Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Magmatism, deformation, and mineralization along the intra-arc Atacama fault system, northern Chile

2020 Spring.Includes bibliographical references.Oblique plate motion is nearly universal across subduction margins, and the lateral component of motion produced by oblique subduction may be accommodated through distributed strain and/or along crustal-scale strike-slip faults in the overriding (upper) plate. Magmatic arcs, another fundamental features of the upper plate, have been suggested to play a key role in the initiation and development of localized intra-arc crustal-scale faults. Significant hydrothermal fluid flow derived from arc plutons has also produced world-class metal deposits along intra-arc faults, and may suggest the processes responsible for the initiation, continued deformation, and eventual abandonment of strike-slip faults may also play an important role in focusing economic mineralization. Here I study the sinistral Atacama fault system (AFS), a fossil intra-arc strike-slip fault that occurs within the Mesozoic Coastal Cordillera arc to better understand how oblique plate motion is accommodated in the upper plate and related to arc magmatism. Mapping along the northern ~70 km of the El Salado segment of the AFS documents the distribution of arc plutons and style of deformation. Petrology, geochemistry, and geo/thermochronology were used to characterize and correlate plutons, and structural data were analyzed to understand progressive changes in the style of deformation. New zircon U-Pb dates document a major pulse of magmatism from 150–120 Ma, with the 135–119 Ma plutons most directly tied to AFS ductile deformation. Mylonitic fabrics along the AFS are uniquely associated with the margins of Early Cretaceous plutons, and are cut by late kinematic intrusions at 120–110 Ma. Steeply dipping N- to NE-striking mylonitic fabrics with sinistral shear sense indicators strike ~8–12° clockwise of the steeply dipping, N- to NW-striking AFS strands, indicating deformation occurred during progressive ductile to brittle sinistral strain. The distinctive synkinematic Cerro del Pingo tonalite was mapped on both sides of the eastern branch of the El Salado segment. Petrography, geochemistry, and geochronology all overlap within error, and therefore I interpret two sinistrally separated exposures of the Cerro del Pingo Complex as an offset marker along the AFS. In addition, I correlate a chain of offset leucocratic granites and hypabyssal intrusions across the western branch of the El Salado segment. The sinistral slip magnitude across the entire the El Salado segment is ~50 ± 6 km and occurred almost entirely between ~133 and ~110 Ma at an average slip rate of ~2.0–2.5 km/Myr. I postulate that thermal softening as a result of Early Cretaceous pluton intrusion into the shallow crust locally elevated geothermal gradients, allowing for ductile deformation at ~5–7 km depths. Spatially variable Early Cretaceous pluton emplacement set up a heterogeneous rheology that produced a segmented system that never evolved into a single regional-scale fault. Zircon (U-Th)/He dates record cooling through ~180°C by 116–99 Ma and relaxation of elevated gradients coeval with the end of slip along the El Salado segment. Along the central El Salado segment ~150–200 km south of the offset Cerro del Pingo Complex tonalites, clear fault branches no longer define the AFS. The main branch of AFS in this region is defined by a ~200–500-m-thick steeply NW-dipping shear zone that does not show evidence for brittle overprint. Zircon U-Pb dates document synkinematic emplacement of a tonalite in the shear zone at ~122 Ma. Kinematic indicators record oblique sinistral-reverse shear, but locally coaxial fabrics dominate, indicating an overall transpressional regime. Shear zone activity overlaps in age with other sections of the AFS. The tonalite records a synkinematic sodic-calcic assemblage of actinolite+epidote+titanite+plagioclase, but mylonitic microstructures are completely annealed. The shear zone is cut by an unstrained ~115 Ma diorite body that contains pervasive actinolite+epidote+andradite+plagioclase sodic-calcic mineralization. Similar hydrothermal alteration assemblages are also present ~20 km east of the AFS in the economic Punta del Cobre copper district near Copiapó. The absence of brittle faulting is likely related to continued magmatism associated with the Copiapó batholith complex, which is younger than most arc plutons in the Coastal Cordillera. Postkinematic mineralization along the AFS is unique to the Copiapó area, and magmatic fluids responsible for alteration were most likely derived from the Copiapó batholith. Together, these data document the development of the AFS as a highly segmented fault system that localized mineralization and slipped at a relatively slow rate over ~20 Myr, and was abandoned as plate motion vectors shifted in the middle Cretaceous and arc magmatism migrated eastward

Thermal evolution of continental rifting in Corsica (France)

