Higher mortality in extracorporealmembrane- oxygenation patients with COVID-19 compared with H1N1-influenza

Introduction/Aim: The use of veno-venous Extracorporeal Membrane Oxygenation (V-V ECMO) in the management of refractory respiratory failure due to viral illnesses has increased with recent pandemics. The aim of this study is to describe the clinical characteristics and outcomes of hospitalized patients with COVID-19 requiring ECMO and compare this population to that observed during the H1N1-influenza pandemic at Royal Prince Alfred Hospital (RPAH). Methods: Between March to October 2021, medical records of inpatients diagnosed with COVID-19 at RPAH requiring v-v ECMO were analysed. The clinical characteristics and outcomes of these patients were compared to data from patients with H1N1 influenza requiring ECMO at RPAH between July 2009 and August 2017. The primary outcome was analysed using Cox Regression Model, categorical variables were analysed using Fisher's exact test and continuous variables were analysed using two-sample T-test. Results: ECMO was used for 18 patients with COVID-19 and 32 patients for H1N1 at RPAH. The COVID-19 group was older. Both groups were obese with low rates of comorbidities prior to admission. The in-hospital mortality rate was significantly higher for the COVID-19 group with an odds ratio of 6.31 (95%CI 1.3-30.0;p = 0.01). Days on ECMO were longer in the COVID-19 group, with similar rates of ECMO related complications. There was a trend to higher rates of secondary infection in the COVID group, with a significant increase in blood stream infections compared to the H1N1 group. Conclusion: Our single centre experience demonstrates the significant in-hospital morbidity and mortality of severe COVID-19 requiring ECMO above and beyond that experienced during the H1N1 pandemic. (Figure Presented).

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease† † Electronic supplementary information (ESI) available. See DOI: 10.1039/d0sc04942e

The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics. Recently, many high-resolution apo and inhibitor-bound structures of Mpro, a cysteine protease, have been determined, facilitating structure-based drug design. Mpro plays a central role in the viral life cycle by catalyzing the cleavage of SARS-CoV-2 polyproteins. In addition to the catalytic dyad His41–Cys145, Mpro contains multiple histidines including His163, His164, and His172. The protonation states of these histidines and the catalytic nucleophile Cys145 have been debated in previous studies of SARS-CoV Mpro, but have yet to be investigated for SARS-CoV-2. In this work we have used molecular dynamics simulations to determine the structural stability of SARS-CoV-2 Mpro as a function of the protonation assignments for these residues. We simulated both the apo and inhibitor-bound enzyme and found that the conformational stability of the binding site, bound inhibitors, and the hydrogen bond networks of Mpro are highly sensitive to these assignments. Additionally, the two inhibitors studied, the peptidomimetic N3 and an α-ketoamide, display distinct His41/His164 protonation-state-dependent stabilities. While the apo and the N3-bound systems favored Nδ (HD) and Nϵ (HE) protonation of His41 and His164, respectively, the α-ketoamide was not stably bound in this state. Our results illustrate the importance of using appropriate histidine protonation states to accurately model the structure and dynamics of SARS-CoV-2 Mpro in both the apo and inhibitor-bound states, a necessary prerequisite for drug-design efforts. The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics.

Optimal Mitigation Policies in a Pandemic: Social Distancing and Working from Home

We study the response of an economy to an unexpected epidemic. Households mitigate the spread of the disease by reducing consumption, reducing hours worked, and working from home. Working from home is subject to learning-by-doing and the capacity of the health care system is limited. A social planner worries about two externalities, an infection externality and a healthcare congestion externality. Private agents’ mitigation incentives are too weak and su?er from a fatalism bias with respect to future infection rates. The planner implements front-loaded mitigation policies and encourages working from home immediately. In our calibration, assuming a CFR of 1% and an initial infection rate of 0.1%, private mitigation reduces the cumulative death rate from 2.5% of the initially susceptible population to about 1.75%. The planner optimally imposes a drastic suppression policy and reduces the death rate to 0.15% at the cost of an initial drop in consumption of around 25%.

