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BACKGROUND/OBJECTIVES: The phase 3 REGAIN study and its open-label extension demonstrated the efficacy of the complement C5 inhibitor eculizumab in patients with treatment-refractory, acetylcholine receptor antibody-positive generalized myasthenia gravis (gMG). The aim of the ELEVATE study was to assess the effectiveness of eculizumab in clinical practice in adults with MG in the United States. METHODS: A retrospective chart review was conducted in adults with MG who initiated eculizumab treatment between October 23, 2017 and December 31, 2019. Outcomes assessed before and during eculizumab treatment using a pre- versus post-treatment study design included Myasthenia Gravis-Activities of Daily Living (MG-ADL) total scores; minimal symptom expression (MSE); physician impression of clinical change; minimal manifestation status (MMS); and concomitant medication use. RESULTS: In total, 119 patients were included in the study. A significant reduction was observed in mean MG-ADL total score, from 8.0 before eculizumab initiation to 5.4 at 3 months and to 4.7 at 24 months after eculizumab initiation (both p

BACKGROUND: Despite the initial evidence supporting the utility of intravascular imaging to guide percutaneous coronary intervention (PCI), adoption remains low. Recent new trial data have become available. An updated study-level meta-analysis comparing intravascular imaging to angiography to guide PCI was performed. This study aimed to evaluate the clinical outcomes of intravascular imaging-guided PCI compared with angiography-guided PCI. METHODS AND RESULTS: A random-effects meta-analysis was performed on the basis of the intention-to-treat principle. The primary outcomes were major adverse cardiac events, cardiac death, and all-cause death. Mixed-effects meta-regression was performed to investigate the impact of complex PCI on the primary outcomes. A total of 16 trials with 7814 patients were included. The weighted mean follow-up duration was 28.8 months. Intravascular imaging led to a lower risk of major adverse cardiac events (relative risk [RR], 0.67 [95% CI, 0.55-0.82]; P

An increasing number of clinical trials are enrolling patients with myasthenia gravis (MG). A lack of standardization in the performance of outcome measures leads to confusion among site research teams and is a source of variability in clinical trial data. MGNet, the NIH-supported Rare Disease Clinical Research Network for MG, views standardization of MG outcome measures as a critical need. To address this issue, a group of experts summarized key outcome measures used in MG clinical trials and a symposium was convened to address issues contributing to outcome measure variability. Consensus recommendations resulted in changes to outcome measure instructions and, in some cases, modifications to specific instruments. Recommended changes were posted for public commentary before finalization. Changes to the MG-Activities of Daily Living, MG-Quality of Life-15r, and MG-Impairment Index were limited to adding details to the administration instructions. Recommendations for proper positioning of participants and how to score items that could not be performed because of non-MG reasons were provided for the MG Composite. The Quantitative MG (QMG) score required the most attention, and changes were made both to the instructions and the performance of certain items resulting in the QMG-Revised. The Postintervention Status was believed to have a limited role in clinical trials, except for the concept of minimal manifestation status. As a next step, training materials and revised source documents, which will be freely available to study teams, will be created and posted on the MGNet website. Further studies are needed to validate changes made to the QMG-Revised.

An increasing number of clinical trials are enrolling patients with myasthenia gravis (MG). A lack of standardization in the performance of outcome measures leads to confusion among site research teams and is a source of variability in clinical trial data. MGNet, the NIH-supported Rare Disease Clinical Research Network for MG, views standardization of MG outcome measures as a critical need. To address this issue, a group of experts summarized key outcome measures used in MG clinical trials and a symposium was convened to address issues contributing to outcome measure variability. Consensus recommendations resulted in changes to outcome measure instructions and, in some cases, modifications to specific instruments. Recommended changes were posted for public commentary before finalization. Changes to the MG-Activities of Daily Living, MG-Quality of Life-15r, and MG-Impairment Index were limited to adding details to the administration instructions. Recommendations for proper positioning of participants and how to score items that could not be performed because of non-MG reasons were provided for the MG Composite. The Quantitative MG (QMG) score required the most attention, and changes were made both to the instructions and the performance of certain items resulting in the QMG-Revised. The Postintervention Status was believed to have a limited role in clinical trials, except for the concept of minimal manifestation status. As a next step, training materials and revised source documents, which will be freely available to study teams, will be created and posted on the MGNet website. Further studies are needed to validate changes made to the QMG-Revised.

