Barriers to participation in biosampling-based translational research: A cross-sectional survey of Canadian critical care researchers.

BACKGROUND AND OBJECTIVE: Collection of biosamples for translational research studies is vital for understanding biological pathways, discovering disease-related biomarkers, and identifying novel therapeutic targets. However, a lack of infrastructure for sample procurement, processing, storage, and shipping may hinder the ability of clinical research units to effectively engage in translational research. The purpose of this study was to identify the barriers to biosampling-based translational research in the critical care setting in Canada. METHODS: We administered an online survey to members of the Canadian Critical Care Trials Group (CCCTG), the Canadian Critical Care Translational Biology Group (CCCTBG), and the Canadian Critical Care Research Coordinators Group (CCCRCG). The survey focused on participants' personal experience of biosampling research, research infrastructure, motivating factors, and perceived barriers. RESULTS: We received 59 responses from 31 sites, including 6 community intensive care unit (ICU) sites. The overall response rate was 11.3%. The majority of respondents were research coordinators (44%), followed by clinician-investigators (33.8%), graduate students (10.2%), and PhD-investigators (8.5%). Although most (63.8%) respondents reported an interest in participating in translational research, they also reported that their ICUs were currently contributing to a third of the number of translational studies compared to clinical studies. For respondents with experience in participating in translational research studies, the most common barriers were lack of funding, lack of time, and insufficient research staff. For respondents without previous experience, the perceived facilitators were more interest from their research group, improved training/mentorship, increased funding, and better access to laboratory equipment. CONCLUSIONS: Our survey found that the majority of participants were interested in and recognize the value of participating in biosampling-based translational research but lacked funding, time, and research personnel trained in biosampling protocols. Our survey also identified factors that might encourage participation at new sites. Addressing these barriers will be a key step towards increasing translational research capacity across Canada.

The impact of COVID-19 workload on psychological distress amongst Canadian intensive care unit healthcare workers during the 1st wave of the COVID-19 pandemic: A longitudinal cohort study.

Intensive care unit healthcare workers (ICU HCW) are at risk of mental health disorders during emerging disease outbreaks. Numerous cross-sectional studies have reported psychological distress, anxiety, and depression amongst ICU HCW during the COVID-19 pandemic. However, few studies have followed HCW longitudinally, and none of these have examined the association between COVID-19 workload and mental health. We conducted a longitudinal cohort study of 309 Canadian ICU HCW from April 2020 to August 2020, during the 1st wave of the COVID-19 pandemic. Psychological distress was assessed using the General Health Questionnaire 12-item scale (GHQ-12) at 3 timepoints: during the acceleration phase of the 1st wave (T1), the deceleration phase of the 1st wave (T2), and after the 1st wave had passed (T3). Clinically relevant psychological distress, defined as a GHQ-12 score ≥ 3, was identified in 64.7% of participants at T1, 41.0% at T2, and 34.6% at T3. Psychological distress was not associated with COVID-19 workload at T1. At T2, psychological distress was associated with the number of COVID-19 patients in the ICU (odds ratio [OR]: 1.06, 95% confidence interval [CI]: 1.00, 1.13) while at T3, when COVID-19 patient numbers were low, it was associated with the number of weekly hospital shifts with COVID-19 exposure (OR: 1.33, 95% CI: 1.09, 1.64). When analyzed longitudinally in a mixed effects model, pandemic timepoint was a stronger predictor of psychological distress (OR: 0.24, 95% CI: 0.15, 0.40 for T2 and OR: 0.16, 95% CI: 0.09, 0.27 for T3) than COVID-19 workload. Participants who showed persistent psychological distress at T3 were compared with those who showed recovery at T3. Persistent psychological distress was associated with a higher number of weekly shifts with COVID-19 exposure (OR: 1.97, 95% CI:1.33, 3.09) but not with a higher number of COVID-19 patients in the ICU (OR: 0.86, 95% CI: 0.76, 0.95). In summary, clinically relevant psychological distress was observed in a majority of ICU HCW during the acceleration phase of the 1st wave of the COVID-19 pandemic but decreased rapidly as the 1st wave progressed. Persistent psychological distress was associated with working more weekly shifts with COVID-19 exposure but not with higher numbers of COVID-19 patients in the ICU. In future emerging disease outbreaks, minimizing shifts with direct disease exposure may help alleviate symptoms for individuals with persistent psychological distress.

COVID-19 vaccine reactogenicity among participants enrolled in the GENCOV study.

