ObjectiveTo analyze the presence of frailty in survivors of severe COVID-19 admitted in the Intensive Care Unit (ICU) and followed six months after discharge.DesignAn observational, prospective and multicenter, nation-wide study.SettingEight adult ICU across eight academic acute care hospitals in Mexico.PatientsAll consecutive adult COVID-19 patients admitted in the ICU with acute respiratory failure between March 8, 2020 to February 28, 2021 were included. Frailty was defined according to the FRAIL scale, and was obtained at ICU admission and 6-month after hospital discharge.InterventionsNone.Main variables of interestThe primary endpoint was the frailty status 6-months after discharge. A regression model was used to evaluate the predictors during ICU stay associated with frailty.Results196 ICU survivors were evaluated for basal frailty at ICU admission and were included in this analysis. After 6-months from discharge, 164 patients were evaluated for frailty: 40 patients (20.4%) were classified as non-frail, 67 patients (34.2%) as pre-frail and 57 patients (29.1%) as frail. After adjustment, the need of invasive mechanical ventilation was the only factor independently associated with frailty at 6 month follow-up (Odds Ratio [OR] 3.70, 95% confidence interval 1.40–9.81, P = .008).ConclusionsDeterioration of frailty was reported frequently among ICU survivors with severe COVID-19 at 6-months. The need of invasive mechanical ventilation in ICU survivors was the only predictor independently associated with frailty.

Abstract Heart failure is a known complication in patients living with human inmmunodeficiency virus (HVI) infection. Detection of subclinical disfunction is nowadays possible by echocardiographic strain techniques. Myocardial work is a novel technique based on global longitudinal strain (GLS) that measures global work efficiency of left ventricle (GWE) and would allow early detection of subclinical myocardial damage. Methods We performed a cross sectional echocardiographic study of patients with long standing HIV infection, and no previous cardiopathy, assessing GLS of left ventricle (LV), left atrium (LA) and free wall of right ventricle (RV-FW GLS). We identified patients with subclinical disfunction expressed by an impaired GWE , and studied its determinants by lineal regression. Results 110 patients, 78.2% male, median age 53.3 (51.2-55.4) were included. Time from diagnosis was 20.5 (18.6-22.3) years. Myocardial work strain analysis showed an impaired GWE: 91.9% (90.9-92.9);p<0.001) and a GW index of 1840.8 mmHg%(1758.7-1922.9):p<0.001. The rest of deformation parameters laid into normal range: LV GLS was -19.5% (-19.0- -20.0) GLS dispersion 55.1 (50.1-60.1), LA GLS (reservoir) 32.8% (31.2-34.5), and RV free wall GLS -22.3% (-21.4 - -23.2). By univariate analysis, determinants of impaired GWE were age, Score2 risk, time from HIV diagnosis, QRS Interval duration, long QTc Interval, LV ejection fraction (LVEF),diastolic disfunction by doppler tissue imaging, CD4 count nadir, initial and maximun viral load, and exposure to didanosine treatment. After adjustment by cardiovascular risk and diastolic function (Ea velocity by tissue Doppler) , GWE impaired depended on duration of infection (Beta 0.3;95%CI:0.04-0.56;p=0.023), initial viral load (Beta -1.1;95%CI:-2.1- -0.02;p=0.046) and exposure to stavudine (Beta -6.3;95%IC: -11.5- -1.1;p=0.019). Conclusions Subclinical myocardial disfunction is prevalent in long standing HIV infection. Global work efficiency is a very sensitive parameter for detection, even in patients with normal GLS values, and it was related to duration of infection, initial viral load, and exposure to stavudine in our patients.Determinants of Global Work Efficiency

