Influence of Face Masks on Physiological and Subjective Response during 130 Min of Simulated Light and Medium Physical Manual Work-An Explorative Study.

BACKGROUND: Undesirable side effects from wearing face masks during the ongoing COVID-19 pandemic continue to be discussed and pose a challenge to occupational health and safety when recommending safe application. Only few studies examined the effects of continuously wearing a face mask for more than one hour. Therefore, the influence of wearing a medical mask (MedMask) and a filtering facepiece class II respirator (FFP2) on the physiological and subjective outcomes in the course of 130 min of manual work was exploratively investigated. Physical work load and cardiorespiratory fitness levels were additionally considered as moderating factors. METHODS: Twenty-four healthy subjects (12 females) from three different cardiorespiratory fitness levels each performed 130 min of simulated manual work with light and medium physical workload using either no mask, a MedMask or FFP2. Heart rate, transcutaneous oxygen and carbon dioxide partial pressure (PtcO2, PtcCO2) as well as perceived physical exertion and respiratory effort were assessed continuously at discrete time intervals. Wearing comfort of the masks were additionally rated after the working period. RESULTS: There was no difference in time-dependent changes of physiological outcomes when using either a MedMask or a FFP2 compared to not wearing a mask. A stronger increase over time in perceived respiratory effort occurred when the face masks were worn, being more prominent for FFP2. Physical workload level and cardiorespiratory fitness level were no moderating factors and higher wearing comfort was rated for the MedMask. CONCLUSION: Our results suggest that using face masks during light and medium physical manual work does not induce detrimental side effects. Prolonged wearing episodes appeared to increase respiratory effort, but without affecting human physiology in a clinically relevant way.

Inhaled prostacyclin therapy in the acute respiratory distress syndrome: a randomized controlled multicenter trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) results in significant hypoxia, and ARDS is the central pathology of COVID-19. Inhaled prostacyclin has been proposed as a therapy for ARDS, but data regarding its role in this syndrome are unavailable. Therefore, we investigated whether inhaled prostacyclin would affect the oxygenation and survival of patients suffering from ARDS. METHODS: We performed a prospective randomized controlled single-blind multicenter trial across Germany. The trial was conducted from March 2019 with final follow-up on 12th of August 2021. Patients with moderate to severe ARDS were included and randomized to receive either inhaled prostacyclin (3 times/day for 5 days) or sodium chloride (Placebo). The primary outcome was the oxygenation index in the intervention and control groups on Day 5 of therapy. Secondary outcomes were mortality, secondary organ failure, disease severity and adverse events. RESULTS: Of 707 patients approached 150 patients were randomized to receive inhaled prostacyclin (n = 73) or sodium chloride (n = 77). Data from 144 patients were analyzed. The baseline PaO2/FiO2 ratio did not differ between groups. The primary analysis of the study was negative, and prostacyclin improved oxygenation by 20 mmHg more than Placebo (p = 0.17). Secondary analysis showed that the oxygenation was significantly improved in patients with ARDS who were COVID-19-positive (34 mmHg, p = 0.04). Mortality did not differ between groups. Secondary organ failure and adverse events were similar in the intervention and control groups. CONCLUSIONS: The primary result of our study was negative. Our data suggest that inhaled prostacyclin might be beneficial treatment in patients with COVID-19 induced ARDS. TRIAL REGISTRATION: The study was approved by the Institutional Review Board of the Research Ethics Committee of the University of Tübingen (899/2018AMG1) and the corresponding ethical review boards of all participating centers. The trial was also approved by the Federal Institute for Drugs and Medical Devices (BfArM, EudraCT No. 2016003168-37) and registered at clinicaltrials.gov (NCT03111212) on April 6th 2017.

COVID-19 does not influence functional status after ARDS therapy.

