Twice‐weekly ixazomib in combination with lenalidomide‐dexamethasone in patients with newly diagnosed multiple myeloma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144661/1/bjh15394.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144661/2/bjh15394_am.pd

Efficacy and Safety of Pacritinib vs Placebo for Patients With Severe COVID-19: A Phase 2 Randomized Clinical Trial

IMPORTANCE: The morbidity and mortality associated with COVID-19 remain high despite advances in standard of care therapy, and the role of anti-inflammatory agents that inhibit the interleukin 6/JAK2 pathway is still being elucidated. OBJECTIVE: To evaluate the efficacy and safety of the oral JAK2/IRAK1 inhibitor pacritinib vs placebo in the treatment of adults with severe COVID-19. DESIGN, SETTING, AND PARTICIPANTS: This phase 2, double-blind, placebo-controlled, randomized clinical trial enrolled hospitalized adult patients with severe COVID-19 at 21 centers across the US between June 2020 and February 2021, with approximately 1.5 months of safety follow-up per patient. Data analysis was performed from September 2021 to July 2022. INTERVENTIONS: Patients were randomized 1:1 to standard of care plus pacritinib (400 mg per os on day 1 followed by 200 mg twice daily on days 2-14) vs placebo, for 14 days. MAIN OUTCOMES AND MEASURES: The primary end point was death or need for invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) by day 28. All-cause mortality and safety were also assessed. RESULTS: A total of 200 patients were randomized to pacritinib (99 patients; 56 men [56.6%]; median [range] age, 60 [19-87] years) or placebo (101 patients; 64 men [63.4%]; median [range] age 59 [28-94] years). The percentage requiring supplementary oxygen was 99.0% (98 patients) in the pacritinib group vs 98.0% (99 patients) in the placebo group. The percentage who progressed to IMV, ECMO, or death was 17.2% (17 patients) in the pacritinib group vs 22.8% (23 patients) in the placebo group (odds ratio, 0.62; 95% CI, 0.28-1.35; P = .23). Among patients with elevated interleukin 6, the rate was 17.5% (11 of 63 patients) in the pacritinib group vs 30.4% (21 of 96 patients) in the placebo group. The adverse event rate was similar for pacritinib vs placebo (78.1% [75 patients] vs 80.2% [81 patients]), with no excess in infection (14.6% [14 patients] vs 19.8% [20 patients]), bleeding (8.3% [8 patients] vs 10.9% [11 patients]), or thrombosis (8.3% [8 patients] vs 7.9% [8 patients]). Rates of grade 3 or higher adverse events were lower with pacritinib than placebo (29.2% [28 patients] vs 40.6% [41 patients]). CONCLUSIONS AND RELEVANCE: The study did not meet its primary end point in patients with severe COVID-19. Subgroup analyses may indicate specific populations with hyperinflammation that could benefit from pacritinib, although further clinical trials would be needed to confirm these effects. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04404361

Think Again – Supplying War: Reappraising Military Logistics and Its Centrality to Strategy and War

This article argues that logistics constrains strategic opportunity while itself being heavily circumscribed by strategic and operational planning. With the academic literature all but ignoring the centrality of logistics to strategy and war, this article argues for a reappraisal of the critical role of military logistics, and posits that the study and conduct of war and strategy are incomplete at best or false at worst when they ignore this crucial component of the art of war. The article conceptualises the logistics–strategy nexus in a novel way, explores its contemporary manifestation in an age of uncertainty, and applies it to a detailed case study of UK operations in Iraq and Afghanistan since 2001

Prophetische Politik

"Prophetische Politik" verkündet während existentieller und politischer Krisen einen radikalen Wandel mithilfe religiöser Sprache. Der Begriff bringt zwei unterschiedliche semantische Felder zusammen. Zum einen das der Prophetie, die in allen Religionen durch Individuen repräsentiert wird, die man als Sprachrohr des Göttlichen betrachtet. Ob heidnisch oder monotheistisch, männlich oder weiblich, antik oder modern, Propheten sind immer Lehrer und Kritiker, mahnend und scheltend. Nie schrecken sie davor zurück, ihre Meinung zu äußern, auch nicht in Lebensgefahr. Das zweite Feld ist das der Politik: Ausgehend von der Idee der polis und der politeia steht die Politik seit Thomas Hobbes für die staatliche Beziehung zwischen Volk und Souverän, für ein vereinigendes Zwangsverhältnis, das die Angst und den Krieg "aller gegen alle" im "Naturzustand" überwindet. Indem sie den Mächtigen die Wahrheit sagt, markiert prophetische Politik Momente der Überschneidung dieser Semantiken. Sie schöpft ihre Legitimität aus einer höheren Macht - sei es die Wahrheit oder göttliche Autorität. In Krisenzeiten wagen es die Propheten, auf gesellschaftliche Missstände aufmerksam zu machen und neue, radikale Wege zu verkünden. Mag prophetische Politik heute auch anachronistisch erscheinen, so hat sie das revolutionäre Potential ihrer langen und wechselhaften Geschichte keineswegs eingebüßt

