Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. METHODS: The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. FINDINGS: We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2-11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75-1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58-1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91-1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70-1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11-0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50-0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38-0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45-0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. INTERPRETATION: Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. FUNDING: Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health

Morbidity and Mortality Conference in Emergency Medicine Residencies and the Culture of Safety

Introduction: Morbidity and mortality conferences (M+M) are a traditional part of residency training and mandated by the Accreditation Counsel of Graduate Medical Education. This study’s objective was to determine the goals, structure, and the prevalence of practices that foster strong safety cultures in the M+Ms of U.S. emergency medicine (EM) residency programs. Methods: The authors conducted a national survey of U.S. EM residency program directors. The survey instrument evaluated five domains of M+M (Organization and Infrastructure; Case Finding; Case Selection; Presentation; and Follow up) based on the validated Agency for Healthcare Research & Quality Safety Culture survey. Results: There was an 80% (151/188) response rate. The primary objectives of M+M were discussing adverse outcomes (53/151, 35%), identifying systems errors (47/151, 31%) and identifying cognitive errors (26/151, 17%). Fifty-six percent (84/151) of institutions have anonymous case submission, with 10% (15/151) maintaining complete anonymity during the presentation and 21% (31/151) maintaining partial anonymity. Forty-seven percent (71/151) of programs report a formal process to follow up on systems issues identified at M+M. Forty-four percent (67/151) of programs report regular debriefing with residents who have had their cases presented. Conclusion: The structure and goals of M+Ms in EM residencies vary widely. Many programs lack features of M+M that promote a non-punitive response to error, such as anonymity. Other programs lack features that support strong safety cultures, such as following up on systems issues or reporting back to residents on improvements. Further research is warranted to determine if M+M structure is related to patient safety culture in residency programs

Morbidity and Mortality Conference in Emergency Medicine Residencies and the Culture of Safety

Introduction: Morbidity and mortality conferences (M+M) are a traditional part of residency training and mandated by the Accreditation Counsel of Graduate Medical Education. This study’s objective was to determine the goals, structure, and the prevalence of practices that foster strong safety cultures in the M+Ms of U.S. emergency medicine (EM) residency programs. Methods: The authors conducted a national survey of U.S. EM residency program directors. The survey instrument evaluated five domains of M+M (Organization and Infrastructure; Case Finding; Case Selection; Presentation; and Follow up) based on the validated Agency for Healthcare Research & Quality Safety Culture survey. Results: There was an 80% (151/188) response rate. The primary objectives of M+M were discussing adverse outcomes (53/151, 35%), identifying systems errors (47/151, 31%) and identifying cognitive errors (26/151, 17%). Fifty-six percent (84/151) of institutions have anonymous case submission, with 10% (15/151) maintaining complete anonymity during the presentation and 21% (31/151) maintaining partial anonymity. Forty-seven percent (71/151) of programs report a formal process to follow up on systems issues identified at M+M. Forty-four percent (67/151) of programs report regular debriefing with residents who have had their cases presented. Conclusion: The structure and goals of M+Ms in EM residencies vary widely. Many programs lack features of M+M that promote a non-punitive response to error, such as anonymity. Other programs lack features that support strong safety cultures, such as following up on systems issues or reporting back to residents on improvements. Further research is warranted to determine if M+M structure is related to patient safety culture in residency programs

The E3 Ubiquitin Ligase, CHIP/STUB1, Inhibits Aggregation of Phosphorylated Proteoforms of Microtubule-associated Protein Tau (MAPT).

