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

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

Testis unis, testis nullas: one witness is no witness. Criticisms of the use of oral history in nursing research

In research, there is no perfection: no perfect method, no perfect sample, and no perfect data analyses tool. Coming to this understanding helps the researcher identify the inadequacies of their preferred method. This paper discusses the criticisms of the oral history method, drawing reference to its challenges and difficulties in relation to its use in nursing research. Oral history has the advantage over more traditional historical approaches in that the narrators can interpret events, personalities and relationships within the interview that are not accessible from written sources. The oral history interview may also provide a forum for unveiling documents and photographs which might not have been otherwise discovered. Nonetheless, oral history, like most methodologies, is not flawless. This paper discusses the limitations of oral history and suggests ways in which a nurse can use oral history to provide an account of aspects of nursing history

The wartime experience of Australian Army nurses in Vietnam, 1967-1971

War and nursing are linked unequivocally. As battles have raged over the centuries, nurses have attended the ill and wounded soldiers, nursing them back to health or into death and the study of this phenomenon forms a significant part of Australia's nursing history. However, a review of the Australian scholarly nursing and military history literature revealed that the experiences of Australian nurses in the Vietnam War has not been widely published. In an attempt to redress this gap in Australian nursing and military history, the aim of this study was to analyse the nature of the nursing work in the Vietnam War, and to increase awareness and understanding of the experience of nurses in the war within the nursing profession. Using oral history interviews, this study investigated the nature of nursing work as experienced by 17 Australian Army nurses who served in the Australian Military Hospital in Vung Tau between 1967 and 1971. The vast majority of the nursing sisters sent to Vietnam knew little about the type of work or the environment into which they were entering and were, therefore, clinically unprepared. It appeared that, by virtue of their being a nurse, it was an expectation that the nurses would adapt to the nature of their work in the war zone. However, this study also revealed that, although the nurses adapted professionally, their memories of their experiences have affected many personally. This paper will increase ucrrent knowledge significantly regarding the phenomenon of nursing in the Vietnam War, enabling a greater understanding of the experienc

Active Target

The ACTAR (Active TARget) collaboration is set out to develop and build new generation of active targets, to be used in reaction and decay studies with beams of exotic nuclei. The active targets are gaseous detectors that function as time-projection chambers (TPCs), recording the tracks of ionizing particles traversing the gas volume. Exotic particle-emission decay channels can be studied by stopping the radioactive nuclei in the gas; alternatively, by using the nuclei of the gas atoms as target nuclei, it becomes possible to study reactions induced by weak beams of exotic ions. The technique yields high efficiencies and allows for the use of a large target thickness with a very small target contribution to the energy resolution. Further, at the same time, the tracking preserves the precision in the determination of the reaction kinematics. Of particular importance is the low detection threshold. Applications of active targets are wide, ranging from direct reactions, such as inelastic scattering and nucleon transfer, to resonant reactions, and exotic decay modes. The validity of the method has been demonstrated by the recent results obtained with the TPC of the Bordeaux group [1] and with the Maya active target [2-4] The new generation of these detectors aims at improving significantly on the performance of the present devices. Several aspects are at study, both by using a specialized simulation package [5] and experimental techniques; an increase of the dynamic range of detected particles, obtained by magnetic confinement or through the use of ancillary detectors; electron amplification methods based on nouvelle technologies based on GEM [6] and Micromegas [7] to give high amplification and data rates; highly segmented pad structure (25 pads/cm²) to reach first-rate resolutions. The ACTAR project is attached to a program called GET (General Electronics for TPCs) where IRFU/Saclay, CENBG/Bordeaux, GANIL/Caen, MSU/Michigan and Riken-Kyoto are placing a common effort to build a generic, micro-electronic based, fully numeric and modular electronic system to cover the front-end to the data acquisition. Time-stamped pulse shape data will be collected on 12 or 14bit ADCs. The scale free system will be able to cover from 300 to 16,000 channels has a numeric multi-level trigger and on-line data treatment and reduction capabilities. Time-stamped data are presented to event-building software to give through-put at a maximum of 1000 events/sec. As a portable instruments, ACTAR or similar detectors will fully exploit the opportunities offered by the upcoming radioactive ion beams facilities, such at GANIL, NSCL ISOLDE, RIKEN and GSI