Gravitational microlensing of planets: the influence of planetary phase and caustic orientation

Recent studies have demonstrated that detailed monitoring of gravitational microlensing events can reveal the presence of planets orbiting the microlensed source stars. With the potential of probing planets in the Galactic Bulge and Magellanic Clouds, such detections greatly increase the volume over which planets can be found. This paper expands on these original studies by considering the effect of planetary phase on the form of the resultant microlensing light curve. It is found that crescent-like sources can undergo substantially more magnification than a uniformly illuminated disk, the model typically employed in studying such planets. In fact, such a circularly symmetric model is found to suffer a minimal degree of magnification when compared to the crescent models. The degree of magnification is also a strong function of the planet's orientation with respect to the microlensing caustic. The form of the magnification variability is also strongly dependent on the planetary phase and from which direction it is swept by the caustic, providing further clues to the geometry of the planetary system. As the amount of light reflected from a planet also depends on its phase, the detection of extreme crescent-like planets requires the advent of 30-m class telescopes, while light curves of planets at more moderate phases can be determined with today's 10-m telescopes.Comment: 7 pages, 7 figures, to appear in the MNRA

Making a U-turn on the Purfleet Interchange: Stone Tool Technology in Marine Isotope Stage 9 Britain and the Emergence of the Middle Palaeolithic in Europe

This paper re-examines earlier Palaeolithic core technology from British sites assigned to MIS 11, 9, and 7 using primarily a châine opératoire approach, with the objective of better understanding the earliest occurrence and distribution of Levallois and other prepared-core technologies across the Old World. Contrary to previous interpretations (White and Ashton in Current Anthropology, 44: 598–609, 2003), we find no evidence for a true Levallois concept in MIS 11 or MIS 9 in Britain. Cores previously described as ‘simple prepared cores’ or ‘proto-Levallois’ cores show neither evidence of core management nor predetermination of the resulting flakes. They can instead be explained as the coincidental result of a simpler technological scheme aimed at exploiting the largest surface area of a core, thereby maximising the size of the flakes produced from it. This may be a more widespread practice, or a local solution derived from existing principles. Levallois appears fully formed in Britain during terminal MIS 8/initial MIS 7. Consequently, Britain does not provide evidence for an in situ evolution of Levallois, rather we argue it was introduced by new settlers after a glacial abandonment: the solution to the emergence and significance of Levallois lies in southern Europe, the Levant and Africa

Substantial metabolic activity of human brown adipose tissue during warm conditions and cold-induced lipolysis of local triglycerides

Current understanding of in vivo human brown adipose tissue (BAT) physiology is limited by a reliance on positron emission tomography (PET)/computed tomography (CT) scanning, which has measured exogenous glucose and fatty acid uptake but not quantified endogenous substrate utilization by BAT. Six lean, healthy men underwent 18fluorodeoxyglucose-PET/CT scanning to localize BAT so microdialysis catheters could be inserted in supraclavicular BAT under CT guidance and in abdominal subcutaneous white adipose tissue (WAT). Arterial and dialysate samples were collected during warm (∼25°C) and cold exposure (∼17°C), and blood flow was measured by 133xenon washout. During warm conditions, there was increased glucose uptake and lactate release and decreased glycerol release by BAT compared with WAT. Cold exposure increased blood flow, glycerol release, and glucose and glutamate uptake only by BAT. This novel use of microdialysis reveals that human BAT is metabolically active during warm conditions. BAT activation substantially increases local lipolysis but also utilization of other substrates such as glutamate

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Not Just Scraping By: Experimental Evidence for Large Cutting Tools in the High Lodge Non-handaxe Industry

Acknowledgements: We are grateful to the British Museum and staff at Franks House for facilitating access to study the High Lodge collection. We would also like to thank George Lazarus for kindly providing the deer carcasses and conducting the butchery experiments, Dr Alastair Key for providing the steel-frame apparatus for the clay and rope-cutting experiment, and to Dr Tomos Proffitt for creating the tools used in this pilot study. FS thanks Dr Matt Pope for supervising his undergraduate dissertation and Dr Andrea Zupancic for sharing his data from the Qesem Cave scrapers with us. NA thanks the Calleva Foundation for funding the Pathways to Ancient Britain project to which this paper is a contribution.AbstractThe presence or absence of handaxes endures as the major criterion of Lower Palaeolithic classification, with contemporaneous core-and-flake industries modelled as simpler counterparts to Acheulean technology. This is based on the supposed absence of formal tools, particularly of large cutting tools (LCTs) which are understood to be important within Acheulean lifeways, functioning as butchery knives among other uses. Scrapers from the core-and-flake industry of High Lodge (MIS 13) evidence formalised flake-tool production techniques, geared towards large tools with long cutting edges and acute angles, comparable in many respects to Acheulean handaxes. A holistic set of experiments was designed to test the production, efficiency, and practical utility of these scrapers. The experiments compared these scraper forms against handaxes and Quina scrapers. Their use in roe deer butchery indicates functional differences but demonstrates the appropriacy of both large, refined scrapers, and handaxes for processing carcasses of this size. The results support the inclusion of High Lodge scraper forms within the standard definition of LCTs. This interpretation challenges perceived discrepancies between handaxe and non-handaxe industries and deterministic explanations for Acheulean material culture. The feasibility of alternative LCTs supports the argument that the Acheulean represents socially inherited behaviours rather than latent reinventions.</jats:p