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

Unstable Angina: Trends and Characteristics Associated with Length of Hospitalization in the Face of Diminishing Frequency-an Evidence of a Paradigm Shift

Background: Unstable angina (UA) has been one of the most common presentations of acute coronary syndrome. The numbers of admitted UA patients have been diminishing in the recent past. However, we are seeing higher costs and higher length of inpatient stay. We attempt to identify the trends and characteristics of length of hospitalization in patients admitted with UA using a nationally representative dataset. Methods: We used the nationwide inpatient sample (NIS) from 2002-2014 to assess the factors associated with length of stay in patients admitted with unstable angina using ICD-9-CM primary diagnosis codes (411.1, 411.81, and 411.89). All variables pertaining to hospitalization were compared across the 3 groups based on varied length of hospital stay. Results: A total of 131,601 patients were admitted with the diagnosis of UA. The length of inpatient stay was /=7 days in 60,309 (45.83%), 67,291 (51.13%), and 4,001 (3.05%) patients, respectively. In a multivariate adjusted model, the percentage increased odds of \u3e/=2 days of inpatient stay was noted as follows: age \u3e/=65 years (29%), female gender(24%), African-American race (28%), obesity (14%), diabetes mellitus (15%), chronic lung disease (33%), congestive heart failure (529%), renal failure (26%), coagulopathy (68%), alcohol abuse (21%), peripheral vascular disease (22%), myocardial infarction (17%), deep vein thrombosis (119%), sepsis (105%), pneumonia (171%), stroke (164%), urinary tract infection (112%), blood loss (95%), cardiac catheterization (86%), percutaneous transluminal coronary angioplasty (24%), and blood transfusion (206%). The percentage of UA patients with \u3e/=2 days of hospital stay has decreased from 15% to 3.7%, whereas the average costs of managing a UA patient in the hospital have increased by 175%. Conclusions: More than half of patients admitted with UA stay in the hospital for \u3e/=2 days, with the most important determinants being pre-existing medical comorbidities and inpatient complications