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AG has received support by NordForsk Nordic Trial Alliance (NTA) grant, by Academy of Finland Fellow grant N. 323116 and the Academy of Finland for PREDICT consortium N. 340541. The Richards research group is supported by the Canadian Institutes of Health Research (CIHR) (365825 and 409511), the Lady Davis Institute of the Jewish General Hospital, the Canadian Foundation for Innovation (CFI), the NIH Foundation, Cancer Research UK, Genome Québec, the Public Health Agency of Canada, the McGill Interdisciplinary Initiative in Infection and Immunity and the Fonds de Recherche Québec Santé (FRQS). TN is supported by a research fellowship of the Japan Society for the Promotion of Science for Young Scientists. GBL is supported by a CIHR scholarship and a joint FRQS and Québec Ministry of Health and Social Services scholarship. JBR is supported by an FRQS Clinical Research Scholarship. Support from Calcul Québec and Compute Canada is acknowledged. TwinsUK is funded by the Welcome Trust, the Medical Research Council, the European Union, the National Institute for Health Research-funded BioResource and the Clinical Research Facility and Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation Trust in partnership with King’s College London. The Biobanque Québec COVID19 is funded by FRQS, Genome Québec and the Public Health Agency of Canada, the McGill Interdisciplinary Initiative in Infection and Immunity and the Fonds de Recherche Québec Santé. These funding agencies had no role in the design, implementation or interpretation of this study. The COVID19-Host(a)ge study received infrastructure support from the DFG Cluster of Excellence 2167 “Precision Medicine in Chronic Inflammation (PMI)” (DFG Grant: “EXC2167”). The COVID19-Host(a)ge study was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the Computational Life Sciences funding concept (CompLS grant 031L0165). Genotyping in COVID19-Host(a)ge was supported by a philantropic donation from Stein Erik Hagen. The COVID GWAs, Premed COVID-19 study (COVID19-Host(a)ge_3) was supported by "Grupo de Trabajo en Medicina Personalizada contra el COVID-19 de Andalucia"and also by the Instituto de Salud Carlos III (CIBERehd and CIBERER). Funding comes from COVID-19-GWAS, COVID-PREMED initiatives. Both of them are supported by "Consejeria de Salud y Familias" of the Andalusian Government. DMM is currently funded by the the Andalussian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018). The Columbia University Biobank was supported by Columbia University and the National Center for Advancing Translational Sciences, NIH, through Grant Number UL1TR001873. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or Columbia University. The SPGRX study was supported by the Consejería de Economía, Conocimiento, Empresas y Universidad #CV20-10150. The GEN-COVID study was funded by: the MIUR grant “Dipartimenti di Eccellenza 2018-2020” to the Department of Medical Biotechnologies University of Siena, Italy; the “Intesa San Paolo 2020 charity fund” dedicated to the project NB/2020/0119; and philanthropic donations to the Department of Medical Biotechnologies, University of Siena for the COVID-19 host genetics research project (D.L n.18 of March 17, 2020). Part of this research project is also funded by Tuscany Region “Bando Ricerca COVID-19 Toscana” grant to the Azienda Ospedaliero Universitaria Senese (CUP I49C20000280002). Authors are grateful to: the CINECA consortium for providing computational resources; the Network for Italian Genomes (NIG) (http://www.nig.cineca.it) for its support; the COVID-19 Host Genetics Initiative (https://www.covid19hg.org/); the Genetic Biobank of Siena, member of BBMRI-IT, Telethon Network of Genetic Biobanks (project no. GTB18001), EuroBioBank, and RD-Connect, for managing specimens. Genetics against coronavirus (GENIUS), Humanitas University (COVID19-Host(a)ge_4) was supported by Ricerca Corrente (Italian Ministry of Health), intramural funding (Fondazione Humanitas per la Ricerca). The generous contribution of Banca Intesa San Paolo and of the Dolce&Gabbana Fashion Firm is gratefully acknowledged. Data acquisition and sample processing was supported by COVID-19 Biobank, Fondazione IRCCS Cà Granda Milano; LV group was supported by MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016-02364358, Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, the European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- “Liver