Nebulized recombinant tissue plasminogen activator (rt-PA) for acute COVID-19-induced severe respiratory failure: an exploratory proof of concept trial (preprint)

Nebulized thrombolysis offers locally targeted therapy with potentially lower bleeding risk than systemic administration for coronavirus disease 2019 (COVID-19) respiratory failure. In a proof-of-concept safety study, adult patients with COVID-19-induced respiratory failure and a <300mmHg PaO2/FiO2 (P/F) ratio, requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received nebulized rt-PA in two cohorts (C1 and C2), alongside standard of care during the first two UK COVID-19 waves. Matched historical controls (MHC; n=18) were used in C1. Safety co-primary endpoints were treatment-related bleeds and fibrinogen reduction to <1.0–1.5 g/L. A dose escalation strategy for improved efficacy with the least safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40–60 mg rt-PA per day for ≤14 days. Nine patients in C1 (IMV, 6/9; NIRS, 3/9) and 26 in C2 (IMV, 12/26; NIRS, 14/26) received nebulized rt-PA for a mean (SD) of 6.7 (4.6) and 9.1(4.6) days, respectively. Four bleeding events (one severe and three mild) in three patients were considered treatment-related. No significant fibrinogen reductions were reported. Greater improvement in mean P/F ratio from baseline to end of study was observed in C1 compared with MHC [C1; 154 to 299 vs MHC; 154 to 212). In C2, there was no difference in the baseline P/F ratio of NIRS and IMV patients. However, a larger improvement in P/F ratio was observed in NIRS patients [NIRS; 126 to 240 vs IMV; 120 to 188) and they required fewer treatment days (NIRS; 7.86 vs IMV; 10.5). Nebulized rt-PA appears to be well-tolerated, showing a trend of improved oxygenation and faster recovery in patients with acute COVID-19-induced respiratory failure requiring respiratory support; this effect was more pronounced in the NIRS group. Further investigation is required to study the potential of this novel treatment approach.

Agilecation: Agile Leadership in a Higher Education Institution (HEI) during the Covid-19 Pandemic a Test Case

The current quantitative research examine how the leadership of a teacher training college in an Israeli Higher Education Institiostion (HEI) have dealt with the Covid19 crisis in an agile manner. This Perspectives presents a case study of agile leadership during the Covid-19 pandemic from the viewpoint of the college lecturers'. The Covid-19 outbreak was a ‘Black swan' events for educational institutions in Israel. Following the unprecedented transition to distance learning. The pandemic forced higher education institutions to adopt agile leadership behaviors. Previous research has given scant attention to the relationship between running an academic institution and application of an agile leadership during a crisis. The Research Goals were: 1. To analyze key processes undertaken by the leadership of the College following the outbreak of the Covid-19 pandemic, to ensure the HEI continued functioning during the crisis. 2. To examine the evaluation (degree of approval) of the lecturers regarding the steps taken by the colleges leadership. As seen from the findings: The lecturers were persistent in the remote teaching process. Their contact with the students was positive. They perceived the college's leadership as maintaining teaching processes in a highly positive way. They were aware of the ongoing training processes. They felt comfortable contacting those in official roles. The conclusions suggest that ensuring the continued functioning of an organization during a crisis requires agile leadership with skills and competencies multifaceted and direct channels of communication. If we want to sum it up in one word, it can be expressed as Agilication = agility + education + action in higher education. © 2023 by Cherkas Global University All rights reserved. Published in the USA

Lateral flow test performance in children for SARS-CoV-2 using anterior nasal and buccal swabbing: sensitivity, specificity, negative and positive predictive values.