RATIONALE: Health-related quality of life after surviving acute respiratory distress syndrome has come into focus in recent years, especially during the coronavirus disease 2019 pandemic. OBJECTIVES: A total of 144 patients with acute respiratory distress syndrome caused by COVID-19 or of other origin were recruited in a randomized multicenter trial. METHODS: Clinical data during intensive care treatment and data up to 180 days after study inclusion were collected. Changes in the Sequential Organ Failure Assessment score were used to quantify disease severity. Disability was assessed using the Barthel index on days 1, 28, 90, and 180. MEASUREMENTS: Mortality rate and morbidity after 180 days were compared between patients with and without COVID-19. Independent risk factors associated with high disability were identified using a binary logistic regression. MAIN RESULTS: The SOFA score at day 5 was an independent risk factor for high disability in both groups, and score dynamic within the first 5 days significantly impacted disability in the non-COVID group. Mortality after 180 days and impairment measured by the Barthel index did not differ between patients with and without COVID-19. CONCLUSIONS: Resolution of organ dysfunction within the first 5 days significantly impacts long-term morbidity. Acute respiratory distress syndrome caused by COVID-19 was not associated with increased mortality or morbidity.

Vaccine Side Effects in Health Care Workers after Vaccination against SARS-CoV-2: Data from TüSeRe:exact Study.

As the Corona Disease 2019 (COVID-19) caused by SARS-CoV-2 persists, vaccination is one of the key measures to contain the spread. Side effects (SE) from vaccination are one of the reasons for reluctance to vaccinate. We systematically investigated self-reported SE after the first, second, and booster vaccinations. The data were collected during the TüSeRe: exact study (Tübinger Monitoring Studie zur exakten Analyse der Immunantwort nach Vakzinierung). Employees of health and research institutions were invited to participate. Study participants were asked to fill out an online questionnaire and report their SE after each dose of SARS-CoV-2 vaccination. A total of 1046 participants (mean age: 44 ± 12.9 years; female, n = 815 (78%); male, n = 231 (22%)) were included in the analysis. Local and systemic SE were more frequent after receiving the vector-based vaccine ChAdOx1 nCoV-19 in the first vaccination. However, local and systemic SE were more common after receiving mRNA vaccines (BNT162b2, mRNA-1273) in the second vaccination. Compared to the BNT162b2 vaccine, more SE have been observed after receiving the mRNA-1273 vaccine in the booster vaccination. In multivariate analysis, local and systemic side effects were associated with vaccine type, age and gender. Local and systemic SE are common after SARS-CoV-2 vaccines. The frequency of self-reported local and systemic SE differ significantly between mRNA and vector-based vaccines.

Longitudinal development of depression and anxiety during COVID-19 pandemic in Germany: Findings from a population-based probability sample survey

The stress response to the COVID-19 pandemic might differ between early and later stages. Longitudinal data on the development of population mental health during COVID-19 pandemic is scarce. We have investigated mental health trajectories and predictors for change in a probability sample of the general population in Germany at the beginning and after 6 months of the pandemic. We conducted a longitudinal survey in a population-based probability sample of German adults. The current study analyzed data from a first assessment in May 2020 (T1;N = 1,412) and a second in November 2020 (T2;N = 743). Mental health was assessed in terms of anxiety and depression using the Patient Health Questionnaire-4 (PHQ-4). Mental health outcomes at T1 were compared with PHQ-4 norm data. Trajectories over time were investigated based on outcome classifications of PHQ-4 scores. Predictors of mental health outcomes and change were identified using multiple regression analysis. In spring 2020, participants showed significantly higher PHQ-4 scores as compared to the norm data, however, overall anxiety and depression remained low also 6 months later. 6.6% of respondents showed a mental health deterioration in autumn 2020, entering subclinical and clinical ranges, outweighing the proportion of people with improved outcomes. Sociodemographic variables associated with mental distress at T1 were mainly not predictive for change at T2. Even under prolonged pandemic-related stress, mental health remained mainly stable in the general population. Further development of the considerable subgroup experiencing deterioration of depression and anxiety should be monitored, in order to tailor prevention and intervention efforts.

Factors Associated with the COVID-19 Vaccination Status of Higher Education Students: Results of an Online Cross-Sectional Survey at Six Universities in Southwestern Germany.