Hyper-phosphorylated tau accumulates as insoluble fibrils in Alzheimers disease (AD) and related dementias. The strong correlation between phosphorylated tau and disease has led to an interest in understanding how cellular factors discriminate it from normal tau. Here, we screen a panel of chaperones containing tetratricopeptide repeat (TPR) domains to identify those that might selectively interact with phosphorylated tau. We find that the E3 ubiquitin ligase, CHIP/STUB1, binds 10-fold more strongly to phosphorylated tau than unmodified tau. The presence of even sub-stoichiometric concentrations of CHIP strongly suppresses aggregation and seeding of phosphorylated tau. We also find that CHIP promotes rapid ubiquitination of phosphorylated tau, but not unmodified tau, in vitro. Binding to phosphorylated tau requires CHIPs TPR domain, but the binding mode is partially distinct from the canonical one. In cells, CHIP restricts seeding by phosphorylated tau, suggesting that it could be an important barrier in cell-to-cell spreading. Together, these findings show that CHIP recognizes a phosphorylation-dependent degron on tau, establishing a pathway for regulating the solubility and turnover of this pathological proteoform

The Impact of Anonymity in Emergency Medicine Morbidity and Mortality Conferences: Findings from a National Survey of Resident Physicians

Introduction: Although the Accreditation Council for Graduate Medical Education mandates structured case review and discussion as a part of residency training, there remains little guidance on how best to structure these conferences to cultivate a culture of safety, promote learning, and ensure that system-based improvements can be made. We hypothesized that anonymous case discussion was associated with a more effective, and less punitive, morbidity and mortality (M&amp;M) conference. Secondarily, we were interested in determining whether this core structural element was correlated with the culture of safety at an institution.Methods: We conducted a national survey at 33 emergency medicine residency programs evaluating residents’ perceptions of M&amp;M and the culture of safety at their institutions. Data was analyzed using descriptive statistics and bivariate analyses. We summarized Likert scores using mean and 95% confidence intervals. We also performed content analysis of the free-text comments and report on the themes identified.Results: There were 1248 residents at the 33 programs surveyed. Of the 1002 who replied (80.3% response rate), 231 respondents reported anonymous case presentations and 744 reported non-anonymous case presentations. Residents at programs with anonymous case presentations were more likely to report that M&amp;M was non-punitive. There were no other significant differences between anonymous and non-anonymous case presentations on any of the culture of safety domains measured. When these comments were systematically analyzed and coded, we found that the comments related to anonymity were both positive and negative. Among the themes identified were anonymity’s impact on punitive response to error, the ability to learn from cases, and professional responsibility.Conclusion: Anonymous M&amp;Ms are associated with a perception of a less-punitive M&amp;M and with better ratings in several conference-specific outcomes; however, there appears to be no association between the other Agency for Healthcare Research and Quality culture of safety scores and anonymity in M&amp;M

Effect of <i>Leptographium terebrantis</i> on Foliage, New Root Dynamics, and Stemwood Growth in a Loblolly Pine (<i>Pinus taeda</i> L.) Plantation

The course of the bark beetle-vectored fungus, Leptographium terebrantis S. J. Barras and T. J. Perry, in stemwood growth loss of declining pines in the southeastern United States was assessed in a 13-year-old loblolly pine (Pinus taeda L.) plantation near Eufaula, Alabama, U.S.A. Using stem inoculation as a surrogate for root infection, we hypothesized that L. terebrantis infection impairs sapwood function and thus limits the tree leaf area (AL), new root production, and stemwood growth. Sterile toothpicks colonized by L. terebrantis at varying inoculum densities was used to elicit host growth responses. In the third year after inoculation, the root pathogen reduced the foliage moisture content, whole-tree leaf area (AL), the ratio of AL to tree sapwood area (AS), and stemwood growth in trees receiving the high inoculation treatment relative to those receiving the low or medium inoculation treatments, or the wound or control treatments after seven months of water deficit. The absence of a similar response to water deficit among trees that were noninoculated, wounded, or inoculated at the low or medium densities suggests that, in the loblolly pine–L. terebrantis pathosystem at our study site, the physiological stress caused by water deficit and the high inoculum density was required for the pathogen to elicit a stemwood growth loss. Thus, in loblolly pine forests of the southeastern United States, where climate and soil conditions yield prolonged periods of physiological stress, the presence of L. terebrantis has the potential to reduce stand volume and widen the gap between the predicted and actual stemwood production