OBJECTIVE: To determine if the sensitivity of the lateral flow test is dependent on the viral load and on the location of swabbing in the respiratory tract in children. DESIGN: Phase 1: Routinely performed reverse transcriptase PCR (RT-PCR) using nose and throat (NT) swabs or endotracheal (ET) aspirates were compared with Innova lateral flow tests (LFTs) using anterior nasal (AN) swabs. Phase 2: RT-PCR-positive children underwent paired AN RT-PCR and LFT and/or paired AN RT-PCR and buccal LFT. SETTING: Tertiary paediatric hospitals. PATIENTS: Children under the age of 18 years. Phase 1: undergoing routine testing, phase 2: known SARS-CoV-2 positive. RESULTS: Phase 1: 435 paired swabs taken in 431 asymptomatic patients resulted in 8 positive RT-PCRs, 9 PCR test failures and 418 negative RT-PCRs from NT or ET swabs. The test performance of AN LFT demonstrated sensitivity: 25% (4%-59%), specificity: 100% (99%-100%), positive predictive value (PPV): 100% (18%-100%) and negative predictive value (NPV): 99% (97%-99%).Phase 2: 14 AN RT-PCR-positive results demonstrated a sensitivity of 77% (50%-92%) of LFTs performed on AN swabs. 15/16 paired buccal LFT swabs were negative. CONCLUSION: The NPV, PPV and specificity of LFTs are excellent. The sensitivity of LFTs compared with RT-PCR is good when the samples are colocated but may be reduced when the LFT swab is taken from the AN. Buccal swabs are not appropriate for LFT testing. Careful consideration of the swabbing reason, the tolerance of the child and the requirements for test processing (eg, rapidity of results) should be undertaken within hospital settings. TRIAL REGISTRATION NUMBER: NCT04629157.

Recurring episodes of bundle branch reentry ventricular tachycardia due to aortitis preceded by SARS-CoV-2 infection: a case report.

BACKGROUND: SARS-CoV-2 may trigger both vasculitis and arrhythmias as part of a multisystem inflammatory syndrome described in children as well as in adults following COVID-19 infection with only minor respiratory symptoms. The syndrome denotes a severe dysfunction of one or more extra-pulmonary organ systems, with symptom onset approximately 2-5 weeks after the COVID-19 infection. In the present case, a seemingly intractable ventricular tachycardia preceded by SARS-CoV2 infection was only managed following the diagnosis and management of aortitis. CASE PRESENTATION: A 69-year-old woman was hospitalized due to syncope, following a mild COVID-19 infection. She presented with paroxysmal atrial fibrillation and intermittent ventricular tachycardia interpreted as a septum-triggered bundle branch reentry ventricular tachycardia, unaffected by amiodaron, lidocaine and adenosine. A CT-scan revealed inflammation of the aortic arch, extending into the aortic root. In the following days, the tachycardia progressed to ventricular storm with intermittent third-degree AV block. A temporary pacemaker was implanted, and radiofrequency ablation was performed to both sides of the ventricular septum after which the ventricular tachycardia was non-inducible. Following supplemental prednisolone treatment, cardiac symptoms and arrythmia subsided, but recurred after tapering. Long-term prednisolone treatment was therefore initiated with no relapse in the following 14 months. CONCLUSION: We present a rare case of aortitis complicated with life-threatening ventricular tachycardia presided by Covid-19 infection without major respiratory symptoms. Given a known normal AV conduction prior to the COVID-19 infection, it seems likely that the ensuing aortitis in turn affected the septal myocardium, enabling the reentry tachycardia. Generally, bundle branch reentry tachycardia is best treated with radiofrequency ablation, but if it is due to aortitis with myocardial affection, long-term anti-inflammatory treatment is mandatory to prevent relapse and assure arrhythmia control. Our case highlights importance to recognize the existence of the multisystem inflammatory syndrome in adults (MIS-A) following COVID-19 infection in patients with alarming cardiovascular symptoms. The case shows that the early use of an CT-scan was crucial for both proper diagnosis and treatment option.

