Biodiversity and food web structure influence short-term accumulation of sediment organic matter in an experimental seagrass system

We tested the effects of grazer diversity and food chain length on the quantity and quality of accumulated sediment organic matter (SOM) in experimental eelgrass (Zostera marina) mesocosms. By use of a factorial manipulation of crustacean grazer species richness and predator presence, we examined the effects of epibenthic consumers on SOM composition by using stable carbon isotopes (delta C-13) and lipid biomarker compounds. Grazer species composition strongly influenced nearly all measures of SOM quantity and quality. In particular, increased densities of the grazing amphipod, Gammarus mucronatus, decreased accumulation of benthic microalgae (chlorophyll a) and the relative abundance of polyunsaturated fatty acids (FA, a proxy for labile algal organic matter) and branched FA (a proxy for bacterial biomass). On average, increasing grazer species richness decreased SOM quantity (percentage of total organic carbon). Increasing food chain length by addition of predatory blue crabs (Callinectes sapidus) resulted in a trophic cascade, increasing algal biomass and accumulation of algal organic matter in sediments, and enhancing the quality of SOM. Concomitantly, the relative proportion of bacterial branched FA increased. The identity and number of epibenthic consumers strongly influence accumulation and composition of SOM and the pathways by which it is processed, and these responses are not easily predictable from bulk measurements (delta C-13, percentage of total organic carbon) alone

Radionuclide and biomarker proxies of past ocean circulation and productivity in the Arabian Sea

We present new excess Pa-231/Th-230 activity ratios and lipid biomarker results from northeastern Arabian Sea sediments (core 93KL) spanning the past 50 ka in an effort to constrain further the relationship between climate at low and high latitudes. Pa-231/Th-230 activity ratios are maintained at values significantly higher than the water-column production ratio of 0.093. Average Pa-231/Th-230 activity ratios are lower during the last glacial period than during the Holocene. The lowest Pa-231/Th-230 activity ratios coincide with the timing of Heinrich Events 1-5. Profiles of lipid biomarker fluxes and Pa-231/Th-230 activity ratios from 32 to 12 ka show similar patterns, suggesting that Pa-231 is more efficiently scavenged relative to Th-230 at times when diatoms make up a proportionally larger part of the primary biomass signal. In the Holocene, high Pa-231/Th-230 activity ratios may indicate enhanced Pa-231 export from the southern to the northern Indian Ocean via intensified thermohaline circulation

A 28-ka history of sea surface temperature, primary productivity and planktonic community variability in the western Arabian Sea

Uranium series radionuclides and organic biomarkers, which represent major groups of planktonic organisms, were measured in western Arabian Sea sediments that span the past 28 ka. Variability in the past strength of the southwest and northeast monsoons and its influence on primary productivity, sea surface temperature (SST), and planktonic community structure were investigated. The average alkenone-derived SST for the last glacial period was similar to 3 degrees C lower than that measured for the Holocene. Prior to the deglacial, the lowest SSTs coincide with the highest measured fluxes of organic biomarkers, which represent primarily a planktonic suite of diatoms, coccolithophorids, dinoflagellates, and zooplankton. We propose that intensification of winter northeast monsoon winds during the last glacial period resulted in deep convective mixing, cold SSTs and enhanced primary productivity. In contrast, postdeglacial (\u3c 17 ka) SSTs are warmer during times in which biomarker fluxes are high. Associated with this transition is a planktonic community structure change, in which the ratio of the average cumulative flux of diatom biomarkers to the cumulative flux of coccolithophorid biomarkers is twice as high during the deglacial and Holocene than the average ratio during the last glacial period. We suggest that this temporal transition represents a shift from a winter northeast monsoon-dominated (pre-17 ka) to a summer southwest monsoon-dominated (post-17 ka) wind system

