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Objective RheumMadness is an online learning collaborative that seeks to actively engage the rheumatology community. The objective of this manuscript is to analyze the educational experience of RheumMadness over two years. Methods Direct measures of participant engagement were obtained using web‐based analytics. An electronic survey was created after the tournament to capture self‐reported engagement and educational experience using the Community of Inquiry framework. Data were analyzed according to the following objectives: (1) compare demographics, engagement, and educational experience of participants between 2021 and 2022; (2) describe the educational experience of those who created scouting reports; (3) explore the impact of RheumMadness on early learners (medical students and residents). Results Compared with 2021, the 2022 tournament had more participants who submitted a bracket, more early learners, and more scouting report creators. Self‐reported engagement and educational experience was high in both years of the tournament among all participants. Over 85% of scouting report creators reported that making a report was a fun and valuable learning experience. Early learners reported significantly higher levels of knowledge integration, sense of belonging in the rheumatology community, social connection, and overall learning experience compared with more advanced participants. Eighty‐five percent of early learners reported that RheumMadness increased their interest in rheumatology. Conclusion RheumMadness expanded from 2021 to 2022, engaging more participants in collaborative learning. Our results demonstrate that RheumMadness is particularly impactful among medical students and residents by helping them explore rheumatology topics and connect with the rheumatology community.

Abstract The author reveals that the power pattern for a particular selected rotating spherical electric current density profile exhibits the following two properties simultaneously: (a) fully omnidirectional in three dimensions (3‐D) and (b) invariant with regards to radio frequency (RF). Specifically, most known antenna designs exhibit either nodal lines or planes for at least some RF frequencies. In contrast, the primary innovation of the subject rotating electric current sphere is that it generates a power pattern that is characterised by no nodal lines nor nodal planes for any RF frequency. In the present analysis, the electro‐magnetic (EM) fields are calculated as an exact solution of Maxwell's equations for the subject electric current density that rotates azimuthally on a spherical surface. As expected, the spatial structure of the resulting EM fields also rotates azimuthally. More surprisingly, this rotating electric current density generates pure magnetic dipole radiation exactly, with the absence of any higher order multipole moments. This proposed antenna concept could offer utility in various applications, including communications beaconing and radar surveillance.

BackgroundOrganizational readiness for change, defined as the collective preparedness of organization members to enact changes, remains understudied in implementing sepsis survivor transition-in-care protocols. Effective implementation relies on collaboration between hospital and post-acute care informants, including those who are leaders and staff. Therefore, our cross-sectional study compared organizational readiness for change among hospital and post-acute care informants.MethodsWe invited informants from 16 hospitals and five affiliated HHC agencies involved in implementing a sepsis survivor transition-in-care protocol to complete a pre-implementation survey, where organizational readiness for change was measured via the Organizational Readiness to Implement Change (ORIC) scale (range 12–60). We also collected their demographic and job area information. Mann-Whitney U-tests and linear regressions, adjusting for leadership status, were used to compare organizational readiness of change between hospital and post-acute care informants.ResultsEighty-four informants, 51 from hospitals and 33 from post-acute care, completed the survey. Hospital and post-acute care informants had a median ORIC score of 52 and 57 respectively. Post-acute care informants had a mean 4.39-unit higher ORIC score compared to hospital informants (p = 0.03).ConclusionsPost-acute care informants had higher organizational readiness of change than hospital informants, potentially attributed to differences in health policies, expertise, organizational structure, and priorities. These findings and potential inferences may inform sepsis survivor transition-in-care protocol implementation. Future research should confirm, expand, and examine underlying factors related to these findings with a larger and more diverse sample. Additional studies may assess the predictive validity of ORIC towards implementation success.