This cross-sectional study explored factors associated with the corona virus disease 2019 (COVID-19) vaccination acceptance among higher education students in southwestern Germany. We conducted a cross-sectional online survey at six state-approved higher education institutions (HEIs) between July and November 2021. In addition to descriptive analyses, univariate as well as multivariate binary logistic regression analyses were conducted. A total of 6556 higher education students aged 18 years and older participated in our survey; 91.4% of participating students had been vaccinated against COVID-19 at least once. The factors that significantly contributed to the explanation of higher education students' vaccination status in the multivariate analysis (area under curve-AUC = 0.94) were variables on the perception of the virus SARS-CoV-2 (affective risk perception: Adjusted odds ratio-aOR = 1.2; perception of the outbreak as a media-hype: aOR = 0.8), attitudes towards personal (aOR = 0.7) and study-related (aOR = 0.8) health and safety measures to prevent transmission of SARS-CoV-2, and attitudes towards COVID-19 vaccination (preservation of own health: aOR = 1.3; confidence in vaccine safety: aOR = 1.7; supporting higher education through vaccination: aOR = 1.2; own contribution to the containment of the pandemic: aOR = 1.7). The findings target assisting HEIs in returning to face-to-face teaching after previous semesters of online teaching.

GLA/DRST real-world outcome analysis of CAR T-cell therapies for large B-cell lymphoma in Germany.

CD19-directed chimeric antigen receptor (CAR) T cells have evolved as a new standard-of-care (SOC) treatment in patients with relapsed/refractory (r/r) large B-cell lymphoma (LBCL). Here, we report the first German real-world data on SOC CAR T-cell therapies with the aim to explore risk factors associated with outcomes. Patients who received SOC axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for LBCL and were registered with the German Registry for Stem Cell Transplantation (DRST) were eligible. The main outcomes analyzed were toxicities, response, overall survival (OS), and progression-free survival (PFS). We report 356 patients who received axi-cel (n = 173) or tisa-cel (n = 183) between November 2018 and April 2021 at 21 German centers. Whereas the axi-cel and tisa-cel cohorts were comparable for age, sex, lactate dehydrogenase (LDH), international prognostic index (IPI), and pretreatment, the tisa-cel group comprised significantly more patients with poor performance status, ineligibility for ZUMA-1, and the need for bridging, respectively. With a median follow-up of 11 months, Kaplan-Meier estimates of OS, PFS, and nonrelapse mortality (NRM) 12 months after dosing were 52%, 30%, and 6%, respectively. While NRM was largely driven by infections subsequent to prolonged neutropenia and/or severe neurotoxicity and significantly higher with axi-cel, significant risk factors for PFS on the multivariate analysis included bridging failure, elevated LDH, age, and tisa-cel use. In conclusion, this study suggests that important outcome determinants of CD19-directed CAR T-cell treatment of LBCL in the real-world setting are bridging success, CAR-T product selection, LDH, and the absence of prolonged neutropenia and/or severe neurotoxicity. These findings may have implications for designing risk-adapted CAR T-cell therapy strategies.

Risk assessment in COVID-19: Prognostic importance of cardiovascular parameters.

BACKGROUND: Cardiovascular risk factors and comorbidities are highly prevalent among COVID-19 patients and are associated with worse outcomes. HYPOTHESIS: We therefore investigated if established cardiovascular risk assessment models could efficiently predict adverse outcomes in COVID-19. Furthermore, we aimed to generate novel risk scores including various cardiovascular parameters for prediction of short- and midterm outcomes in COVID-19. METHODS: We included 441 consecutive patients diagnosed with SARS-CoV-2 infection. Patients were followed-up for 30 days after the hospital admission for all-cause mortality (ACM), venous/arterial thromboembolism, and mechanical ventilation. We further followed up the patients for post-COVID-19 syndrome for 6 months and occurrence of myocarditis, heart failure, acute coronary syndrome (ACS), and rhythm events in a 12-month follow-up. Discrimination performance of DAPT, GRACE 2.0, PARIS-CTE, PREDICT-STABLE, CHA2-DS2-VASc, HAS-BLED, PARIS-MB, PRECISE-DAPT scores for selected endpoints was evaluated by ROC-analysis. RESULTS: Out of established risk assessment models, GRACE 2.0 score performed best in predicting combined endpoint and ACM. Risk assessment models including age, cardiovascular risk factors, echocardiographic parameters, and biomarkers, were generated and could successfully predict the combined endpoint, ACM, venous/arterial thromboembolism, need for mechanical ventilation, myocarditis, ACS, heart failure, and rhythm events. Prediction of post-COVID-19 syndrome was poor. CONCLUSION: Risk assessment models including age, laboratory parameters, cardiovascular risk factors, and echocardiographic parameters showed good discrimination performance for adverse short- and midterm outcomes in COVID-19 and outweighed discrimination performance of established cardiovascular risk assessment models.

