BACKGROUND: Primary angle-closure glaucoma (PACG) is characterized by a rise in intraocular pressure (IOP) secondary to aqueous outflow obstruction, with relative pupillary block being the most common underlying mechanism. There is increasing evidence that lens extraction may relieve pupillary block and thereby improve IOP control. As such, comparing the effectiveness of lens extraction against other commonly used treatment modalities can help inform the decision-making process. OBJECTIVES: To assess the effectiveness of lens extraction compared with other interventions in the treatment of chronic PACG in people without previous acute angle-closure attacks. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, one other database, and two trials registers (December 2019). We also screened the reference lists of included studies and the Science Citation Index database. We had no date or language restrictions. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing lens extraction with other treatment modalities for chronic PACG. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. MAIN RESULTS: We identified eight RCTs with 914 eyes. We obtained data for participants meeting our inclusion criteria for these studies (PACG only, no previous acute angle-closure attacks), resulting in 513 eyes included in this review. The participants were recruited from a diverse range of countries. We were unable to conduct meta-analyses due to different follow-up periods and insufficient data. One study compared phacoemulsification with laser peripheral iridotomy (LPI) as standard care. Participants in the phacoemulsification group were less likely to experience progression of visual field loss (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.13 to 0.91; 216 eyes; moderate certainty evidence), and required fewer IOP-lowering medications (mean difference [MD] -0.70, 95% CI -0.89 to -0.51; 263 eyes; moderate certainty evidence) compared with standard care at 12 months. Moderate certainty evidence also suggested that phacoemulsification improved gonioscopic findings at 12 months or later (MD -84.93, 95% CI -131.25 to -38.61; 106 eyes). There was little to no difference in health-related quality of life measures (MD 0.04, 95% CI -0.16 to 0.24; 254 eyes; moderate certainty evidence), and visual acuity (VA) (MD 2.03 ETDRS letter, 95% CI -0.77 to 4.84; 242 eyes) at 12 months, and no observable difference in mean IOP (MD -0.03mmHg, 95% CI -2.34 to 2.32; 257 eyes; moderate certainty evidence) compared to standard care. Irreversible loss of vision was observed in one participant in the phacoemulsification group, and three participants in standard care at 36 months (moderate-certainty evidence). One study (91 eyes) compared phacoemulsification with phaco-viscogonioplasty (phaco-VGP). Low-certainty evidence suggested that fewer IOP-lowering medications were needed at 12 months with phacoemulsification (MD -0.30, 95% CI -0.55 to -0.05). Low-certainty evidence also suggested that phacoemulsification may have improved gonioscopic findings at 12 months or later compared to phaco-VGP (angle grading MD -0.60, 95% CI -0.91 to -0.29; TISA500 MD -0.03, 95% CI -0.06 to -0.01; TISA750 MD -0.03, 95% CI -0.06 to -0.01; 91 eyes). Phacoemulsification may result in little to no difference in best corrected VA at 12 months (MD -0.01 log MAR units, 95% CI -0.10 to 0.08; low certainty evidence), and the evidence is very uncertain about its effect on IOP at 12 months (MD 0.50 mmHg, 95% CI -2.64 to 3.64; very low certainty evidence). Postoperative fibrin reaction was observed in two participants in the phacoemulsification group and four in the phaco-VGP group. Three participants in the phaco-VGP group experienced hyphema. No data were available for progression of visual field loss and quality of life measurements at 12 months. Two studies compared phacoemulsification with phaco-goniosynechialysis (phaco-GSL). Low-certainty evidence suggested that there may be little to no difference in mean IOP at 12 months (MD -0.12 mmHg, 95% CI -4.72 to 4.48; 1 study, 32 eyes) between the interventions. Phacoemulsification did not reduce the number of IOP-lowering medications compared to phaco-GSL at 12 months (MD -0.38, 95% CI -1.23 to 0.47; 1 study, 32 eyes; moderate certainty evidence). Three eyes in the phaco-GSL group developed hyphemas. No data were available at 12 months for progression of visual field loss, gonioscopic findings, visual acuity, and quality of life measures. Three studies compared phacoemulsification with combined phaco-trabeculectomy, but the data were only available for one study (63 eyes). In this study, low-certainty evidence suggested that there was little to no difference between groups in mean change in IOP from baseline (MD -0.60 mmHg, 95% CI -1.99 to 0.79), number of IOP-lowering medications at 12 months (MD 0.00, 95% CI -0.42 to 0.42), and VA measured by the Snellen chart (MD -0.03, 95% CI -0.18 to 0.12). Participants in the phacoemulsification group had fewer complications (risk ratio [RR] 0.59, 95% CI 0.34 to 1.04), and the phaco-trabeculectomy group required more IOP-lowering procedures (RR 5.81, 95% CI 1.41 to 23.88), but the evidence was very uncertain. No data were available for other outcomes. AUTHORS' CONCLUSIONS: Moderate certainty evidence showed that lens extraction has an advantage over LPI in treating chronic PACG with clear crystalline lenses over three years of follow-up; ultimately, the decision for intervention should be part of a shared decision-making process between the clinician and the patient. For people with chronic PACG and visually significant cataracts, low certainty evidence suggested that combining phacoemulsification with either viscogonioplasty or goniosynechialysis does not confer any additional benefit over phacoemulsification alone. There was insufficient evidence to draw any meaningful conclusions regarding phacoemulsification versus trabeculectomy. Low certainty evidence suggested that combining phacoemulsification with trabeculectomy does not confer any additional benefit over phacoemulsification alone, and may cause more complications instead. These conclusions only apply to short- to medium-term outcomes; studies with longer follow-up periods can help assess whether these effects persist in the long term.

