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

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

Understanding network meta-analysis methodology for the ophthalmologist.

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

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

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

Patient-Reported Outcome Measure Use in Guidelines Published by the American Academy of Ophthalmology: A Review.

TOPIC: We reviewed the use of patient-reported outcome measures (PROMs) in the treatment of ophthalmologic conditions as recommended by the Clinical Practice Guidelines (CPGs) published by the American Academy of Ophthalmology (AAO). CLINICAL RELEVANCE: Patient-reported outcome measures are standardized instruments that provide information regarding a patient's health status or health-related quality of life. Patient-reported outcome measures are increasingly used to inform study end points in ophthalmology studies. However, the extent to which PROMs are ultimately informing patient management recommendations in ophthalmology as part of CPGs remains an area of evidence gap. METHODS: We included all CPGs published by the AAO from inception to June 2022. We also included all primary studies and systematic reviews cited in the treatment sections of the CPGs evaluating treatment of an ophthalmic condition. The primary outcome was the frequency of PROMs discussed in CPGs and in cited studies evaluating treatment. Secondary outcomes included frequency of minimal important difference (MID) use to contextualize PROM results and percentage of strong and discretionary recommendations supported by PROMs. We published a study protocol a priori on PROSPERO (CRD42022307427). Reporting followed the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. We assessed risk of bias using the Appraisal of Guidelines, Research and Evaluation II (AGREE II) instrument. RESULTS: We identified 24 eligible CPGs, providing 2458 cited studies (2191 primary, 267 secondary) evaluating treatment of eye conditions. Ten CPGs (41.7%) reported consideration of PROMs. Of these, 31 of 94 (33%) recommendations were informed by studies evaluating a PROM as an outcome. Across all studies cited in the development of CPGs, 221 (9.0%) used PROMs as a primary or secondary outcome, of which 4 PROM results (1.8%) were interpreted using an empirically determined MID. Overall, the risk of bias was low for all CPGs. CONCLUSIONS: Overall, outcomes of PROMs are seldom used in ophthalmology CPGs published by the AAO and in cited primary and secondary research on treatments. When PROMs were considered, their interpretation was seldom based on an MID. To improve patient care, guideline developers may consider incorporating PROMs and applicable MIDs to inform key outcomes when formulating treatment recommendations. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Robust Wnt signaling is maintained by a Wg protein gradient and Fz2 receptor activity in the developing Drosophila wing.

Wnts are secreted proteins that regulate cell fate during development of all metazoans. Wnt proteins were proposed to spread over several cells to activate signaling directly at a distance. In the Drosophila wing epithelium, an extracellular gradient of the Wnt1 homolog Wingless (Wg) was observed extending over several cells away from producing cells. Surprisingly, however, it was also shown that a membrane-tethered Neurotactin-Wg fusion protein (NRT-Wg) can largely replace endogenous Wg, leading to proper patterning of the wing. Therefore, the functional range of Wg and whether Wg spreading is required for correct tissue patterning remains controversial. Here, by capturing secreted Wg on cells away from the source, we show that Wg acts over a distance of up to 11 cell diameters to induce signaling. Furthermore, cells located outside the reach of extracellular Wg depend on the Frizzled2 receptor to maintain signaling. Frizzled2 expression is increased in the absence of Wg secretion and is required to maintain signaling and cell survival in NRT-wg wing discs. Together, these results provide insight into the mechanisms by which robust Wnt signaling is achieved in proliferating tissues.

The 12- and 24-Month Effects of Intravitreal Ranibizumab, Aflibercept, and Bevacizumab on Intraocular Pressure: A Network Meta-Analysis.