Peroxisome Proliferator-Activated Receptor-γ Receptor Ligand Partially Prevents the Development of Endometrial Explants in Baboons: A Prospective, Randomized, Placebo-Controlled Study

A prospective, randomized, placebo-controlled study was conducted in a baboon model to determine if a thiazolidinedione agonist of peroxisome proliferator-activated receptor-γ, pioglitazone, can impede the development of endometriosis. Endometriosis was induced using laparoscopic, intrapelvic injection of eutopic menstrual endometrium, previously incubated with placebo or pioglitazone for 30 min, in 12 female baboons with a normal pelvis that had undergone at least one menstrual cycle since the time of captivity. At this point, the 12 baboons were randomized into two groups and treated from the day of induction. They received either PBS tablets (n = 6, placebo control, placebo tablets once a day by mouth) or pioglitazone (n = 6, test drug, 7.5 mg by mouth each day). A second and final laparoscopy was performed in the baboons to record the extent of endometriotic lesions between 24 and 42 d after induction (no difference in length of treatment between the two groups, P = 0.38). A videolaparoscopy was performed to document the number and surface area of endometriotic lesions. The surface area and volume of endometriotic lesions were significantly lower in pioglitazone treated baboons than the placebo group (surface area, 48.6 vs. 159.0 mm2, respectively, P = 0.049; vol, 23.7 vs. 131.8 mm3, respectively, P = 0.041). The surface area (3.5 vs. 17.8 mm2, P = 0.017, pioglizatone vs. placebo) and overall number (1.5 vs. 9.5, P = 0.007, pioglizatone vs. placebo) of red lesions were lower in the pioglitazone group. A peroxisome proliferator-activated receptor-γ ligand, pioglitazone, effectively reduced the initiation of endometriotic disease in the baboon endometriosis model. Using this animal model, we have shown that thiazolidinedione is a promising drug for preventive treatment of endometriosis

Predictors of Survival in De Novo Cardiac Amyloidosis

Abstract The natural history of de novo cardiac amyloidosis is poorly described, a limitation that makes clinical decision-making difficult given the growing number of therapies for light-chain (AL)-amyloidosis (AL). We identified all patients presenting to our center from 3/99 to 8/07 at, or within 4 months of, diagnosis with symptomatic cardiac amyloidosis, and analyzed the baseline and post-treatment factors influencing survival for those with AL. During that period, 34.5% (157/455) of amyloid patients were diagnosed with de novo cardiac amyloidosis: 112 men and 45 women with a median age of 62 (31–83). Heart biopsies were obtained and were positive in 39% of men (44/112) and 31% of women (14/45). AL was diagnosed in 86% of patients (n=135) and hereditary (n=7) and senile cardiac (n=15) in the rest. Eight patients underwent heart transplant for hereditary (2 men) and AL (5 men, 1 woman). AL was diagnosed in 81% of men and 98% of women (p=0.005, chi square). We analyzed survival from diagnosis based on intention-to-treat. Ninety percent of patients with AL (n=122) received chemotherapy. Hematologic responses were scored as complete (CR), partial (PR, > 50% reduction) or non. Patients received IV melphalan with stem cell transplant (SCT, n=45), oral melphalan and dexamethasone (MDex, n=42) or other regimens (n = 35). Selection for SCT was based on age and extent of organ disease. Thirty-eight patients (28%) subsequently received second- and third-line therapies. The median survival for all patients was 10 months (range, 1 to 94). Baseline predictors of survival included age, gender and troponin I. Patients ≤ 60 years old had a median survival of 22 and those > 60 of 8 months (p=0.007). Women had a median survival of 24 and men of 8 months (p=0.02). Patients with troponin I ≤ 0.10 lived a median of 21 and those with levels > 0.10 of 9 months (p=0.01). Median ages at diagnosis of the 91 men and 44 women with AL were 59 (31–83) and 63 (38–82) respectively (p=0.19), and there were no differences in baseline albumin, alkaline phosphatase, CRP, brain natriuretic peptide, troponin I or clonal free light chains. There was a significant difference in serum creatinine (medians of 1.35 and 1.00 in men and women, p < 0.01). Overall, 60% of patients responded to chemotherapy: 55% of men and 74% of women (p=0.04, chi-square). Responders lived a median of 40 and non-responders 7 months (p<0.0001), and there was no difference in median survival based on gender. With SCT, mobilization-related and 100-day mortality was 6.7% (3/45, all men) and deaths due to progression of disease after mobilization pre-SCT were 11% (5/45, 4 men, 1 women). With SCT the median survival is not yet reached, median follow up of survivors is 39 mos (range 12–94), and there is no difference in median survival by gender. With MDex, the median survival is 14 months and for men is 9 and for women 20 months (p=0.08). With other therapies the median survival is 7 months with no difference by gender. In patients who received second- and third-line therapies median survival is 37 months. In sum, in patients with de novo cardiac AL, factors influencing survival include age, gender, troponin I and response to therapy. Achievement of a prompt hematologic response should be a primary goal of initial therapy and should guide adjuvant and second-line treatments. The gender-related difference in overall survival with cardiac AL merits further study