Persisting Symptoms After COVID-19.

BACKGROUND: After recovering from coronavirus disease 2019 (COVID-19), a considerable number of patients report long-term sequelae. The epidemiologic data vary widely in the studies published to date, depending on the study design and the patient cohorts analyzed. Using a population-based approach, we report symptoms and clinical characteristics following COVID-19 (long COVID), focusing on symptoms ≥ 12 weeks (post-COVID-19). METHODS: In three German administrative districts, all adult patients with a diagnosis of COVID-19 confirmed by polymerase chain reaction (PCR) between March and September 2020 (n = 4632) were invited to complete a questionnaire. Predictors for post-COVID-19 were identified by multiple ordinal regression analysis. Study registration: DRKS00023069. RESULTS: A total of 1459 patients were included in the study, 175 (12%) of whom had been hospitalized for treatment of the acute phase of COVID-19. The prevalence of post-COVID-19 was 72.6% (n = 127) and 46.2% (n = 588) for hospitalized and non-hospitalized patients, respectively. The most frequently occurring long-term symptoms were fatigue (41.5% of all symptoms ≥ 12 weeks, n = 297), physical exhaustion (40.8%, n = 292), difficulty in concentrating (30.6%, n = 219), and loss of the senses of taste (25.9%, n = 185) and smell (25.5%, n = 182). Quality of life was significantly impaired in patients with post-COVID-19. The strongest risk factors for post-COVID-19 were female sex, overall severity of comorbidities, and severity of acute COVID-19. CONCLUSION: Patients who are not hospitalized also frequently experience continued symptoms following COVID-19. The heterogeneity of symptoms calls for a multi - disciplinary stepped-care approach, for which identification of patients at risk is crucial. A limitation of the study is the lack of a control group.

Influences on Attitudes Regarding COVID-19 Vaccination in Germany.

Trust in institutions and democracy may be a major contributor to the willingness to be vaccinated. We investigated these factors and others with regard to COVID-19 vaccine uptake in Germany. Even though effective vaccination is a major contributor to slowing down the current pandemic, vaccine hesitancy remains a major challenge. To analyze attitudes toward vaccine hesitancy, a web-based cross-sectional survey was used to understand and describe the influences of attitudes about vaccination against COVID-19 in the German population. A descriptive analysis for the entire dataset was carried out, and multiple proportional odds regression, path model, and structural equation modeling (SEM) were subsequently used to analyze any relationship between latent variables and COVID-19 vaccine acceptance. In total, 1092 responses from across Germany were analyzed. SEM modeling revealed that trust in institutions, trust in non-pharmaceutical interventions, and various demographic factors were associated with intent to vaccinate. Descriptive analysis and multiple proportional odds regression confirmed that a history of influenza vaccination and level of satisfaction with democratic institutions were highly predictive (p < 0.05) for COVID-19 vaccine acceptance. Additionally, social determinants of health such as gender, age, number of children in the family, and the degree of satisfaction with life were also predictors (p < 0.05) for COVID-19 vaccine acceptance. Results also demonstrated a significant relationship between receiving the flu vaccine and acceptance of the COVID-19 vaccination. Governments that provide COVID-19 vaccines and control messaging should strive for trust and transparency to maximize vaccine uptake. Government-based vaccine measures should also involve measures to communicate trust in democratic and scientific institutions.

Effects of Face Masks on Physical Performance and Physiological Response during a Submaximal Bicycle Ergometer Test.