RBC-Enhance: A Randomized Pilot Feasibility Trial of Red Cell Transfusion Thresholds in Myelodysplastic Syndromes

Background Red blood cell (RBC) transfusion dependence (TD) and anemia are associated with inferior quality of life (QOL) and survival in myelodysplastic syndromes (MDS). As part of a research programme to identify the optimal transfusion hemoglobin (Hb) threshold that translates into significantly improved QOL, we conducted a pilot randomized study of two transfusion algorithms (liberal versus restrictive) to determine the feasibility of a larger study. This trial was aligned with the REDDS study (ISRCTN26088319, Stanworth et al., BJH 2019) and followed the same pre-defined statistical analysis plan. Methods The study was undertaken at 3 cancer centers (NCT02099669). We included patients with MDS, CMML, low blast AML (20-30%) or myeloproliferative neoplasms who were TD (> 1 RBC/8 weeks x 16 weeks). Patients on disease modifying therapy for > 6 months were permitted only if they had remained stably RBC-TD with a life expectancy of > 3 months. Central randomization was to one of two RBC transfusion strategies over a 12-week period: 1. Restrictive strategy to maintain Hb between 85 and 105g/L. To achieve this, 2 RBC units were transfused when Hb < 85 g/L 2. Liberal strategy to maintain Hb between 110 and 120 g/L. To achieve this, 2 RBC units were transfused when Hb < 105 g/L and 1 unit for Hb 105-110 g/L. The first 4 weeks were considered a run-in period to achieve the target Hb. The primary outcomes of this feasibility study were 1. The percentage compliance of Hb being within or above the target range of the assigned transfusion threshold (after the 4 week run-in). Feasibility was set at 70%. 2. Achievement of at least a 15 g/L difference between the mean pre-transfusion Hb of the liberal and restrictive strategy groups. Secondary outcomes included changes and differences in QOL scores, rates of transfusion reactions and alloimmunizations, overall blood utilization and visit numbers and impact on serum ferritin. The primary analysis was intention to treat. The study was closed early due to COVID-19, with 28 patients randomized of planned 30. Results 30 patients were enrolled over 5 years and 28 patients randomized (n=15, liberal;n=13 restrictive). Median age was 74 (range 58-84), 26/28 had MDS or CMML and there were no significant imbalances in baseline disease and patient characteristics although patients in the restrictive group tended to have lower risk disease (IPSS-R very low + low 69% versus 53% liberal). Compared with the restrictive arm, liberal arm patients had more complete blood counts, were transfused more RBC units (only during the 4-week run-in) and were transfused at shorter intervals (Table 1). There were no differences in adverse events. Over the 12 weeks, the mean Hb value was 90 ± 4 g/L (restrictive) versus 101 ± 4 g/L (liberal), (p <0.0001, Figure 1). The pretransfusion difference was 11.8 g/L (95% CI 9.4-14.3) with mean pre-transfusion Hb values of 98.6 (± 10.6) g/L and 86.7 (± 8.6) in the liberal and restrictive arms respectively. Percentage compliance of pre-transfusion Hb falling within or above the target Hb range was 48% for restrictive patients but only 14% for liberal patients. Adherence with QOL completion (minimum of 4 serial) was 93%. While sample sizes are small and comparisons exploratory, the area under the curve for several serial quality of life scores was numerically higher and the curve more stable for the liberal arm (EQ5D (figure 2), EORTC cognitive and emotional functioning). Similarly, a higher % of patients in the liberal arm achieved pre-defined clinically meaningful increases in several symptom and function domains (emotional, social, fatigue, dyspnea, financial problems). Discussion Whilst our study results did not meet our feasibility endpoints, this small randomized trial in MDS patients demonstrated clinically important differences in mean Hb achievable with different transfusion thresholds. Poor rates of compliance with Hb targets were clearly identified for patients in the liberal arm, suggesting a need to understand the barriers to protocol adherence in this rm prior to embarking on larger trials. Compared with the REDDS trial, we did not document a significant excess of RBC transfusions needed (post run-in period) to maintain the higher Hb threshold. Similar to REDDS, we did observe some signals of improved QOL with a liberal transfusion strategy. A formal analysis of pooled results with REDDS study patients is planned. (Funding, CCSRI grant QOLL-14 and MOSPI Fund 2014). [Formula presented] Disclosures: Buckstein: Novartis: Honoraria;Astex: Honoraria;Celgene: Honoraria;Celgene: Research Funding;Takeda: Research Funding. Prica: seattle genetics: Honoraria;Gilead: Honoraria;astra zeneca: Honoraria. Leber: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees;Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Takeda/Palladin: Honoraria, Membership on an entity's Board of Directors or advisory committees;Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chodirker: Hoffman Laroche: Honoraria. Lin: Novartis: Research Funding;Pfizer: Honoraria. Callum: Octapharma: Research Funding;Canadian Blood Services: Research Funding.

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease.