The trend over time and across different geographical areas of outcomes and management with noninvasive ventilation or invasive mechanical ventilation in patients admitted for acute exacerbations of chronic obstructive pulmonary disease and treated with ventilatory support is unknown. The purpose of this study was to describe outcomes and identify variables associated with survival for patients admitted to an intensive care unit (ICU) with acute exacerbation of chronic obstructive pulmonary disease [aeCOPD] who received noninvasive or invasive mechanical ventilation worldwide. Retrospective, multi-national, and multicenter studies, including four observational cohort studies, were carried out in 1998, 2004, 2010, and 2016 for the VENTILAGROUP following the same methodology. A total of 1,848 patients from 1,253 ICUs in 38 countries admitted for aeCOPD and need of ventilatory support were identified in the four study cohorts and included in the study. The overall incidence of aeCOPD as a cause for ventilatory support at ICU admission significantly decreased over time and varied widely according to the gross national income. The mortality of patients admitted to ICU for aeCOPD and ventilatory support significantly decreased over time regardless of the geographical area and gross national income; however, there is a remarkable variability in ICU mortality according to geographical area and gross national income. The use of NPPV as the first attempt at ventilatory support has significantly increased over time, with a parallel reduction of invasive mechanical ventilation regardless of gross national income. In this worldwide observational study, including four sequential cohorts of patients over 18 years from 1998 to 2016, the mortality of patients admitted to ICU for aeCOPD and ventilatory support significantly decreased regardless of the geographical area and gross national income. Future research will need to investigate the reason for the remarkable variability in ICU mortality according to the geographical area, gross national income, and methods to select patients for the appropriate ventilatory support.

BACKGROUND: Prone positioning reduces mortality in patients with moderate/severe ARDS. It remains unclear which physiological parameters could guide clinicians to assess which patients are likely to benefit from prone position. This study aimed to determine the association between relative changes in physiological parameters at 24 h of prone positioning and ICU mortality in adult subjects with ARDS. METHODS: We conducted a cohort study using the VENTILA database, including adults with ARDS receiving prone positioning. We used multivariable logistic regression to assess the association between relative changes in physiological parameters (PaO2/FIO2, dynamic driving pressure, PaCO2, and ventilatory ratio defined as [minute ventilation [mL/min] × PaCO2 [mm Hg]]/[predicted body weight × 100 [mL/min] × 37.5 [mm Hg] with ICU mortality) (primary outcome). We report adjusted odds ratios with 95% CI as measures of association. RESULTS: We included 156 subjects of which 82 (53%) died in the ICU. A relative decline in the ventilatory ratio at 24 h was associated with lower ICU mortality (odds ratio 0.80 [95% CI 0.66–0.97], every 10% decrease). Relative changes in PaO2/FIO2 (odds ratio 0.89 [95% CI 0.77–1.03], every 25% increase), PaCO2 (odds ratio 0.97 [95% CI 0.82–1.16], every 10% decrease), and dynamic driving pressure (odds ratio 0.98 [95% CI 0.89–1.07], every 10% decrease) were not associated with ICU mortality. CONCLUSIONS: In subjects with ARDS receiving prone positioning, a relative decline in the ventilatory ratio at 24 h was associated with lower ICU mortality.

Introduction: The main reason for high mortality in breast cancer is local recurrence and metastasis, despite surgery as the first therapeutic option. The anesthesia used in the operation room can determine the immune response. Methods: A prospective, comparative and non-randomized study in patients undergoing breast cancer surgery was conducted in our hospital after obtaining approval from the Hospital's Institutional Review Board. Patients were divided in two groups: Group A received general anesthesia with propofol and opioids. Group B, in addition to general anesthesia, three interfascial blocks (Pec I, Pec II and BRILMA) were performed in all patients. Three blood samples were taken 1) previous anesthetic induction; 2) two hours after the end of the surgery and 3) 24-48 hours after surgery. Leukocytes, CD3, CD4, CD8 and Natural Killer cells were determined at each time. Results: 103 patients were included. 59 (group A) received general anesthesia and 54 (group B) general anesthesia and interfascial blocks. Regarding baseline characteristics, age was significantly higher in the group that received general anesthesia and mastectomy was more frequent in the group that received interfascial blocks. We observed after surgery an increase in leukocytes level that returns close to baseline levels. On the other hand, a reduction in the immune response was observed that also returns to the previous level 48 hours after surgery. Group A and B get similar results and also subgroups of hormonal receptors (HER+, PR and/or ER+). Conclusions: Interfascial blocks in chest wall added to general anesthesia in breast cancer surgery has not shown a significant difference in the inflammatory response or immunological depression compared to general anesthesia as the only anesthetic technique. It seems to trend less immunological depression in the interfascial block group. (c) 2021 Sociedad Espanola de Anestesiologia, Reanimacion y Terapeutica del Dolor. Published by Elsevier Espana, S.L.U. All rights reserved.