Quantification de la transmission transplacentaire du virus SARS-CoV-2 et de ses anticorps chez 165 patientes et leurs nouveau-nés selon le terme d'infection : une étude française, prospective et multicentrique

Objectifs Quantifier au cours de la grossesse le risque de transmission verticale du SARS-CoV-2 et le transfert transplacentaire des immunoglobulines selon le terme d'infection maternelle. Matériels et méthode Il s'agit d'une étude prospective, observationnelle, multicentrique conduite dans 11 maternités françaises incluant des patientes enceintes infectées par le SARS-CoV-2 entre avril à décembre 2020. L'infection maternelle était définie par une PCR positive ou une sérologie positive à SARS-CoV-2. La population étudiée regroupait 165 couples mère-enfants. Cette étude a été menée de façon à obtenir des prélèvements biologiques systématisés, réalisés à la naissance pour chaque couple mère-enfant. La charge virale du SRAS-CoV-2 a été mesurée par RT-PCR. Les anticorps IgG et IgM dirigés contre le domaine de liaison au récepteur de la protéine de pointe du SRAS-CoV-2 ont été mesurés par dosage immunoenzymatique. Les concentrations d'anticorps et les taux de transfert transplacentaires ont été analysés en fonction du terme de l'infection maternelle. L'ensemble des patientes avait donné son consentement éclairé. Résultats Il a été identifié un cas de transmission verticale (n = 1 (0,63 %) IC95 % [0,02 % ;3,48 %]). Parmi les 165 patientes, 107 (64,8 %) avaient une concentration d'IgG > 25,6 BAU/mL. Le transfer ratio médian était 1,26 (IC [1,15–1,34]). Le transfert ratio des IgG augmente avec le temps qui s'écoule entre le début de l'infection maternelle et l'accouchement. Conclusion Ces résultats confirment que le risque de transmission verticale du SARS Cov-2 est faible. La transmission transplacentaire des anticorps maternels semble être augmentée en cas d'infection maternelle durant le premier et le deuxième trimestre de grossesse.

Predicted impact of an emergency department influenza vaccine program

Study Objective: Seasonal influenza is associated with significant healthcare resource utilization. An estimated 490,000 hospitalizations and 34,000 deaths were attributed to influenza during the 2018 - 2019 season. Despite robust influenza vaccination programs in both the inpatient and outpatient setting, the emergency department (ED) represents a missed opportunity to vaccinate patients at high risk for influenza who do not have access to routine preventive care. Feasibility and implementation of ED-based influenza vaccination programs have been previously described but have stopped short of describing the predicted health resource impact. The goal of our study was to describe the potential impact of an influenza vaccination program in an urban adult emergency department population using historic patient data.

COVID-19 Cases Prediction Using Different LSTM Models and Comparison of Effectiveness of Different Models

Large infectivity and transmissibility of COVID-19 caused severe damage to the economy, education and health of many countries. Due to the increasing number of COVID-19 cases in the world, some predictive methods are therefore needed to forecast the number of cases of COVID-19 in the future. Long short-term memory (LSTM) predicts the correlation between confirmed cases and predicts COVID-19 spread over time. The system shall be trained using training data containing confirmed cases. Various parameters considered are the no of positive cases, the number of recovered cases and the no of deaths every day. LSTM models in different types are evaluated for the time series forecasting confirmed cases, deaths and recovery and the accuracy of the prediction is compared. Different LSTM models like bidirectional LSTM, Gated Recurrent unit, W-LSTM and simple LSTM are helps to predict the no of cases in each country. Model performance is measured using the root mean square error, mean absolute percentage error and r2-score indices. Proposed method can be used to predict other types of pandemics for improved planning. © 2022, The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

The impact of COVID-19 pandemic on caustic ingestion at a tertiary care center in South India

