Optical Coherence Tomography Biomarkers for Conversion to Exudative Neovascular Age-related Macular Degeneration.

PURPOSE: To identify optical coherence tomography (OCT) biomarkers, including thin and thick double-layer sign (DLS) for the progression from intermediate AMD (iAMD) to exudative macular neovascularization (MNV) over 24 months. DESIGN: Retrospective cohort study. METHODS: Setting: Retina consultants of Texas. PATIENT POPULATION: 458 eyes of 458 subjects with iAMD in at least 1 eye with 24 months of follow-up data. MAIN OUTCOMES MEASURES: The following biomarkers were assessed at baseline: high central drusen volume (≥0.03 mm3), intraretinal hyper-reflective foci (IHRF), subretinal drusenoid deposits, hyporeflective drusen cores, thick DLS, thin DLS, and central choroidal thickness. A binary logistic regression was computed to investigate the association between baseline OCT covariates and the conversion to exudative MNV within 24 months. In addition, fellow eye status was also included in the model. RESULTS: During follow-up, 18.1% (83 of 458) of eyes with iAMD progressed to exudative MNV. Thick DLS, IHRF, and fellow eye exudative MNV were found to be independent predictors for the development of exudative MNV within 2 years. The baseline frequencies, odds ratios, 95% confidence intervals, and P values for these biomarkers were as follows: thick DLS (9.6%, 4.339, 2.178-8.644; P < .001), IHRF (36.0%, 2.340, 1.396-3.922; P = 0.001), and fellow eye exudative MNV (35.8%, 1.694, 1.012-2.837; P = .045). CONCLUSIONS: Thick DLS, IHRF, and fellow eye exudative MNV were associated with an increased risk of progression from iAMD to exudative MNV. These biomarkers, which are readily identified by the review of OCT volume scans, may aid in risk prognostication for patients and for identifying patients for early intervention trials.

Longitudinal analysis of aqueous humour cytokine expression and OCT-based imaging biomarkers in retinal vein occlusions treated with anti-vascular endothelial growth factor therapy in the IMAGINE study.

BACKGROUND/OBJECTIVES: Retinal vein occlusion (RVO) is the second most common retinal vascular disorder. Despite promising advances with anti-VEGF therapy, select patients are unresponsive to therapy. A precision medicine-based approach for therapeutic decision-making based on underlying biomarkers may facilitate treatment based on the underlying pathway. This study aims to identify the baseline and longitudinal cytokine profiles of RVO-related macular oedema and correlating these expression profiles with higher order OCT features using a novel retinal segmentation and feature extraction platform. SUBJECTS/METHODS: The IMAGINE study is a post-hoc assessment of aqueous humour cytokines with correlation to higher level analysis of imaging studies. OCT scans underwent machine learning enhanced segmentation of the internal limiting membrane (ILM), ellipsoid zone (EZ) and retinal pigment epithelium (RPE), as well as evaluating volumetric fluid metrics. Samples of aqueous humour were obtained at baseline, as well as months 4 and 9 prior to treatment. These samples were analysed for the expression of multiple cytokines. Patients were divided into Responders and Non-Responders based on OCT profiles. Additionally, patients were categorised as a Rebounder if their CST increased by 50% after initial improvement. RESULTS: Twenty-six eyes were included. The OCT-based response schema identified 21 Responders (81%) and 5 Non-Responders (19%). VEGF levels directly correlated with intraretinal fluid volume and angiogenin was inversely correlated with fluid indices. Multiple cytokines, including ANGPTL4, were directly correlated with ellipsoid zone disruption. The baseline VEGF levels were significantly higher in all responders compared to Non-Responders (p = 0.02). Rebounders tended to have significantly decreased levels of angiogenin and TIMP-1 (p = 0.019, p = 0.015). CONCLUSIONS: Cytokine expression was linked to specific OCT features and treatment response in RVO. Identification of an imaging phenotype that could serve as a surrogate for underlying active disease pathways could enhance treatment decision-making and precision medicine.

OCT Risk Factors for Development of Atrophy in Eyes with Intermediate Age-Related Macular Degeneration.

