Correction: The Tight Junction Associated Signalling Proteins ZO-1 and ZONAB Regulate Retinal Pigment Epithelium Homeostasis in Mice.

[This corrects the article DOI: 10.1371/journal.pone.0015730.].

Face-down positioning or posturing after macular hole surgery.

BACKGROUND: Macular holes cause severe impairment of sight. With the aim of improving the outcome of surgery for macular holes, particularly larger macular holes (those measuring over 400 µm), a variable period of face-down positioning may be advised. This review is an update of a Cochrane Review published in 2011. OBJECTIVES: To evaluate the effect of postoperative face-down positioning on the outcome of surgery for macular hole. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2022, Issue 5), which contains the Cochrane Eyes and Vision Trials Register, Ovid MEDLINE, Ovid Embase, the ISRCTN registry, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform. There were no date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 25 May 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in which postoperative face-down positioning was compared to no face-down positioning following surgery for macular holes. The primary outcome of interest was closure of the macular hole. Other outcomes of interest included visual outcomes, quality of life outcomes, and the occurrence of adverse events. Pairs of review authors independently selected studies for inclusion, extracted data, assessed risk of bias, and evaluated the certainty of evidence using GRADE. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We analysed dichotomous data as risk ratios (RRs), and continuous data as mean differences (MDs), with 95% confidence intervals (CI). The unit of analysis was eyes. MAIN RESULTS: We included eight studies allocating a total of 709 eyes (699 participants). There was heterogeneity in study design, including the control group treatment (from no positioning to strict maintenance of other 'face-forward' postures) and surgical procedures (with or without inner limiting membrane peeling, with or without cataract surgery). There were also different durations of positioning, with two studies using 3 days, two studies using 5 days, and three studies using 10 days of face-down positioning. Whilst the overall risk of bias was low, all included studies were judged to be at high or unclear risk of bias due to absence of assessment of adherence to the 'prescribed' intervention of face-down positioning or posturing. The primary outcome of successful anatomical hole closure at one to six months following surgery was reported in 95 of every 100 eyes of participants advised to position face-down for at least three days after surgery, and in 85 of every 100 eyes of participants not advised to position face-down (RR 1.05, 95% CI 0.99 to 1.12, 709 eyes, 8 studies, I² = 44%). Amongst the 327 eyes of participants with macular holes of at least 400 µm, hole closure was noted in 94 of every 100 eyes of participants advised to position face-down, and in 84 of every 100 eyes of participants not advised to position face-down (RR 1.08, 95% CI 0.93 to 1.26, 5 studies, I² = 62%). Amongst the 129 eyes of participants with macular holes of less than 400 µm, hole closure was noted in 100 of every 100 eyes of participants advised to position face-down, and in 96 of every 100 eyes of participants not advised to position face-down (RR 1.03, CI 0.97 to 1.11, 4 studies, I² = 0%). The certainty of the evidence was low, downgraded for imprecision (CIs including no effect) and study design limitations (with different durations of face-down posturing used in the absence of a dose-response gradient, and limitations in measuring the exposure). Meta-analysis of visual acuity data was challenging given the use of different definitions of postoperative visual outcome across studies. Three studies reported findings by gain in Early Treatment Diabetic Retinopathy Study (ETDRS) letters (MD 2.04, 95% CI -0.01 to 4.09, very low-certainty evidence). Meta-analyses of quality of life data were not possible because of inconsistency in outcome metrics across studies. One study reported no difference between groups in quality of life, as reported on a validated quality of life metric scale (the National Eye Institute Visual Function Questionnaire - 25 (NEI VFQ-25), between face-down positioning for five days and non-face-down positioning (median NEI VFQ-25 score was 89 (interquartile range (IQR) 76 to 94) in the face-down group versus 87 (IQR 73 to 93) in the non-face-down group (adjusted mean difference on a logistic scale 0.02, 95% CI -0.03 to 0.07, P = 0.41)). Two studies reported increased ease of positioning and less pain in non-face-down positioning groups on non-validated 0-to-10-point visual analogue scores. On an ease-of-positioning score running from 0 (very difficult) to 10 (very easy), there were consistent reports of the discomfort associated with face-down positioning: the median participant-reported ease-of-positioning score was 6 (IQR 4 to 8) in those undergoing 5 days of face-down positioning versus 9 (IQR 7 to 10) in the comparator group (P = 0.01). On a pain score with 0 being pain-free and 10 being in severe pain, mean pain score was 6.52 ± 2.48 in the face-down positioning group versus 2.53 ± 2.6 in the non-face-down positioning group. The adverse event of postoperative nerve compression occurred in less than 1 in every 100 (3 per 1000) participants advised to position face-down, and 0 in every 100 participants not advised to position face-down (699 participants, 8 studies, moderate-certainty evidence). AUTHORS' CONCLUSIONS: We identified eight RCTs evaluating face-down positioning following surgery for macular hole. The included studies were not all directly comparable due to differences in the surgical techniques used and the durations of postoperative positioning advised. Low-certainty evidence suggests that face-down positioning may have little or no effect on macular hole closure after surgery. Face-down positioning is a low-risk intervention, with serious adverse events affecting fewer than 1 in 300 people. We suggest that any future trials focus on patients with larger macular holes, with interventions and outcome measures used in previous trials (i.e. with inner limiting membrane peeling, positioning durations of three to five days, and validated quality of life metrics) to allow future meta-analyses to determine any effect with greater precision and confidence.

