Modeling the Miocene Climatic Optimum: Ocean Circulation

Ocean circulation is investigated using the Community Climate System Model 3 (CCSM3) forced with early to middle Miocene (∼20–14 Ma) topography, bathymetry, vegetation and modern CO2. Significant bottom water formation is modeled in the Weddell Sea along with intermediate North Component Water formation in the North Atlantic. This is attributed primarily to stronger- and weaker-than-modern convective preconditioning in the Weddell and Labrador Seas, respectively. Global meridional overturning and gyre circulation is weaker in the Miocene due to weaker midlatitude westerlies in the southern hemisphere, caused by lowering of the meridional surface temperature gradient, in addition to regional influences on convection. Subsurface temperatures in the Miocene are significantly higher in the far North Atlantic, Greenland-Norwegian Seas and Arctic basin compared to the present. Ocean heat transport is symmetrical about the equator and resembles that simulated for late Cretaceous and early Cenozoic climates, suggesting the northern hemisphere dominated ocean heat transport active today developed after the middle Miocene. Simulated deep water warming in the Miocene is more than an order of magnitude lower than indicated by proxies. This discrepancy is not reconciled by higher CO2 due to the persistence of sea-ice at sites of deep water formation. This suggests that either the CCSM3 is insufficiently sensitive to Miocene boundary conditions, greater greenhouse forcing existed than is currently reconstructed, or that proxy records of warming are exaggerated. Given the diversity of global Miocene proxy records and their near-unanimous estimate of a significantly warmer Earth, the first two options are more likely

Thymol–Menthol Deep Eutectic Solvents and Eutectogels as Pharmaceutical Crystallization Media

Deep eutectic solvents (DES) employing natural products represent a green alternative to conventional crystallization solvents in the pharmaceutical industry. In this work we report the use of the thymol–menthol DES as an effective crystallization solvent for a variety of active pharmaceutical ingredients and pharmaceutical cocrystals, namely aspirin, paracetamol, nicotinamide, benzamide, carbamazepine, mexiletine hydrochloride and ROY. While the involatile nature of thymol–menthol means that evaporative crystallization typically yielded the most thermodynamically stable forms, cooling crystallization yielded surprising metastable forms of the olanzapine precursor ROY depending on the composition of the DES. The 30:70 DES produced the triclinic YN form, the 70:30 composition formed monoclinic ON, while the thermodynamic Y form was obtained from a 50:50 DES mixture. Using l-menthol in the DES instead of racemic menthol resulted in dissolution rate differences in the case of ornidazole and offered the unusual property of chirality in a solvent medium. The DES was successfully used to form salicylic acid–nicotinamide and nevirapine–benzoic acid pharmaceutical cocrystals. It was also gelled by a small molecular bis(urea) gelator allowing supramolecular gel phase DES crystallization

Tectonic evolution of Western Tethys from Jurassic to present day: coupling geological and geophysical data with seismic tomography models

The geodynamic evolution of the Western Tethys is characterized by multiple phases of rifting, seafloor spreading, subduction, and collisional events. Regional reconstructions are highly dependent on the kinematic history of the major plates bounding the Atlantic and Tethyan tectonic domains, as well as small micro-plates resulted from the fragmentation of northern Gondwanaland. The complexity of tectonic events in this area leads to major discrepancies between competing models about the timing, location, and polarity of subduction zones, for both the Cenozoic evolution and earlier phases. We focus on unravelling the Mesozoic evolution of the Western Tethys. We first reassessed kinematic models for the Early Jurassic–Late Cretaceous opening of the central, north central, and north Atlantic and used these as boundary conditions on the kinematic reconstructions of the Tethyan realm. We combined reconstructions of rifting and early seafloor spreading in northern Pangea that incorporate quantitative estimates of continental extension, and suggest a transtensional motion of Iberia relative to Europe in Early Cretaceous time to fit within the refined plate configuration of Central North Atlantic. We combined this regional framework with a recently published model for the motion of smaller blocks within the Western Tethys; from this model, we created synthetic isochrons for extinct oceanic basins and built evolving topological plate boundaries based on the new rigid plate model to derive a self-consistent and time-dependant model for the last 200 million years. We then examined the consistency of subduction history implied by the kinematic reconstructions, by comparing reconstructed plate boundary configurations to mantle velocity structure imaged by a range of seismic tomography models. Our results show that a satisfactory match can be made between Cenozoic subduction events in the Western Tethys region and observed shallow tomographic high-velocity material. However, the match is less clear for older subducted material. Correlations between surface reconstructions and deep Earth structure suggest that mid-deep mantle seismic features under present day Northeast-Central and Northwest Africa-Arabia may correspond with the Mesozoic subduction systems in the Vardar Ocean, Alpine Tethys, and Western Neotethys, respectively. These correlations support a model with intra-oceanic subduction of the Vardar Ocean from Middle Jurassic to Early Cretaceous, and mid-Early Cretaceous initiation of oceanic subduction in the Ligurian-Piemont Ocean. The results from the plate-tomography comparison suggest the existence of oceanic subduction in the Alpine Tethys Oceans in late early Cretaceous time. We investigated the uncertainties in the tectonic model in terms of absolute and relative plate motion and surface velocities and showed that choice of absolute reference frame can partially account for the lateral offset between the Vardar subduction zone and associated slab material in deep mantle; additional mismatches may be attributable to the limitations of our methodology, such as the assumption that slabs sink vertically. © 2016 Informa UK Limited, trading as Taylor & Francis Group.Australian Research Council via [Grant number FL0992245]; (MH, SW, RDM) and [grant number FT130101564] (MS)