Cardiovascular disease (CVD) significantly contributes to morbidity and mortality after liver transplantation (LT). Cirrhotic cardiomyopathy (CCM) is a risk factor for CVD after transplant. CCM criteria were originally introduced in 2005 with a revision proposed in 2020 reflecting echocardiographic technology advancements. This study assesses the two criteria sets in predicting major adverse cardiac events (MACE) after transplant. This single-center retrospective study reviewed adult LT recipients between January 1, 2009, and December 31, 2018. Patients with insufficient pre-LT echocardiographic data, prior ischemic heart disease, portopulmonary hypertension, or longitudinal care elsewhere were excluded. The primary composite outcome was MACE (arrhythmia, heart failure, cardiac arrest, and/or cardiac death) after transplant. Of 1165 patients, 210 met the eligibility criteria. CCM was present in 162 patients (77%) per the original criteria and 64 patients (30%) per the revised criteria. There were 44 MACE and 31 deaths in the study period. Of the deaths, 38.7% occurred secondary to CVD. CCM defined by the original criteria was not associated with MACE after LT (p = 0.21), but the revised definition was significantly associated with MACE (hazard ratio [HR], 1.93; 95% confidence interval, 1.05-3.56; p = 0.04) on multivariable analysis. Echocardiographic variable analysis demonstrated low septal e as the most predictive variable for MACE after LT (HR, 3.45; p

Objective inpatient frailty assessments in decompensated cirrhosis are understudied. We examined the feasibility of inpatient frailty measurements and associations with nonhome discharge, readmission, and all-cause mortality among patients admitted for cirrhosis complications. We conducted a prospective study at 3 liver transplantation (LT) centers. Frailty was assessed using the liver frailty index (LFI). Multivariable logistic and competing risk models evaluated associations between frailty and clinical outcomes. We included 211 patients with median MELD-Na score 21 (interquartile range [IQR],15-27); 96 (45%) were women, and 102 (48%) were on the LT waiting list. At a median follow-up of 8.3 months, 29 patients (14%) were nonhome discharged, 144 (68%) were readmitted, 70 (33%) underwent LT, and 44 (21%) died. A total of 124 patients (59%) were frail, with a median LFI of 4.71 (IQR, 4.07-5.54). Frail patients were older (mean, 59 versus 54 years) and more likely to have chronic kidney disease (40% versus 20%; P = 0.002) and coronary artery disease (17% versus 7%; P = 0.03). Frailty was associated with hospital-acquired infections (8% versus 1%; P = 0.02). In multivariable models, LFI was associated with nonhome discharge (odds ratio, 1.81 per 1-point increase; 95% confidence interval [CI], 1.14-2.86). Frailty (LFI≥4.5) was associated with all-cause mortality in models accounting for LT as competing risk (subhazard ratio [sHR], 2.4; 95% CI, 1.13-5.11); results were similar with LFI as a continuous variable (sHR, 1.62 per 1-point increase; 95% CI, 1.15-2.28). A brief, objective inpatient frailty assessment was feasible and predicted nonhome discharge and mortality in decompensated cirrhosis. Inpatient point-of-care frailty assessment prior to hospital discharge can be useful for risk stratification and targeted interventions to improve physical fitness and reduce adverse outcomes.

Expanding markets for renewable energy feedstocks have increased demand for woody biomass. Concerns associated with forest biomass harvesting include increased erosion, the applicability of conventional forestry Best Management Practices (BMPs) for protecting water quality, and reduced woody debris retention for soil nutrients and cover. We regionally compared the data and results from three prior independent studies that estimated erosion, BMP implementation, and residual woody debris following biomass and conventional forest harvests in the Mountains, Piedmont, and Coastal Plain of Virginia. Estimated erosion was higher in the Mountains due to steep slopes and operational challenges. Mountain skid trails were particularly concerning, comprising only 8.47% of the total area but from 37.9 to 81.1% of the total site-wide estimated erosion. BMP implementation varied by region and harvest type, with biomass sites having better implementation than conventional sites, and conventional Mountain sites having lower implementation than other regions. Sufficient woody debris remained for BMPs on both harvest types in all regions, with conventional Mountain sites retaining twice that of Coastal Plain sites. BMPs reduced the estimated erosion on both site types suggesting increased implementation could reduce potential erosion in problematic areas. Therefore, proper BMP implementation should be ensured, particularly in Mountainous terrain, regardless of harvest type.