Role of HIF1α and HIF2α in Cre Recombinase-Induced Retinal Pigment Epithelium Pathology and Its Secondary Effect on Choroidal Neovascularization.

CreTrp1 mice are widely used for conditional retinal pigment epithelium (RPE) gene function studies. Like other Cre/LoxP models, phenotypes in CreTrp1 mice can be affected by Cre-mediated cellular toxicity, leading to RPE dysfunction, altered morphology and atrophy, activation of innate immunity, and consequent impairment of photoreceptor function. These effects are common among the age-related alterations of RPE that feature in early/intermediate forms of age-related macular degeneration. This article characterizes Cre-mediated pathology in the CreTrp1 line to elucidate the impact of RPE degeneration on both developmental and pathologic choroidal neovascularization. Nonredundant roles of the two major components of the hypoxia-inducible factor (HIF) family of transcription regulators, HIF1α and HIF2α, were identified. Genetic ablation of Hif1a protected against Cre-induced degeneration of RPE and choroid, whereas ablation of Hif2a exacerbated this degeneration. Furthermore, HIF1α deficiency protected CreTrp1 mice against laser-induced choroidal neovascularization, whereas HIF2α deficiency exacerbated the phenotype. Cre-mediated degeneration of the RPE in CreTrp1 mice offers an opportunity to investigate the impact of hypoxia signaling in the context of RPE degeneration. These findings indicate that HIF1α promotes Cre recombinase-mediated RPE degeneration and laser-induced choroidal neovascularization, whereas HIF2α is protective.

Early vitrectomy for exogenous endophthalmitis following surgery.