TOPIC: To investigate the effect of anti-vascular endothelial growth factor (VEGF) therapy on intraocular pressure (IOP) 12 and 24 months after initiation. CLINICAL RELEVANCE: It is unclear whether serial anti-VEGF injections result in sustained IOP increases. METHODS: Randomized controlled trials (RCTs) comparing anti-VEGF agents with each other or with controls for the treatment of neovascular age-related macular degeneration, retinal vein occlusions, or diabetic macular edema were included. Pairwise meta-analysis and Bayesian network meta-analysis examined the proportion of patients whose IOP (1) increased 5 mmHg or more from baseline on consecutive visits, (2) increased 10 mmHg or more from baseline at any visit, (3) was 21 mmHg or more on consecutive visits, (4) was 25 mmHg or more at any visit, (5) was 30 mmHg or more at any visit, (6) prompted initiation of IOP-lowering medications, or (7) increased as per the clinicians' discretion. Grading of Recommendations Assessments, Development, and Evaluations methodology informed the certainty of evidence. RESULTS: Twenty-six RCTs of 12 522 eyes were included. Aflibercept, bevacizumab, ranibizumab (0.3 mg and 0.5 mg), and noninjection controls were analyzed. Eighty-three of 84 network estimates for comparisons between anti-VEGF agents demonstrated no statistically significant difference (low to moderate certainty of evidence). Ranibizumab 0.5 mg showed higher rates than bevacizumab of IOP measurements of 30 mmHg or more at 12 months (low certainty of evidence). Fifty-three of 56 network estimates for comparisons between anti-VEGF agents and controls demonstrated no statistically significant difference (low to moderate certainty of evidence). Ranibizumab 0.5 mg showed higher rates of consecutive IOP increases of 5 mmHg or more at 24 months (low certainty of evidence) and higher rates of IOP increases as per the clinicians' discretion at 12 and 24 months (low and very low certainty of evidence, respectively). The 95% credible intervals in comparisons without statistically significant effects did not rule out important clinical effects. The certainty of evidence in these comparisons is limited by imprecision. CONCLUSION: This network meta-analysis does not show any clear difference in IOP increases 12 and 24 months after treatment initiation between anti-VEGF agents and controls. Imprecision precludes definitive conclusions.

Complications of intravitreal injections: 2022.

PURPOSE OF REVIEW: This review highlights the complications of both intravitreal injection procedure as well as different intravitreal medications including antivascular endothelial growth factors, antibiotics, antivirals, antifungals, methotrexate, and steroids. Techniques for reducing rates of endophthalmitis will also be discussed. RECENT FINDINGS: Intravitreal vancomycin can cause hemorrhagic occlusive retinal vasculitis resulting in severe vision loss. Intravitreal brolucizumab is associated with intraocular inflammation and retinal vasculitis resulting in significant vision loss. Face mask use by both patient and physician is not associated with increased risk of endophthalmitis and may decrease culture positive endophthalmitis. SUMMARY: Intravitreal injections continue to be one of the most commonly performed procedures by ophthalmologists. Although the injections are generally well tolerated, sight-threatening complications can occur including endophthalmitis, retinal detachment, and/or retinal vasculitis. Adverse events associated with specific medications are outlined below. Several safety measures have been shown to reduce rates of endophthalmitis, the most concerning complication of this procedure.

IMPACT OF FLUID COMPARTMENTS ON FUNCTIONAL OUTCOMES FOR PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Systematic Literature Review.

PURPOSE: Understanding the impact of fluid in different retinal compartments is critical to developing treatment paradigms that optimize visual acuity and reduce treatment burden in neovascular age-related macular degeneration. This systematic review aimed to determine the impact of persistent/new subretinal fluid, intraretinal fluid, and subretinal pigment epithelial fluid on visual acuity over 1 year of treatment. METHODS: Publication eligibility and data extraction were conducted according to Cochrane methods: 27 of the 1,797 screened records were eligible. RESULTS: Intraretinal fluid negatively affected visual acuity at baseline and throughout treatment, with foveal intraretinal fluid associated with lower visual acuity than extrafoveal intraretinal fluid. Some studies found that subretinal fluid (particularly subfoveal) was associated with higher visual acuity at Year 1 and longer term, and others suggested subretinal fluid did not affect visual acuity at Years 1 and 2. Data on the effects of subretinal pigment epithelial fluid were scarce, and consensus was not reached. Few studies reported numbers of injections associated with fluid status. CONCLUSION: To optimally manage neovascular age-related macular degeneration, clinicians should understand the impact of fluid compartments on visual acuity. After initial treatment, antivascular endothelial growth factor regimens that tolerate stable subretinal fluid (if visual acuity is stable/improved) but not intraretinal fluid may enable patients to achieve their best possible visual acuity. Confirmatory studies are required to validate these findings.

A MULTICENTER REVIEW EVALUATING THE RISK OF RHEGMATOGENOUS RETINAL DETACHMENT POST ENDOPHTHALMITIS: A Canadian Retina Research Network Investigation.