Investigation: Testing Marker Utility in Steatohepatitis”, Programme “Photonics” under grant agreement “101016726” for the project “REVEAL: Neuronal microscopy for cell behavioural examination and manipulation”, Fondazione Patrimonio Ca’ Granda “Liver Bible” PR-0361. DP was supported by Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, CV PREVITAL “Strategie di prevenzione primaria nella popolazione Italiana” Ministero della Salute, and Associazione Italiana per la Prevenzione dell’Epatite Virale (COPEV). Genetic modifiers for COVID-19 related illness (BeLCovid_1) was supported by the "Fonds Erasme". The Host genetics and immune response in SARS-Cov-2 infection (BelCovid_2) study was supported by grants from Fondation Léon Fredericq and from Fonds de la Recherche Scientifique (FNRS). The INMUNGEN-CoV2 study was funded by the Consejo Superior de Investigaciones Científicas. KUL is supported by the German Research Foundation (LU 1944/3-1) SweCovid is funded by the SciLifeLab/KAW national COVID-19 research program project grant to Michael Hultström (KAW 2020.0182) and the Swedish Research Council to Robert Frithiof (2014-02569 and 2014-07606). HZ is supported by Jeansson Stiftelser, Magnus Bergvalls Stiftelse. The COMRI cohort is funded by Technical University of Munich, Munich, Germany. Genotyping for the COMRI cohort was performed and funded by the Genotyping Laboratory of Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki, Helsinki, Finland. These funding agencies had no role in the design, implementation or interpretation of this study. Background: There is considerable variability in COVID-19 outcomes amongst younger adults—and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium. Method: The major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors. Findings: We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1·4, 95% confidence interval [CI] 1·2–1·6) and COVID-19 related mortality (HR 1·5, 95%CI 1·3–1·8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2·0, 95%CI 1·6-2·6), venous thromboembolism (OR 1·7, 95%CI 1·2-2·4), and hepatic injury (OR 1·6, 95%CI 1·2-2·0). Risk allele carriers ≤ 60 years had higher odds of death or severe respiratory failure (OR 2·6, 95%CI 1·8-3·9) compared to those > 60 years OR 1·5 (95%CI 1·3-1·9, interaction p-value=0·04). Amongst individuals ≤ 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31·8% (95%CI 27·6-36·2) were risk variant carriers, compared to 13·9% (95%CI 12·6-15·2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those ≤ 60 years improved when including the risk allele (AUC 0·82 vs 0·84, p=0·016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors. Interpretation: The major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality—and these are more pronounced amongst individuals ≤ 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management. CV PREVITAL “Strategie di prevenzione primaria nella popolazione Italiana” Ministero della Salute, and Associazione Italiana per la Prevenzione dell’Epatite Virale (COPEV) Genotyping Laboratory of Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki, Helsinki, Finland Clinical Research Facility and Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation Trust McGill Interdisciplinary Initiative in Infection and Immunity and the Fonds de Recherche Québec Santé (FRQS) CIHR scholarship and a joint FRQS and Québec Ministry of Health and Social Services scholarship European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) "Grupo de Trabajo en Medicina Personalizada contra el COVID-19 de Andalucia" “Intesa San Paolo 2020 charity fund” dedicated to the project NB/2020/0119 Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico SciLifeLab/KAW national COVID-19 research program project (KAW 2020.0182) Andalusian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018) Consejería de Economía, Conocimiento, Empresas y Universidad #CV20-10150 Canadian Institutes of Health Research (CIHR) (365825 and 409511) Japan Society for the Promotion of Science for Young Scientists "Consejeria de Salud y Familias" of the Andalusian Government McGill Interdisciplinary Initiative in Infection and Immunity Ricerca Finalizzata Ministero della Salute RF-2016-02364358 National Institute for Health Research-funded BioResource Fondazione Patrimonio Ca’ Granda “Liver Bible” PR-0361 Swedish Research Council (2014-02569 and 2014-07606) Instituto de Salud Carlos III (CIBERehd and CIBERER) National Center for Advancing Translational