Background: Interest in cementless total knee arthroplasty (TKA) has increased with advancement of biomaterials and implant design and associated improved longevity. We sought to evaluate the gap patterns and radiolucent zones radiographically for 2 newer-generation cementless TKA designs. Methods: We retrospectively reviewed our single-institution database between January 2017 and December 2019. We identified patients with a porous keeled tibia baseplate with 4-bullet cruciform spikes and peri-apatite coated femoral component (study group 1) and patients who received a cementless porous coated femoral component and rotating platform tibia baseplate with 4 peripheral porous coated pegs around a central cone (study group 2). We identified gap patterns at 6 weeks and at 1 year or more postoperatively on radiographs, noting indications for reoperation. Results: We identified 228 patients in study group 1 and 41 patients in study group 2. At 1-year follow-up, we found evidence of resolved femoral gaps in 52 (72.2%) of 72 patients in study group 1 and 10 (58.8%) of 17 patients in study group 2 (p = 0.124). We identified 27 (84.3%) of 32 patients in study group 1 and 7 (70.0%) of 10 patients in study group 2 with resolved tibia gaps (p = 0.313). After 1 year, there were significantly more Zone 3 a femoral zonal radiolucent gaps (p = 0.001) and Zone 8 tibia zonal radiolucent gaps (p = 0.002) in study group 2 than in study group 1. There were 4 reoperations for study group 1 and 0 reoperations for study group 2. Conclusion: The modern cementless TKA systems have varied gap patterns in postoperative radiographs, which may be attributed to the implant design. Most radiolucent gaps resolve radiographically on follow-up. Contexte : Les perc es dans les biomat riaux et la conception des proth ses, associ es une long vit accrue de ces derni res, ont entra n un regain d'int r t pour l'arthroplastie totale du genou (ATG) non ciment e. Nous avons cherch valuer par radiographie les espaces et les zones radiotransparentes pour 2 ATG de nouvelle g n ration sans ciment. M thodes : Nous avons r trospectivement pass en revue notre base de donn es (un seul tablissement) pour la p riode de janvier 2017 d cembre 2019. Nous y avons rep r les patients ayant re u une pi ce tibiale poreuse quille avec 4 pointes cruciformes et une composante f morale rev tement de peri-apatite (groupe 1) et les patients ayant re u une composante f morale poreuse rev tue non ciment e et une pi ce tibiale en rotation avec 4 plots p riph riques poreux rev tus autour d'un c ne central (groupe 2). Six semaines puis au moins 1 an apr s l'intervention, nous avons identifi sur des radiographies les espaces en notant les indications de r intervention. R sultats : Nous avons tudi 228 patients dans le groupe 1 et 41 patients dans le groupe 2. Au suivi apr s 1 an, nous avons trouv des signes d'espace f moral r sorb chez 52 patients sur 72 (72,2%) du groupe 1 et chez 10 patients sur 17 (58,8%) du groupe 2 (p = 0,124). Nous avons trouv chez 27 patients sur 32 (84,3%) du groupe 1 et 7 patients sur 10 (70,0%) du groupe 2 un espace tibial r sorb (p = 0,313). Apr s 1 an, il y avait consid rablement plus d'espaces radiotransparents dans la zone f morale 3a (p = 0,001) et d'espaces radiotransparents dans la zone tibiale 8 (p = 0,002) dans le groupe 2 que dans le groupe 1. Il y a eu 4 r interventions dans le groupe 1 et aucune dans le groupe 2. Conclusion : Les syst mes d'ATG modernes sans ciment pr sentent des espaces vari s sur les radiographies postop ratoires, ce qui peut tre attribu la conception de la proth se. La plupart des espaces radiotransparents se sont r sorb s la radiographie de suivi., Knee end-stage osteoarthritis is successfully treated with total knee arthroplasty (TKA), with more than 55 000 TKA procedures performed in Canada in 2020-2021 alone. (1) Cemented TKA is typically preferred [...]

