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

2,4,6-Trinitrotoluene (TNT) Air Concentrations, Hemoglobin Changes, and Anemia Cases in Respirator Protected TNT Munitions Demilitarization Workers

2,4,6-Trinitrotoluene, TNT, is an explosive used in munitions production that is known to cause both aplastic and hemolytic anemia in exposed workers. Deaths have been reported secondary to both varieties of anemia. Studies have shown that TNT systemic absorption is significant by both the respiratory and dermal routes. A literature review revealed that the most recent review article on TNT exposure arguing for a TWA drop from the PEL to the TLV was in 1977 -- this article cited anemia issues in addition to other untoward effects of TNT. No studies encountered looked at hemoglobin change or anemia cases in respiratory protected workers, this present effort may be the first. TNT PEL (1.5mg/m^3), REL (0.5mg/m^3), and TLV (0.1 mg/m^3) 8 hr TWAs all with skin notations (based on animal models and TNT urine metabolite extrapolation in TNT workers suggesting important role of skin absorption). The earliest effects of systemic TNT poisoning involve hgb and hematocrit drop. The investigator hypothesized that respiratory protection alone is insufficient to protect TNT workers from the risk of anemia development and hemoglobin concentration drop. A retrospective observational study design was incorporated utilizing a records review of TNT vapor air concentration values and worker Hgb values for 8 sets of workers in respiratory protection at a demilitarization operation from October 2006 to April 2007 in order to observe whether or not respiratory protection provided adequate protection against anemia development and hemoglobin change; and to help characterize the probable role of TNT skin absorption on hemoglobin change and anemia risk. Worker baseline hgbs were compared with their exposure hgbs for statistically significant hgb concentration changes (two-tailed paired t-tests), and anemia cases were recorded. Mean hgb changes within each of the 8 groups of workers were then regressed on mean TNT air concentrations (10 hr TWAs) using air sampling levels that were performed closest in time to exposure hgbs. Statistically significant hgb concentration drops and anemia cases were apparent at values about the REL and PEL in respiratory protected workers. There were no anemia cases or statistically significant hgb drops at values about the TLV, however. For mean TNT air concentrations from 0.12/m 3 to 0.31/m 3 there was strong positive linear association with regard to magnitude of hgb change (r=0.996). The results appear to confirm the necessity of the skin notation for TNT. However, the TLV seems to be protective against the possibility of anemia risk principally by the dermal route in workers who are respiratory protected. A question does still remain, however, as to anemia risk in workers who are below the TLV who may not be using respiratory protection. The absence of a continued linear association between mean TNT air concentrations and mean hgb change above the 0.31 mg/m 3 TNT level most likely reflects a marrow response, as the TNT levels evident in the study are reported to be mainly associated with extravascular hemolysis with a minimal, or non-existent, aplastic component assumed. This study adds evidence to the argument that the TLV should be adopted as the new PEL

2,4,6-Trinitrotoluene (TNT) Air Concentrations, Hemoglobin Changes, and Anemia Cases in Respirator Protected TNT Munitions Demilitarization Workers

2,4,6-Trinitrotoluene, TNT, is an explosive used in munitions production that is known to cause both aplastic and hemolytic anemia in exposed workers. Deaths have been reported secondary to both varieties of anemia. Studies have shown that TNT systemic absorption is significant by both the respiratory and dermal routes. A literature review revealed that the most recent review article on TNT exposure arguing for a TWA drop from the PEL to the TLV was in 1977 -- this article cited anemia issues in addition to other untoward effects of TNT. No studies encountered looked at hemoglobin change or anemia cases in respiratory protected workers, this present effort may be the first. TNT PEL (1.5mg/m^3), REL (0.5mg/m^3), and TLV (0.1 mg/m^3) 8 hr TWAs all with skin notations (based on animal models and TNT urine metabolite extrapolation in TNT workers suggesting important role of skin absorption). The earliest effects of systemic TNT poisoning involve hgb and hematocrit drop. The investigator hypothesized that respiratory protection alone is insufficient to protect TNT workers from the risk of anemia development and hemoglobin concentration drop. A retrospective observational study design was incorporated utilizing a records review of TNT vapor air concentration values and worker Hgb values for 8 sets of workers in respiratory protection at a demilitarization operation from October 2006 to April 2007 in order to observe whether or not respiratory protection provided adequate protection against anemia development and hemoglobin change; and to help characterize the probable role of TNT skin absorption on hemoglobin change and anemia risk. Worker baseline hgbs were compared with their exposure hgbs for statistically significant hgb concentration changes (two-tailed paired t-tests), and anemia cases were recorded. Mean hgb changes within each of the 8 groups of workers were then regressed on mean TNT air concentrations (10 hr TWAs) using air sampling levels that were performed closest in time to exposure hgbs. Statistically significant hgb concentration drops and anemia cases were apparent at values about the REL and PEL in respiratory protected workers. There were no anemia cases or statistically significant hgb drops at values about the TLV, however. For mean TNT air concentrations from 0.12/m 3 to 0.31/m 3 there was strong positive linear association with regard to magnitude of hgb change (r=0.996). The results appear to confirm the necessity of the skin notation for TNT. However, the TLV seems to be protective against the possibility of anemia risk principally by the dermal route in workers who are respiratory protected. A question does still remain, however, as to anemia risk in workers who are below the TLV who may not be using respiratory protection. The absence of a continued linear association between mean TNT air concentrations and mean hgb change above the 0.31 mg/m 3 TNT level most likely reflects a marrow response, as the TNT levels evident in the study are reported to be mainly associated with extravascular hemolysis with a minimal, or non-existent, aplastic component assumed. This study adds evidence to the argument that the TLV should be adopted as the new PEL

Value Creation from Public Healthcare IS

Part 1: Creating ValueInternational audienceThe obtainment of value from IT is a recurring theme that has diffused into healthcare information systems (HIS). Having completed the implementation of an integrated HIS, the Faroese Health Service (FHS) has started discussions regarding the obtainment of value from its IT investment which is the subject of this paper. Based on an action research project focusing on the improvement of the stroke process, this paper reveals that it is not possible to distinguish between working processes and HIS and that the realization of value in this context has a much broader significance than mere financial value. During the project, specific key performance indicators (KPIs) were identified and a baseline was established for the stroke process. The outcome is a framework for measuring IS public value as: professional, organizational, patient-perceived and employee-perceived quality as well as learning. Selected non-financial measures for each dimension and their development are presented, e.g., a decrease in mortality

Los efectos ambientales del beneficio de minerales metálicos: un marco de análisis para la historia ambiental The environmental effects of the improvement of metallic minerals: an analysis landmark for environmental history

<abstract language="por">Os efeitos ambientais das operações compreendidas no beneficiamento dos minerais metálicos variaram historicamente, de acordo com o desenvolvimento das mesmas. À medida que tais operações se tornaram mais complexas e rigorosas, provocaram efeitos ambientais cada vez mais complexos, diversos e profundos. Este artigo desenvolve um esquema de análise que permite descobrir e compreender historicamente a origem e a evolução desses efeitos.<br>The environmental effects of the operations comprised in the improvement of metallic minerals have varied historically, according to their development. As such operations became more and more complex and rigorous, they have caused environmental effects increasingly more complex, diverse and profound. This article develops an analysis scheme with the objective of historically discovering and understanding the origin and evolution of these effects