BACKGROUND: Endophthalmitis is a sight-threatening emergency that requires prompt diagnosis and treatment. The condition is characterised by purulent inflammation of the intraocular fluids caused by an infective agent. In exogenous endophthalmitis, the infective agent is foreign and typically introduced into the eye through intraocular surgery or open globe trauma. OBJECTIVES: To assess the potential role of combined pars plana vitrectomy and intravitreal antibiotics in the acute management of exogenous endophthalmitis, versus the standard of care, defined as vitreous tap and intravitreal antibiotics. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2022, Issue 5); Ovid MEDLINE; Ovid Embase; the International Standard Randomised Controlled Trial Number registry; ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. There were no restrictions to language or year of publication. The date of the search was 5 May 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared pars plana vitrectomy and intravitreal injection of antibiotics versus intravitreal injection of antibiotics alone, for the immediate management of exogenous endophthalmitis. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. Two review authors independently screened search results and extracted data. We considered the following outcomes: visual acuity improvement and change in visual acuity at three and six months; additional surgical procedures, including vitrectomy and cataract surgery, at any time during follow-up; quality of life and adverse effects. We assessed the certainty of the evidence using the GRADE approach.  MAIN RESULTS: We identified a single RCT that met our inclusion criteria. The included RCT enrolled a total of 420 participants with clinical evidence of endophthalmitis, within six weeks of cataract surgery or secondary intraocular lens implantation. Participants were randomly assigned according to a 2 x 2 factorial design to either treatment with vitrectomy (VIT) or vitreous tap biopsy (TAP) and to treatment with or without systemic antibiotics. Twenty-four participants did not have a final follow-up: 12 died, five withdrew consent to be followed up, and seven were not willing to return for the visit.  The study did not report visual acuity according to the review's predefined outcomes. At three months, 41% of all participants achieved 20/40 or better visual acuity and 69% had 20/100 or better acuity. The study authors reported that there was no statistically significant difference in visual acuity between treatment groups (very low-certainty evidence). There was low-certainty evidence of a similar requirement for additional surgical procedures (risk ratio RR 0.90, 95% confidence interval 0.66 to 1.21). Adverse effects included: VIT group: dislocated intraocular lens (n = 2), macular infarction (n = 1). TAP group: expulsive haemorrhage (n = 1). Quality of life and mean change in visual acuity were not reported.  AUTHORS' CONCLUSIONS: We identified a single RCT (published 27 years ago) for the role of early vitrectomy in exogenous endophthalmitis, which suggests that there may be no difference between groups (VIT vs TAP) for visual acuity at three or nine months' follow-up.   We are of the opinion that there is a clear need for more randomised studies comparing the role of primary vitrectomy in exogenous endophthalmitis. Moreover, since the original RCT study, there have been incremental changes in the surgical techniques with which vitrectomy is performed. Such advances are likely to influence the outcome of early vitrectomy in exogenous endophthalmitis.

Spatiotemporal control of actomyosin contractility by MRCKß signaling drives phagocytosis.

Phagocytosis requires actin dynamics, but whether actomyosin contractility plays a role in this morphodynamic process is unclear. Here, we show that in the retinal pigment epithelium (RPE), particle binding to Mer Tyrosine Kinase (MerTK), a widely expressed phagocytic receptor, stimulates phosphorylation of the Cdc42 GEF Dbl3, triggering activation of MRCKß/myosin-II and its coeffector N-WASP, membrane deformation, and cup formation. Continued MRCKß/myosin-II activity then drives recruitment of a mechanosensing bridge, enabling cytoskeletal force transmission, cup closure, and particle internalization. In vivo, MRCKß is essential for RPE phagocytosis and retinal integrity. MerTK-independent activation of MRCKß signaling by a phosphomimetic Dbl3 mutant rescues phagocytosis in retinitis pigmentosa RPE cells lacking functional MerTK. MRCKß is also required for efficient particle translocation from the cortex into the cell body in Fc receptor-mediated phagocytosis. Thus, conserved MRCKß signaling at the cortex controls spatiotemporal regulation of actomyosin contractility to guide distinct phases of phagocytosis in the RPE and represents the principle phagocytic effector pathway downstream of MerTK.

Antioxidant and lipid supplementation improve the development of photoreceptor outer segments in pluripotent stem cell-derived retinal organoids.

The generation of retinal organoids from human pluripotent stem cells (hPSC) is now a well-established process that in part recapitulates retinal development. However, hPSC-derived photoreceptors that exhibit well-organized outer segment structures have yet to be observed. To facilitate improved inherited retinal disease modeling, we determined conditions that would support outer segment development in maturing hPSC-derived photoreceptors. We established that the use of antioxidants and BSA-bound fatty acids promotes the formation of membranous outer segment-like structures. Using new protocols for hPSC-derived retinal organoid culture, we demonstrated improved outer segment formation for both rod and cone photoreceptors, including organized stacked discs. Using these enhanced conditions to generate iPSC-derived retinal organoids from patients with X-linked retinitis pigmentosa, we established robust cellular phenotypes that could be ameliorated following adeno-associated viral vector-mediated gene augmentation. These findings should aid both disease modeling and the development of therapeutic approaches for the treatment of photoreceptor disorders.

Intravitreal administration of recombinant human opticin protects against hyperoxia-induced pre-retinal neovascularization.