Background: The COVID-19 pandemic has had a significant impact on the mental health of individuals which has sometimes led to attempts at deliberate self-harm including the ingestion of caustic substances. This study was aimed to compare the rates of caustic substance ingestion during the pandemic to a similar period in the preceding year at our center. Methodology: We carried out a retrospective analysis, in which patients' details (demographic, clinical, endoscopic, and outcomes) were collected and compared between April 2019 and December 2019 (pre-COVID-19 pandemic) and from April 2020 to December 2020 (during the COVID-19 pandemic). Results: A total of 41 patients were included in this study, 26 (63.4%) in the pandemic period and 15 (36.5%) in the prepandemic period. The majority were female in both the prepandemic (60%) and pandemic periods (53.9%). More adolescents (<18 years of age) were seen in the pandemic period (15.3%) than in the prepandemic period (6.7%). The proportion of patients admitted with caustic substance ingestion in the pandemic period (3.53%) was significantly higher than in the prepandemic period (1.57%) (P = 0.0094). Conclusion: Caustic substance ingestion almost doubled in our center during the COVID-19 pandemic highlighting the burden of mental health issues during a pandemic.

Impact of the COVID-19 pandemic on preterm birth and stillbirth: A nationwide, population-based retrospective cohort study

Objective: This study aimed to establish whether there was a decrease in the rate of prematurity in France after the beginning of lockdown (March 17, 2020) and whether there was an increase in the rate of stillbirths compared with 2017 to 2019. Study design: We included all births from January to September of each year from 2017 to 2020 from the national Programme de Médicalisation des Systèmes d'Information database: 496,171 newborns from women with singleton pregnancies and 15,441 newborns from women with multiple pregnancies were included for 2020. Concerning the 2017 to 2019 period, we included a mean of 518,798 newborns from women with singleton pregnancies and 16,441 newborns from women with multiple pregnancies per year. Results: Between April to May 2017 to 2019 and April to May 2020, there was a decrease of - 7.53% in the rate of prematurity (from 5.31% to 4.91%;P < 0.01) for singleton pregnancies. Between these 2 periods, the rate of change was −12.90% between 22 and 27 WG (P = 0.03), +1.96% between 28 and 31 WG (P = 0.69), and −8.24% between 32 and 36 WG (P < 0.01). The decrease in the rate of prematurity was still observed after the end of lockdown (from June to September 2020). For multiple births, there was no decrease in prematurity between January to September 2017 to 2019 and January to September 2020: 50.14% vs. 50.36% (P = 0.63), respectively, for twins and 95.51% vs. 94.9% (P = 0.62), respectively, for high-order multiple pregnancies. In January to September, there were 363 stillbirths among singleton pregnancies in 2017 to 2019 and 114 in 2020 (0.00% change rate). Among the 1752 women with a diagnosis of SARS-CoV-2 infection with singleton pregnancies, the rate of prematurity was higher in 2020 than in 2017 to 2019 (9.93% vs. 5.32%;P < 0.01), regardless of the severity of prematurity (P < 0.05 for all). Conclusion: Large-scale socioenvironmental modifications like the lockdown in spring 2020 may be associated with beneficial effects on perinatal morbidity. We did not find an increase in the rate of stillbirth since the beginning of the pandemic. At this stage, the practical consequences are not obvious, but our results encourage further reflection regarding behaviors that could modify the risk of prematurity outside of the context of an epidemic.

Newly arrived migrant students' perceptions of emergency remote teaching: A Q methodology study.

In an attempt to curb the spread of COVID-19, Emergency Remote Teaching was implemented worldwide. The global educational disruption led to a rise in quantitative studies investigating the effect of this shift on student outcomes. These studies suggest a greater negative impact of the pandemic on students from disadvantaged backgrounds, but often fall short of exploring learners' perspectives on online teaching practices. A Q study with 23 Newly Arrived Migrant Students in Flemish upper secondary education was conducted to investigate these pupils' perceptions of blended Emergency Remote Teaching. The results show that these students hold at least four different viewpoints regarding Emergency Remote Teaching. The importance pupils assign to interaction and the role of the teacher is an important grouping variable in these analyses.

Association between SARS-Cov-2 infection during pregnancy and adverse pregnancy outcomes: A re-analysis of the data reported by Wei et al. (2021).