AIMS: The effect of atrial fibrillation catheter ablation on cardiovascular outcomes in heart failure is an important outstanding research question. We undertook a meta-analysis of randomized controlled trials comparing ablation to medical therapy in patients with AF and heart failure. METHODS AND RESULTS: We systematically identified all trials comparing catheter ablation to medical therapy in patients with heart failure and atrial fibrillation. The pre-specified primary endpoint was all-cause mortality in trials with at least 2 years of follow-up. The secondary endpoint was heart failure hospitalization. Sensitivity analyses were performed for trials with any follow-up and trials deemed at low risk of bias. Eight trials (1390 patients) were included. Seven hundred and seven patients were randomized to catheter ablation and 683 to medical therapy. In the primary analysis (three trials, n = 977), catheter ablation reduced mortality compared with medical therapy [relative risk (RR): 0.61, 95% confidence interval (CI): 0.44 to 0.84, P = 0.003]. Catheter ablation also reduced heart failure hospitalizations compared with medical therapy (RR: 0.60, 95% CI: 0.49-0.74, P < 0.001). The effect on stroke was not statistically significant (RR: 0.62, 95% CI: 0.28-1.37, P = 0.237). There was low heterogeneity between studies. Sensitivity analyses were consistent with the primary analyses. CONCLUSION: In patients with atrial fibrillation and heart failure, catheter ablation reduces mortality and the occurrence of heart failure hospitalizations.