Opticin is an extracellular glycoprotein present in the vitreous. Its antiangiogenic properties offer the potential for therapeutic intervention in conditions such as proliferative diabetic retinopathy and retinopathy of prematurity. Here, we investigated the hypothesis that intravitreal administration of recombinant human opticin can safely protect against the development of pathological angiogenesis and promote its regression. We generated and purified recombinant human opticin and investigated its impact on the development and regression of pathological retinal neovascularization following intravitreal administration in murine oxygen-induced retinopathy. We also investigated its effect on normal retinal vascular development and function, following intravitreal injection in neonatal mice, by histological examination and electroretinography. In oxygen-induced retinopathy, intravitreal administration of human recombinant opticin protected against the development of retinal neovascularization to similar extent as aflibercept, which targets VEGF. Opticin also accelerated regression of established retinal neovascularization, though the effect at 18 h was less than that of aflibercept. Intravitreal administration of human recombinant opticin in neonatal mice caused no detectable perturbation of subsequent retinal vascular development or function. In summary we found that intraocular administration of recombinant human opticin protects against the development of pathological angiogenesis in mice and promotes its regression.

RNAi-mediated suppression of vimentin or glial fibrillary acidic protein prevents the establishment of Müller glial cell hypertrophy in progressive retinal degeneration.

Gliosis is a complex process comprising upregulation of intermediate filament (IF) proteins, particularly glial fibrillary acidic protein (GFAP) and vimentin, changes in glial cell morphology (hypertrophy) and increased deposition of inhibitory extracellular matrix molecules. Gliosis is common to numerous pathologies and can have deleterious effects on tissue function and regeneration. The role of IFs in gliosis is controversial, but a key hypothesized function is the stabilization of glial cell hypertrophy. Here, we developed RNAi approaches to examine the role of GFAP and vimentin in vivo in a murine model of inherited retinal degeneration, the Rhodopsin knockout (Rho-/- ) mouse. Specifically, we sought to examine the role of these IFs in the establishment of Müller glial hypertrophy during progressive degeneration, as opposed to (more commonly assessed) acute injury. Prevention of Gfap upregulation had a significant effect on the morphology of reactive Müller glia cells in vivo and, more strikingly, the reduction of Vimentin expression almost completely prevented these cells from undergoing degeneration-associated hypertrophy. Moreover, and in contrast to studies in knockout mice, simultaneous suppression of both GFAP and vimentin expression led to severe changes in the cytoarchitecture of the retina, in both diseased and wild-type eyes. These data demonstrate a crucial role for Vimentin, as well as GFAP, in the establishment of glial hypertrophy and support the further exploration of RNAi-mediated knockdown of vimentin as a potential therapeutic approach for modulating scar formation in the degenerating retina.

Restoration of visual function in advanced disease after transplantation of purified human pluripotent stem cell-derived cone photoreceptors.

Age-related macular degeneration and other macular diseases result in the loss of light-sensing cone photoreceptors, causing irreversible sight impairment. Photoreceptor replacement may restore vision by transplanting healthy cells, which must form new synaptic connections with the recipient retina. Despite recent advances, convincing evidence of functional connectivity arising from transplanted human cone photoreceptors in advanced retinal degeneration is lacking. Here, we show restoration of visual function after transplantation of purified human pluripotent stem cell-derived cones into a mouse model of advanced degeneration. Transplanted human cones elaborate nascent outer segments and make putative synapses with recipient murine bipolar cells (BCs), which themselves undergo significant remodeling. Electrophysiological and behavioral assessments demonstrate restoration of surprisingly complex light-evoked retinal ganglion cell responses and improved light-evoked behaviors in treated animals. Stringent controls exclude alternative explanations, including material transfer and neuroprotection. These data provide crucial validation for photoreceptor replacement therapy and for the potential to rescue cone-mediated vision.

Surgery for idiopathic epiretinal membrane.