OBJECTIVES AND BACKGROUND: Wei et al. have published a meta-analysis (MA), which aimed to evaluate the association between SARS-CoV-2 infection during pregnancy and adverse pregnancy outcomes. Using classical random-effects model, they found that SARS-CoV-2 infection was associated with preeclampsia, preterm birth and stillbirth. Performing MA with low event rates or with few studies may be challenging insofar as MA relies on several within and between-study distributional assumptions. The objective was to assess the robustness of the results provided by Wei et al. METHODS: We performed a sensitivity analysis using frequentist and Bayesian meta-analysis methods. We also estimated fragility indexes. RESULTS: For eclampsia, the confidence intervals of most frequentist models contain 1. All beta-binomial models (Bayesian) lead to credible intervals containing 1. The prediction interval, based on DL method, ranges from 0.75 to 2.38. The fragility index is 2 for the DL method. For preterm, the confidence (credible) intervals exclude 1. The prediction interval is broad, ranging from 0.84 to 20.61. The fragility index ranges from 27 to 10. For stillbirth, the confidence intervals of most frequentist models contain 1. Six Bayesian MA models lead to credible intervals containing 1. The prediction interval ranges from 0.52 to 8.49. The fragility index is 3. CONCLUSION: Given the available data and the results of our broad sensitivity analysis, we can suggest that SARS-CoV-2 infection during pregnancy is associated with preterm, and that it may be associated with preeclampsia. For stillbirth, more data are needed as none of the Bayesian analyses are conclusive.

Impact of COVID-19 on primary care contacts with children and young people in England: longitudinal trends study 2015-2020.

BACKGROUND: The NHS response to COVID-19 altered provision and access to primary care. AIM: To examine the impact of COVID-19 on GP contacts with children and young people (CYP) in England. DESIGN AND SETTING: A longitudinal trends analysis was undertaken using electronic health records from the Clinical Practice Research Datalink (CPRD) Aurum database. METHOD: All CYP aged <25 years registered with a GP in the CPRD Aurum database were included. The number of total, remote, and face-to-face contacts during the first UK lockdown (March to June 2020) were compared with the mean contacts for comparable weeks from 2015 to 2019. RESULTS: In total, 47 607 765 GP contacts with 4 307 120 CYP were included. GP contacts fell 41% during the first lockdown compared with previous years. Children aged 1-14 years had greater falls in total contacts (≥50%) compared with infants and those aged 15-24 years. Face-to-face contacts fell by 88%, with the greatest falls occurring among children aged 1-14 years (>90%). Remote contacts more than doubled, increasing most in infants (over 2.5-fold). Total contacts for respiratory illnesses fell by 74% whereas contacts for common non-transmissible conditions shifted largely to remote contacts, mitigating the total fall (31%). CONCLUSION: During the COVID-19 pandemic, CYP's contact with GPs fell, particularly for face-to-face assessments. This may be explained by a lower incidence of respiratory illnesses because of fewer social contacts and changing health-seeking behaviour. The large shift to remote contacts mitigated total falls in contacts for some age groups and for common non-transmissible conditions.

Remote non‐pharmacologic interventions for sleep problems in healthcare workers during the COVID‐19 pandemic

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects of remote non‐pharmacologic interventions, compared with other specific intervention, non‐intervention or alternative intervention for sleep problems in in healthcare workers during the coronavirus disease 2019 outbreak.

Remote non‐pharmacologic interventions for sleep problems in adults during the COVID‐19 pandemic

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects of remote non‐pharmacologic interventions, compared with other specific intervention, non‐intervention or alternative intervention for sleep problems in adults during the coronavirus disease 2019 outbreak.

Which children and young people are at higher risk of severe disease and death after hospitalisation with SARS-CoV-2 infection in children and young people: A systematic review and individual patient meta-analysis.