PURPOSE: To determine the frequency of multiple OCT biomarkers of intermediate age-related macular degeneration (iAMD) and their relationship with the development of complete retinal pigment epithelium and outer retinal atrophy (cRORA) after 2 years. DESIGN: Retrospective cohort study. PARTICIPANTS: This retrospective analysis included 330 eyes of 330 consecutive patients with iAMD in ≥ 1 eye who had 24 months of follow-up data. METHODS: Spectralis OCT volume scans (49 B-scans over 6 × 6 mm, automatic real time = 6, fovea-centered) at baseline were evaluated for the previously described iAMD biomarkers, including a high-central drusen volume (DV; ≥ 0.03 mm3), intraretinal hyper-reflective foci (IHRF), subretinal drusenoid deposits (SDDs), hypo-reflective drusen cores (hDCs), and a thin or thick (multilayered) double-layer sign (DLS). The age-related macular degeneration (AMD) status in the fellow eye was also assessed and classified as normal or early AMD, iAMD, exudative macular neovascularization, or cRORA. MAIN OUTCOME MEASURES: Incidence of cRORA, odds ratio for demographics, and OCT features. RESULTS: At month 24, 16.36% (54/330) of the iAMD eyes developed cRORA. Several baseline features, including high-central DV, IHRF, SDD, hDC, thin DLS, and cRORA in the fellow eye, were associated with a significantly greater risk for development of cRORA at 2 years. The odds ratio, 95% confidence interval, P value, and baseline frequencies of these biomarkers were DV (6.510, 2.467-17.176, P < 0.001, 49.1%), IHRF (12.763, 4.763-34.202, P < 0.001, 38.8%), SDD (2.307, 1.003-5.304, P = 0.049, 34.2%), hDC (3.012, 1.152-7.873, P = 0.024, 13.0%), thin DLS (4.517, 1.555-13.126, P = 0.006, 11.8%), and cRORA in the fellow eye (7.184, 1.938-26.623, P = 0.003, 8.2%). CONCLUSIONS: In addition to the 4 previously reported factors that are present in a significant proportion of iAMD (DV, IHRF, hDC, and SDD), a thin DLS and cRORA in the fellow eye were associated with an increased risk of progression to cRORA over 2 years. These biomarkers may aid in prognostication, risk stratification, and selection of patients for clinical trials. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

CD3e-immunotoxin spares CD62Llo Tregs and reshapes organ-specific T-cell composition by preferentially depleting CD3ehi T cells.

CD3-epsilon(CD3e) immunotoxins (IT), a promising precision reagent for various clinical conditions requiring effective depletion of T cells, often shows limited treatment efficacy for largely unknown reasons. Tissue-resident T cells that persist in peripheral tissues have been shown to play pivotal roles in local and systemic immunity, as well as transplant rejection, autoimmunity and cancers. The impact of CD3e-IT treatment on these local cells, however, remains poorly understood. Here, using a new murine testing model, we demonstrate a substantial enrichment of tissue-resident Foxp3+ Tregs following CD3e-IT treatment. Differential surface expression of CD3e among T-cell subsets appears to be a main driver of Treg enrichment in CD3e-IT treatment. The surviving Tregs in CD3e-IT-treated mice were mostly the CD3edimCD62Llo effector phenotype, but the levels of this phenotype markedly varied among different lymphoid and nonlymphoid organs. We also found notable variations in surface CD3e levels among tissue-resident T cells of different organs, and these variations drive CD3e-IT to uniquely reshape T-cell compositions in local organs. The functions of organs and anatomic locations (lymph nodes) also affected the efficacy of CD3e-IT. The multi-organ pharmacodynamics of CD3e-IT and potential treatment resistance mechanisms identified in this study may generate new opportunities to further improve this promising treatment.

Comparison of CD3e Antibody and CD3e-sZAP Immunotoxin Treatment in Mice Identifies sZAP as the Main Driver of Vascular Leakage.

