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

Externally-fired combined cycle: An effective coal fueled technology for repowering and new generation

The Externally-Fired Combined Cycle (EFCC) is an attractive emerging technology for powering high efficiency combined gas and steam turbine cycles with coal or other ash bearing fuels. In the EFCC, the heat input to a gas turbine is supplied indirectly through a ceramic air heater. The air heater, along with an atmospheric coal combustor and ancillary equipment, replaces the conventional gas turbine combustor. A steam generator located downstream from the ceramic air heater and steam turbine cycle, along with an exhaust cleanup system, completes the combined cycle. A key element of the EFCC Development Program, the 25 MMBtu/h heat-input Kennebunk Test Facility (KTF), has recently begun operation. The KTF has been operating with natural gas and will begin operating with coal in early 1995. The US Department of Energy selected an EFCC repowering of the Pennsylvania Electric Company`s Warren Station for funding under the Clean Coal Technology Program Round V. The project focuses on repowering an existing 48 MW (gross) steam turbine with an EFCC power island incorporating a 30 MW gas turbine, for a gross power output of 78 MW and a net output of 72 MW. The net plant heat rate will be decreased by approximately 30% to below 9,700 Btu/kWh. Use of a dry scrubber and fabric filter will reduce sulfur dioxide (SO{sub 2}) and particulate emissions to levels under those required by the Clean Air Act Amendments (CAAA) of 1990. Nitrogen oxides (NO{sub x}) emissions are controlled by the use of staged combustion. The demonstration project is currently in the engineering phase, with startup scheduled for 1997. This paper discusses the background of the EFCC, the KTF, the Warren Station EFCC Clean Coal Technology Demonstration Project, the commercial plant concept, and the market potential for the EFCC

Anticoagulant selection in relation to the SAMe-TT2R2 score in patients with atrial fibrillation: The GLORIA-AF registry

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007. © 2020 Hellenic Society of Cardiolog