Metabolism is a major regulator of immune cell function, but it remains difficult to study the metabolic status of individual cells. Here, we present Compass, an algorithm to characterize cellular metabolic states based on single-cell RNA sequencing and flux balance analysis. We applied Compass to associate metabolic states with T helper 17 (Th17) functional variability (pathogenic potential) and recovered a metabolic switch between glycolysis and fatty acid oxidation, akin to known Th17/regulatory T cell (Treg) differences, which we validated by metabolic assays. Compass also predicted that Th17 pathogenicity was associated with arginine and downstream polyamine metabolism. Indeed, polyamine-related enzyme expression was enhanced in pathogenic Th17 and suppressed in Treg cells. Chemical and genetic perturbation of polyamine metabolism inhibited Th17 cytokines, promoted Foxp3 expression, and remodeled the transcriptome and epigenome of Th17 cells toward a Treg-like state. In vivo perturbations of the polyamine pathway altered the phenotype of encephalitogenic T cells and attenuated tissue inflammation in CNS autoimmunity.

PurposeTo investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide in patients with recurrent high-grade astrocytoma.Patients and methodsThis two-stage phase I trial determined the MTD of zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) temozolomide using a Bayesian Optimal Interval design; then a randomized cohort expansion compared the progression-free survival rate at 4 months (PFS4) of the two arms for an efficient determination of a temozolomide schedule to combine with zotiraciclib at MTD. Pharmacokinetic and pharmacogenomic profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden.ResultsFifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250 mg in both arms and thus selected for the cohort expansion. Dose-dense temozolomide plus zotiraciclib (PSF4 40%) compared favorably with metronomic temozolomide (PFS4 25%). Symptom burden worsened at cycle 2 but stabilized by cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12-24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. Pharmacokinetic/pharmacogenomic analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUCinf value.ConclusionsZotiraciclib combined with temozolomide is safe in patients with recurrent high-grade astrocytomas. Zotiraciclib-induced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib.

The Review summarizes much of particle physics and cosmology. Using data from previous editions, plus 3,324 new measurements from 878 papers, we list, evaluate, and average measured properties of gauge bosons and the recently discovered Higgs boson, leptons, quarks, mesons, and baryons. We summarize searches for hypothetical particles such as supersymmetric particles, heavy bosons, axions, dark photons, etc. Particle properties and search limits are listed in Summary Tables. We give numerous tables, figures, formulae, and reviews of topics such as Higgs Boson Physics, Supersymmetry, Grand Unified Theories, Neutrino Mixing, Dark Energy, Dark Matter, Cosmology, Particle Detectors, Colliders, Probability and Statistics. Among the 120 reviews are many that are new or heavily revised, including a new review on High Energy Soft QCD and Diffraction and one on the Determination of CKM Angles from B Hadrons. The Review is divided into two volumes. Volume 1 includes the Summary Tables and 98 review articles. Volume 2 consists of the Particle Listings and contains also 22 reviews that address specific aspects of the data presented in the Listings. The complete Review (both volumes) is published online on the website of the Particle Data Group (pdg.lbl.gov) and in a journal. Volume 1 is available in print as the PDG Book. A Particle Physics Booklet with the Summary Tables and essential tables, figures, and equations from selected review articles is available in print and as a web version optimized for use on phones as well as an Android app.