Sciences Academy of Finland for PREDICT consortium N. 340541. Lady Davis Institute of the Jewish General Hospital MIUR grant “Dipartimenti di Eccellenza 2018-2020” Technical University of Munich, Munich, Germany Jeansson Stiftelser, Magnus Bergvalls Stiftelse Tuscany Region “Bando Ricerca COVID-19 Toscana” Consejo Superior de Investigaciones Científicas Ricerca Corrente (Italian Ministry of Health) Academy of Finland Fellow grant N. 323116 Fonds de la Recherche Scientifique (FNRS) German Research Foundation (LU 1944/3-1) Canadian Foundation for Innovation (CFI) Fondazione Humanitas per la Ricerca FRQS Clinical Research Scholarship Fondazione IRCCS Cà Granda Milano Network for Italian Genomes (NIG) COVID-19 Host Genetics Initiative Fonds de Recherche Québec Santé Public Health Agency of Canada NIH Grant Number UL1TR001873 Dolce&Gabbana Fashion Firm MyFirst Grant AIRC n.16888 COVID-PREMED initiatives Genetic Biobank of Siena Fondation Léon Fredericq “Photonics” “101016726” (CompLS grant 031L0165) Banca Intesa San Paolo Medical Research Counc (DFG Grant: “EXC2167”) King’s College London Columbia University Cancer Research UK CINECA consortium COVID-19 Biobank Stein Erik Hagen Compute Canada "Fonds Erasme" NIH Foundation European Union Genome Québec COVID-19-GWAS Calcul Québec Welcome Trust EuroBioBank RD-Connect

Background The incidence of infective endocarditis (IE) has increased in recent decades. Societal lockdown including reorganization of the healthcare system during the COVID-19 pandemic may influence the incidence of IE. This study sets out to investigate the incidence of IE during the Danish national lockdown. Methods In this nationwide cohort study, patients admitted with IE in either one of two periods A) A combined period of 1 January to 7 May for 2018 and 2019, or B) 1 January to 6 May 2020, were identified using Danish nationwide registries. Weekly incidence rates of IE admissions for the 2018/2019-period and 2020-period were computed and incidence rate ratios (IRR) for 2020-incidence vs 2018/2019-incidence were calculated using Poisson regression analysis. Results In total, 208 (67.3% men, median age 74.1 years) and 429 (64.1% men, median age 72.7 years) patients were admitted with IE in 2020 and 2018/2019, respectively. No significant difference in incidence rates were found comparing the 2020-period and 2018/2019-period (IRR: 0.96 (95% CI: 0.82–1.14). The overall incidence rate pre-lockdown (week 1–10: 1 January to 11 March 2020) was 14.2 IE cases per 100,000 person years (95% CI: 12.0–16.9) as compared with 11.4 IE cases per 100,000 person years (95% CI: 9.1–14.1) during lockdown (week 11–18: 12 March to 6 May 2020) corresponding to an IRR of 0.80 (95% CI: 0.60–1.06) and thus no significant difference pre- versus post-lockdown. Conclusion In this nationwide cohort study, no significant difference in the incidence of IE admissions during the national lockdown due to the COVID-19 pandemic was found. Highlights • The incidence of IE during lockdown was 11.1 IE cases per 100,000 PY. • No reduction in the incidence of IE during the lockdown compared to preceding years. • No difference in the incidence of IE pre- versus post-lockdown in 2020.

The availability of viral entry factors is a prerequisite for the cross-species transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Large-scale single-cell screening of animal cells could reveal the expression patterns of viral entry genes in different hosts. However, such exploration for SARS-CoV-2 remains limited. Here, we perform single-nucleus RNA sequencing for 11 non-model species, including pets (cat, dog, hamster, and lizard), livestock (goat and rabbit), poultry (duck and pigeon), and wildlife (pangolin, tiger, and deer), and investigated the co-expression of ACE2 and TMPRSS2. Furthermore, cross-species analysis of the lung cell atlas of the studied mammals, reptiles, and birds reveals core developmental programs, critical connectomes, and conserved regulatory circuits among these evolutionarily distant species. Overall, our work provides a compendium of gene expression profiles for non-model animals, which could be employed to identify potential SARS-CoV-2 target cells and putative zoonotic reservoirs. Here the authors report single-nucleus RNA sequencing for several anatomical locations in 11 species, including cat, dog, hamster, lizard, goat, rabbit, duck, pigeon, pangolin, tiger, and deer, highlighting coexpression of SARS-CoV-2 entry factors ACE2 and TMPRSS2.