Background: The rate of major surgical complications for high-volume orthopedic surgeons using the direct anterior approach (DAA) in Ontario, Canada, is not known. The purpose of this study was to investigate the rate of major surgical complications after total hip arthroplasty (THA) using DAA performed by experienced orthopedic surgeons at a high-volume tertiary care centre in Ontario. Methods: We conducted a retrospective cohort review of primary THA through DAA performed by 2 experienced fellowship-trained surgeons at an academic hospital in London, Ontario, between Jan. 1, 2012, and May 1, 2019. We excluded the first 100 cases to allow for surgeon learning curves. We recorded major surgical complications (intraoperative events, postoperative periprosthetic fractures, dislocation requiring closed or open reduction, implant failure [aseptic loosening or subsidence], early (< 6 wk) deep wound infection requiring irrigation and debridement, late ([greater than or equal to] 6 wk) deep wound infection requiring irrigation and debridement, and wound complications [wound dehiscence, stitch abscess, erythema, hematoma or seroma]) within 1 year of THA. Results: A total of 875 primary DAA THA procedures were included. The rates of surgical complications were 0.9% for intraoperative events, 1.5% for postoperative periprosthetic fractures, 0.8% for implant failure, 0.7% for early deep wound infection, 0.1% for late deep wound infection and 3.2% for wound complications; there were no cases of dislocation. The rate of revision for implant failure within 1 year was 0.1%. Male sex was associated with a greater risk of implant failure (p = 0.01), and having a higher body mass index was associated with both increased rates of infection (p < 0.01) and having a wound complication (p < 0.01). Conclusion: Intraoperative events, postoperative periprosthetic fractures, implant failure, deep wound infection and wound complications accounted for the major surgical complications within 1 year of THA through DAA. The low revision rate suggests that DAA is a safe approach for THA. Contexte: On ignore quel est le taux de complications majeures des chirurgies pour prothèse totale de la hanche (PTH) par abord antérieur direct (AAD) d'une équipe de chirurgie orthopédique de fort volume en Ontario, au Canada. Cette étude avait pour but d'analyser le taux de complications chirurgicales majeures suite à des PTH par AAD effectuées par une équipe d'orthopédistes chevronnés dans un centre de soins tertiaires achalandé de l'Ontario. Méthodes: Nous avons procédé à une analyse de cohorte rétrospective des PTH primaires par AAD effectuées par 2 spécialistes expérimentés dans un hôpital universitaire de London, en Ontario, entre le 1er janvier 2012 et le 1er mai 2019. Nous avons exclu les 100 premiers cas pour permettre l'établissement des courbes d'apprentissage en chirurgie. Nous avons consigné les complications chirurgicales majeures (événements peropératoires, fractures périprothétiques postopératoires, dislocation nécessitant une réduction fermée ou ouverte, défaillance de la prothèse [descellement aseptique ou enfoncement], infection profonde rapide (< 6 semaines) de la plaie nécessitant un traitement par irrigation et débridement, infection profonde tardive ([supérieur ou égal à ] 6 semaines) de la plaie nécessitant un traitement par irrigation et débridement, et complications de plaies [déhiscence, abcès aux points de suture, érythème, hématome ou sérome]) au cours de l'année suivant la PTH. Résultats : En tout, 875 interventions primaires pour PTH par AAD ont été incluses. Les taux de complications chirurgicales ont été de 0,9% pour les événements peropératoires, de 1,5% pour les fractures périprothétiques postopératoires, de 0,8% pour la défaillance de la prothèse, de 0,7% pour l'infection de plaie profonde rapide, de 0,1% pour l'infection de plaie profonde tardive et de 3,2% pour les complications de plaies; on n'a noté aucun cas de dislocation. Le taux de révision pour défaillance de la prothèse dans l'année suivant l'intervention a été de 0,1%. Le fait d'être de sexe masculin a été associé à un risque plus élevé de défaillance de la prothèse (p = 0,01) et le fait d'avoir un indice de masse corporelle plus haut a été associé à des taux plus élevés d'infection (p < 0,01) et de complications de plaies (p < 0,01). Conclusion : Les événements peropératoires, les fractures périprothétiques postopératoires, la défaillance de la prothèse, l'infection de plaie profonde et les complications de plaies ont été les complications chirurgicales majeures enregistrées durant la période d'un an suivant les interventions pour PTH par AAD. Le taux faible de révision permet de supposer que l'AAD est une approche sécuritaire pour la PTH., Total hip arthroplasty (THA) is an appropriate treatment option for severe hip osteoarthritis. It is one of the most reliable and reproducible procedures in orthopedic surgery, achieving a success rate [...]

In May 2022, mpox cases were detected in multiple non-mpox-endemic countries. Increasing numbers of cases worldwide, primarily within sexual networks of gay and bisexual men, prompted the World Health Organization [...]

BACKGROUND: The prognostic impact of ventricular tachycardia (VT) catheter ablation is an important outstanding research question. We undertook a reconstructed individual patient data meta-analysis of randomised controlled trials comparing ablation to medical therapy in patients developing VT after MI. METHODS: We systematically identified all trials comparing catheter ablation to medical therapy in patients with VT and prior MI. The prespecified primary endpoint was reconstructed individual patient assessment of all-cause mortality. Prespecified secondary endpoints included trial-level assessment of all-cause mortality, VT recurrence or defibrillator shocks and all-cause hospitalisations. Prespecified subgroup analysis was performed for ablation approaches involving only substrate modification without VT activation mapping. Sensitivity analyses were performed depending on the proportion of patients with prior MI included. RESULTS: Eight trials, recruiting a total of 874 patients, were included. Of these 874 patients, 430 were randomised to catheter ablation and 444 were randomised to medical therapy. Catheter ablation reduced all-cause mortality compared with medical therapy when synthesising individual patient data (HR 0.63; 95% CI [0.41-0.96]; p=0.03), but not in trial-level analysis (RR 0.91; 95% CI [0.67-1.23]; p=0.53; I2=0%). Catheter ablation significantly reduced VT recurrence, defibrillator shocks and hospitalisations compared with medical therapy. Sensitivity analyses were consistent with the primary analyses. CONCLUSION: In patients with postinfarct VT, catheter ablation reduces mortality.

