First order transition and phase separation in pyrochlores with colossal-magnetoresistance

Tl$_{2}$Mn$_{2}$O$_{7}$ pyrochlores present colossal magnetoresistance (CMR) around the long range ferromagnetic ordering temperature (T$_{C}$). The character of this magnetic phase transition has been determined to be first order, by purely magnetic methods, in contrast to the second order character previously reported by Zhao et al. (Phys. Rev. Lett. 83, 219 (1999)). The highest CMR effect, as in Tl$_{1.8}$Cd$_{0.2}$Mn$_{2}$O$_{7}$, corresponds to a stronger first order character. This character implies a second type of magnetic interaction, besides the direct superexchange between the Mn$^{4+}$ ions, as well as a phase coexistence. A model is proposed, with a complete Hamiltonian (including superexchange and an indirect interaction), which reproduce the observed phenomenology.Comment: 6 pages. Figures include

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Delay times in chaotic quantum systems

Based on recent results of the joint moments of proper delay times of open chaotic systems with ideal coupling, a new insight to obtain the partial delay times distribution, for an arbitrary number of channels and symmetry, is given. This distribution is completely verified for all symmetry classes by means of random matrix theory simulations of ballistic chaotic cavities. In addition, the normalization constant of the Laguerre ensemble is obtained

Rationale and design of the PeriOperative ISchemic Evaluation-3 (POISE-3): a randomized controlled trial evaluating tranexamic acid and a strategy to minimize hypotension in noncardiac surgery

Background For patients undergoing noncardiac surgery, bleeding and hypotension are frequent and associated with increased mortality and cardiovascular complications. Tranexamic acid (TXA) is an antifibrinolytic agent with the potential to reduce surgical bleeding; however, there is uncertainty about its efficacy and safety in noncardiac surgery. Although usual perioperative care is commonly consistent with a hypertension-avoidance strategy (i.e., most patients continue their antihypertensive medications throughout the perioperative period and intraoperative mean arterial pressures of 60 mmHg are commonly accepted), a hypotension-avoidance strategy may improve perioperative outcomes. Methods The PeriOperative Ischemic Evaluation (POISE)-3 Trial is a large international randomized controlled trial designed to determine if TXA is superior to placebo for the composite outcome of life-threatening, major, and critical organ bleeding, and non-inferior to placebo for the occurrence of major arterial and venous thrombotic events, at 30 days after randomization. Using a partial factorial design, POISE-3 will additionally determine the effect of a hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of major cardiovascular events, at 30 days after randomization. The target sample size is 10,000 participants. Patients ≥45 years of age undergoing noncardiac surgery, with or at risk of cardiovascular and bleeding complications, are randomized to receive a TXA 1 g intravenous bolus or matching placebo at the start and at the end of surgery. Patients, health care providers, data collectors, outcome adjudicators, and investigators are blinded to the treatment allocation. Patients on ≥ 1 chronic antihypertensive medication are also randomized to either of the two blood pressure management strategies, which differ in the management of patient antihypertensive medications on the morning of surgery and on the first 2 days after surgery, and in the target mean arterial pressure during surgery. Outcome adjudicators are blinded to the blood pressure treatment allocation. Patients are followed up at 30 days and 1 year after randomization. Discussion Bleeding and hypotension in noncardiac surgery are common and have a substantial impact on patient prognosis. The POISE-3 trial will evaluate two interventions to determine their impact on bleeding, cardiovascular complications, and mortality.Trial registration ClinicalTrials.gov NCT03505723. Registered on 23 April 2018.Maura Marcucci, Thomas W. Painter, David Conen, Kate Leslie, Vladimir V. Lomivorotov, Daniel Sessler ... et al

Tranexamic Acid in Patients Undergoing Noncardiac Surgery

BACKGROUND Perioperative bleeding is common in patients undergoing noncardiac surgery. Tranexamic acid is an antifibrinolytic drug that may safely decrease such bleeding. METHODS We conducted a trial involving patients undergoing noncardiac surgery. Patients were randomly assigned to receive tranexamic acid (1-g intravenous bolus) or placebo at the start and end of surgery (reported here) and, with the use of a partial factorial design, a hypotension-avoidance or hypertension-avoidance strategy (not reported here). The primary efficacy outcome was life-threatening bleeding, major bleeding, or bleeding into a critical organ (composite bleeding outcome) at 30 days. The primary safety outcome was myocardial injury after noncardiac surgery, nonhemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism (composite cardiovascular outcome) at 30 days. To establish the noninferiority of tranexamic acid to placebo for the composite cardiovascular outcome, the upper boundary of the one-sided 97.5% confidence interval for the hazard ratio had to be below 1.125, and the one-sided P value had to be less than 0.025. RESULTS A total of 9535 patients underwent randomization. A composite bleeding outcome event occurred in 433 of 4757 patients (9.1%) in the tranexamic acid group and in 561 of 4778 patients (11.7%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.67 to 0.87; absolute difference, −2.6 percentage points; 95% CI, −3.8 to −1.4; two-sided P<0.001 for superiority). A composite cardiovascular outcome event occurred in 649 of 4581 patients (14.2%) in the tranexamic acid group and in 639 of 4601 patients (13.9%) in the placebo group (hazard ratio, 1.02; 95% CI, 0.92 to 1.14; upper boundary of the one-sided 97.5% CI, 1.14; absolute difference, 0.3 percentage points; 95% CI, −1.1 to 1.7; one-sided P = 0.04 for noninferiority). CONCLUSIONS Among patients undergoing noncardiac surgery, the incidence of the composite bleeding outcome was significantly lower with tranexamic acid than with placebo. Although the between-group difference in the composite cardiovascular outcome was small, the noninferiority of tranexamic acid was not established.P.J. Devereaux, M. Marcucci, T.W. Painter, D. Conen, V. Lomivorotov, D.I. Sessler, M.T.V. Chan, F.K. Borges, M.J. Martínez, Zapata, C.Y. Wang, D. Xavier, S.N. Ofori, M.K. Wang, S. Efremov, G. Landoni, Y.V. Kleinlugtenbelt, W. Szczeklik, D. Schmartz, A.X. Garg, T.G. Short, M. Wittmann, C.S. Meyhoff, M. Amir, D. Torres, A. Patel, E. Duceppe, K. Ruetzler, J.L. Parlow, V. Tandon, E. Fleischmann, C.A. Polanczyk, A. Lamy, S.V. Astrakov, M. Rao, W.K.K. Wu, K. Bhatt, M. de Nadal, V.V. Likhvantsev, P. Paniagua, H.J. Aguado, R.P. Whitlock, M.H. McGillion, M. Prystajecky, J. Vincent, J. Eikelboom, I. Copland, K. Balasubramanian, A. Turan, S.I. Bangdiwala, D. Stillo, P.L. Gross, T. Cafaro, P. Alfonsi, P.S. Roshanov, E.P. Belley, Côté, J. Spence, T. Richards, T. VanHelder, W. McIntyre, G. Guyatt, S. Yusuf, and K. Leslie, for the POISE-, Investigator