Abstract Background Heart failure (HF) is a main health problem in western countries, and a major cause of hospitalizations and death, particularly in older people. Few data are available about clinical features and prognosis of very old patients, those aged 90 or more years. Purpose To analyse the clinical features and short-term prognosis (in-hospital mortality and 30-day readmission rate) of patients aged 90 or more years hospitalized with HF in Spain in the last years. Methods We conducted a retrospective analysis of patients discharged with an ICD-10 main diagnosis of HF from the Spanish National Health System (SNHS) public hospitals between 2016 and 2019, using as source of data the Minimum Basic Data Set of the SNHS. A comparison of clinical profile, in-hospital mortality and 30-day cardiovascular readmission rate between patients aged 75 to 89 years and those with 90 or more years was performed. Results From 2016 to 2019, 354,792 episodes of people older than 74-year and principal diagnosis of HF were included, being 59.2% female. Mean age of the whole population was 85.2±5.5 years, crude in-hospital mortality rate was 12.7% and crude cardiovascular 30-day readmission rate, 11.8%. The very older patients' subgroup (90 or more year-old) comprised 78.777 patients (22.2%). Table 1 shows the differences in clinical features between these patients and those aged 75 to 89 (77.8%). Patients aged 90 or more years were female in a higher proportion and showed a higher prevalence of cognitive impairment and renal failure, but a lower prevalence of most comorbidities (coronary artery revascularization, valve heart disease, cancer, diabetes mellitus, chronic liver disease). The diagnosis of previous myocardial infarction, stroke and systemic hypertension was similar in both groups (Table 1). Crude 30-day cardiovascular readmission rate was slightly but significantly lower in the oldest subgroup (10.9% vs 12%, p<0.001), while crude in-hospital mortality was higher (18.5% vs 11%, p<0.001). Conclusions Patients aged 90 or more years represents almost a fourth part of elderly patients hospitalized with HF in Spain within the last years. In general, prevalence of comorbidities and associated heart disease was similar or lower, but in-hospital mortality was twice higher, as compared with less older patients. Funding Acknowledgement Type of funding sources: None.

Purpose: To evaluate changes in the disconnection of mechanical ventilation in Spain from 1998 to 2016. Design: Post-hoc analysis of four cohort studies. Ambit: 138 Spanish ICUs. Patients: 2141 patients scheduled extubated. Interventions: None. Variables of interest: Demographics, reason for mechanical ventilation, complications, methods for disconnection, failure on the first attempt at disconnection, duration of weaning, reintubation, post-reintubation tracheotomy, ICU stay and mortality. Results: There was a significant increase (p < 0.001) in the use of gradual reduction of support pressure. The adjusted probability of using the gradual reduction in pressure support versus a spontaneous breathing trial has increased over time, both for the first attempt at disconnection (taking the 1998 study as a reference: odds ratio 0.99 in 2004, 0.57 in 2010 and 2.43 in 2016) andfor difficult/prolonged disconnection (taking the 1998 study as a reference: odds ratio 2.29 in 2004, 1.23 in 2010 and 2.54 in 2016). The proportion of patients extubated after the first attemptat disconnection has increased over time. There is a decrease in the ventilation time dedicated to weaning (from 45% in 1998 to 36% in 2016). However, the duration in difficult/prolonged weaning has not decreased (median 3 days in all studies, p = 0.435). Conclusions: There have been significant changes in the mode of disconnection of mechanical ventilation, with a progressive increase in the use of gradual reduction of pressure support. No relevant changes in outcomes have been observed. (C) 2021 Elsevier Espana, S.L.U. y SEMICYUC. All rights reserved.

