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

Development-driven archaeology: bane or boon for bioarchaeology?

Summary. Through much of the world there is a move towards policies of in situ preservation of the buried archaeological heritage, typically supported by small-scale investigative excavations (often called 'evaluations'). In this review we attempt to judge the success of these policies in England and Wales, from the standpoint of bioarchaeology. We consider particularly the value of data for plant and insect macrofossils from trial excavations associated with development (a) in producing information which contributes towards research agendas, and (b) as a guide to the preservational condition of organic archaeological deposits

On Decomposing Net Final Values: Eva, Sva and Shadow Project

A decomposition model of Net Final Values (NFV), named Systemic Value Added (SVA), is proposed for decision-making purposes, based on a systemic approach introduced in Magni [Magni, C. A. (2003), Bulletin of Economic Research 55(2), 149–176; Magni, C. A. (2004) Economic Modelling 21, 595–617]. The model translates the notion of excess profit giving formal expression to a counterfactual alternative available to the decision maker. Relations with other decomposition models are studied, among which Stewart’s [Stewart, G.B. (1991), The Quest for Value: The EVAâ„¢ Management Guide, Harper Collins, Publishers Inc]. The index here introduced differs from Stewart’s Economic Value Added (EVA) in that it rests on a different interpretation of the notion of excess profit and is formally connected with the EVA model by means of a shadow project. The SVA is formally and conceptually threefold, in that it is economic, financial, accounting-flavoured. Some results are offered, providing sufficient and necessary conditions for decomposing NFV. Relations between a project’s SVA and its shadow project’s EVA are shown, all results of Pressacco and Stucchi [Pressacco, F. and Stucchi, P. (1997), Rivista di Matematica per le Scienze Economiche e Sociali 20, 165–185] are proved by making use of the systemic approach and the shadow counterparts of those results are also shown. Copyright Springer 2005decomposition, excess profit, systemic, shadow project, EVA, SVA, Net Final Value, C00, G00, G31,

Associations between executive attention and objectively measured physical activity in adolescence : findings from ALSPAC, a UK cohort

Studies of relationships between physical activity and children's attention skills are often constrained by small samples, lack of objective measurements and lack of control for confounders. The present study explores the relationship using objective measures of physical activity from a large birth cohort which permits both longitudinal and cross-sectional analyses. Data from 4755 participants (45% male) with valid measurement of physical activity (total volume and intensity) by accelerometry at age 11 from the Avon Longitudinal Study of Parents and Children (UK) were analysed. Attention was evaluated by the Test of Everyday Attention for Children (TEA-Ch) at 11 years and by the Cognitive Drug Research (CDR) computerised cognitive assessment system at 13 years. Males engaged in an average of 29 min (SD 17) of daily moderate-to-vigorous physical activity (MVPA) at age 11 years compared with 18 min (SD 12) among females. In unadjusted models, higher total volume of physical activity was associated with lower performance across attention tasks. When total volume of physical activity and potential confounding variables were controlled for, higher MVPA was associated with better performance at both 11 and 13 years. Correction for regression dilution approximately doubled the standardised β coefficients. We observed complex associations but results suggest that MVPA may be beneficial for attention processes in adolescence, especially in males. This has implications for interventions aimed at improving executive attention but may also be supportive of the benefits of physical activity for educational and mental health outcomes