PURPOSE: To describe the characteristics of rhegmatogenous retinal detachments (RDs) that developed after endophthalmitis and to provide insight regarding incidence, management, and outcomes. METHODS: Retrospective chart review of consecutive patients diagnosed with endophthalmitis at two Canadian institutions and from one surgeon at a third center over a 10-year period. RESULTS: Three hundred sixteen eyes presented with endophthalmitis of which 32 (10%) were complicated by subsequent RD. The mean age (SD) of patients was 72.0 (13.77) years. Intravitreal injections (33%) and cataract surgery (31%) were the most common inciting events for the endophthalmitis. Cases were managed with tap and inject (16%), vitrectomy (30%), or both (47%). There were no differences in the rate of RD when comparing the inciting events, microbial growth, or management approaches. Baseline visual acuity was the only predictor of RD ( P = 0.009). There was an improvement in visual acuity following management of the RD (logarithm of the minimum angle of resolution 2.33 vs. 1.69 or Snellen hand motion vs. 20/980, P = 0.009), but final visual acuity in these patients was worse than in those who did not develop RD (logarithm of the minimum angle of resolution 1.69 vs. 1.27 or Snellen 20/980 vs. 20/372, P = 0.029). CONCLUSION: All patients with RD post endophthalmitis required additional surgery, and functional outcomes remained poor. Nevertheless, repair of these RDs can preserve some vision and be globe saving.

Supplemental Scleral Buckle for the Management of Rhegmatogenous Retinal Detachment by Pars Plana Vitrectomy: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: The present review aimed to synthesize evidence from randomized controlled trials (RCTs) that compared outcomes of pars plana vitrectomy (PPV) with and without a supplementary scleral buckle (SB) for management of rhegmatogenous retinal detachment (RRD). METHODS: The authors searched MEDLINE, Embase, and CENTRAL to identify RCTs in English that compared PPV with and without supplemental SB. Risk of bias was assessed according to the Cochrane Risk of Bias 2 tool. We present risk ratios (RRs), mean differences (MDs), and 95% confidence intervals (CIs) estimated using random-effects meta-analyses. RESULTS: We identified 6 RCTs involving 705 eyes. Primary reattachment (6 studies, 345 eyes PPV, 324 eyes PPV + SB; RR 0.99, 95% CI 0.93-1.06, I2 = 0%, p = 0.78) and final anatomic success rates (4 studies, 272 eyes PPV, 267 eyes PPV + SB; RR 1.00, 95% CI 0.98-1.02, I2 = 0%, p = 0.89) were similar between the 2 groups. Postoperative visual acuity improvement (5 studies, 244 eyes PPV, 222 eyes PPV + SB; MD 6.09 letters, 95% CI -0.47-12.64, I2 = 69%, p = 0.07) and frequency of adverse events (6 studies, 1,294 observations PPV, 1,221 observations PPV + SB; RR 0.76, 95% CI 0.57-1.01, I2 = 25%, p = 0.06) likewise did not differ significantly between the treatment groups. CONCLUSION: Low-certainty evidence from RCTs did not demonstrate a benefit in placement of a supplemental SB during vitrectomy for management of RRD in the current analysis. Additional high-quality trials are needed to provide more precise estimates of the effect.

Exocyst-mediated apical Wg secretion activates signaling in the Drosophila wing epithelium.

Wnt proteins are secreted signaling factors that regulate cell fate specification and patterning decisions throughout the animal kingdom. In the Drosophila wing epithelium, Wingless (Wg, the homolog of Wnt1) is secreted from a narrow strip of cells at the dorsal-ventral boundary. However, the route of Wg secretion in polarized epithelial cells remains poorly understood and key proteins involved in this process are still unknown. Here, we performed an in vivo RNAi screen and identified members of the exocyst complex to be required for apical but not basolateral Wg secretion. Specifically blocking the apical Wg secretion leads to reduced downstream signaling. Using an in vivo 'temporal-rescue' assay, our results further indicate that apically secreted Wg activates target genes that require high signaling activity. In conclusion, our results demonstrate that the exocyst is required for an apical route of Wg secretion from polarized wing epithelial cells.

Publication trends in telemedicine research originating from Canada.