Despite the need for specific weaning strategies in neurological patients, evidence is generally insufficient or lacking. We aimed to describe the evolution over time of weaning and extubation practices in patients with acute brain injury compared with patients who are mechanically ventilated (MV) due to other reasons. We performed a secondary analysis of three prospective, observational, multicenter international studies conducted in 2004, 2010, and 2016 in adults who had need of invasive MV for more than 12 h. We collected data on baseline characteristics, variables related to management ventilator settings, and complications while patients were ventilated or until day 28. Among the 20,929 patients enrolled, we included 12,618 (60

BACKGROUND: The growing proportion of elderly intensive care patients constitutes a public health challenge. The benefit of critical care in these patients remains unclear. We compared outcomes in elderly versus very elderly subjects receiving mechanical ventilation. METHODS: In total, 5,557 mechanically ventilated subjects were included in our post hoc retrospective analysis, a subgroup of the VENTILA study. We divided the cohort into 2 subgroups on the basis of age: very elderly subjects (age >= 80 y; n = 1,430), and elderly subjects (age 65-79 y; n = 4,127). A propensity score on being very elderly was calculated. Evaluation of associations with 28-d mortality was done with logistic regression analysis. RESULTS: Very elderly subjects were clinically sicker as expressed by higher SAPS II scores (53 +/- 18 vs 50 +/- 18, P < .001), and their rates of plateau pressure < 30 cm H2O were higher, whereas other parameters did not differ. The 28-d mortality was higher in very elderly subjects (42% vs 34%, P < .001) and remained unchanged after propensity score adjustment (adjusted odds ratio 1.31 [95% CI 1.16-1.49], P < .001). CONCLUSIONS: Age was an independent and unchangeable risk factor for death in mechanically ventilated subjects. However, survival rates of very elderly subjects were > 50%. Denial of critical care based solely on age is not justified.

Background Coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented pressure on healthcare system globally. Lack of high-quality evidence on the respiratory management of COVID-19-related acute respiratory failure (C-ARF) has resulted in wide variation in clinical practice. Methods Using a Delphi process, an international panel of 39 experts developed clinical practice statements on the respiratory management of C-ARF in areas where evidence is absent or limited. Agreement was defined as achieved when > 70% experts voted for a given option on the Likert scale statement or > 80% voted for a particular option in multiple-choice questions. Stability was assessed between the two concluding rounds for each statement, using the non-parametric Chi-square ( χ 2 ) test ( p < 0·05 was considered as unstable). Results Agreement was achieved for 27 (73%) management strategies which were then used to develop expert clinical practice statements. Experts agreed that COVID-19-related acute respiratory distress syndrome (ARDS) is clinically similar to other forms of ARDS. The Delphi process yielded strong suggestions for use of systemic corticosteroids for critical COVID-19; awake self-proning to improve oxygenation and high flow nasal oxygen to potentially reduce tracheal intubation; non-invasive ventilation for patients with mixed hypoxemic-hypercapnic respiratory failure; tracheal intubation for poor mentation, hemodynamic instability or severe hypoxemia; closed suction systems; lung protective ventilation; prone ventilation (for 16–24 h per day) to improve oxygenation; neuromuscular blocking agents for patient-ventilator dyssynchrony; avoiding delay in extubation for the risk of reintubation; and similar timing of tracheostomy as in non-COVID-19 patients. There was no agreement on positive end expiratory pressure titration or the choice of personal protective equipment. Conclusion Using a Delphi method, an agreement among experts was reached for 27 statements from which 20 expert clinical practice statements were derived on the respiratory management of C-ARF, addressing important decisions for patient management in areas where evidence is either absent or limited. Trial registration : The study was registered with Clinical trials.gov Identifier: NCT04534569.

Background: Current incidence and outcome of patients with acute hypoxaemic respiratory failure requiring mechanical ventilation in the intensive care unit (ICU) are unknown, especially for patients not meeting criteria for acute respiratory distress syndrome (ARDS). Methods: An international, multicentre, prospective cohort study of patients presenting with hypoxaemia early in the course of mechanical ventilation, conducted during four consecutive weeks in the winter of 2014 in 459 ICUs from 50 countries (LUNG SAFE). Patients were enrolled with arterial oxygen tension/inspiratory oxygen fraction ratio <= 300 mmHg, new pulmonary infiltrates and need for mechanical ventilation with a positive end-expiratory pressure of >= 5 cmH(2)O. ICU prevalence, causes of hypoxaemia, hospital survival and factors associated with hospital mortality were measured. Patients with unilateral versus bilateral opacities were compared. Findings: 12 906 critically ill patients received mechanical ventilation and 34.9% with hypoxaemia and new infiltrates were enrolled, separated into ARDS (69.0%), unilateral infiltrate (22.7%) and congestive heart failure (CHF; 8.2%). The global hospital mortality was 38.6%. CHF patients had a mortality comparable to ARDS (44.1% versus 40.4%). Patients with unilateral-infiltrate had lower unadjusted mortality, but similar adjusted mortality compared to those with ARDS. The number of quadrants on chest imaging was associated with an increased risk of death. There was no difference in mortality comparing patients with unilateral-infiltrate and ARDS with only two quadrants involved. Interpretation: More than one-third of patients receiving mechanical ventilation have hypoxaemia and new infiltrates with a hospital mortality of 38.6%. Survival is dependent on the degree of pulmonary involvement whether or not ARDS criteria are reached.