BACKGROUND: Oral anticoagulation (OAC) has been considered the standard of care for stroke prophylaxis for patients with nonvalvular atrial fibrillation; however, many individuals are unable or unwilling to take long-term OAC. The safety and efficacy of percutaneous left atrial appendage closure (LAAC) have been controversial, and new trial data have recently emerged. We therefore sought to perform an updated meta-analysis of randomized clinical trials (RCTs) comparing OAC to percutaneous LAAC, focusing on individual clinical endpoints. METHODS: We performed a systematic search of the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from January 2000 through December 2021 for all RCTs comparing percutaneous LAAC to OAC in patients with nonvalvular atrial fibrillation. Fixed and random effects meta-analyses of hazard ratios (HRs) were performed using the longest follow-up duration available by intention-to-treat. The prespecified primary endpoint was all-cause mortality. RESULTS: Three RCTs enrolling 1516 patients were identified. The weighted mean follow-up was 54.7 months. LAAC was associated with a reduced risk of all-cause mortality (HR 0.76; 95% confidence interval [CI], 0.59-0.96; p = 0.023), hemorrhagic stroke (HR 0.24; 95% CI, 0.09-0.61; p = 0.003), and major nonprocedural bleeding (HR 0.52; 95% CI, 0.37-0.74; p < 0.001). There was no significant difference between LAAC and OAC for any other endpoints. CONCLUSIONS: The available evidence from RCTs suggests LAAC therapy is associated with reduced long-term risk of death compared with OAC. This may be driven by reductions in hemorrhagic stroke and major nonprocedural bleeding. There were no significant differences in the risk of all stroke. Further large-scale clinical trials are needed to validate these findings.

BackgroundPlacement of a subcutaneous ureteral bypass (SUB) device is an effective method to relieve all causes of ureteral obstruction in cats. Complications involving migration within the gastrointestinal tract have been seldomly described.ObjectivesTo characterize transmural migration of SUB devices within the digestive tract in cats.AnimalsEleven migrated SUB catheters identified in 8 cats between 2017 and 2021.MethodsRetrospective review of medical records of cats with a SUB device in which migration into the gastrointestinal tract was identified.ResultsThe median time from SUB device placement to implant migration was 928 days (201-2298 days). Seven cats had obstruction of the SUB device and a positive urine culture at diagnosis. The migration was identified by ultrasound in 6/11, pre-operative contrast radiography in 2/2, and only at time of surgery in 3 SUB devices. All cats underwent surgical correction. Four nephrostomy and 7 cystotomy catheters migrated. Migration occurred into the duodenum (3/11), jejunum (7/11), and colon (1/11). SUB devices were removed in 7 cats and replaced in 2 cats, with 1 cat diagnosed with 2 migration events. Gastrointestinal resection and anastomosis were performed in 7/8 cats and an enterotomy in 2 cats. Six cats survived to discharge. The median follow-up time after migration diagnosis was 365 days (range, 0-1114 days) and 2 cats are still alive.Conclusions and clinical importanceAlthough a rare complication, migration of SUB device should be considered in cats with SUB device obstruction and a positive urine culture.

AIMS: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have now been evaluated for the treatment of heart failure in several placebo-controlled randomized controlled trials (RCTs) across various ejection fraction ranges, but these trials were powered for composite outcomes rather than individual clinical endpoints. We therefore performed a meta-analysis to assess their safety and efficacy on all-cause mortality, cardiovascular mortality, and heart failure hospitalizations. METHODS AND RESULTS: We performed a prospectively registered random-effects meta-analysis of all RCTs comparing SGLT-2 inhibitors to placebo in patients with heart failure. The pre-specified primary endpoint was all-cause mortality. Secondary endpoints included cardiovascular mortality, heart failure hospitalizations, and the composite of cardiovascular mortality or heart failure hospitalization. Four trials with 15 684 patients were eligible. The SGLT-2 inhibitor tested was empagliflozin in two trials, dapagliflozin in one trial, and sotagliflozin in one trial. The weighted-mean follow-up was 20.0 months. The hazard ratio (HR) for all-cause mortality was 0.91, 95% confidence interval (CI) 0.82-1.01, P = 0.071. There was a 12% reduction in cardiovascular mortality (HR 0.88, 95% CI 0.79 to 0.97, P = 0.012), and a 30% reduction in heart failure hospitalization (HR 0.70, 95% CI 0.64 to 0.77, P