Telemedicine modalities for patient care have seen significant global uptake during the COVID-19 pandemic. This study aimed to bibliometrically evaluate the evolution and current landscape of telemedicine literature in Canada. The Scopus database was searched to identify telemedicine publications for which the first or last author had a Canadian institutional affiliation. Study selection and data abstraction were conducted by two pairs of independent reviewers. Between 1976 and January 2021, 810 of 3,620 retrieved citations were telemedicine publications originating from Canada, including 29 randomized controlled trials and 6 systematic reviews. The annual publication output increased substantially from 1/year in 1976 to 80/year in 2020. Based on author keyword analysis, the most frequently investigated disciplines or disease entities were primary care, COVID-19, telepsychiatry, heart failure, and mental health. The insights this study provides will aid scientists, policy makers, and other stakeholders in identifying opportunities for future investigation and clinical application.

Small-Molecule Inhibitor Prevents Insulin Fibrillogenesis and Preserves Activity.

Amyloidosis is a well-known but poorly understood phenomenon caused by the aggregation of proteins, often leading to pathological conditions. For example, the aggregation of insulin poses significant challenges during the preparation of pharmaceutical insulin formulations commonly used to treat diabetic patients. Therefore, it is essential to develop inhibitors of insulin aggregation for potential biomedical applications and for important mechanistic insights into amyloidogenic pathways. Here, we have identified a small molecule M1, which causes a dose-dependent reduction in insulin fibril formation. Biophysical analyses and docking results suggest that M1 likely binds to partially unfolded insulin intermediates. Further, M1-treated insulin had lower cytotoxicity and remained functionally active in regulating cell proliferation in cultured Drosophila wing epithelium. Thus, M1 is of great interest as a novel agent for inhibiting insulin aggregation during biopharmaceutical manufacturing.

Mechanochemically Processed Nd-Fe-Co-Cr-B Nanoparticles with High Coercivity and Reduced Spin Reorientation Transition Temperature.

Nd-Fe-B magnets, possessing the highest energy product, are extensively used in cutting-edge applications, including electrical machines and electrical vehicles. An environmentally benign and cost effective synthesis method of Cr alloyed Nd2 (Fe,Co)14 B magnetic nanoparticles using a dry mechanochemical process is reported. The method is solvent free, facile, energy efficient and scalable. The reduction of mixed oxides of Nd, Fe, Co, B and Cr is performed by using Ca. The coercivity (HC ) of the nanoparticles is found to depend on the dispersant content, with the highest value obtained for Nd2 (Fe11.25 Co2 Cr0.75 )B with 40 % CaO dispersant. The HC of isolated Nd2 (Fe11.25 Co2 Cr0.75 )B nanoparticles and nanoparticles embedded in a CaO matrix is found to be 11.5 kOe and 14.4 kOe, respectively, largest values for heavy rare earth free Nd-Fe-B nanoparticles with reasonable saturation and remanent magnetization, regardless of synthesis route. Considering the density of Nd2 Fe14 B, an energy product of 14.2 MGOe is obtained for the nanoparticles. The thermal coefficient of remanence and thermal coefficient of coercivity for aligned samples are -0.06 % and -0.29 %, respectively, in the temperature range between 100 K and 400 K. The spin reorientation temperature is found to be ∼30 K less than that of bulk Nd2 Fe14 B magnets.

Hot exciton cooling and multiple exciton generation in PbSe quantum dots.

Multiple exciton generation (MEG) is a promising process to improve the power conversion efficiency of solar cells. PbSe quantum dots (QDs) have shown reasonably high MEG quantum yield (QY), although the photon energy threshold for this process is still under debate. One of the reasons for this inconsistency is the complicated competition of MEG and hot exciton cooling, especially at higher excited states. Here, we investigate MEG QY and the origin of the photon energy threshold for MEG in PbSe QDs of three different sizes by studying the transient absorption (TA) spectra, both at the band gap (near infrared, NIR) and far from the band gap energy (visible range). The comparison of visible TA spectra and dynamics for different pump wavelengths, below, around and above the MEG threshold, provides evidence of the role of the Σ transition in slowing down the exciton cooling process that can help MEG to take over the phonon relaxation process. The universality of this behavior is confirmed by studying QDs of three different sizes. Moreover, our results suggest that MEG QY can be determined by pump-probe experiments probed above the band gap.