Life history, environment and extinction of the scallop Carolinapecten eboreus (Conrad) in the Plio-Pleistocene of the U.S. eastern seaboard.

Plio-Pleistocene mass extinction of marine bivalves on the U.S. eastern seaboard has been attributed to declines in temperature and primary production. We investigate the relationship of growth rate in the scallop Carolinapecten eboreus to variation in these parameters to determine which contributed to its extinction. We use ontogenetic profiles of shell d18O to estimate growth rate and seasonal temperature, microgrowth-increment data to validate d18O-based figures for growth rate, and shell d13C to supplement assemblage evidence of production. Postlarval growth started in the spring/summer in individuals from the Middle Atlantic Coastal Plain but in the autumn/winter in some from the Gulf Coastal Plain. Growth rate typically declined with age and was usually higher in summer than winter. Many individuals died in winter but the largest forms typically died in spring, possibly on spawning for the first time. No individuals lived longer than two years and some grew exceedingly fast overall, up to 60% more rapidly than any other scallop species (, 145.7 mm in a year). Faster growth was generally achieved by secreting more rather than larger microgrowth increments. Some very fast-growing individuals lived in settings of high production and low temperature. No individuals grew slowly under high production whereas most if not all grew slowly under ‘average’ production and low temperature. In that the rapid growth evidently enabled by high production would have afforded protection from predators, Plio-Pleistocene decline in production was probably contributory to the extinction of C. eboreus. However, the negative impact of low temperature on growth under ‘average’ production suggests that temperature decline played some part.British Geological Survey (BUFI S157), NERC Isotope Goscience Facilities (IP-1351-1112), University of Derby (Research-Inspired Curriculum Fund

Sclerochronological evidence of pronounced seasonality from the late Pliocene of the southern North Sea basin and its implications

Oxygen isotope (δ18O) sclerochronology of benthic marine molluscs provides a means of reconstructing the seasonal range in seafloor temperature, subject to use of an appropriate equation relating shell δ18O to temperature and water δ18O, a reasonably accurate estimation of water δ18O, and due consideration of growth-rate effects. Taking these factors into account, δ18O data from late Pliocene bivalves of the southern North Sea basin (Belgium and the Netherlands) indicate a seasonal seafloor range a little smaller than now in the area. Microgrowth-increment data from Aequipecten opercularis, together with the species composition of the bivalve assemblage and aspects of preservation, suggest a setting below the summer thermocline for all but the latest material investigated. This implies a higher summer temperature at the surface than on the seafloor and consequently a greater seasonal range. A reasonable (3 ∘C) estimate of the difference between maximum seafloor and surface temperature under circumstances of summer stratification points to seasonal surface ranges in excess of the present value (12.4 ∘C nearby). Using a model-derived estimate of water δ18O (0.0 ‰), summer surface temperature was initially in the cool temperate range (20 ∘C) before reverting to cool temperate values (in conjunction with shallowing and a loss of summer stratification). This pattern is in agreement with biotic-assemblage evidence. Winter temperature was firmly in the cool temperate range (<10 ∘C) throughout, contrary to previous interpretations. Averaging of summer and winter surface temperatures for the MPWP provides a figure for annual sea surface temperature that is 2–3 ∘C higher than the present value (10.9 ∘C nearby) and in close agreement with a figure obtained by averaging alkenone and TEX86 temperatures for the MPWP from the Netherlands. These proxies, however, respectively, underestimate summer temperature and overestimate winter temperature, giving an incomplete picture of seasonality. A higher annual temperature than now is consistent with the notion of global warmth in the MPWP, but a low winter temperature in the southern North Sea basin suggests regional reduction in oceanic heat supply, contrasting with other interpretations of North Atlantic oceanography during the interval. Carbonate clumped isotope (Δ47) and biomineral unit thermometry offer means of checking the δ18O-based temperatures

Marine climate and hydrography of the Coralline Crag (early Pliocene, UK): isotopic evidence from 16 benthic invertebrate taxa.

The taxonomic composition of the biota of the Coralline Crag Formation (early Pliocene, eastern England) provides conflicting evidence of seawater temperature during deposition, some taxa indicating cool temperate conditions by analogy with modern representatives or relatives, others warm temperate to subtropical/tropical conditions. Previous isotopic (δ18O) evidence of seasonal seafloor temperatures from serial ontogenetic sampling of bivalve mollusk shells indicated cool temperate winter (< 10 °C) and/or summer (< 20 °C) conditions but was limited to nine profiles from two species, one ranging into and one occurring exclusively in cool temperate settings at present. We supplement these results with six further profiles from the species concerned and supply seven more from three other taxa (two supposedly indicative of warm waters) to provide an expanded and more balanced database. We also supply isotopic temperature estimates from 81 spot and whole-shell samples from these five taxa and 11 others, encompassing ‘warm’, ‘cool’ and ‘eurythermal’ forms by analogy with modern representatives or relatives. Preservation tests show no shell alteration. Subject to reasonable assumptions about water δ18O, the shell δ18O data either strongly indicate or are at least consistent with cool temperate seafloor conditions. The subtropical/tropical conditions suggested by the presence of the bryozoan Metrarabdotos did not exist. Microgrowth-increment and δ13C evidence indicate summer water-column stratification during deposition of the Ramsholt Member, unlike in the adjacent southern North Sea at present (well mixed due to shallow depth and strong tidal currents). Summer maximum surface temperature was probably about 5 °C above seafloor temperature and thus often slightly higher than now (17–19 °C rather than 16–17 °C), but only sometimes in the warm temperate range. Winter minimum surface temperature was below 10 °C and possibly the same as at present (6–7 °C). An expanded surface temperature range compared to now may reflect withdrawal of oceanic heat supply in conjunction with higher global temperature.British Geological Survey (BUFI S157), NERC Isotope Geoscience Facilities (IP-1155- 1109

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Environmental variability supports chimpanzee behavioural diversity.

Funder: Max-Planck-Gesellschaft (Max Planck Society); doi: https://doi.org/10.13039/501100004189Funder: Heinz L. Krekeler FoundationLarge brains and behavioural innovation are positively correlated, species-specific traits, associated with the behavioural flexibility animals need for adapting to seasonal and unpredictable habitats. Similar ecological challenges would have been important drivers throughout human evolution. However, studies examining the influence of environmental variability on within-species behavioural diversity are lacking despite the critical assumption that population diversification precedes genetic divergence and speciation. Here, using a dataset of 144 wild chimpanzee (Pan troglodytes) communities, we show that chimpanzees exhibit greater behavioural diversity in environments with more variability - in both recent and historical timescales. Notably, distance from Pleistocene forest refugia is associated with the presence of a larger number of behavioural traits, including both tool and non-tool use behaviours. Since more than half of the behaviours investigated are also likely to be cultural, we suggest that environmental variability was a critical evolutionary force promoting the behavioural, as well as cultural diversification of great apes

Author Correction: Environmental variability supports chimpanzee behavioural diversity

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21010-z

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

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men