BackgroundSatralizumab, a humanised monoclonal antibody targeting the interleukin-6 receptor, reduced the risk of relapse in patients with neuromyelitis optica spectrum disorder (NMOSD) when added to immunosuppressant therapy. This study assessed the safety and efficacy of satralizumab monotherapy in patients with the disorder.MethodsIn this phase 3, double-blind, placebo-controlled, parallel-group trial, we enrolled adults aged 18-74 years with aquaporin-4 antibody seropositive or seronegative NMOSD at 44 investigational sites in 13 countries. Eligible participants had experienced at least one documented NMOSD attack or relapse in the past 12 months and had a score of 6·5 or less on the Expanded Disability Status Scale. Exclusion criteria included clinical relapse 30 days or fewer before baseline. Participants were randomly assigned (2:1) to receive satralizumab 120 mg or visually matched placebo subcutaneously at weeks 0, 2, 4, and every 4 weeks thereafter. Taking immunosuppressants concomitantly was prohibited. The primary endpoint was time to the first protocol-defined relapse, based on the intention-to-treat population and analysed with stratification for two randomisation factors (previous therapy for prevention of attacks and nature of the most recent attack). Safety was assessed in all participants who received at least one dose of satralizumab or placebo. The double-blind phase was due to last until 44 protocol-defined relapses occurred or 1·5 years after random assignment of the last patient enrolled, whichever occurred first; participants could enter an open-label phase after the occurrence of a protocol-defined relapse or at the end of the double-blind phase. The study is registered with ClinicalTrials.gov, NCT02073279.Findings95 (57%) of 168 screened participants were randomly assigned to treatment (63 to satralizumab; 32 to placebo) between Aug 5, 2014, and April 2, 2017. Protocol-defined relapses occurred in 19 (30%) patients receiving satralizumab and 16 (50%) receiving placebo (hazard ratio 0·45, 95% CI 0·23-0·89; p=0·018). 473·9 adverse events per 100 patient-years occurred in the satralizumab group, as did 495·2 per 100 patient-years in the placebo group; the incidence of serious adverse events and adverse events leading to withdrawal was similar between groups.InterpretationSatralizumab monotherapy reduced the rate of NMOSD relapse compared with placebo in the overall trial population, with a favourable safety profile. The patient population included a ratio of aquaporin-4 antibody seropositive and seronegative patients that was reflective of clinical practice. Satralizumab has the potential to become a valuable treatment option for patients with NMOSD.FundingChugai Pharmaceutical (Roche).

Abstract Maintenance of immunological homeostasis between tolerance and autoimmunity is essential for the prevention of human diseases ranging from autoimmune disease to cancer. Accumulating evidence suggests that p53 can mitigate phagocytosis-induced adjuvanticity thereby promoting immunological tolerance following programmed cell death. Here we identify Inhibitor of Apoptosis Stimulating p53 Protein (iASPP), a negative regulator of p53 transcriptional activity, as a regulator of immunological tolerance. iASPP-deficiency promoted lung adenocarcinoma and pancreatic cancer tumorigenesis, while iASPP-deficient mice were less susceptible to autoimmune disease. Immune responses to iASPP-deficient tumors exhibited hallmarks of immunosuppression, including activated regulatory T cells and exhausted CD8+ T cells. Interestingly, iASPP-deficient tumor cells and tumor-infiltrating myeloid cells, CD4+, and γδ T cells expressed elevated levels of PD-1H, a recently identified transcriptional target of p53 that promotes tolerogenic phagocytosis. Identification of an iASPP/p53 axis of immune homeostasis provides a therapeutic opportunity for both autoimmune disease and cancer.

Typical fMRI studies have focused on either the mean trend in the blood-oxygen-level-dependent (BOLD) time course or functional connectivity (FC). However, other statistics of the neuroimaging data may contain important information. Despite studies showing links between the variance in the BOLD time series (BV) and age and cognitive performance, a formal framework for testing these effects has not yet been developed. We introduce the variance design general linear model (VDGLM), a novel framework that facilitates the detection of variance effects. We designed the framework for general use in any fMRI study by modeling both mean and variance in BOLD activation as a function of experimental design. The flexibility of this approach allows the VDGLM to (a) simultaneously make inferences about a mean or variance effect while controlling for the other and (b) test for variance effects that could be associated with multiple conditions and/or noise regressors. We demonstrate the use of the VDGLM in a working memory application and show that engagement in a working memory task is associated with whole-brain decreases in BOLD variance.