Anti-CD3-epsilon (CD3e) monoclonal antibodies (mAbs) and CD3e immunotoxins (ITs) are promising targeted therapy options for various T-cell disorders. Despite significant advances in mAb and IT engineering, vascular leakage syndrome (VLS) remains a major dose-limiting toxicity for ITs and has been poorly characterized for recent "engineered" mAbs. This study undertakes a direct comparison of non-mitogenic CD3e-mAb (145-2C11 with Fc-silentTM murine IgG1: S-CD3e-mAb) and a new murine-version CD3e-IT (saporin-streptavidin (sZAP) conjugated with S-CD3e-mAb: S-CD3e-IT) and identifies their distinct toxicity profiles in mice. As expected, the two agents showed different modes of action on T cells, with S-CD3e-mAb inducing nearly complete modulation of CD3e on the cell surface, while S-CD3e-IT depleted the cells. S-CD3e-IT significantly increased the infiltration of polymorphonuclear leukocytes (PMNs) into the tissue parenchyma of the spleen and lungs, a sign of increased vascular permeability. By contrast, S-CD3e-mAbs-treated mice showed no notable signs of vascular leakage. Treatment with control ITs (sZAP conjugated with Fc-silent isotype antibodies) induced significant vascular leakage without causing T-cell deaths. These results demonstrate that the toxin portion of S-CD3e-IT, not the CD3e-binding portion (S-CD3e-mAb), is the main driver of vascular leakage, thus clarifying the molecular target for improving safety profiles in CD3e-IT therapy.

Scleral Buckling Alone or in Combination with Pars Plana Vitrectomy for Rhegmatogenous Retinal Detachment Repair: A Meta-Analysis of 7,212 Eyes.

PURPOSE: The efficacy and safety of scleral buckling (SB) versus combination SB and pars plana vitrectomy (SB + PPV) for rhegmatogenous retinal detachment (RRD) repair remains unclear. METHODS: A systematic review and meta-analysis was conducted to identify comparative studies published from Jan 2000-Jun 2021 that reported on the efficacy and/or safety following SB and SB + PPV for RRD repair. Final best-corrected visual acuity (BCVA) represented the primary endpoint, while reattachment rates and ocular adverse events were secondary endpoints. A random-effects meta-analysis was performed, and 95% confidence intervals were calculated. RESULTS: Across 18 studies, 3912 SB and 3300 SB + PPV eyes were included. Final BCVA was nonsignificantly different between SB and SB + PPV (20/38 vs. 20/66 Snellen; WMD = -0.11 LogMAR; 95% CI: [-0.29, 0.07]; p = 0.23). Primary reattachment rate was similar between procedures (p = 0.74); however, SB alone achieved a significantly higher final reattachment rate (97.40% vs. 93.86%; RR = 1.03; 95% CI: [1.00, 1.06]; p = 0.04). Compared to SB + PPV, SB alone had a significantly lower risk of postoperative macular edema (RR = 0.69; 95% CI: [0.47, 1.00]; p = 0.05) and cataract formation (RR = 0.34; 95% CI: [0.12, 0.96]; p = 0.04). The incidence of macular hole, epiretinal membrane, residual subretinal fluid, proliferative vitreoretinopathy, elevated intraocular pressure, and extraocular muscle dysfunction were similar between SB and SB + PPV. CONCLUSIONS: There was no significant difference in final BCVA between SB + PPV and SB alone in RRD. SB alone offers a slightly higher final reattachment rate along with a reduced risk of macular edema and cataract. Primary reattachment rate and the incidence of other complications were similar between the two procedures.

Final Outcomes from the Randomized RECOVERY Trial of Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy.