The ongoing COVID-19 pandemic requires wearing face masks in many areas of our daily life; hence, the potential side effects of mask use are discussed. Therefore, the present study explores whether wearing a medical face mask (MedMask) affects physical working capacity (PWC). Secondary, the influence of a filtering facepiece mask with exhalation valve class 2 (FFP2exhal) and a cotton fabric mask (community mask) on PWC was also investigated. Furthermore, corresponding physiological and subjective responses when wearing face masks as well as a potential moderating role of subjects' individual cardiorespiratory fitness and sex on face mask effects were analyzed. Thirty-nine subjects (20 males, 19 females) with different cardiorespiratory fitness levels participated in a standardized submaximal bicycle ergometer protocol using either a MedMask, FFP2exhal, community mask, or no mask (control) on four days, in randomized order. PWC130 and PWC150 as the mechanical load at the heart rates of 130 and 150 beats per minute were measured as well as transcutaneous carbon dioxide partial pressure, saturation of peripheral capillary oxygen, breathing frequency, blood pressure, perceived respiratory effort, and physical exhaustion. Using the MedMask did not lead to changes in PWC or physiological response compared to control. Neither appeared changes exceeding normal ranges when the FFP2exhal or community mask was worn. Perceived respiratory effort was up to one point higher (zero-to-ten Likert scale) when using face masks (p < 0.05) compared to control. Sex and cardiorespiratory fitness were not factors influencing the effects of the masks. The results of the present study provide reason to believe that wearing face masks for infection prevention during the COVID-19 pandemic does not pose relevant additional physical demands on the user although some more respiratory effort is required.

Testing for SARS-CoV-2 seroprevalence: experiences of a tertiary eye centre.

INTRODUCTION: The actual prevalence of a SARS-CoV-2 infection and the individual assessment of being or having been infected may differ. Facing the great uncertainty-especially at the beginning of the pandemic-and the possibility of asymptomatic or mildly symptomatic, subclinical infections, we evaluate the experience of SARS-CoV-2 antibody screening at a tertiary clinical setting. METHODS AND ANALYSIS: All employees of a tertiary eye centre and a research institute of ophthalmology were offered antibody testing in May 2020, using a sequential combination of different validated assays/antigens and point-of-care (POC) testing for a subset (NCT04446338). Before taking blood, a systematic inquiry into past symptoms, known contacts and a subjective self-assessment was documented. The correlations between serostatus, patient contacts and demographic characteristics were analysed. Different tests were compared by Kappa statistics. RESULTS: Among 318 participants, SARS-CoV-2 antibodies were detected in 9 employees. Chemiluminescence assays (chemiluminescence immunoassay and electrochemiluminescence) showed superior specificity and high reproducibility, compared with ELISA and POC results.In contrast to the low seropositivity (2.8%) of healthcare workers, higher than that of the other departments of the hospital, a large proportion mistakenly assumed that they might have already been infected. Antiviral antibody titres increased and remained on a plateau for at least 3 months. CONCLUSIONS: The great demand and acceptance confirmed the benefit of highly sensitive testing methods in the early phase of the pandemic. The coincidence of low seroprevalence and anxious employees may have contributed to internalising the need of hygiene measures.

Impaired Myocardial Function Is Prognostic for Severe Respiratory Failure in the Course of COVID-19 Infection.

COVID-19 may lead to severe acute respiratory distress syndrome (ARDS) resulting in increased morbidity and mortality. Heart failure and/or pre-existing cardiovascular disease may correlate with poor outcomes and thus require special attention from treating physicians. The present study sought to investigate a possible impact of impaired myocardial function as well as myocardial distress markers on mortality or ARDS with need for mechanical ventilation in 157 consecutive patients with confirmed SARS-CoV-2 infection. All patients were admitted and treated at the University Hospital of Tübingen, Germany, during the first wave of the pandemic. Electrocardiography, echocardiography, and routine blood sampling were performed at hospital admission. Impaired left-ventricular and right-ventricular function, tricuspid regurgitation > grade 1, and elevated RV-pressure as well as thrombotic and myocardial distress markers (D-dimers, NT-pro-BNP, and troponin-I) were associated with mechanical ventilation and/or all-cause mortality. Impaired cardiac function is more frequent amidst ARDS, leading to subsequent need for mechanical ventilation, and thus denotes a poor outcome in COVID-19. Since a causal treatment for SARS-CoV-2 infection is still lacking, guideline-compliant cardiovascular evaluation and treatment remains the best approach to improve outcomes in COVID-19 patients with cardiovascular comorbidities.

Severe SARS-CoV-2 Infection Inhibits Fibrinolysis Leading to Changes in Viscoelastic Properties of Blood Clot: A Descriptive Study of Fibrinolysis in COVID-19.