Elucidating the cellular architecture of the human cerebral cortex is central to understanding our cognitive abilities and susceptibility to disease. Here we used single-nucleus RNA-sequencing analysis to perform a comprehensive study of cell types in the middle temporal gyrus of human cortex. We identified a highly diverse set of excitatory and inhibitory neuron types that are mostly sparse, with excitatory types being less layer-restricted than expected. Comparison to similar mouse cortex single-cell RNA-sequencing datasets revealed a surprisingly well-conserved cellular architecture that enables matching of homologous types and predictions of properties of human cell types. Despite this general conservation, we also found extensive differences between homologous human and mouse cell types, including marked alterations in proportions, laminar distributions, gene expression and morphology. These species-specific features emphasize the importance of directly studying human brain.

Previous research has found that functional connectivity (FC) can accurately predict the identity of a subject performing a task and the type of task being performed. These results are replicated using a large data set collected at the Ohio State University Center for Cognitive and Behavioral Brain Imaging. This work introduces a novel perspective on task and subject identity prediction: blood-oxygen-level-dependent variability (BV). Conceptually, BV is a region-specific measure based on the variance within each brain region. BV is simple to compute, interpret, and visualize. This work shows that both FC and BV are predictive of task and subject, even across scanning sessions separated by multiple years. Subject differences rather than task differences account for the majority of changes in BV and FC. Similar to results in FC, BV is reduced during cognitive tasks relative to rest.

ObjectiveThe efficacy and safety of ocrelizumab, versus interferon (IFN) β-1a, for the treatment of relapsing multiple sclerosis (RMS) from the identically designed OPERA I (NCT01247324) and OPERA II (NCT01412333) phase III studies has been reported; here we present subgroup analyses of efficacy endpoints from the pooled OPERA I and OPERA II populations.MethodsPatients with RMS were randomized to either ocrelizumab 600 mg administered by intravenous infusion every 24 weeks or subcutaneous IFN β-1a 44 µg three times per week throughout the 96-week treatment period. Relapse, disability, and MRI outcomes were analyzed for predefined and post hoc subgroups based on demographic and disease characteristics along with prior treatment using appropriate statistical tests to determine the treatment effect in subgroups and treatment-by-subgroup interactions.ResultsThe significant treatment benefit of ocrelizumab, versus IFN β-1a, observed in the overall OPERA I and OPERA II pooled populations was maintained across most subgroup strata for all endpoints, including annualized relapse rate, disability progression, and MRI outputs.ConclusionsThe treatment effect of ocrelizumab versus IFN β-1a, measured by clinical and MRI outcomes, was maintained across most of the subgroups and strata of interest, and the pattern of treatment benefit across all subgroups was consistent with that from the pooled OPERA studies.

Affinity matured self-reactive antibodies are found in autoimmune diseases like systemic lupus erythematous. Here, we used fate-mapping reporter mice and single-cell transcriptomics coupled to antibody repertoire analysis to characterize the post-germinal center (GC) B cell compartment in a new mouse model of autoimmunity. Antibody-secreting cells (ASCs) and memory B cells (MemBs) from spontaneous GCs grouped into multiple subclusters. ASCs matured into two terminal clusters, with distinct secretion, antibody repertoire and metabolic profiles. MemBs contained FCRL5+ and CD23+ subsets, with different in vivo localization in the spleen. GC-derived FCRL5+ MemBs share transcriptomic and repertoire properties with atypical B cells found in aging and infection and localize to the marginal zone, suggesting a similar contribution to recall responses. While transcriptomically diverse, ASC and MemB subsets maintained an underlying clonal redundancy. Therefore, self-reactive clones could escape subset-targeting therapy by perpetuation of self-reactivity in distinct subsets.