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

Validity of the ACS NSQIP surgical risk calculator as a tool to predict postoperative outcomes in subacute orthopedic trauma diagnoses

Purpose: This retrospective study aimed to validate the ACS NSQIP Surgical Risk Calculator (SCR) to predict 30-day postoperative outcomes in patients with one of the following subacute orthopedic trauma diagnoses; multiple rib fractures, pelvic ring/acetabular fracture, or unilateral femoral fracture.Methods: Data of patients with these diagnoses treated between January 1, 2015 and September 19, 2020 were extracted from the patients’ medical files. Diagnostic performance, discrimination, calibration, and accuracy of the ACS NSQIP SRC to predict specific outcomes developing within 30 days after surgery was determined.Results: The total cohort of the three diagnoses consisted of 435 patients. ACS NSQIP SRC underestimated the risk for serious complications, especially in patients with multiple rib fractures (8.3% predicted vs 17.2% observed) or pelvic ring/acetabular fracture (6.1% vs 19.8%). Underestimation was more pronounced for the composite outcome ‘any complication’. Sensitivity ranged from 16.7% to 100% and specificity from 41.1% to 97.1%. Specificity exceeded sensitivity for pelvic ring/acetabular and femoral fractures. Discrimination was good for predicting death (femoral fracture), fair for readmission (femoral fracture), serious complication (multiple rib fractures), and any complication (multiple rib fractures), but poor in all other outcomes and diagnoses. Calibration and accuracy were adequate for all three diagnoses (p-value for Hosmer-Lemeshow test &gt;0.05 and Brier scores &lt;0.25). Conclusion: Performance of the ACS NSQIP SRC in the studied cohort was variable for all three diagnoses. Although it underestimated the risk of most outcomes, calibration and accuracy seemed generally adequate. For most outcomes, adequate diagnostic performance and discrimination could not be confirmed.</p

Chemical Contaminants in the Wadden Sea: sources, transport, fate and effects

The Wadden Sea receives contaminants from various sources and via various transport routes. The contaminants described in this overview are various metals (Cd, Cu, Hg, Pb and Zn) and various organic contaminants (polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs) and lindane (hexachlorocyclohexane, γ-HCH)). In addition, information is presented about other and emerging contaminants such as antifouling biocides (e.g. TBT and Irgarol), brominated flame retardants (BFRs), poly- and perfluorinated compounds (PFCs) and pharmaceutical and personal care products (PPCPs).Special attention is given to biogeochemical processes that contribute to the mobilization of contaminants in the surface sediments of the Wadden Sea. Finally, the effects on organisms of contaminants are reviewed and discussed.The main source of contaminants in the Wadden Sea are the rivers Rhine (via de Dutch coastal zone), Elbe and Weser. The Wadden Sea is not a sink for contaminants and adsorbed contaminants are transported from east to west. The surface sediments of the Wadden Sea are an important source for contaminants to the water above. The input and concentration of most contaminants have significantly decreased in water, sediments, organisms (e.g., mussel, flounder and bird eggs) in various parts of the Wadden Sea in the last three decades. Remarkably, the Cd concentration in mussels is increasing the last decades.In recent decades, the effects of contaminants on organisms (e.g., flounder, seal) have fallen markedly. Most of the affected populations have recovered, except for TBT induced effects in snails. Little is known about the concentration and effects of most emerging contaminants and the complex environmental mixtures of contaminants.It is recommended to install an international coordinated monitoring programme for contaminants and their effects in the whole Wadden Sea and to identify the chemical contaminants that really cause the effect. © 2013 Elsevier B.V

Validity of the ACS NSQIP surgical risk calculator as a tool to predict postoperative outcomes in subacute orthopedic trauma diagnoses

Purpose: This retrospective study aimed to validate the ACS NSQIP Surgical Risk Calculator (SCR) to predict 30-day postoperative outcomes in patients with one of the following subacute orthopedic trauma diagnoses; multiple rib fractures, pelvic ring/acetabular fracture, or unilateral femoral fracture. Methods: Data of patients with these diagnoses treated between January 1, 2015 and September 19, 2020 were extracted from the patients’ medical files. Diagnostic performance, discrimination, calibration, and accuracy of the ACS NSQIP SRC to predict specific outcomes developing within 30 days after surgery was determined. Results: The total cohort of the three diagnoses consisted of 435 patients. ACS NSQIP SRC underestimated the risk for serious complications, especially in patients with multiple rib fractures (8.3% predicted vs 17.2% observed) or pelvic ring/acetabular fracture (6.1% vs 19.8%). Underestimation was more pronounced for the composite outcome ‘any complication’. Sensitivity ranged from 16.7% to 100% and specificity from 41.1% to 97.1%. Specificity exceeded sensitivity for pelvic ring/acetabular and femoral fractures. Discrimination was good for predicting death (femoral fracture), fair for readmission (femoral fracture), serious complication (multiple rib fractures), and any complication (multiple rib fractures), but poor in all other outcomes and diagnoses. Calibration and accuracy were adequate for all three diagnoses (p-value for Hosmer-Lemeshow test >0.05 and Brier scores <0.25). Conclusion: Performance of the ACS NSQIP SRC in the studied cohort was variable for all three diagnoses. Although it underestimated the risk of most outcomes, calibration and accuracy seemed generally adequate. For most outcomes, adequate diagnostic performance and discrimination could not be confirmed