Integrated safety profile of atacicept: an analysis of pooled data from the atacicept clinical trial programme.

OBJECTIVE: To characterize the overall safety profile of atacicept, we conducted an integrated analysis of pooled safety data from all 17 clinical studies to date. METHODS: Three data sets were used to investigate safety endpoints: a double-blind placebo-controlled set (n = 1568), an SLE set (n = 761) and a full analysis set (n = 1845; including all 17 studies). RESULTS: Of 1568 patients in the double-blind placebo-controlled-set, 30.8% received placebo, and 8.2, 24.5 and 36.5% received atacicept 25, 75 and 150 mg, respectively. Treatment-emergent adverse event (TEAE) rates (adjusted by treatment-exposure) were generally higher with atacicept vs placebo, but no consistent association was found between atacicept dose and specific TEAEs or mortality. Serious infection and serious TEAE rates were similar for atacicept and placebo. The TEAE-related discontinuation rates were higher with atacicept vs placebo (16.1 vs 10.9/100 patient-years). In the full analysis set, 11 deaths occurred during treatment. Across indications, exposure-adjusted mortality rates/100 patient-years (95% CI) were 3.60 (0.90, 14.38), 0.34 (0.05, 2.43) and 1.18 (0.49, 2.82) with atacicept 25, 75 and 150 mg, respectively, and 0.44 (0.06, 3.12) with placebo. In SLE patients, exposure-adjusted mortality rates were 1.45 (0.54, 3.87) with atacicept 150 mg and 0.78 (0.29, 2.07) across all atacicept-treated patients. No deaths occurred with atacicept 75 mg or placebo. In the SLE and double-blind placebo-controlled sets, pharmacodynamic effects of atacicept were not associated with increased infection rates. CONCLUSION: The results of this integrated safety analysis support further development and evaluation of atacicept in selected patients for whom potential benefits might outweigh risks

Magnetism in the Brown Dwarf Regime

A suite of discoveries in the last two decades demonstrate that we are now at a point where incorporating magnetic behavior is key for advancing our ability to characterize substellar and planetary systems. The next decade heralds the exciting maturation of the now-burgeoning field of brown dwarf magnetism, and investing now in brown dwarf magnetism will provide a key platform for exploring exoplanetary magnetism and habitability beyond the solar system. We anticipate significant discoveries including: the nature of substellar and planetary magnetic dynamos, the characterization of exo-aurora physics and brown dwarf magnetospheric environments, and the role of satellites in manifestations of substellar magnetic activity. These efforts will require significant new observational capabilities at radio and near infrared wavelengths, dedicated long-term monitoring programs, and committed support for the theoretical modeling efforts underpinning the physical processes of the magnetic phenomenaComment: Decadal 2020 science white pape

Real-Time Electronic Health Record Mortality Prediction During the COVID-19 Pandemic: A Prospective Cohort Study

Background: The SARS-CoV-2 virus has infected millions of people, overwhelming critical care resources in some regions. Many plans for rationing critical care resources during crises are based on the Sequential Organ Failure Assessment (SOFA) score. The COVID-19 pandemic created an emergent need to develop and validate a novel electronic health record (EHR)-computable tool to predict mortality. Research Questions: To rapidly develop, validate, and implement a novel real-time mortality score for the COVID-19 pandemic that improves upon SOFA. Study Design and Methods: We conducted a prospective cohort study of a regional health system with 12 hospitals in Colorado between March 2020 and July 2020. All patients >14 years old hospitalized during the study period without a do not resuscitate order were included. Patients were stratified by the diagnosis of COVID-19. From this cohort, we developed and validated a model using stacked generalization to predict mortality using data widely available in the EHR by combining five previously validated scores and additional novel variables reported to be associated with COVID-19-specific mortality. We compared the area under the receiver operator curve (AUROC) for the new model to the SOFA score and the Charlson Comorbidity Index. Results: We prospectively analyzed 27,296 encounters, of which 1,358 (5.0%) were positive for SARS-CoV-2, 4,494 (16.5%) included intensive care unit (ICU)-level care, 1,480 (5.4%) included invasive mechanical ventilation, and 717 (2.6%) ended in death. The Charlson Comorbidity Index and SOFA scores predicted overall mortality with an AUROC of 0.72 and 0.90, respectively. Our novel score predicted overall mortality with AUROC 0.94. In the subset of patients with COVID-19, we predicted mortality with AUROC 0.90, whereas SOFA had AUROC of 0.85. Interpretation: We developed and validated an accurate, in-hospital mortality prediction score in a live EHR for automatic and continuous calculation using a novel model, that improved upon SOFA. Study Question: Can we improve upon the SOFA score for real-time mortality prediction during the COVID-19 pandemic by leveraging electronic health record (EHR) data? Results: We rapidly developed and implemented a novel yet SOFA-anchored mortality model across 12 hospitals and conducted a prospective cohort study of 27,296 adult hospitalizations, 1,358 (5.0%) of which were positive for SARS-CoV-2. The Charlson Comorbidity Index and SOFA scores predicted all-cause mortality with AUROCs of 0.72 and 0.90, respectively. Our novel score predicted mortality with AUROC 0.94. Interpretation: A novel EHR-based mortality score can be rapidly implemented to better predict patient outcomes during an evolving pandemic