Language of Lullabies: The Russification and De-Russification of the Baltic States

This article argues that the laws for promotion of the national languages are a legitimate means for the Baltic states to establish their cultural independence from Russia and the former Soviet Union

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

Using research to prepare for outbreaks of severe acute respiratory infection

Severe acute respiratory infections (SARI) remain one of the leading causes of mortality around the world in all age groups. There is large global variation in epidemiology, clinical management and outcomes, including mortality. We performed a short period observational data collection in critical care units distributed globally during regional peak SARI seasons from 1 January 2016 until 31 August 2017, using standardised data collection tools. Data were collected for 1 week on all admitted patients who met the inclusion criteria for SARI, with follow-up to hospital discharge. Proportions of patients across regions were compared for microbiology, management strategies and outcomes. Regions were divided geographically and economically according to World Bank definitions. Data were collected for 682 patients from 95 hospitals and 23 countries. The overall mortality was 9.5%. Of the patients, 21.7% were children, with case fatality proportions of 1% for those less than 5 years. The highest mortality was in those above 60 years, at 18.6%. Case fatality varied by region: East Asia and Pacific 10.2% (21 of 206), Sub-Saharan Africa 4.3% (8 of 188), South Asia 0% (0 of 35), North America 13.6% (25 of 184), and Europe and Central Asia 14.3% (9 of 63). Mortality in low-income and low-middle-income countries combined was 4% as compared with 14% in high-income countries. Organ dysfunction scores calculated on presentation in 560 patients where full data were available revealed Sequential Organ Failure Assessment (SOFA) scores on presentation were significantly associated with mortality and hospital length of stay. Patients in East Asia and Pacific (48%) and North America (24%) had the highest SOFA scores of >12. Multivariable analysis demonstrated that initial SOFA score and age were independent predictors of hospital survival. There was variability across regions and income groupings for the critical care management and outcomes of SARI. Intensive care unit-specific factors, geography and management features were less reliable than baseline severity for predicting ultimate outcome. These findings may help in planning future outbreak severity assessments, but more globally representative data are required

Spontaneous Coronary Artery Dissection in the Third Trimester -- implications for investigation and delivery.

Spontaneous coronary artery dissection (SCAD) is a rare condition which occurs predominantly in the postpartum period in young women. A SCAD whilst pregnant is very rare and poses significant risk to the mother and unborn child, and with minimal data on SCAD antenatally, this case highlights antepartum clinical considerations.</jats:p

Spontaneous coronary artery dissection in the third trimester-Implications for investigation and delivery

This case of spontaneous coronary artery dissection in pregnancy highlights the diagnostic, treatment and delivery dilemmas in the antepartum period. This is a rare condition that usually manifests in the postpartum period. This case provides multidisciplinary considerations that were encountered for optimal maternal and fetal outcome.Full Tex

Stabilizing a solid-solid interface with a molecular-scale adhesive

The industrial importance of molecular materials chemistry has promoted great interest in areas such as self-assembled surface coatings, multi-layer formation on solid substrates, crystallization from solutions, crystal morphology and structure predictions, solving structures from powders and control of polymorphism. Improvements in our understanding of the role of intermolecular interactions in driving molecular self-assembly and interfacial processes have led to technological advances-both in controlling the assembly of molecules at the nanometre scale, and in manipulating processes and products in which crystal nucleation and growth are key elements. But there has been relatively little work on molecular-scale engineering at solid-solid interfaces, despite their importance in polymeric composites for structured and electronic applications, in adhesives and in formulated pharmaceutical and agrochemical products. Here we report the use of molecules as tailored adhesives - a molecular 'glue' is selected to bond across an interfacial region and hence stabilize a solid-solid interface. We consider a simple interface occurring in a twinned crystal of saccharin; additive molecules with predictable dimensions and hydrogen-bonding functionality can span the interface. The stabilization is reflected in an enhanced frequency of twin-crystal formation