OBJECTIVES:To describe the changes in ventilator management over time in patients with neurologic disease at ICU admission and to estimate factors associated with 28-day hospital mortality.DESIGN:Secondary analysis of three prospective, observational, multicenter studies.SETTING:Cohort studies conducted in 2004, 2010, and 2016.PATIENTS:Adult patients who received mechanical ventilation for more than 12 hours.INTERVENTIONS:None.MEASUREMENTS AND MAIN RESULTS:Among the 20,929 patients enrolled, we included 4,152 (20%) mechanically ventilated patients due to different neurologic diseases. Hemorrhagic stroke and brain trauma were the most common pathologies associated with the need for mechanical ventilation. Although volume-cycled ventilation remained the preferred ventilation mode, there was a significant (p < 0.001) increment in the use of pressure support ventilation. The proportion of patients receiving a protective lung ventilation strategy was increased over time: 47% in 2004, 63% in 2010, and 65% in 2016 (p < 0.001), as well as the duration of protective ventilation strategies: 406 days per 1,000 mechanical ventilation days in 2004, 523 days per 1,000 mechanical ventilation days in 2010, and 585 days per 1,000 mechanical ventilation days in 2016 (p < 0.001). There were no differences in the length of stay in the ICU, mortality in the ICU, and mortality in hospital from 2004 to 2016. Independent risk factors for 28-day mortality were age greater than 75 years, Simplified Acute Physiology Score II greater than 50, the occurrence of organ dysfunction within first 48 hours after brain injury, and specific neurologic diseases such as hemorrhagic stroke, ischemic stroke, and brain trauma.CONCLUSIONS:More lung-protective ventilatory strategies have been implemented over years in neurologic patients with no effect on pulmonary complications or on survival. We found several prognostic factors on mortality such as advanced age, the severity of the disease, organ dysfunctions, and the etiology of neurologic disease.

Background Mechanical Ventilation (MV) is a complex and central treatment process in the care of critically ill patients. It influences acid–base balance and can also cause prognostically relevant biotrauma by generating forces and liberating reactive oxygen species, negatively affecting outcomes. In this work we evaluate the use of a Recurrent Neural Network (RNN) modelling to predict outcomes of mechanically ventilated patients, using standard mechanical ventilation parameters. Methods We performed our analysis on VENTILA dataset, an observational, prospective, international, multi-centre study, performed to investigate the effect of baseline characteristics and management changes over time on the all-cause mortality rate in mechanically ventilated patients in ICU. Our cohort includes 12,596 adult patients older than 18, associated with 12,755 distinct admissions in ICUs across 37 countries and receiving invasive and non-invasive mechanical ventilation. We carry out four different analysis. Initially we select typical mechanical ventilation parameters and evaluate the machine learning model on both, the overall cohort and a subgroup of patients admitted with respiratory disorders. Furthermore, we carry out sensitivity analysis to evaluate whether inclusion of variables related to the function of other organs, improve the predictive performance of the model for both the overall cohort as well as the subgroup of patients with respiratory disorders. Results Predictive performance of RNN-based model was higher with Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) of 0.72 (± 0.01) and Average Precision (AP) of 0.57 (± 0.01) in comparison to RF and LR for the overall patient dataset. Higher predictive performance was recorded in the subgroup of patients admitted with respiratory disorders with AUC of 0.75 (± 0.02) and AP of 0.65 (± 0.03). Inclusion of function of other organs further improved the performance to AUC of 0.79 (± 0.01) and AP 0.68 (± 0.02) for the overall patient dataset and AUC of 0.79 (± 0.01) and AP 0.72 (± 0.02) for the subgroup with respiratory disorders. Conclusion The RNN-based model demonstrated better performance than RF and LR in patients in mechanical ventilation and its subgroup admitted with respiratory disorders. Clinical studies are needed to evaluate whether it impacts decision-making and patient outcomes. Trial registration : NCT02731898 ( https://clinicaltrials.gov/ct2/show/NCT02731898 ), prospectively registered on April 8, 2016.