Despite advances in understanding the structural development of magma-poor rift margins, the temporal and thermal evolution of lithospheric hyperextension during rifting remains poorly understood. In contrast to classic pure-shear models, multi-stage rift models that include depth-dependent thinning predict significant conductive crustal reheating during the necking phase due to buoyant rise of the asthenosphere. The Santa Lucia nappe of NE Corsica is an ideal laboratory to test for lower- and upper-crustal reheating as it preserves both Permian lower crust exhumed from granulitic conditions during Tethyan rifting and upper crust in contact with syn- and post-rift Mesozoic strata. This study uses novel zircon, rutile, and apatite LA-ICP-MS depth-profile U-Pb petro-and thermochronology coupled with garnet trace-element thermometry to constrain the syn-rift thermal evolution of this lower-crustal section during progressive lithospheric necking hyperextension, providing compelling evidence for significant early reheating due to depth-dependent thinning. Jurassic reheating is recorded in the footwall of the Belli Piani Shear Zone (BPSZ), where 200-180 Ma zircon U-Pb overgrowths on Permian core populations and preservation of stranded-diffusion profiles in garnets resorbed during D2 deformation imply that the dominant footwall fabric formed as a result of large-magnitude ductile thinning and reheating to ~800°C during Jurassic hyperextension. Conductive reheating of the upper crust in the lower hanging wall to 500-550°C due to either juxtaposition against the hot BPSZ footwall during lower crustal exhumation or wholesale crustal reheating due to conductive steepening of geothermal gradients during early rifting. Rapid post-reheating cooling in response to extensional unroofing of the footwall underscores the importance of ductile shearing and thinning during crustal hyperextension. The results of this study suggest that the thermal evolution of magma-poor rifted margins mimics their multi-phase structural evolution, beginning with diffuse rifting and tectonic subsidence. Depth-dependent thinning triggers dramatic crustal reheating at the onset of necking and hyperextension, demonstrated here in the footwall and lower hanging wall of the Belli Piani subunit. Rapid cooling and exhumation of the lower crust and extreme crustal attenuation during continued hyperextension culminates in mantle exhumation, followed by thermal relaxation and subsidence to a steady-state thermal field coeval with the start of sea-floor spreading.Geological Science

Apatite fission-track (AFT) data from the Calabrian Forearc in southern Italy

Bedrock apatite fission-track (AFT) data from the Calabrian Forearc in southern Italy. Analyses were conducted at GeoSep Sevices (http://geoseps.com/). Results are presented in Gallen et al. (2023). References: Gallen, S.F., Seymour, N.M., Glotzbach, C., Stockli, D.F., O’Sullivan, P., 2023, Calabrian forearc uplift paced by slab-mantle interactions during subduction retreat: Nature Geoscience</p

Apatite (U-Th)/He data from the Calabrian Forearc in southern Italy

Bedrock apatite (U-Th)/He data from the Calabrian Forearc in southern Italy. Analyses were conducted at the University of Texas UTChron Laboratory (https://www.jsg.utexas.edu/utchron-lab/u-th-he-lab/). Results are presented in Gallen et al. (2023). References: Gallen, S.F., Seymour, N.M., Glotzbach, C., Stockli, D.F., O’Sullivan, P., 2023, Calabrian forearc uplift paced by slab-mantle interactions during subduction retreat: Nature Geoscience</p

Inoculating Legumes: A Practical Guide

This handbook was written by a group of Australian experts in the field of rhizobiology and nitrogen fixation from universities and state departments of agriculture and primary industries, many of whom work within the National Rhizobium Program (NRP) ... The major geographic focus of the handbook is the wheat-sheep belt (essentially 100% of Australia's grain production and &gt;50% of wool production), with a minor focus on the high-rainfall belt (about 30% of Australia's wool production). The key audiences are growers, grower groups, commercial and government advisers, agribusiness, research agronomists, legume breeders, seed pelleters, resellers and seed merchants. It is intended that material from this handbook can be extracted and used in training workshops. Workshops would need to be tailored to the particular group. For example, the material used in workshops for individual growers/grower groups may be different for seed pelleters. By using the handbook and/or after participating in workshops that use materials from the handbook, users should have an increased knowledge of legumes and legume nodulation in farming systems, should more effectively use inoculation as a key farm practice, and should have achieved higher farm productivity through enhanced legume nitrogen fixation and system N supply

Inoculating Legumes: Practice and Science

Atmospheric nitrogen (N) is fixed by symbiotic root-nodule bacteria (rhizobia) associated with pasture and pulse legumes and has a national value of about $3.5 billion annually. This is based on nitrogen fixation rates of about 70 kilograms per hectare per year, crop and pasture legume areas of close to 50 million ha and fertiliser N costed to the grower at$0.76/kg, which equates to $1.00/kg plant-available N in the soil after accounting for N losses. The price of carbon-based fossil fuels, used in the production of nitrogenous fertilisers, is expected to increase in the future which will push fertiliser costs higher. Added to that are the environmental costs associated with the production, distribution and application of nitrogenous fertilisers. Therefore, the historical and ongoing interest by Australian farmers in using legumes which fix nitrogen in their farming systems makes good economic and environmental sense and needs to be sustained into the future

Decreased Ebola Transmission after Rapid Response to Outbreaks in Remote Areas, Liberia, 2014

We measured the reproduction number before and after interventions were implemented to reduce Ebola transmission in 9 outbreaks in Liberia during 2014. We evaluated risk factors for secondary cases and the association between patient admission to an Ebola treatment unit (ETU) and survival. The reproduction number declined 94% from 1.7 (95% CI 1.1–2.6) to 0.1 (95% CI 0.02–0.6) after interventions began. The risk for secondary infections was 90% lower for patients admitted to an ETU (risk ratio 0.1, 95% CI 0.04–0.3) than for those who died in the community. The case-fatality rate was 68% (95% CI 60–74), and ETU admission was associated with a 50% reduction in death (hazard ratio 0.5, 95% CI 0.4–0.8). Isolation and treatment of Ebola patients had the dual benefit of interrupting community transmission and improving survival

Secondary Infections with Ebola Virus in Rural Communities, Liberia and Guinea, 2014–2015

Persons who died of Ebola virus disease at home in rural communities in Liberia and Guinea resulted in more secondary infections than persons admitted to Ebola treatment units. Intensified monitoring of contacts of persons who died of this disease in the community is an evidence-based approach to reduce virus transmission in rural communities