Abstract Objectives Patients with diabetes are - compared to people without diabetes - at increased risk of worse outcomes from COVID-19 related pneumonia during hospitalization. We aim to investigate whether telemetric continuous glucose monitoring (CGM) in quarantined hospitalized patients with diabetes and confirmed SARS-CoV-2 infection or another contagious infection can be successfully implemented and is associated with better glycaemic control than usual blood glucose monitoring (finger prick method) and fewer patient-health care worker contacts. Furthermore, we will assess whether glucose variables are associated with the clinical outcome. The hypothesis is that by using remote CGM to monitor glucose levels of COVID-19 infected patients and patients with other contagious infections with diabetes, we can still provide satisfactory (and maybe even better) in-hospital diabetes management despite patients being quarantined. Furthermore, the number of patient-personnel contacts can be lowered compared to standard monitoring with finger-prick glucose. This could potentially reduce the risk of transmitting contagious diseases from the patient to other people and reduces the use of PPE’s. Improved glucose control may reduce the increased risk of poor clinical outcomes associated with combined diabetes and infection. Trial Design This is a single centre, open label, exploratory, randomised, controlled, 2-arm parallel group (1:1 ratio), controlled trial. Participants The trial population is patients with diabetes (both type 1 diabetes, type 2 diabetes, newly discovered diabetes that is not classified yet, and all other forms of diabetes) admitted to Nordsjællands Hospital that are quarantined due to COVID-19 infection or another infection. Inclusion criteria: 1. Hospitalized with confirmed COVID-19 infection by real-time PCR or another validated method OR hospitalized with a non-COVID-19 diagnosis and quarantined at time of inclusion. 2. A documented clinically relevant history of diabetes or newly discovered during hospitalization as defined by The World Health Organizations diagnostic criteria for diabetes. 3. Written informed consent obtained before any trial related procedures are performed. 4. Male or female aged over 18 years of age. 5. Must be able to communicate with the study personnel. 6. The subject must be willing and able to comply with trial protocol. Exclusion criteria: 1. Known hypersensitivity to the band-aid of the Dexcom G6 sensors Intervention and comparator Participants will be randomized to either real-time CGM with the Dexcom G6, a CGM system that does not need to be calibrated, or finger-prick glucose monitoring. Blinded CGM will be mounted in the finger-prick group. In the open CGM group, the glucose values will be transmitted to a Smartdevice in the nurse office where glucose levels can be monitored remotely. Main Outcomes The primary endpoint is the difference between groups in distribution of glucose values being in time in range (TIR), defined as 3.9 to 10 mmol/l. In addition, the primary endpoint is reported as the percentage of days of the whole admission, the patient reaches TIR. Secondary endpoints are the estimated number of saved patient-personnel contacts related to blood glucose measurements, incl. time healthcare providers spent on diabetes related tasks and PPE related tasks, during the patients’ hospitalization. Furthermore, we will assess additional glucose outcomes and associations of glucose variables and patient outcomes (As specified in the protocol). Randomisation The service used for generating the randomization lists is www.random.org. Randomization is stratified by COVID-19 status and an allocation ratio of 1:1 to either CGM or finger-prick groups. Blinding (Masking) The design of the trial is open, however blinded CGM is recorded in the finger-prick group. Numbers to be randomized (sample size) A sample size of N=72 is required for the primary endpoint analysis based on 80% power to detect a 10% difference between groups in TIR and to allow for a 15% dropout. The 72 participants will be randomized 1:1 to open CGM or finger-prick with 36 in each group. Trial status This structured protocol summary is based on the CGM-ISO protocol version 1.3, dated 13.05.2020. Date of first patient enrolled: 25.05.2020. Expected last recruiting is May 2021. Patients enrolled to date: 20 in total. 8 with confirmed COVID-19 infection and 12 with other infections. Trial registration ClinicalTrials.gov Identifier: NCT04430608. Registered 12.06.2020 Full protocol The full protocol is attached as an additional file from the Trial website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; This Letter serves as a summary of the key elements of the full protocol.