PURPOSE: Retinoschisis (RS), rhegmatogenous retinal detachment (RRD) and combined RS retinal detachment (RSRD) may resemble clinically and pose a diagnostic challenge. This study investigates the role of the fundus autofluorescence (AF) in differentiating RS, RRD and RSRD. METHODS: Fundus AF changes of 34 eyes diagnosed with RRD, 30 eyes with RS and 12 eyes with RSRD were retrospectively analysed. Ultra-widefield AF (UW-AF) image intensities obtained with the Optomap 200Tx were interpreted as hypo-, hyper- and isoautofluorescent or a mixed pattern with hypo- and hyperautofluorescence over and at the posterior margin (PM) of RRD, RS and RSRD. RESULTS: All RS eyes revealed isoautofluorescence over the area of RS, and nine eyes (30%) showed hypoautofluorescent PM. Among RRD, acute (≤2 weeks) and chronic (>2 weeks) RRD demonstrated distinct AF characteristics. Sixty-two per cent of RRD eyes had acute RRD. From those, 16 eyes (76%) demonstrated hypoautofluorescence over the detached area and 19 (90%) eyes with hyperautofluorescent PM. Sixty-two per cent of chronic RRD eyes demonstrated isoautofluorecence over the detached area. Eight RSRD eyes (67%) revealed hyperautofluorescence in the detached area. The positive predictive value (PPV) for hypoautofluorescence over the area of subretinal fluid (SRF) in RRD was 95%. The PPV for hyperautofluorescence over the area of SRF in RSRD was 100% and for isoautofluorescence for schitic area in RSRD and RS was 76%. CONCLUSION: The UW-AF can be a useful non-invasive adjuvant tool to distinguish between RRD, RS and RSRD. Hypo- or hyperautofluorescence over the area of interest and hyperautofluorescent PM indicates the presence of SRF.

In the last two decades rodents have been on the rise as a dominant model for visual neuroscience. This is particularly true for earlier levels of information processing, but a number of studies have suggested that also higher levels of processing such as invariant object recognition occur in rodents. Here we provide a quantitative and comprehensive assessment of this claim by comparing a wide range of rodent behavioral and neural data with convolutional deep neural networks. These networks have been shown to capture hallmark properties of information processing in primates through a succession of convolutional and fully connected layers. We find that performance on rodent object vision tasks can be captured using low to mid-level convolutional layers only, without any convincing evidence for the need of higher layers known to simulate complex object recognition in primates. Our approach also reveals surprising insights on assumptions made before, for example, that the best performing animals would be the ones using the most abstract representations-which we show to likely be incorrect. Our findings suggest a road ahead for further studies aiming at quantifying and establishing the richness of representations underlying information processing in animal models at large.

Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary addition to the burgeoning field of immunotherapy. CAR T-cells are engineered by combining a T-cell receptor with the antigen-binding site of an immunoglobulin that allows the hybrid cell to target antigens of interest. CAR T-cell therapy has been approved to treat various hematologic malignancies, including relapsed or refractory B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma. While the treatment efficacy is exciting, challenges remain in understanding the unique spectrum of adverse effects of CAR T-cell therapy, including cytokine release syndrome and neurotoxicity. Innovative research is underway to expand this therapy into solid tumors and fields beyond hematology and oncology. To date, there has been limited research into ophthalmic uses and considerations of CAR T-cell therapy. This review focuses on preclinical investigations into CAR T-cell therapy for retinoblastoma and uveal melanoma, as well as ophthalmic complications of CAR T-cell therapy.