BACKGROUND: Epiretinal membrane is an abnormal sheet of avascular fibrocellular tissue that develops on the inner surface of the retina. Epiretinal membrane can cause impairment of sight as a consequence of progressive distortion of retinal architecture. OBJECTIVES: To determine the effects of surgery compared to no intervention for epiretinal membrane. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase Ovid, ISRCTN registry, US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). There were no restrictions to language or year of publication. The databases were last searched on 20 May 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) assessing surgical removal of idiopathic epiretinal membrane compared to placebo, no treatment or sham treatment. Paired or within-person studies were included, as well as those where both eyes of a single participant were treated. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane, and assessed certainty using the GRADE system. We considered the following five outcome measures: mean change in best corrected visual acuity (BCVA) in the study eye between baseline (before randomisation), 6 months and 12 months later; proportion of people with a gain of 0.3 logMAR or more of visual acuity in the study eye as measured by a logMAR chart at a starting distance of 4 m at 6 months and 12 months after randomisation; proportion of people with a loss of 0.3 logMAR or more of visual acuity in the study eye as measured by a logMAR chart at a starting distance of 4 m at 6 months and 12 months after randomisation; mean quality of life score at 6 months and 12 months following surgery, measured using a validated questionnaire; and any harm identified during follow-up. MAIN RESULTS: We included one study in the review. This was a RCT including 53 eyes of 53 participants with mild symptomatic epiretinal membrane and BCVA of 65 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Participants were randomly allocated to immediate surgery or to watchful waiting with deferred surgery if indicated by evidence of disease progression. The study was limited by imprecision owing to the small number of participants and was at some risk of bias owing to inconsistencies in the time points for outcome assessment and in the management of lens opacity. At 12 months, the visual acuity in the immediate surgery group was higher by a mean of 2.1 (95% confidence interval (CI) -2.0 to 6.2 ETDRS letters; 53 participants; low-certainty evidence) than the watchful waiting/deferred surgery group. The evidence of the effect of immediate surgery on gains of 0.3 logMAR or more of visual acuity is very uncertain (risk ratio (RR) 0.55, 95% CI 0.06 to 4.93; 53 participants; very low-certainty evidence). At 12 months, no participant in either group sustained a loss of 0.3 logMAR or more of visual acuity (53 participants; low-certainty evidence). The included study did not measure quality of life. At 12 months, no serious adverse event was identified in any participant. One participant developed chronic minimal cystoid macular oedema following immediate surgery (53 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: We found no RCT that directly investigated the effect of surgery compared to no intervention. For severe disabling epiretinal membrane, the lack of a RCT comparing surgery to no intervention may reflect evidence from non-randomised studies in favour of surgery; a RCT may be considered unnecessary and ethically unacceptable because a superior effect of surgery is widely accepted. For mild symptomatic epiretinal membrane, however, the value of surgery is uncertain. Low-certainty evidence from this review suggests that watchful waiting or deferred surgery may offer outcomes as favourable as immediate surgery. However, this finding needs to be confirmed in further RCTs with appropriate statistical power, masking of treatment allocation, consistent management of cataract, and measurement of outcomes including patient-reported quality of life over a more extended time frame.

Pathological Angiogenesis Requires Syndecan-4 for Efficient VEGFA-Induced VE-Cadherin Internalization.

[Figure: see text].

A Comprehensive Study of the Retinal Phenotype of Rpe65-Deficient Dogs.

The Rpe65-deficient dog has been important for development of translational therapies of Leber congenital amaurosis type 2 (LCA2). The purpose of this study was to provide a comprehensive report of the natural history of retinal changes in this dog model. Rpe65-deficient dogs from 2 months to 10 years of age were assessed by fundus imaging, electroretinography (ERG) and vision testing (VT). Changes in retinal layer thickness were assessed by optical coherence tomography and on plastic retinal sections. ERG showed marked loss of retinal sensitivity, with amplitudes declining with age. Retinal thinning initially developed in the area centralis, with a slower thinning of the outer retina in other areas starting with the inferior retina. VT showed that dogs of all ages performed well in bright light, while at lower light levels they were blind. Retinal pigment epithelial (RPE) inclusions developed and in younger dogs and increased in size with age. The loss of photoreceptors was mirrored by a decline in ERG amplitudes. The slow degeneration meant that sufficient photoreceptors, albeit very desensitized, remained to allow for residual bright light vision in older dogs. This study shows the natural history of the Rpe65-deficient dog model of LCA2.

Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions.

Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness in the developed world. Antivascular endothelial growth factor therapy has transformed the management and outcome of neovascular AMD (nAMD), although the need for repeated intravitreal injections-even lifelong-and the related complications, high drug costs, frequent clinic visits and repeated imaging have resulted in an enormous burden both to healthcare systems and patients. The application of gene therapy approaches for sustained delivery of a range of antiangiogenic proteins has the promise of helping to address these aforementioned challenges. A number of early phase clinical trials of gene therapy in nAMD have provided encouraging results, with many more ongoing or anticipated. There remain significant areas of controversy, including regarding the optimal treatment targets, routes of administration and potential safety concerns. In this review we aim to provide an update of the current status of gene therapy for nAMD and briefly discuss future prospects.

Validation of a Vision-Guided Mobility Assessment for RPE65-Associated Retinal Dystrophy.

Purpose: To validate a vision-guided mobility assessment for individuals affected by RPE65-associated retinal dystrophy (RPE65-RD). Methods: In this comparative cross-sectional study, 29 subjects, comprising 19 subjects with RPE65-RD and 10 normally-sighted subjects undertook three assessments of mobility: following a straight line, navigating a simple maze, and stepping over a sidewalk "kerb." Performance was quantified as the time taken to complete each assessment, number of errors made, walking speed, and percent preferred walking speed, for each assessment. Subjects also undertook assessments of visual acuity, contrast sensitivity, full-field static perimetry, and age-appropriate quality of life questionnaires. To identify the most relevant metric to quantify vision-guided mobility, we investigated repeatability, as well as convergent, discriminant, and criterion validity. We also measured the effect of illumination on mobility. Results: Walking speed through the maze assessment best discriminated between RPE65-RD and normally-sighted subjects, with both convergent and discriminant validity. Walking speed also approached statistical significance when assessed for criterion validity (P = 0.052). Subjects with RPE65-RD had quantifiably poorer mobility at lower illumination levels. A relatively small mean difference (-0.09 m/s) was identified in comparison to a relatively large repeatability coefficient (1.10 m/s). Conclusions: We describe a novel, quantifiable, repeatable, and valid assessment of mobility designed specifically for subjects with RPE65-RD. The assessment is sensitive to the visual impairment of individuals with RPE65-RD in low illumination, identifies the known phenotypic heterogeneity and will furthermore provide an important outcome measure for RPE65-RD. Translational Relevance: This assessment of vision-guided mobility, validated in a dedicated cohort of subjects with RPE65-RD, is a relevant and quantifiable outcome measure for RPE65-RD.

Advancing Clinical Trials for Inherited Retinal Diseases: Recommendations from the Second Monaciano Symposium.

Major advances in the study of inherited retinal diseases (IRDs) have placed efforts to develop treatments for these blinding conditions at the forefront of the emerging field of precision medicine. As a result, the growth of clinical trials for IRDs has increased rapidly over the past decade and is expected to further accelerate as more therapeutic possibilities emerge and qualified participants are identified. Although guided by established principles, these specialized trials, requiring analysis of novel outcome measures and endpoints in small patient populations, present multiple challenges relative to study design and ethical considerations. This position paper reviews recent accomplishments and existing challenges in clinical trials for IRDs and presents a set of recommendations aimed at rapidly advancing future progress. The goal is to stimulate discussions among researchers, funding agencies, industry, and policy makers that will further the design, conduct, and analysis of clinical trials needed to accelerate the approval of effective treatments for IRDs, while promoting advocacy and ensuring patient safety.

Contemporary Outcomes and Prognostic Factors of 23-Gauge Vitrectomy for Retained Lens Fragments After Phacoemulsification.