BACKGROUND: Driving pressure (Delta P) has been described as a risk factor for mortality in patients with ARDS. However, the role of Delta P in the outcome of patients without ARDS and on mechanical ventilation has received less attention. Our objective was to evaluate the association between Delta P on the first day of mechanical ventilation with the development of ARDS. METHODS: This was a post hoc analysis of a multicenter, prospective, observational, international study that included subjects who were on mechanical ventilation for > 12 h. Our objective was to evaluate the association between Delta P on the first day of mechanical ventilation with the development of ARDS. To assess the effect of Delta P, a logistic regression analysis was performed when adjusting for other potential risk factors. Validation of the results obtained was performed by using a bootstrap method and by repeating the same analyses at day 2. RESULTS: A total of 1,575 subjects were included, of whom 65 (4.1%) developed ARDS. The Delta P was independently associated with ARDS (odds ratio [OR] 1.12, 95% CI 1.07-1.18 for each cm H2O of Delta P increase, P < .001). The same results were observed at day 2 (OR 1.14, 95% CI 1.07-1.21; P < .001) and after bootstrap validation (OR 1.13, 95% CI 1.04-1.22; P < .001). When taking the prevalence of ARDS in the lowest quartile of Delta P (<= 9 cm H2O) as a reference, the subjects with Delta P > 12-15 cm H2O and those with Delta P > 15 cm H2O presented a higher probability of ARDS (OR 3.65, 95% CI 1.32-10.04 [P 5.01] and OR 7.31, 95% CI, 2.89-18.50 [P < .001], respectively). CONCLUSIONS: In the subjects without ARDS, a higher level of Delta P on the first day of mechanical ventilation was associated with later development of ARDS.

BACKGROUND:Information is lacking regarding long-term survival and predictive factors for mortality in patients with acute hypoxemic respiratory failure due to coronavirus disease 2019 (COVID-19) and undergoing invasive mechanical ventilation. We aimed to estimate 180-day mortality of patients with COVID-19 requiring invasive ventilation, and to develop a predictive model for long-term mortality. METHODS:Retrospective, multicentre, national cohort study between March 8 and April 30, 2020 in 16 intensive care units (ICU) in Spain. Participants were consecutive adults who received invasive mechanical ventilation for COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection detected in positive testing of a nasopharyngeal sample and confirmed by real time reverse-transcriptase polymerase chain reaction (rt-PCR). The primary outcomes was 180-day survival after hospital admission. Secondary outcomes were length of ICU and hospital stay, and ICU and in-hospital mortality. A predictive model was developed to estimate the probability of 180-day mortality. RESULTS:868 patients were included (median age, 64 years [interquartile range [IQR], 56-71 years]; 72% male). Severity at ICU admission, estimated by SAPS3, was 56 points [IQR 50-63]. Prior to intubation, 26% received some type of noninvasive respiratory support. The unadjusted overall 180-day survival rates was 59% (95% CI 56-62%). The predictive factors measured during ICU stay, and associated with 180-day mortality were: age [Odds Ratio [OR] per 1-year increase 1.051, 95% CI 1.033-1.068)), SAPS3 (OR per 1-point increase 1.027, 95% CI 1.011-1.044), diabetes (OR 1.546, 95% CI 1.085-2.204), neutrophils to lymphocytes ratio (OR per 1-unit increase 1.008, 95% CI 1.001-1.016), failed attempt of noninvasive positive pressure ventilation prior to orotracheal intubation (OR 1.878 (95% CI 1.124-3.140), use of selective digestive decontamination strategy during ICU stay (OR 0.590 (95% CI 0.358-0.972) and administration of low dosage of corticosteroids (methylprednisolone 1 mg/kg) (OR 2.042 (95% CI 1.205-3.460). CONCLUSION:The long-term survival of mechanically ventilated patients with severe COVID-19 reaches more than 50% and may help to provide individualized risk stratification and potential treatments. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT04379258. Registered 10 April 2020 (retrospectively registered).