BACKGROUND: Accumulating evidence indicates toward an association between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and procoagulatory state in blood. Thromboelastographic investigations are useful point-of-care devices to assess coagulation and fibrinolysis. OBJECTIVES: We investigated the hypothesis that the procoagulatory state in COVID-19 patients is associated with impaired fibrinolysis system. METHODS: Altogether, 29 COVID-19 patients admitted to normal wards or to the intensive care unit (ICU) were included in this descriptive study. Whole blood samples were investigated by thromboelastography to assess coagulation and fibrinolysis. Additionally, standard routine coagulation testing and immunoassays for factors of fibrinolysis as plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), plasminogen activity and α2-antiplasmin (A2AP) were performed. RESULTS: A significantly increased lysis resistance and a significantly longer time of lysis after adding tissue plasminogen activator were observed in blood samples from ICU COVID-19 patients compared with healthy controls (maximal lysis: 3.25 ± 0.56 vs. 6.20 ± 0.89%, p = 0.0127; lysis time: 365.7 ± 44.6 vs. 193.2 ± 16.3 seconds, p = 0.0014). PAI-1 activity was significantly higher in plasma samples of ICU COVID-19 patients (PAI-1: 4.92 ± 0.91 vs. 1.28 ± 0.33 U/mL, p = 0.001). A positive correlation between the activity of PAI-1 and lysis time of the formed clot (r = 0.70, p = 0.0006) was observed. CONCLUSION: Our data suggest that severe SARS-CoV-2 infection is associated with impaired fibrinolytic activity in blood, where fibrinolytic inhibitors are elevated leading to an increased resistance to clot lysis. Thromboelastography could offer a tool to investigate the contribution of the fibrinolytic status to the procoagulatory condition in COVID-19.

Test and treat COVID 65 plus - Hydroxychloroquine versus placebo in early ambulatory diagnosis and treatment of older patients with COVID19: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The aim of this trial is to identify the effect of ambulatory treatment in early COVID-19 disease with hydroxychloroquine on the rate of hospitalization or death in older patients above the age of 64. TRIAL DESIGN: Parallel, 2:1 randomization, double blind, placebo-controlled, multi-center trial. PARTICIPANTS: Male and female patients above the age of 64 (i.e. ≥65 years of age) with COVID-19 diagnosis confirmed by SARS-CoV2 positive throat swab (PCR). Patients can only be included within 3 days of symptom onset in ambulatory care if they consent to the study procedure and are able to adhere to the study visit schedule and protocol requirements (including telephone visits concerning symptoms and side effects). Severity of disease at inclusion is mild to moderate defined as not requiring hospital admission: SpO2 >94%, respiratory rate <20, mental state alert, no signs of septic shock. Cardiac risk is minimised by requiring a Tisdale score ≤ 6. Patients are recruited in the two german cities of Ulm and Tübingen in various ambulatory care settings. INTERVENTION AND COMPARATOR: Each patient will be given a first dose of 600 mg Hydroxychloroquine or the equivalent number of placebo capsules (3 capsules) at the day of inclusion. From the 2nd day on, each patient will get 200 mg or the equivalent number of placebo capsules twice a day (400mg/day) until day 7 (6 more does of 400 mg); a cumulative dose of 3 g. MAIN OUTCOMES: Rate of hospitalization or death at day 7 after study inclusion RANDOMISATION: All consenting adult patients having confirmed COVID-19 are randomly and blindly allocated in a 2:1 ratio to either IMP or placebo. The biostatistical center produced a randomization list (block randomization) with varying block length and stratified for the study center. This list is provided for packaging to the pharmaceutical unit which is providing encapsulated placebo and IMP. Only the pharmaceutical unit is aware of group allocation according to the randomization list. BLINDING (MASKING): Patients and investigators, as well as treating physicians are blinded to the treatment- allocation. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): In the first stage of an adaptive design 120 patients in a 2:1 ration: 72 Verum and 36 Placebo, plus an increase for 10% drop outs. After interim analysis, the total sample size will be calculated based on the effect seen in the first stage. Total sample size is estimated approximately n = 300-400 patients. TRIAL STATUS: Protocol version number: V3, 19.05.2020 Recruitment not yet started but is anticipated to begin by June 2020 and be complete by December 2020 TRIAL REGISTRATION: ClinicalTrials.gov: NCT04351516 , date: 17 April 2020 EudraCT: 2020-001482-37, date: 30 March 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in 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.