Hypotension-Avoidance Versus Hypertension-Avoidance Strategies in Noncardiac Surgery : An International Randomized Controlled Trial

Background: Among patients having noncardiac surgery, perioperative hemodynamic abnormalities are associated with vascular complications. Uncertainty remains about what intraoperative blood pressure to target and how to manage long-term antihypertensive medications perioperatively. Objective: To compare the effects of a hypotension-avoidance and a hypertension-avoidance strategy on major vascular complications after noncardiac surgery. Design: Partial factorial randomized trial of 2 perioperative blood pressure management strategies (reported here) and tranexamic acid versus placebo. (ClinicalTrials.gov: NCT03505723) Setting: 110 hospitals in 22 countries. Patients: 7490 patients having noncardiac surgery who were at risk for vascular complications and were receiving 1 or more long-term antihypertensive medications. Intervention: In the hypotension-avoidance strategy group, the intraoperative mean arterial pressure target was 80mm Hg or greater; before and for 2 days after surgery, renin– angiotensin–aldosterone system inhibitors were withheld and the other long-term antihypertensive medications were administered only for systolic blood pressures 130mm Hg or greater, following an algorithm. In the hypertension-avoidance strategy group, the intraoperative mean arterial pressure target was 60mm Hg or greater; all antihypertensive medications were continued before and after surgery. Measurements: The primary outcome was a composite of vascular death and nonfatal myocardial injury after noncardiac surgery, stroke, and cardiac arrest at 30 days. Outcome adjudicators were masked to treatment assignment. Results: The primary outcome occurred in 520 of 3742 patients (13.9%) in the hypotension-avoidance group and in 524 of 3748 patients (14.0%) in the hypertension-avoidance group (hazard ratio, 0.99 [95% CI, 0.88 to 1.12]; P =0.92). Results were consistent for patients who used 1 or more than 1 antihypertensive medication in the long term. Limitation: Adherence to the assigned strategies was suboptimal; however, results were consistent across different adherence levels. Conclusion: In patients having noncardiac surgery, our hypotension-avoidance and hypertension-avoidance strategies resulted in a similar incidence of major vascular complications.Maura Marcucci, Thomas W. Painter, David Conen, Vladimir Lomivorotov, Daniel I. Sessler, Matthew T.V. Chan, Flavia K. Borges, Kate Leslie, Emmanuelle Duceppe, María Jose Martínez-Zapata, Chew Yin Wang, Denis Xavier, Sandra N. Ofori, Michael Ke Wang, Sergey Efremov, Giovanni Landoni, Ydo V. Kleinlugtenbelt, Wojciech Szczeklik, Denis Schmartz, Amit X. Garg, Timothy G. Short, Maria Wittmann, Christian S. Meyhoff, Mohammed Amir, David Torres, Ameen Patel, Kurt Ruetzler, Joel L. Parlow, Vikas Tandon, Edith Fleischmann, Carisi A. Polanczyk, Andre Lamy, Raja Jayaram, Sergey V. Astrakov, William Ka Kei Wu, Chao Chia Cheong, Sabry Ayad, Mikhail Kirov, Miriam de Nadal, Valery V. Likhvantsev, Pilar Paniagua, Hector J. Aguado, Kamal Maheshwari, Richard P. Whitlock, Michael H. McGillion, Jessica Vincent, Ingrid Copland, Kumar Balasubramanian, Bruce M. Biccard, Sadeesh Srinathan, Samandar Ismoilov, Shirley Pettit, David Stillo, Andrea Kurz, Emilie P. Belley-Côte, Jessica Spence, William F. McIntyre, Shrikant I. Bangdiwala, Gordon Guyatt, Salim Yusuf, and P.J. Devereaux, on behalf of the POISE-3 Trial Investigators and Study Group