PURPOSE: To provide data on visual acuity (VA) outcomes and prognostic factors of microincision (23-gauge) vitrectomy surgery (MIVS) for retained lens fragments after complicated cataract surgery. DESIGN: Retrospective, interventional case series from 2012 to 2017. METHODS: Precataract surgery and intraoperative (vitrectomy) parameters, postvitrectomy complications, and best-corrected visual acuities (BCVAs) were identified. Vitrectomy was performed as early as corneal clarity permitted. Univariate and multivariate logistic regression were used to characterize factors associated with achieving VA better than 20/40, or worse than 20/200 at 6 months. RESULTS: This study included 291 consecutive eyes (291 patients). LogMAR BCVA improved from 0.73 ± 0.70 before cataract surgery to 0.46 ± 0.63 (P < .001) after vitrectomy. The previtrectomy VA was 1.43 ± 0.79. At 6 months, 183 (62.9%) and 45 patients (15.5%) achieved BCVAs better than 20/40 and worse than 20/200, respectively. Most frequent complications were de novo ocular hypertension (29 eyes, 10%) and transient cystoid macular edema (25 eyes, 8.6%). Postvitrectomy retinal detachment occurred in 9 eyes (3.1%). Final VA of 20/40 or better was independently associated only with better precataract surgery VA, age <75 years, absence of preexisting diabetic macular edema (DME) or postvitrectomy persistent cystoid macular edema (P < .05). Only poorer precataract surgery VA, delaying vitrectomy to later than 2 weeks, and final aphakic status were independently predictive of 20/200 or worse VA (P < .05). CONCLUSION: Contemporary VA outcomes of 23-gauge vitrectomy for retained lens fragments are comparable with that of prior predominantly non-MIVS cohorts, but fall short of benchmarks for uncomplicated cataract surgery. IOL type or timing of placement do not impact final VA.

Intravitreal Pharmacokinetic Study of the Antiangiogenic Glycoprotein Opticin.

Opticin is an endogenous vitreous glycoprotein that may have therapeutic potential as it has been shown that supranormal concentrations suppress preretinal neovascularization. Herein we investigated the pharmacokinetics of opticin following intravitreal injection in rabbits. To measure simultaneously concentrations of human and rabbit opticin, a selected reaction monitoring mass spectrometry assay was developed. The mean concentration of endogenous rabbit opticin in 7 uninjected eyes was measured and found to be 19.2 nM or 0.62 µg/mL. When the vitreous was separated by centrifugation into a supernatant and collagen-containing pellet, 94% of the rabbit opticin was in the supernatant. Intravitreal injection of human opticin (40 µg) into both eyes of rabbits was followed by enucleation at 5, 24, and 72 h and 7, 14, and 28 days postinjection (n = 6 at each time point) and measurement of vitreous human and rabbit opticin concentrations in the supernatant and collagen-containing pellet following centrifugation. The volume of distribution of human opticin was calculated to be 3.31 mL, and the vitreous half-life was 4.2 days. Assuming that rabbit and human opticin are cleared from rabbit vitreous at the same rate, opticin is secreted into the vitreous at a rate of 0.14 µg/day. We conclude that intravitreally injected opticin has a vitreous half-life that is similar to currently available antiangiogenic therapeutics. While opticin was first identified bound to vitreous collagen fibrils, here we demonstrate that >90% of endogenous opticin is not bound to collagen. Endogenous opticin is secreted by the nonpigmented ciliary epithelium into the rabbit vitreous at a remarkably high rate, and the turnover in vitreous is approximately 15% per day.

Facedown Positioning Following Surgery for Large Full-Thickness Macular Hole: A Multicenter Randomized Clinical Trial.

Importance: The value of facedown positioning following surgery for large full-thickness macular holes is unknown. Objective: To determine whether advice to position facedown postoperatively improves the outcome for large macular holes. Design, Setting, and Participants: This randomized, parallel group superiority trial with 1:1 randomization stratified by site with 3 months' follow-up was conducted at 9 sites across the United Kingdom and included participants with an idiopathic full-thickness macular hole of at least 400 µm minimum linear diameter and a duration of fewer than 12 months. All participants had vitrectomy surgery with peeling of the internal limiting membrane and injection of perfluoropropane (14%) gas, with or without simultaneous surgery for cataract. Interventions: Following surgery, participants were randomly advised to position either facedown or face forward for 8 hours daily for 5 days. Main Outcomes and Measures: The primary outcome was closure of the macular hole determined 3 months following surgery by masked optical coherence tomography evaluation. Secondary outcome measures at 3 months were visual acuity, participant-reported experience of positioning, and quality of life measured by the National Eye Institute Visual Function Questionnaire 25. Results: A total of 185 participants (45 men [24.3%]; 156 white [84.3%]; 9 black [4.9%]; 10 Asian [5.4%]; median age, 69 years [interquartile range, 64-73 years]) were randomized. Macular hole closure was observed in 90 (85.6%) who were advised to position face forward and 88 (95.5%) advised to position facedown (adjusted odds ratio, 3.15; 95% CI, 0.87-11.41; P = .08). The mean (SD) improvement in best-corrected visual acuity at 3 months was 0.34 (0.69) logMAR (equivalent to 1 Snellen line) in the face-forward group and 0.57 (0.42) logMAR (equivalent to 3 Snellen lines) in the facedown group (adjusted mean difference, 0.22 [95 % CI, 0.05-0.38]; equivalent to 2 Snellen lines); 95% CI, 0.05-0.38; P = .01). The median National Eye Institute Visual Function Questionnaire 25 score was 89 (interquartile range, 76-94) in the facedown group and 87 (interquartile range, 73-93) in the face-forward group (mean [SD] change on a logistic scale, 0.08 [0.26] face forward and 0.11 [0.25] facedown; adjusted mean [SD] difference on a logistic scale, 0.02; 95% CI, -0.03 to 0.07; P = .41). Conclusions and Relevance: The results do not prove that facedown positioning following surgery is more likely to close large macular holes compared with facing forward but do support the possibility that visual acuity outcomes may be superior. Trial Registration: Isrctn.org Identifier: 12410596.