PURPOSE: Retinal nonperfusion (RNP) is an important biomarker for diabetic retinopathy (DR). Data suggest that consistent anti-VEGF pharmacotherapy can slow RNP development. The RECOVERY trial evaluated the impact of aflibercept (Eylea, Regeneron) on RNP among eyes with proliferative DR (PDR). DESIGN: Prospective, randomized clinical trial with treatment crossover in the second year. SUBJECTS: Eyes with PDR and RNP. METHODS: At baseline, the subjects were randomized 1:1 to monthly (arm 1) or quarterly (arm 2) intravitreal 2 mg aflibercept. At the beginning of year 2, the treatment arms were crossed over so that the monthly-dosed subjects subsequently received quarterly dosing and the quarterly-dosed subjects subsequently received monthly dosing. MAIN OUTCOME MEASURES: Change in total RNP area (mm2) through year 2. Secondary outcomes included Diabetic Retinopathy Severity Scale (DRSS) scores; best-corrected visual acuity; central subfield thickness; additional measures of RNP, including ischemic index (ISI); and adverse event incidence. Means and 95% confidence intervals were calculated. RESULTS: Among all subjects, from baseline to year 2, the mean RNP increased from 235 mm2 to 402 mm2 (P < 0.0001), and the ISI increased from 25.8% to 50.4% (P < 0.0001). Increases in the mean RNP (P < 0.0001) and ISI (P < 0.0001) were also observed from year 1 to year 2. The mean total RNP increased from 264 mm2 at baseline to 386 mm2 (P < 0.0001) at year 2 in arm 1 and from 207 mm2 at baseline to 421 mm2 (P < 0.0001) at year 2 in arm 2 (P = 0.023, arm 1 vs. arm 2). Increases in the mean RNP for both treatment arms (P < 0.0001) were also specifically observed within year 2 (P = 0.32, arm 1 vs. arm 2). Compared with baseline, the DRSS scores at the end of year 2 improved in 82% (n = 27) of subjects and remained stable in 18% (n = 6), with no subjects experiencing worsening; at 2 years, the DRSS scores had improved by 2 or more steps in 65% (n = 11) and 81% (n = 13) of subjects in arms 1 and 2, respectively. CONCLUSIONS: Through year 2 of the RECOVERY trial, both treatment arms experienced significant increases in RNP. Despite the expansion of the RNP area in nearly all subjects, 82% of subjects demonstrated an improvement in DRSS levels from baseline, with no subjects experiencing worsening in DRSS scores.

Pars Plana Vitrectomy with and without Supplemental Scleral Buckle for the Repair of Rhegmatogenous Retinal Detachment: A Meta-analysis.

TOPIC: It is unclear whether there are differences in safety and efficacy between pars plana vitrectomy (PPV) alone and PPV with a supplemental scleral buckle (SB; PPV-SB) for the treatment of rhegmatogenous retinal detachment. CLINICAL RELEVANCE: This meta-analysis aimed to compare the safety and efficacy of these surgical procedures. METHODS: In this meta-analysis, Ovid MEDLINE, Embase, and Cochrane Library were systematically searched (January 2000-June 2021). The primary outcome was the final best corrected visual acuity (BCVA), whereas the secondary outcomes were reattachment rates and complications. The risk of bias was assessed using the Cochrane risk-of-bias tool for randomized controlled trials (RCTs) and the risk of bias in nonrandomized studies of interventions tool for nonrandomized studies. RESULTS: This study included 15 661 eyes from 38 studies (32 observational studies and 6 RCTs). The median follow-up duration was 6 months. The final BCVA was similar between PPV and PPV-SB (weighted mean difference [WMD], -0.03 logarithm of the minimum angle of resolution [-0.14 to 0.07]; P = 0.55). There was a significant difference in the single-operation success rate (SOSR) (88.2% versus 86.3%; relative risk [RR], 0.97 [0.95-1.00]; P = 0.03), favoring PPV-SB; however, there was no significant difference in the final reattachment rate (RR, 1.00 [0.99-1.01]; P = 0.56). Pars plana vitrectomy required a significantly higher number of operations to achieve final anatomical reattachment (WMD, 0.13 [0.02-0.24]; P = 0.02). In terms of complications, PPV was significantly less likely to be associated with macular edema (RR, 0.47 [0.25-0.88]; P = 0.02) and epiretinal membrane formation (RR, 0.70 [0.52-0.94]; P = 0.02), but these differences were no longer significant in studies published after 2010 or in RCTs. Significant proliferative vitreoretinopathy, lens status, and macular attachment status did not mediate differences in these effects. CONCLUSIONS: There were no significant differences in the final visual acuity outcomes between PPV and PPV-SB. Pars plana vitrectomy with supplemental SB was associated with a greater SOSR than standalone PPV, although the magnitude of the effect was small, with a high number needed to treat. The final reattachment rate was similar. In recent studies and in RCTs, the risk of complications was similar between the procedures.

Outcomes of Eyes Undergoing Multiple Surgical Interventions after Failure of Primary Rhegmatogenous Retinal Detachment Repair.

