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

The Oak Ridge Research Reactor: safety analysis: Volume 2, supplement 2

The Oak Ridge Research Reactor Safety Analysis was last updated via ORNL-4169, Vol. 2, Supplement 1, in May of 1978. Since that date, several changes have been effected through the change-memo system described below. While these changes have involved the cooling system, the electrical system, and the reactor instrumentation and controls, they have not, for the most part, presented new or unreviewed safety questions. However, some of the changes have been based on questions or recommendations stemming from safety reviews or from reactor events at other sites. This paper discusses those changes which were judged to be safety related and which include revisions to the syphon-break system and changes related to seismic considerations which were very recently completed. The maximum hypothetical accident postulated in the original safety analysis requires dynamic containment and filtered flow for compliance with 10CFR100 limits at the site boundary

Oak Ridge Research Reactor quarterly report, April, May, and June 1981

The ORR operated at an average power level of 29.8 MW for 90.7% of the time during April, May, and June 1981. The reactor was shut down on eight occasions, one of which was unscheduled. Reactor downtime needed for refueling, maintenance, and checks was normal, with the reactor remaining available for operation 91.6% of the time. Maintenance activities, both mechanical and instrument, were essentially routine in nature. In-service inspection completed during the quarter is described

Bulk shielding facility. Quarterly report, April, May, and June 1979

The BSR operated at an average power level of 1967 kW for 72.58% of the time during April, May, and June. Water-quality control in both the reactor primary and secondary cooling systems was satisfactory. The BSR was operated at low and variable power during this quarter for 27.750 hours as part of the training programs for nuclear engineering students from the University of Tennessee. The PCA was also used in the above-mentioned training programs and was operated on one occasion when Mississippi State University students actively participated in training laboratories. The PCA was also operated on twenty-eight occasions for the Reactivity Determination using Spectra Density Measurements Experiment and on eighteen occasions for the Pressure Vessel Simulator Benchmark Experiment

Bulk shielding facility quarterly report, January-March 1979

The BSR was operated at an average power of 1,815 kW for 77.64% of the time this quarter. Water quality control in both the primary and secondary cooling systems was satisfactory. The PCA was operated 182.80 hours for the usual training activities involving university students and TVA personnel

Bulk Shielding Facility quarterly report, July, August, and September of 1977

The BSR operated at an average power level of 1,868 kW for 23.58 percent of the time during July, August, and September. Water-quality control in both the reactor primary and secondary cooling systems was satisfactory. The PCA was used in training programs and was operated on two occasions when the Oak Ridge Associated Universities' students actively participated in training laboratories

Bulk Shielding Facility quarterly report, April, May, and June 1981

The BSR operated at an average power level of 1825 kW for 76.75% of the time during April, May, and June. Water-quality control in both the reactor primary and secondary cooling systems was satisfactory. The BSR was operated at low and variable power during this quarter for 45 hours as part of the training programs for nuclear engineering students from Mississippi State University and the University of Tennessee. The PCA was also used in the above mentioned training programs and was operated on five occasions when nuclear engineering students from Mississippi State University and the University of Kentucky actively participated in training laboratories. The PCA was also operated on eighteen occasions for the Reactivity Measurements experiment and the Reduced Enrichment in Research and Test Reactors experiment (RERTR)