Retinal Structure in RPE65-Associated Retinal Dystrophy.

Purpose: RPE65-associated retinal dystrophy (RPE65-RD) is an early onset, progressive, severe retinal dystrophy. We sought to characterize the natural history of retinal degeneration in affected individuals. Methods: We performed cross-sectional and longitudinal quantitative and qualitative assessments of retinal architecture in RPE65-RD using spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) imaging. Twenty-six subjects (mean age, 14.8 years, range, 5-24 years) with RPE65-RD underwent SD-OCT and FAF imaging, of whom 14 subjects were followed up over time. Foveal thickness (FT), outer nuclear layer thickness (ONLT), ellipsoid zone width (EZW), and ellipsoid zone area (EZA) were calculated where possible. These were correlated with age, best corrected visual acuity (BCVA), and central 30° retinal sensitivity (V30). Intra-observer agreement, test-retest repeatability, and interocular symmetry were also investigated. Results: We identified structural interocular symmetry, the presence of autofluorescence in 46% (12/26) of subjects, and the presence of foveal hypoplasia (associated with significantly worse BCVA) in 50% of subjects. EZW and EZA were measurable in 67% (35/52) and 37% (19/52) of eyes, respectively, with both demonstrating good agreement on repeated measurement. The annual rate of progression using EZW was -300.63 µm/year, and -1.17 mm2/year in EZA. EZW was found to have a statistically significant correlation with BCVA and V30. Conclusions: We identified the presence of autofluorescence in half of our subjects, with foveal hypoplasia also noted in half of our cohort. EZW, and to a lesser extent EZA, were robust measures of retinal degeneration and represent valuable metrics to determine the impact of intervention. (ClinicalTrials.gov number NCT02714816.).

Nystagmus and optical coherence tomography findings in CNGB3-associated achromatopsia.

PURPOSE: To describe the nystagmus characteristics of subjects with molecularly confirmed CNGB3-associated achromatopsia and report the spectral domain optical coherence tomography (SD-OCT) findings in these individuals. METHODS: Adults and children with CNGB3-achromatopsia underwent visual acuity testing, ocular motility assessments, video nystagmography, and SD-OCT imaging. Qualitative assessment of foveal structure was performed by grading SD-OCT images into one of five categories. RESULTS: A total of 18 subjects (11 adults) were included. The majority demonstrated a phoria, with manifest strabismus present in only 3 subjects. The predominant nystagmus waveform within the cohort was pure pendular. Nine individuals demonstrated a mixture of waveforms. Nystagmus frequencies were 4-8 cycles/second, with no notable differences in eye movements between adults and children. SD-OCT imaging revealed a continuous ellipsoid zone (EZ) at the fovea in 2 subjects (grade 1) and EZ disruption (grade 2) in the remaining 16. Retinal structure characteristics were symmetrical in both eyes in each subject. CONCLUSIONS: In our study cohort, nystagmus in CNGB3-associated achromatopsia had distinctive features, and the majority of subjects had retinal abnormalities at the fovea on SD-OCT. Early use of SD-OCT in the clinical work-up may eliminate the need for more invasive investigations, such as neuro-imaging.