BACKGROUND: We aimed to describe pre-existing factors associated with severe disease, primarily admission to critical care, and death secondary to SARS-CoV-2 infection in hospitalised children and young people (CYP), within a systematic review and individual patient meta-analysis. METHODS: We searched Pubmed, European PMC, Medline and Embase for case series and cohort studies published between 1st January 2020 and 21st May 2021 which included all CYP admitted to hospital with ≥ 30 CYP with SARS-CoV-2 or ≥ 5 CYP with PIMS-TS or MIS-C. Eligible studies contained (1) details of age, sex, ethnicity or co-morbidities, and (2) an outcome which included admission to critical care, mechanical invasive ventilation, cardiovascular support, or death. Studies reporting outcomes in more restricted groupings of co-morbidities were eligible for narrative review. We used random effects meta-analyses for aggregate study-level data and multilevel mixed effect models for IPD data to examine risk factors (age, sex, comorbidities) associated with admission to critical care and death. Data shown are odds ratios and 95% confidence intervals (CI).PROSPERO: CRD42021235338. FINDINGS: 83 studies were included, 57 (21,549 patients) in the meta-analysis (of which 22 provided IPD) and 26 in the narrative synthesis. Most studies had an element of bias in their design or reporting. Sex was not associated with critical care or death. Compared with CYP aged 1-4 years (reference group), infants (aged <1 year) had increased odds of admission to critical care (OR 1.63 (95% CI 1.40-1.90)) and death (OR 2.08 (1.57-2.86)). Odds of death were increased amongst CYP over 10 years (10-14 years OR 2.15 (1.54-2.98); >14 years OR 2.15 (1.61-2.88)).The number of comorbid conditions was associated with increased odds of admission to critical care and death for COVID-19 in a step-wise fashion. Compared with CYP without comorbidity, odds ratios for critical care admission were: 1.49 (1.45-1.53) for 1 comorbidity; 2.58 (2.41-2.75) for 2 comorbidities; 2.97 (2.04-4.32) for ≥3 comorbidities. Corresponding odds ratios for death were: 2.15 (1.98-2.34) for 1 comorbidity; 4.63 (4.54-4.74) for 2 comorbidities and 4.98 (3.78-6.65) for ≥3 comorbidities. Odds of admission to critical care were increased for all co-morbidities apart from asthma (0.92 (0.91-0.94)) and malignancy (0.85 (0.17-4.21)) with an increased odds of death in all co-morbidities considered apart from asthma. Neurological and cardiac comorbidities were associated with the greatest increase in odds of severe disease or death. Obesity increased the odds of severe disease and death independently of other comorbidities. IPD analysis demonstrated that, compared to children without co-morbidity, the risk difference of admission to critical care was increased in those with 1 comorbidity by 3.61% (1.87-5.36); 2 comorbidities by 9.26% (4.87-13.65); ≥3 comorbidities 10.83% (4.39-17.28), and for death: 1 comorbidity 1.50% (0.00-3.10); 2 comorbidities 4.40% (-0.10-8.80) and ≥3 co-morbidities 4.70 (0.50-8.90). INTERPRETATION: Hospitalised CYP at greatest vulnerability of severe disease or death with SARS-CoV-2 infection are infants, teenagers, those with cardiac or neurological conditions, or 2 or more comorbid conditions, and those who are obese. These groups should be considered higher priority for vaccination and for protective shielding when appropriate. Whilst odds ratios were high, the absolute increase in risk for most comorbidities was small compared to children without underlying conditions. FUNDING: RH is in receipt of a fellowship from Kidney Research UK (grant no. TF_010_20171124). JW is in receipt of a Medical Research Council Fellowship (Grant No. MR/R00160X/1). LF is in receipt of funding from Martin House Children's Hospice (there is no specific grant number for this). RV is in receipt of a grant from the National Institute of Health Research to support this work (grant no NIHR202322). Funders had no role in study design, data collection, analysis, decision to publish or preparation of the manuscript.