Thermoelectric magnetohydrodynamic control of melt pool flow during laser directed energy deposition additive manufacturing

Melt flow is critical to build quality during additive manufacturing (AM). When an external magnetic field is applied, it causes forces that alter the flow through the thermoelectric magnetohydrodynamic (TEMHD) effect, potentially altering the final microstructure. However, the extent of TEMHD forces and their underlying mechanisms, remain unclear. We trace the flow of tungsten particles using in situ high-speed synchrotron X-ray radiography and ex situ tomography to reveal the structure of TEMHD-induced flow during directed energy deposition AM (DED-AM). When no magnetic field is imposed, Marangoni convection dominates the flow, leading to a relatively even particle distribution. With a magnetic field parallel to the scan direction, TEMHD flow is induced, circulating in the cross-sectional plane, causing particle segregation to the bottom and side of the pool. Further, a downward magnetic field causes horizontal circulation, segregating particles to the other side. Our results demonstrate that TEMHD can disrupt melt pool flow during DED-AM

attainment of treat to target endpoints in sle patients with high disease activity in the atacicept phase 2b address ii study

Abstract Objective Low disease activity (LDA) and remission are emerging treat-to-target (T2T) endpoints in SLE. However, the rates at which these endpoints are met in patients with high disease activity (HDA) are unknown. Atacicept, which targets B lymphocyte stimulator and a proliferation-inducing ligand, improved disease outcomes in SLE patients with HDA (SLEDAI-2K ≥10) at baseline in the phase 2b ADDRESS II study. This is a post hoc analysis of T2T endpoints in these patients. Methods Patients received weekly atacicept (75 or 150 mg s.c.) or placebo for 24 weeks (1:1:1 randomization). Attainment of three T2T endpoints, LDA (SLEDAI-2K ≤ 2), Lupus Low Disease Activity State (LLDAS) and remission (clinical SLEDAI-2K = 0, prednisone-equivalent ≤5mg/day and Physician's Global Assessment <0.5), was assessed and compared with SLE Responder Index (SRI)-4 and SRI-6 response. Results Of 306 randomized patients, 158 (51.6%) had baseline HDA. At week 24, 37 (23.4%) HDA patients attained LDA, 25 (15.8%) LLDAS and 17 (10.8%) remission. Each of these endpoints was more stringent than SRI-4 (n = 87; 55.1%) and SRI-6 (n = 67; 42.4%). Compared with placebo (n = 52), at week 24, patients treated with atacicept 150 mg (n = 51) were more likely to attain LDA [odds ratio (OR) 3.82 (95% CI: 1.44, 10.15), P = 0.007], LLDAS [OR 5.03 (95% CI: 1.32, 19.06), P = 0.018] or remission [OR 3.98 (95% CI: 0.78, 20.15), P = 0.095]. Conclusion At week 24, LDA, LLDAS and remission were more stringent than SRI-4 and SRI-6 response, were attainable in the HDA population and discriminated between treatment with atacicept 150 mg and placebo. These results suggest that T2T endpoints are robust outcome measures in SLE clinical trials and support further evaluation of atacicept in SLE. Trail registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01972568