Ruxolitinib in addition to standard of care for the treatment of patients admitted to hospital with COVID-19 (RUXCOVID): a randomised, double-blind, placebo-controlled, phase 3 trial

Background COVID-19 is associated with acute respiratory distress and cytokine release syndrome. The Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib reduces inflammatory cytokine concentrations in disorders characterised by cytokine dysregulation, including graft-versus-host disease, myelofibrosis, and secondary hemophagocytic lymphohistiocytosis. We assessed whether treatment with the JAK1/JAK2 inhibitor ruxolitinib would be beneficial in patients with COVID-19 admitted to hospital. Methods RUXCOVID was an international, randomised, double-blind, phase 3 trial of ruxolitinib plus standard of care versus placebo plus standard of care in patients with COVID-19. Patients who were hospitalised but not on mechanical ventilation or in the intensive care unit [ICU] were randomly assigned (2:1) to oral ruxolitinib 5 mg twice per day or placebo for 14 days (14 additional days were allowed if no improvement). The primary endpoint was a composite of death, respiratory failure (invasive ventilation), or ICU care by day 29, analysed by logistic regression including region, treatment, baseline clinical status, age, and sex as covariates. This trial is registered with ClinicalTrials.gov, NCT04362137. Findings Between May 4 and Sept 19, 2020, 432 patients were randomly assigned to ruxolitinib (n=287) or placebo (n=145) plus standard of care; the mean age was 56·5 years (SD 13·3), 197 (46%) were female, and 235 (54%) were male. The primary objective was not met: the composite endpoint occurred in 34 (12%) of 284 ruxolitinib-treated patients versus 17 (12%) of 144 placebo-treated patients (odds ratio 0·91, 95% CI 0·48–1·73; p=0·77). By day 29, nine (3%) of 286 ruxolitinib-treated patients had died compared with three (2%) of 145 placebo-treated patients; 22 (8%) of 286 ruxolitinib-treated patients had received invasive ventilation compared with ten (7%) of 145 placebo-treated patients; and 30 (11%) of 284 ruxolitinib-treated patients had received ICU care compared with 17 (12%) of 144 placebo-treated patients. In an exploratory analysis, median time to recovery was 1 day faster with ruxolitinib versus placebo (8 days vs 9 days; hazard ratio 1·10, 95% CI 0·89–1·36). Adverse events included headache (23 [8%] of 281 on ruxolitinib vs 11 [8%] of 143 on placebo) and diarrhoea (21 [7%] vs 12 [8%]). Interpretation Ruxolitinib 5 mg twice per day showed no benefit in the overall study population. A larger sample is required to determine the clinical importance of trends for increased efficacy in patient subgroups. Funding Novartis and Incyte

Magnetic ordering through itinerant ferromagnetism in a metal–organic framework

Materials that combine magnetic order with other desirable physical attributes could find transformative applications in spintronics, quantum sensing, low-density magnets and gas separations. Among potential multifunctional magnetic materials, metal-organic frameworks, in particular, bear structures that offer intrinsic porosity, vast chemical and structural programmability, and the tunability of electronic properties. Nevertheless, magnetic order within metal-organic frameworks has generally been limited to low temperatures, owing largely to challenges in creating a strong magnetic exchange. Here we employ the phenomenon of itinerant ferromagnetism to realize magnetic ordering at TC = 225 K in a mixed-valence chromium(II/III) triazolate compound, which represents the highest ferromagnetic ordering temperature yet observed in a metal-organic framework. The itinerant ferromagnetism proceeds through a double-exchange mechanism, which results in a barrierless charge transport below the Curie temperature and a large negative magnetoresistance of 23% at 5 K. These observations suggest applications for double-exchange-based coordination solids in the emergent fields of magnetoelectrics and spintronics

Reconstructions of the Mediterranean Outflow Water during the quaternary based on the study of changes in buried mounded drift stacking pattern in the Gulf of Cadiz

Contourite deposits in the central sector of the middle slope of the Gulf of Cadiz have been studied using a comprehensive acoustic, seismic and core database. Buried, mounded, elongated and separated drifts developed under the influence of the lower core of the Mediterranean Outflow Water are preserved in the sedimentary record. These are characterised by depositional features in an area where strong tectonic and erosive processes are now dominant. The general stacking pattern of the depositional system is mainly influenced by climatic changes through the Quaternary, whereas changes in the depositional style observed in two, buried, mounded drifts, the Guadalquivir and Huelva Drifts, are evidence of a tectonic control. In the western Guadalquivir Drift, the onset of the sheeted drift construction (aggrading QII unit) above a mounded drift (prograding QI unit) resulted from a new Lower Mediterranean Core Water hydrodynamic regime. This change is correlated with a tectonic event coeval with the Mid Pleistocene Revolution (MPR) discontinuity that produced new irregularities of the seafloor during the Mid- to Late-Pleistocene. Changes in the Huelva Drift from a mounded to a sheeted drift geometry during the Late-Pleistocene, and from a prograding drift (QI and most part of QII) to an aggrading one (upper seismic unit of QII), highlight a new change in oceanographic conditions. This depositional and then oceanographic change is associated with a tectonic event, coeval with the Marine Isotope Stage (MIS) 6 discontinuity, in which a redistribution of the diapiric ridges led to the development of new local gateways, three principal branches of the Mediterranean Lower Core Water, and associated contourite channels. As a result, these buried contourite drifts hold a key palaeoceanographic record of the evolution of Mediterranean Lower Core Water, influenced by both neotectonic activity and climatic changes during the Quaternary. This study is an example of how contourite deposits and erosive elements in the marine environment can provide evidence for the reconstruction of palaeoceanographic and recent tectonic changes