Host Immune-Protein Signature Combining TRAIL, IP-10 and CRP for Early and Accurate Prediction of Severe COVID-19 Outcome

Background. Accurately identifying COVID-19 patients at-risk to deteriorate remains challenging. Dysregulated immune responses impact disease progression and development of life-threatening complications. Tools integrating host immune-protein expression have proven useful in determining infection etiology and hold potential for prognosticating disease severity. Methods. Adults with COVID-19 were enrolled at medical centers in Israel, Germany, and the United States (Figure 1). Severe outcome was defined as intensive care unit admission, non-invasive or invasive ventilation, or death. Tumor necrosis factor related apoptosis inducing ligand (TRAIL), interferon gamma inducible protein-10 (IP-10) and C-reactive protein (CRP) were measured using an analyzer providing values within 15 minutes (MeMed Key®). A signature indicating the likelihood of severe outcome was derived generating a score (0-100). Description of derivation cohort RT-PCR, reverse transcription polymerase chain reaction. Results. Between March and November 2020, 518 COVID-19 patients were enrolled, of whom 394 were eligible, 29% meeting a severe outcome. Age ranged between 19-98 (median 61.5), with 59.1% male. Patients meeting severe outcomes exhibited higher levels of CRP and IP-10 and lower levels of TRAIL (Figure 2;p < 0.001). Likelihood of severe outcome increased significantly (p < 0.001) with higher scores. The signature's area under the receiver operating characteristic curve (AUC) was 0.86 (95% confidence interval: 0.81-0.91). Performance was not confounded by age, sex, or comorbidities and was superior to IL-6 (AUC 0.77;p = 0.033) and CRP (AUC 0.78;p < 0.001). Clinical deterioration proximal to blood draw was associated with higher signature score. Scores of patients meeting a first outcome over 3 days after blood draw were significantly (p < 0.001) higher than scores of non-severe patients (Figure 3). Moreover, the signature differentiated patients who further deteriorated after meeting a severe outcome from those who improved (p = 0.004) and projected 14-day survival probabilities (p < 0.001;Figure 4). TRAIL, IP-10, CRP and the severity signature score are differentially expressed in severe and non-severe COVID-19 infection Dots represent patients and boxes denote median and interquartile range (IQR) The signature score of patients meeting a severe outcome on or after the day of blood draw is significantly (p < 0.001) higher than the signature score of non-severe patients. Dots represents patients and boxes denote median and IQR Kaplan-Meier survival estimates for signature score bins Conclusion. The derived signature combined with a rapid measurement platform has potential to serve as an accurate predictive tool for early detection of COVID-19 patients at risk for severe outcome, facilitating timely care escalation and de-escalation and appropriate resource allocation.

Ethics review of COVID-19 human challenge studies: A joint HRA/WHO workshop.

This report of a joint World Health Organization (WHO) and United Kingdom (UK) Health Research Authority (HRA) workshop discusses the ethics review of the first COVID-19 human challenge studies, undertaken in the midst of the pandemic. It reviews the early efforts of international and national institutions to define the ethical standards required for COVID-19 human challenge studies and create the frameworks to ensure rigorous and timely review of these studies. This report evaluates the utility of the WHO's international guidance document Key criteria for the ethical acceptability of COVID-19 human challenge studies (WHO Key Criteria) as a practical resource for the ethics review of COVID-19 human challenge studies. It also assesses the UK HRA's approach to these complex ethics reviews, including the formation of a Specialist Ad-Hoc Research Ethics Committee (REC) for COVID-19 Human Challenge Studies to review all current and future COVID-19 human challenge studies. In addition, the report outlines the reflections of REC members and researchers regarding the ethics review process of the first COVID-19 human challenge studies. Finally, it considers the potential ongoing scientific justification for COVID-19 human challenge studies, particularly in relation to next-generation vaccines and optimisation of vaccination schedules. Overall, there was broad agreement that the WHO Key Criteria represented an international consensus document that played a powerful role in setting norms and delineating the necessary conditions for the ethical acceptability of COVID-19 human challenge studies. Workshop members suggested that the WHO Key Criteria could be practically implemented to support researchers and ethics reviewers, including in the training of ethics committee members. In future, a wider audience may be engaged by the original document and potential additional materials, informed by the experiences of those involved in the first COVID-19 human challenge studies outlined in this document.