The COVID-19 pandemic not only impacted people's lives globally, but also pushed faculty to quickly adapt to an online teaching environment and continue it until the end of the school or academic year. This study is urgently needed to gain an understanding of the challenges STEM faculty members face during the COVID-19 era as they make the transition to teaching online, while many of them engage in this shift for the first time. The initial results of an online survey of 101 International STEM faculty members showed that online evaluation and pedagogy are the most disrupted dimensions of e-learning when instructors struggled to re-orchestrate their teaching during such an unprecedented event. In addition, while the affective domain of teaching is identified as the missing dimension of an e-learning framework, adoption of the new technology is rated as the area of least concern for teaching STEM online.

Abstract Background Hidradenitis Suppurativa (HS) is a chronic inflammatory skin condition with recurrent nodules and abscesses that culminate in purulent discharge and scarring. It has significant physical, psychological and financial impact. Objectives This study plans to analyse patient costs associated with HS. Direct costs include prescription items. Indirect or out‐of‐pocket costs include dressings, analgesia, and healthcare‐related travel costs. This study will also assess disease impact on quality‐of‐life (QOL). Methods Patients with HS diagnosis attending dermatology OPD at our public tertiary centre were invited to participate. Ethical approval was secured, and informed consent was obtained. Participants completed an anonymous survey which was analysed to identify costs associated with HS as well as demographics and QOL impact. Results A total of 25 patients completed the survey; median age was 29% and 80% were female. Median time from HS onset to diagnosis was 2 years, with 24% waiting >10 years to be diagnosed. In the past 3 months, 20% spent >€200 in both categories; prescription and non‐prescription items. In the non‐prescription category, 36% of patients reported expenditure >€100 in the past 3 months. Dressings were the most common out‐of‐pocket expense (in 15/25 patients), followed by analgesia and protective clothing. Attendance at medical appointments cost 24% of patients €50–€200. Four participants reported difficulty accessing HS treatments due to associated costs. Mean number of absence days from work/education as result of HS was 8.7 in the past 3 months. Two patients reported being on disability allowance, and two on unemployment benefit as result of their skin disorder. In the QOL question; 96% reported disease impact on QOL, and 11 participants reported that it affected their life ‘very much’. Conclusions HS is a chronic inflammatory skin condition with significant financial burden alongside the well‐analysed biopsychosocial disease impact. Financial burden can be divided into direct prescription costs and indirect costs such as non‐prescription items, protective clothing and travel costs which we have explored in this study. Further research is needed in this area to identify and optimise both the financial and QOL implications of HS in acute flares and chronic disease management.