The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics. Recently, many high-resolution apo and inhibitor-bound structures of Mpro, a cysteine protease, have been determined, facilitating structure-based drug design. Mpro plays a central role in the viral life cycle by catalyzing the cleavage of SARS-CoV-2 polyproteins. In addition to the catalytic dyad His41-Cys145, Mpro contains multiple histidines including His163, His164, and His172. The protonation states of these histidines and the catalytic nucleophile Cys145 have been debated in previous studies of SARS-CoV Mpro, but have yet to be investigated for SARS-CoV-2. In this work we have used molecular dynamics simulations to determine the structural stability of SARS-CoV-2 Mpro as a function of the protonation assignments for these residues. We simulated both the apo and inhibitor-bound enzyme and found that the conformational stability of the binding site, bound inhibitors, and the hydrogen bond networks of Mpro are highly sensitive to these assignments. Additionally, the two inhibitors studied, the peptidomimetic N3 and an α-ketoamide, display distinct His41/His164 protonation-state-dependent stabilities. While the apo and the N3-bound systems favored N δ (HD) and N ϵ (HE) protonation of His41 and His164, respectively, the α-ketoamide was not stably bound in this state. Our results illustrate the importance of using appropriate histidine protonation states to accurately model the structure and dynamics of SARS-CoV-2 Mpro in both the apo and inhibitor-bound states, a necessary prerequisite for drug-design efforts.

Triage tool for the rationing of blood for massively bleeding patients during a severe national blood shortage: guidance from the National Blood Transfusion Committee

The emerging COVID-19 pandemic has overwhelmed healthcare resources worldwide, and for transfusion services this could potentially result in rapid imbalance between supply and demand due to a severe shortage of blood donors. This may result in insufficient blood components to meet every patient's needs resulting in difficult decisions about which patients with major bleeding do and do not receive active transfusion support. This document, which was prepared on behalf of the National Blood Transfusion Committee in England, provides a framework and triage tool to guide the allocation of blood for patients with massive haemorrhage during severe blood shortage. Its goal is to provide blood transfusions in an ethical, fair, and transparent way to ensure that the greatest number of life years are saved. It is based on an evidence- and ethics-based Canadian framework, and would become operational where demand for blood greatly exceeds supply, and where all measures to manage supply and demand have been exhausted. The guidance complements existing national shortage plans for red cells and platelets.

Susceptibility of domestic swine to experimental infection with SARS-CoV-2 (preprint)

SARS-CoV-2, the agent responsible for COVID-19 has been shown to infect a number of species. The role of domestic livestock and the risk associated for humans in close contact remains unknown for many production animals. Determination of the susceptibility of pigs to SARS-CoV-2 is critical towards a One Health approach to manage the potential risk of zoonotic transmission. Here, we show pigs are susceptible to SARS-CoV-2 following oronasal inoculation. Viral RNA was detected in group oral fluids and nasal wash from at least two animals while live virus was isolated from a pig. Further, antibodies could be detected in two animals at 11 and 13 days post infection, while oral fluid samples at 6 days post inoculation indicated the presence of secreted antibodies. These data highlight the need for additional livestock assessment to determine the potential role domestic animals may contribute towards the SARS-CoV-2 pandemic.

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease (preprint)

The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics. Recently, many high-resolution apo and inhibitor-bound structures of Mpro, a cysteine protease, have been determined, facilitating structure-based drug design. Mpro plays a central role in the viral life cycle by catalyzing the cleavage of SARS-CoV-2 polyproteins. In addition to the catalytic dyad His41-Cys145, Mpro contains multiple histidines including His163, His164, and His172. The protonation states of these histidines and the catalytic nu-cleophile Cys145 have been debated in previous studies of SARS-CoV Mpro, but have yet to be investigated for SARS-CoV-2. In this work we have used molecular dynamics simulations to determine the structural stability of SARS-CoV-2 Mpro as a function of the protonation assignments for these residues. We simulated both the apo and inhibitor-bound enzyme and found that the conformational stability of the binding site, bound inhibitors, and the hydrogen bond networks of Mpro are highly sensitive to these assignments. Additionally, the two inhibitors studied, the peptidomimetic N3 and an -ketoamide, display distinct His41/His164 protonation-state-dependent stabilities. While the apo and the N3-bound systems favored N{delta} (HD) and N{epsilon} (HE) protonation of His41 and His164, respectively, the -ketoamide was not stably bound in this state. Our results illustrate the importance of using appropriate histidine protonation states to accurately model the structure and dynamics of SARS-CoV-2 Mpro in both the apo and inhibitor-bound states, a necessary prerequisite for drug-design efforts.