PURPOSE: To assess outcomes among eyes undergoing surgery for recurrent rhegmatogenous retinal detachment (RRD) and investigate variables that correlate with visual and anatomic outcomes. DESIGN: Retrospective, consecutive case series. PARTICIPANTS: Eyes in which initial RRD repair failed that underwent ≥2 surgeries for RRD repair between January 1, 2016, and December 31, 2020. METHODS: A retrospective analysis of eyes that underwent ≥2 RRD repairs. Eyes with etiologies of retinal detachment other than RRD, previous vitreoretinal surgery, and proliferative diabetic retinopathy were excluded. One-way analysis of variance with Tukey honestly significant difference testing and multivariate regression analyses were used to assess statistical significance. MAIN OUTCOME MEASURES: Anatomic success rate and habitual best recorded visual acuity (VA) at postoperative time intervals and at final follow-up. RESULTS: The single-operation success rate (SOSR) among eyes that underwent primary RRD repair over a 5-year period was 92.4% (2021 of 2187 eyes). The remaining 166 eyes (164 patients) in which primary RRD repair failed were included in this study. Although the anatomic success rates after the second and third RRD repairs were lower than the SOSR (71.7% and 68.1%, respectively), the final anatomic success rates did not significantly differ between eyes that underwent ≥2 RRD repairs (range, 90.6%-100%) (P > 0.05), and final anatomic success was achieved in 95.8% of the eyes. The average VA at both postoperative time intervals and final follow-up decreased with an increased total number of RRD repairs. Eyes that received silicone oil endotamponade during the second RRD repair were 20.3% (P = 0.03) and 38.4% (P = 0.04) less likely to require a third RRD repair compared with eyes that received octafluoropropane and sulfur hexafluoride gases, respectively. Eyes that developed a third RRD due to proliferative vitreoretinopathy (PVR) (n = 43) were 110% more likely to require a fourth RRD repair than eyes that developed a third RRD due to a new tear or failure to reattach (n = 4) (P = 0.04). CONCLUSIONS: In this series, the rates of anatomic success appeared consistent after each surgery when multiple reoperations were required for RRD. The VA decreased with an increased total number of RRD repairs, and the endotamponade choice might have affected the risk of additional reoperations. Proliferative vitreoretinopathy was a significant prognostic factor for RRD recurrence.

Retinal non-perfusion in diabetic retinopathy.

Diabetic retinopathy is a major cause of vision loss worldwide and areas of retinal non-perfusion (RNP) are a key pathologic feature of the vascular component of diabetic retinopathy. While there is a need for a more complete understanding of the natural history of RNP development and progression, overall, increasing RNP has been closely linked with worsening DR severity. Both traditional and novel approaches to quantitative image assessment are being explored to advance our understanding of the vascular, physiologic and functional changes associated with progressive RNP. Retinal ischemia secondary to RNP leads to tissue hypoxia and changes in the expression of a host of signalling molecules. Current anti-vascular endothelial growth factor and steroid pharmaceutical agents appear to be unable to reperuse areas of RNP, but may be able to slow the progressive longitudinal accumulation of RNP with regular retreatments. There remains a tremendous unmet need for pharmacotherapies that can slow RNP progression and ultimately reperfuse areas of the non-perfused retina. Towards this end, novel targets including the semaphorin family are being investigated.

Exploring the angiographic-biologic phenotype in the IMAGINE study: quantitative UWFA and cytokine expression.

BACKGROUND: This study investigates the association of intraocular cytokine expression and ultrawide-field fluorescein angiography (UWFA) quantitative imaging biomarkers and their association with angiographical feature response after antivascular endothelial growth factor (VEGF) therapy in diabetic macular oedema (DME). METHODS: The IMAGINE DME study is a post hoc imaging biomarker and intraocular cytokine assessment from the DAVE study, a prospective DME clinical trial that included aqueous humour sampling and UWFA imaging. Fifty-four cytokines associated with inflammation and angiogenesis were evaluated through multiplex arrays. UWFA parameters were assessed using an automated feature analysis platform to determine ischaemic and leakage indices and microaneurysm (MA) count. Eyes were classified into UWFA responder or non-responder groups based on longitudinal quantitative UWFA parameter improvement. Cytokine expression was correlated with UWFA metrics and evaluated in the context of therapeutic response. RESULTS: Twenty-one eyes were included with a mean age of 55±10 years. Increased panretinal leakage index correlated with VEGF (r=0.70, p=0.0005), angiopoietin-like 4 (r=0.77, p=4.6E-5) and interleukin (IL)-6 (r=0.64, p=0.002). Panretinal ischaemic index was associated with tissue inhibitor of metalloproteinases 1 (TIMP-1, r=0.49, p=0.03) and peripheral ischaemia correlated with VEGF (r=0.45, p=0.05). MA count correlated with increased monocyte chemotactic protein-4 (MCP-4, r=0.60, p=0.004) and platelet and endothelial cell adhesion molecule 1 (PECAM-1, r=0.58, p=0.005). Longitudinal MA reduction was associated with decreased baseline VEGF and urokinase receptor (uPAR) (p<0.05). High baseline VEGF and IL-6 were associated with dramatic reduction in macular leakage (p<0.05). CONCLUSIONS: Baseline and longitudinal quantitative UWFA imaging parameters correlated with multiple aqueous humour cytokine concentrations, including VEGF and IL-6. Further research is needed to assess the possible implications of using these findings for evaluating treatment response.