Abstract The paper focuses on crisis responses and resilience within hospitals. The study is based on structured expert interviews with medical directors in selected hospital departments in two of the five regions of Denmark and primary care physicians in the same regions. We investigate stage 3 (Shock impact and management) and stage 4 (Recovery and learning) within hospital organizations using Denmark as case country, and we pay particular attention to issues of “organisational learning”, “purchasing flexibility and reallocation of funding”, “distribution of human and physical resources” and “motivated and well-supported workforce”. Particular attention is paid to care for patients with chronic care needs and lessons for the long-term resilience building in the health system. The study highlights strategic choices and lessons for the long-term resilience within hospitals. It demonstrates, how the initial strategy of organizing specific COVID-19 response units was abandoned relatively early, as it appeared more efficient to integrate COVID-19 patients in the regular specialized department structure. Emergency wards experienced increasing pressure during the pandemic as primary care clinics were referring (too) many patients suspected of COVID-19. This raises questions about capacity and relations between primary and specialized care in crisis situations. Management of human resources is crucial. While the initial phases of the pandemic response were characterized by flexibility and “team-spirit”, there has been a negative long-term impact particularly among the nursing staff, where burnouts and attrition are major issues. Pandemic crises place significant strain on health systems and personnel. This raises issues about communication of strategies and principles for organizing efforts. The Danish health system managed the crisis adequately, but there are also lessons that should be learned regarding long-term implications and preparedness for future crises.

RationaleSevere viral respiratory infections are often characterised by extensive myeloid cell infiltration and activation and persistent lung tissue injury. However, the immunological mechanisms driving excessive inflammation in the lung remain poorly understood.ObjectivesTo identify the mechanisms that drive immune cell recruitment in the lung during viral respiratory infections and identify novel drug targets to reduce inflammation and disease severity.MethodsPreclinical murine models of influenza A virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.ResultsOxidised cholesterols and the oxysterol-sensing receptor GPR183 were identified as drivers of monocyte/macrophage infiltration to the lung during influenza A virus (IAV) and SARS-CoV-2 infection. Both IAV and SARS-CoV-2 infection upregulated the enzymes cholesterol 25-hydroxylase (CH25H) and cytochrome P450 family 7 subfamily member B1 (CYP7B1) in the lung, resulting in local production of the oxidised cholesterols 25-hydroxycholesterol (25-OHC) and 7α,25-dihydroxycholesterol (7α,25-OHC). Loss-of-function mutation of Gpr183 or treatment with a GPR183 antagonist reduced macrophage infiltration and inflammatory cytokine production in the lungs of IAV- or SARS-CoV-2-infected mice. The GPR183 antagonist significantly attenuated the severity of SARS-CoV-2 infection and viral loads. Analysis of single-cell RNA-sequencing data on bronchoalveolar lavage samples from healthy controls and COVID-19 patients with moderate and severe disease revealed thatCH25H,CYP7B1andGPR183are significantly upregulated in macrophages during COVID-19.ConclusionThis study demonstrates that oxysterols drive inflammation in the lungviaGPR183 and provides the first preclinical evidence for the therapeutic benefit of targeting GPR183 during severe viral respiratory infections.

ABSTRACT Antivirals targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could improve treatment of COVID-19. We evaluated the efficacy of clinically relevant hepatitis C virus (HCV) NS3 protease inhibitors (PIs) against SARS-CoV-2 and their interactions with remdesivir, the only direct-acting antiviral approved for COVID-19 treatment. HCV PIs showed differential potency in short-term treatment assays based on the detection of SARS-CoV-2 spike protein in Vero E6 cells. Linear PIs boceprevir, telaprevir, and narlaprevir had 50% effective concentrations (EC50) of ∼40 μM. Among the macrocyclic PIs, simeprevir had the highest (EC50, 15 μM) and glecaprevir the lowest (EC50, >178 μM) potency, with paritaprevir, grazoprevir, voxilaprevir, vaniprevir, danoprevir, and deldeprevir in between. Acyclic PIs asunaprevir and faldaprevir had EC50s of 72 and 23 μM, respectively. ACH-806, inhibiting the HCV NS4A protease cofactor, had an EC50 of 46 μM. Similar and slightly increased PI potencies were found in human hepatoma Huh7.5 cells and human lung carcinoma A549-hACE2 cells, respectively. Selectivity indexes based on antiviral and cell viability assays were highest for linear PIs. In short-term treatments, combination of macrocyclic but not linear PIs with remdesivir showed synergism in Vero E6 and A549-hACE2 cells. Longer-term treatment of infected Vero E6 and A549-hACE2 cells with 1-fold EC50 PI revealed minor differences in the barrier to SARS-CoV-2 escape. Viral suppression was achieved with 3- to 8-fold EC50 boceprevir or 1-fold EC50 simeprevir or grazoprevir, but not boceprevir, in combination with 0.4- to 0.8-fold EC50 remdesivir; these concentrations did not lead to viral suppression in single treatments. This study could inform the development and application of protease inhibitors for optimized antiviral treatments of COVID-19.