An NHS doctor’s lived experience of burnout during the first wave of Covid-19

This article offers the lived experiences of an NHS doctor working on the front line in an English NHS Trust during the first wave of the Covid-19 pandemic. The overall aim of the article is to offer a context-specific perspective on the employee experience of burnout by drawing out the interplay of organisational and external/socio-political factors during an atypical time. The narrative also highlights an as yet unexplored pattern of burnout with active maintenance of professional efficacy as the starting point which then interacts with high levels of work intensification prevalent in the NHS, leading to the coping mechanisms of depersonalisation and detachment. Existing research has predominantly focused on how/why employees experience burnout at the organisational level of analysis, leaving a gap in the literature on how external/socio-political and time contexts may impact employee burnout

Interdisciplinary research for occupational safety and health knowledge

This is an Accepted Manuscript of an article published by Taylor & Francis in Policy and Practice in Health and Safety on 28 October 2016, available online: http://www.tandfonline.com/10.1080/14773996.2016.1235832.In this article we argue for an interdisciplinary and pluralistic account of how occupational safety and health (OSH) is enacted in practice, informed by a critical understanding of OSH management and flow knowledge in organisations. We compare how in human factors and ergonomics, organisation studies, and safety science this question is approached through different theoretical ‘lenses’, and with different analytical consequences. These approaches work with different concepts (systems, practices and behaviours) that situate human agency, and possibilities for practical intervention differently. To demonstrate this we draw on interdisciplinary research in to ‘Management of OSH in Networked Systems’, showing how mobilising the concept of knowledge through different disciplinary frameworks can have implications for understanding safe working in networked organisations

Exploring a Tetrahydroquinoline Antimalarial Hit from the Medicines for Malaria Pathogen Box and Identification of its Mode of Resistance as PfeEF2

New antimalarial treatments with novel mechanism of action are needed to tackle Plasmodium falciparum infections that are resistant to first-line therapeutics. Here we report the exploration of MMV692140 ( 2 ) from the Pathogen Box, a collection of 400 compounds that was made available by Medicines for Malaria Venture (MMV) in 2015. Compound 2 was profiled in in vitro models of malaria and was found to be active against multiple life-cycle stages of Plasmodium parasites. The mode of resistance, and putatively its mode of action, was identified as Plasmodium falciparum translation elongation factor 2 ( Pf eEF2), which is responsible for the GTP-dependent translocation of the ribosome along mRNA. The compound maintains activity against a series of drug-resistant parasite strains. The structural motif of the tetrahydroquinoline ( 2 ) was explored in a chemistry program with its structure-activity relationships examined, resulting in the identification of an analog with 30-fold improvement of antimalarial asexual blood stage potency

Substituted Aminoacetamides as Novel Leads for Malaria Treatment

Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 μm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification

Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy

The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC50 = 120 nM) was optimized to lead molecules with low nanomolar in vitro potency. Improvement of the pharmacokinetic profile led to several compounds showing excellent oral efficacy in the P. berghei malaria mouse model with ED90 values below 1 mg/kg when dosed orally for 4 days. The favorable potency, selectivity, DMPK properties, and efficacy coupled with a novel mechanism of action, inhibition of translation elongation factor 2 (PfEF2), led to progression of 2 (DDD107498) to preclinical development

Trisubstituted Pyrimidines as Efficacious and Fast-acting Antimalarials

In this paper we describe the optimization of a phenotypic hit against Plasmodium falciparum, based on a trisubstituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria. The most promising compound (13) showed a reduction in parasitemia of 96% when dosed at 30 mg/kg orally once a day for 4 days in the P. berghei mouse model of malaria. It also demonstrated a rapid rate of clearance of the erythrocytic stage of P. falciparum in the SCID mouse model with an ED90 of 11.7 mg/kg when dosed orally. Unfortunately, the compound is a potent inhibitor of cytochrome P450 enzymes, probably due to a 4-pyridyl substituent. Nevertheless, this is a lead molecule with a potentially useful antimalarial profile, which could either be further optimized or be used for target hunting

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