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

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Trade Unions Strategies and Productivity: A Suggested Framework

Digitised version produced by the EUI Library and made available online in 2020

Fanya Kaplan

Directed by: Brad Tucker ; Michael Gluzman, Screenplay: Wesley Wingo, Cinematography: Alan Melling, Original Score: Rolan Duvvury, Editing: Matt Bigelow ; James Murphy, Cast - Fanya Kaplan: Becky Tucker, Yuri: Michael Gluzman, Mikhail: Matt Perry, Cheka Officer: Nick Tecosky, Vladimir Lenin: Patrick Bradshaw, Suit #1: Ildar Musin, Suit #2: David Rutter, Suit #3: Rolan Duvvury, Firing Squad Officer: Brad Tucker, Crew - Chief Lighting Technician: Wryen Meek, Gaffer: Tamil Perisamy ; John Swisshelm ; Dave Lillethun, Best Boy: Ildar Musin, Camera Assistant: Amaris Gutierrez-Ray, Make up Artist: Becky Tucker, Costume Designer: Becky Tucker ; Brad Tucker ; Michael Gluzman, Sound Technician: Matt Bigelow, Boom Operator: Ildar Musin ; Tamil Perisamy ; Dave Lillethun, Translation: Yury Gluzman ; Michael Gluzman, Dialog Coach: Michael Gluzman ; Ildar Musin, Historical Consultant: Yury Gluzman, Foley Artist: Matt Bigelow, Assistant to Mrs. Tucker: John Swisshelm ; Jason King, Armorer: Alan Melling, "Varshavianka" Performed by: Yury Gluzman, Extras: Jonathan Diaz ; Michelle Vela ; Ignacio Becerra-Licha ; Emily Weigel ; Jason King ; Aaron May ; Nicole Rennalls ; James Murphy ; Tamil Perisamy ; Steven Sloan ; Troy Whyte ; James Ford ; Walker Kirkland ; Wryen Meek ; Dave Lillithun ; Terrill Turner, Special Thanks: Yury and Lyudmila Gluzman ; Alan Melling ; Travis Ekmark ; Walker Kirkland ; Drew Dickerson ; Wesley Wingo ; Wryen Meek ; Jason King ; Nick Tecosky ; John Swisshelm ; BuzzStudios ; Georgia Institute of Technology ; The City of Atlanta ; a 1.6.18 Films Production in coordination with: Xero Films ; Ey3 Soar Productions.Q & A session: http://hdl.handle.net/1853/14238Runtime: 06:35 minutesTake a trip back to revolutionary Russia, 1918. This Campus Moviefest award-winner revisits the fascinating story of Fanya Kaplan, a zealous socialist revolutionary, and her attempted assassination of Vladimir Leni