Two-year results for ranibizumab for radiation retinopathy (RRR): a randomized, prospective trial.

PURPOSE: To assess the efficacy of a treat-and-extend strategy with intravitreal ranibizumab for radiation-related macular edema. METHODS: Forty eyes with radiation-induced macular edema and decreased visual acuity were enrolled in the phase IIb, prospective clinical trial and randomized into 3 cohorts: (A) monthly ranibizumab, (B) monthly ranibizumab with targeted retinal photocoagulation (TRP), or (C) as-needed ranibizumab and TRP. In year 2, all subjects entered a treat-and-extend protocol for ranibizumab. The primary outcome measure was mean change in early treatment diabetic retinopathy study (ETDRS) best-corrected visual acuity (BCVA) from baseline. RESULTS: Through year 1, the mean change in ETDRS BCVA was significantly different between the three cohorts (p < 0.001); cohort A saw the largest gain with + 4.0 letters. Significant anatomic improvements were also seen in all cohorts. Comparatively, through year 2, cohorts A, B, and C had a mean change in ETDRS BCVA of - 1.9, - 3.9, and + 1.3 letters, respectively; additionally, no significant differences were found in absolute ETDRS BCVA across time (ANOVA, p = 0.123). Overall, 90% of eyes maintained VA 20/200 or better and 33.3% of subjects gained at least one line of vision. There were no significant differences in mean central macular thickness for any cohort compared to baseline (p = 0.09). The presence of retinal hemorrhage and intraretinal exudates stayed consistent from year 1 to year 2 for all cohorts. CONCLUSIONS: Among eyes with radiation-related macular edema, a treat-and-extend regimen with ranibizumab may not result in as many visual and anatomic improvements as monthly injections. However, treat-and-extend still may prevent serious visual complications compared to historical controls. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02222610.

Expanded Clinical Spectrum of Pentosan Polysulfate Maculopathy: A Macula Society Collaborative Study.

PURPOSE: Explore the spectrum of clinical manifestations of pentosan polysulfate sodium (PPS) maculopathy observed across a range of practice settings. DESIGN: Multi-institutional retrospective study. PARTICIPANTS: Patients exhibiting findings suggestive of PPS maculopathy identified from April 30, 2019, to December 4, 2020. METHODS: Members of the Macula Society submitted cases of presumed PPS maculopathy for consideration in this series. Diagnosis was confirmed by masked review of fundus imaging. Clinical characteristics of confirmed cases were summarized with descriptive statistics. MAIN OUTCOME MEASURES: Pentosan polysulfate exposure characteristics and fundus imaging features. RESULTS: There were 74 patients with PPS maculopathy included in the current study. Median (interquartile range) age at diagnosis was 62.0 years (56.0-65.8). The median duration of exposure to PPS was 14.0 years (10.2-18.9), with a median cumulative exposure of 1.5 kg (0.9-2.4). The most common presenting symptom was decreased or blurry vision (66.2%), followed by prolonged dark adaption or nyctalopia (32.4%). The most common referral diagnosis was age-related macular degeneration (54.1%); 16.2% of patients were referred for suspected PPS maculopathy. Novel imaging findings emerged, including highly asymmetric disease in 2 patients and a prominent vitelliform maculopathy in 2 patients. CONCLUSIONS: Most patients with PPS maculopathy exhibit characteristic findings on multimodal fundus imaging in the setting of high cumulative exposure to the oral drug. Some patients in the current study manifested novel imaging findings, expanding our understanding of the phenotypic spectrum of this condition. We recommend considering standardized ophthalmic screening of patients treated with PPS.