Importance: The role of anti-vascular endothelial growth factor injections for the management of nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) has not been clearly established. Objective: To determine the efficacy of intravitreous aflibercept injections compared with sham treatment in preventing potentially vision-threatening complications in eyes with moderate to severe NPDR. Design, Setting, and Participants: Data for this study were collected between January 15, 2016, and May 28, 2020, from the ongoing DRCR Retina Network Protocol W randomized clinical trial, conducted at 64 US and Canadian sites among 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study severity level, 43-53), without CI-DME. Analyses followed the intent-to-treat principle. Interventions: Eyes were randomly assigned to 2.0 mg of aflibercept injections (n = 200) or sham (n = 199) given at baseline; 1, 2, and 4 months; and every 4 months through 2 years. Between 2 and 4 years, treatment was deferred if the eye had mild NPDR or better. Aflibercept was administered in both groups if CI-DME with vision loss (≥10 letters at 1 visit or 5-9 letters at 2 consecutive visits) or high-risk proliferative diabetic retinopathy (PDR) developed. Main Outcomes and Measures: Development of CI-DME with vision loss or PDR through May 2020, when the last 2-year visit was completed. Results: Among the 328 participants (57.6% men [230 of 399 eyes]; mean [SD] age, 56 [11] years), the 2-year cumulative probability of developing CI-DME with vision loss or PDR was 16.3% with aflibercept vs 43.5% with sham. The overall hazard ratio for either outcome was 0.32 (97.5% CI, 0.21-0.50; P < .001), favoring aflibercept. The 2-year cumulative probability of developing PDR was 13.5% in the aflibercept group vs 33.2% in the sham group, and the 2-year cumulative probability of developing CI-DME with vision loss was 4.1% in the aflibercept group vs 14.8% in the sham group. The mean (SD) change in visual acuity from baseline to 2 years was -0.9 (5.8) letters with aflibercept and -2.0 (6.1) letters with sham (adjusted mean difference, 0.5 letters [97.5% CI, -1.0 to 1.9 letters]; P = .47). Conclusions and Relevance: In this randomized clinical trial, among eyes with moderate to severe NPDR, the proportion of eyes that developed PDR or vision-reducing CI-DME was lower with periodic aflibercept compared with sham treatment. However, through 2 years, preventive treatment did not confer visual acuity benefit compared with observation plus treatment with aflibercept only after development of PDR or vision-reducing CI-DME. The 4-year results will be important to assess longer-term visual acuity outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02634333.

To describe a database of longitudinally graded telemedicine retinal images to be used as a comparator for future studies assessing grader recall bias and ability to detect typical progression (e.g. International Classification of Retinopathy of Prematurity (ICROP) stages) as well as incremental changes in retinopathy of prematurity (ROP). Cohort comprised of retinal images from 84 eyes of 42 patients who were sequentially screened for ROP over 6 consecutive weeks in a telemedicine program and then followed to vascular maturation or treatment, and then disease stabilization. De-identified retinal images across the 6 weekly exams (2520 total images) were graded by an ROP expert based on whether ROP had improved, worsened, or stayed the same compared to the prior week's images, corresponding to an overall clinical "gestalt" score. Subsequently, we examined which parameters might have influenced the examiner's ability to detect longitudinal change; images were graded by the same ROP expert by image view (central, inferior, nasal, superior, temporal) and by retinal components (vascular tortuosity, vascular dilation, stage, hemorrhage, vessel growth), again determining if each particular retinal component or ROP in each image view had improved, worsened, or stayed the same compared to the prior week's images. Agreement between gestalt scores and view, component, and component by view scores was assessed using percent agreement, absolute agreement, and Cohen's weighted kappa statistic to determine if any of the hypothesized image features correlated with the ability to predict ROP disease trajectory in patients. The central view showed substantial agreement with gestalt scores (κ = 0.63), with moderate agreement in the remaining views. Of retinal components, vascular tortuosity showed the most overall agreement with gestalt (κ = 0.42-0.61), with only slight to fair agreement for all other components. This is a well-defined ROP database graded by one expert in a real-world setting in a masked fashion that correlated with the actual (remote in time) exams and known outcomes. This provides a foundation for subsequent study of telemedicine's ability to longitudinally assess ROP disease trajectory, as well as for potential artificial intelligence approaches to retinal image grading, in order to expand patient access to timely, accurate ROP screening.

BACKGROUND: Pragmatic and comparative effectiveness randomized controlled trials (RCTs) aim to be highly generalizable studies, with broad applicability and flexibility in methods. These trials also address recruitment issues by minimizing exclusions. The trials may also appeal to potential subjects because of lower risk and lower burdens of participation. We sought to examine rates of refusal and uses of waivers of informed consent in pragmatic and comparative effectiveness RCTs. METHODS: A systematic review of pragmatic and comparative effectiveness RCTs performed wholely or in part in the United States and first published in 2014 and 2017. RESULTS: 103 studies involving 105 discrete populations were included for review. Refusal data was collected for 71 RCTs. Overall, studies reported an average rate of 31.9% of potential subjects refused participation; on an individual basis, 38.4% of people asked to take part refused at some point during recruitment. 23 trials (22%) were performed, at least in part, with a waiver of informed consent, 7 (30%) of which provided any form of notice to subjects. CONCLUSIONS: Overall refusal rates for pragmatic and comparative effectiveness RCTs appear roughly the same as other types of research, with studies reporting about a third of people solicited for participation refuse. Moreover, informed consent was waived in 22% (95% Binomial exact Confidence Interval 13.9-30.5%) of the trials, and further study is needed to understand when waivers are justified and when notice should be provided.

Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2TMPRSS2 cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.