Effect of Leptographium terebrantis on Foliage, New Root Dynamics, and Stemwood Growth in a Loblolly Pine (Pinus taeda L.) Plantation

The course of the bark beetle-vectored fungus, Leptographium terebrantis S. J. Barras and T. J. Perry, in stemwood growth loss of declining pines in the southeastern United States was assessed in a 13-year-old loblolly pine (Pinus taeda L.) plantation near Eufaula, Alabama, U.S.A. Using stem inoculation as a surrogate for root infection, we hypothesized that L. terebrantis infection impairs sapwood function and thus limits the tree leaf area (AL), new root production, and stemwood growth. Sterile toothpicks colonized by L. terebrantis at varying inoculum densities was used to elicit host growth responses. In the third year after inoculation, the root pathogen reduced the foliage moisture content, whole-tree leaf area (AL), the ratio of AL to tree sapwood area (AS), and stemwood growth in trees receiving the high inoculation treatment relative to those receiving the low or medium inoculation treatments, or the wound or control treatments after seven months of water deficit. The absence of a similar response to water deficit among trees that were noninoculated, wounded, or inoculated at the low or medium densities suggests that, in the loblolly pine&ndash;L. terebrantis pathosystem at our study site, the physiological stress caused by water deficit and the high inoculum density was required for the pathogen to elicit a stemwood growth loss. Thus, in loblolly pine forests of the southeastern United States, where climate and soil conditions yield prolonged periods of physiological stress, the presence of L. terebrantis has the potential to reduce stand volume and widen the gap between the predicted and actual stemwood production

Emergency Medicine Morbidity and Mortality Conference and Culture of Safety: The Resident Perspective

ObjectiveMorbidity and mortality conference (M&amp;M) is common in emergency medicine (EM) and an Accreditation Council for Graduate Medical Education (ACGME) requirement. We aimed to characterize the prevalence of elements of EM M&amp;M conferences that foster a strong culture of safety.MethodsEmergency medicine residents at 33 programs across the United States were surveyed using questions adapted from a previously tested survey of EM program directors and the Agency for Healthcare Research and Quality (AHRQ) Culture of Safety Survey.ResultsThe survey response rate was 80.3% (1,002/1,248). A total of 60.3% (601/997) of residents had not submitted a case of theirs to M&amp;M in the past year. A total of 7.6% (73/954) reported that issues raised at M&amp;M always led to change while 88.3% (842/954) reported that they sometimes did and 4.1% (39/954) reported that they never did. A total of 56.2% (536/954) responded that changes made due to M&amp;M were reported back to the residents. Of residents who had cases presented at M&amp;M, 24.2% (130/538) responded that there was regular debriefing, 65.2% (351/538) responded that there was not, and 10.6% (57/578) were unsure. A total of 10.2% (101/988) of respondents agreed that M&amp;M was punitive, 17.4% were neutral (172/988), and 72.4% (715/988) disagreed. A total of 18.0% (178/987) of residents agreed that they felt pressure to order unnecessary tests because of M&amp;M, 22.3% (220/987) were neutral, and 59.6% (589/987) disagreed. A total of 87.4% (862/986) felt that M&amp;M was a valuable educational didactic session, and 78.3% (766/978) believed that M&amp;M contributes to a culture of safety in their institution.ConclusionsWhile most residents believe that M&amp;M is a valuable didactic session and contributes to institutional culture of safety, there are opportunities to improve by communicating changes made in response to M&amp;M, debriefing residents who have had cases presented, and taking steps to make M&amp;M not feel punitive to some residents

members, without whom none of our work would be possible. NRDC Reports Manager

ABOUT NRDC The Natural Resources Defense Council is a national nonprofit environmental organization with more than 500,000 members. Since 1970, our lawyers, scientists, and other environmental specialists have been working to protect the world’s natural resources and improve the quality of the human environment. NRDC has offices i