AIMS: This meta-analysis aims to quantify the association of reduced coronary flow with all-cause mortality and major adverse cardiovascular events (MACE) across a broad range of patient groups and pathologies. METHODS AND RESULTS: We systematically identified all studies between 1 January 2000 and 1 August 2020, where coronary flow was measured and clinical outcomes were reported. The endpoints were all-cause mortality and MACE. Estimates of effect were calculated from published hazard ratios (HRs) using a random-effects model. Seventy-nine studies with a total of 59 740 subjects were included. Abnormal coronary flow reserve (CFR) was associated with a higher incidence of all-cause mortality [HR: 3.78, 95% confidence interval (CI): 2.39-5.97] and a higher incidence of MACE (HR 3.42, 95% CI: 2.92-3.99). Each 0.1 unit reduction in CFR was associated with a proportional increase in mortality (per 0.1 CFR unit HR: 1.16, 95% CI: 1.04-1.29) and MACE (per 0.1 CFR unit HR: 1.08, 95% CI: 1.04-1.11). In patients with isolated coronary microvascular dysfunction, an abnormal CFR was associated with a higher incidence of mortality (HR: 5.44, 95% CI: 3.78-7.83) and MACE (HR: 3.56, 95% CI: 2.14-5.90). Abnormal CFR was also associated with a higher incidence of MACE in patients with acute coronary syndromes (HR: 3.76, 95% CI: 2.35-6.00), heart failure (HR: 6.38, 95% CI: 1.95-20.90), heart transplant (HR: 3.32, 95% CI: 2.34-4.71), and diabetes mellitus (HR: 7.47, 95% CI: 3.37-16.55). CONCLUSION: Reduced coronary flow is strongly associated with increased risk of all-cause mortality and MACE across a wide range of pathological processes. This finding supports recent recommendations that coronary flow should be measured more routinely in clinical practice, to target aggressive vascular risk modification for individuals at higher risk.

Immune cells infiltrate the peripheral nervous system (PNS) after injury and with autoimmunity, but their net effect is divergent. After injury, immune cells are reparative, while in inflammatory neuropathies (e.g., Guillain Barré Syndrome and chronic inflammatory demyelinating polyneuropathy), immune cells are proinflammatory and promote autoimmune demyelination. An understanding of immune cell phenotypes that distinguish these conditions may, therefore, reveal new therapeutic targets for switching immune cells from an inflammatory role to a reparative state. In an autoimmune regulator (Aire)-deficient mouse model of inflammatory neuropathy, we used single-cell RNA sequencing of sciatic nerves to discover a transcriptionally heterogeneous cellular landscape, including multiple myeloid, innate lymphoid, and lymphoid cell types. Analysis of cell-cell ligand-receptor interactions uncovered a macrophage-mediated tumor necrosis factor-α (TNF-α) signaling axis that is induced by interferon-γ and required for initiation of autoimmune demyelination. Developmental trajectory visualization suggested that TNF-α signaling is associated with metabolic reprogramming of macrophages and polarization of macrophages from a reparative state in injury to a pathogenic, inflammatory state in autoimmunity. Autocrine TNF-α signaling induced macrophage expression of multiple genes (Clec4e, Marcksl1, Cxcl1, and Cxcl10) important in immune cell activation and recruitment. Genetic and antibody-based blockade of TNF-α/TNF-α signaling ameliorated clinical neuropathy, peripheral nerve infiltration, and demyelination, which provides preclinical evidence that the TNF-α axis may be effectively targeted to resolve inflammatory neuropathies.

BACKGROUND: Guidelines provide class I recommendations for aortic valve intervention for patients with symptomatic severe aortic stenosis (AS) or reduced ejection fraction, but the cornerstone of management for asymptomatic patients has been watchful waiting. This is based on historical nonrandomized data, but randomized controlled trials (RCTs) have now been performed of early surgical aortic valve replacement (SAVR) for asymptomatic severe AS. We performed a meta-analysis of RCTs comparing early SAVR to watchful waiting for asymptomatic severe AS, focusing on individual end points of death and heart failure (HF) hospitalization. METHODS: We systematically identified all RCTs comparing early SAVR to watchful waiting in patients with asymptomatic severe AS and synthesized the data in a random-effects meta-analysis. The prespecified primary end point was all-cause mortality. RESULTS: Two trials randomizing 302 patients were included. Early SAVR lead to a 55% reduction in all-cause mortality (hazard ratio, 0.45; 95% confidence interval, 0.24-0.85; P = .014). There was no heterogeneity (I2 = 0.0%). Early SAVR also lead to a 79% reduction in HF hospitalization (hazard ratio, 0.21; 95% confidence interval, 0.05-0.96; P = .044). CONCLUSIONS: In patients with severe asymptomatic AS and normal ejection fraction, early SAVR reduces death and HF hospitalization compared to initial conservative management. This challenges current treatment standards and has implications for the clinical care of these patients and for guidelines.