BACKGROUND: GENCOV is a prospective, observational cohort study of COVID-19-positive adults. Here, we characterize and compare side effects between COVID-19 vaccines and determine whether reactogenicity is exacerbated by prior SARS-CoV-2 infection. METHODS: Participants were recruited across Ontario, Canada. Participant-reported demographic and COVID-19 vaccination data were collected using a questionnaire. Multivariable logistic regression was performed to assess whether vaccine manufacturer, type, and previous SARS-CoV-2 infection are associated with reactogenicity. RESULTS: Responses were obtained from n = 554 participants. Tiredness and localized side effects were the most common reactions across vaccine doses. For most participants, side effects occurred and subsided within 1-2 days. Recipients of Moderna mRNA and AstraZeneca vector vaccines reported reactions more frequently compared to recipients of a Pfizer-BioNTech mRNA vaccine. Previous SARS-CoV-2 infection was independently associated with developing side effects. CONCLUSIONS: We provide evidence of relatively mild and short-lived reactions reported by participants who have received approved COVID-19 vaccines.

Association of Epigenetic Age and Outcome in Critically Ill Patients.

OBJECTIVES: DNA methylation can be used to determine an individual's biological age, as opposed to chronological age, an indicator of underlying health status. This study aimed to assess epigenetic age in critically ill patients with and without sepsis to determine if higher epigenetic age is associated with admission diagnosis or mortality. DESIGN: Secondary analysis of whole blood DNA methylation data generated from a nested case-control study of critically ill septic and nonseptic patients. SETTING: Four tertiary care hospitals in Canada. INTERVENTIONS: None. PATIENTS: Critically ill patients with and without sepsis. MEASUREMENTS AND MAIN RESULTS: Epigenetic age was derived from DNA methylation data using the Hannum and PhenoAge algorithms and deviation from the patient's chronological age in years was determined. Of the 66 patients with sepsis, 34 were male (51.5%), the mean age was 65.03 years and 25 patients (37.8%) died before discharge. Of the 68 nonseptic patients, 47 were male (69.1%), the mean age was 64.92 years and 25 (36.7%) died before discharge. Epigenetic age calculated using the PhenoAge algorithm showed a significant age acceleration of 4.97 years in septic patients (p = 0.045), but no significant acceleration in nonseptic patients. Epigenetic age calculated using the Hannum algorithm showed no significant acceleration in the septic or nonseptic patients. Similarly, in the combined septic and nonseptic cohorts, nonsurvivors showed an epigenetic age acceleration of 7.62 years (p = 0.004) using the PhenoAge algorithm while survivors showed no significant age acceleration. Survivor status was not associated with age acceleration using the Hannum algorithm. CONCLUSIONS: In critically ill patients, epigenetic age acceleration, as calculated by the PhenoAge algorithm, was associated with sepsis diagnosis and mortality.

Modelling the potential increase in eligible participants in clinical trials with inclusion of community intensive care unit patients in Alberta, Canada: a decision tree analysis.

PURPOSE: Critical care research in Canada is conducted primarily in academically affiliated intensive care units (ICUs) with established research infrastructure. Efforts are made to engage community hospital ICUs in research, although the impacts of their inclusion in clinical research have never been explicitly quantified. We therefore sought to determine the number of additional eligible patients that could be recruited into critical care trials and the change in time to study completion if community ICUs were included in clinical research. METHODS: We conducted a decision tree analysis using 2018 Alberta Health Services data. Patient demographics and clinical characteristics for all ICU patients were compared against eligibility criteria from ten landmark, randomized, multicentre critical care trials. Individual patients from academic and community ICUs were assessed for eligibility in each of the ten studies, and decision tree analysis models were built based on prior inclusion and exclusion criteria from those trials. RESULTS: The number of potentially eligible patients for the ten trials ranged from 2,082 to 10,157. Potentially eligible participants from community ICUs accounted for 40.0% of total potentially eligible participants. The recruitment of community ICU patients in trials would have increased potential enrolment by an average of 64.0%. The inclusion of community ICU patients was predicted to decrease time to trial completion by a mean of 14 months (43% reduction). CONCLUSION: Inclusion of community ICU patients in critical care research trials has the potential to substantially increase enrolment and decrease time to trial completion.

RéSUMé: OBJECTIF: La recherche en soins intensifs au Canada est principalement réalisée dans des unités de soins intensifs affiliées à des centres universitaires jouissant d'infrastructures de recherche bien établies. Des efforts ont été déployés pour engager les unités de soins intensifs des hôpitaux communautaires en recherche, mais les impacts de leur participation à la recherche clinique n'ont jamais été explicitement quantifiés. Nous avons conséquemment cherché à déterminer le nombre de patient·es additionnel·les pouvant être recruté·es dans des études de soins critiques ainsi que la variation du temps nécessaire pour compléter les études si la patientèle issue d'unités de soins intensifs d'hôpitaux communautaires participait à la recherche clinique. MéTHODE: Une analyse par arbre de décision a été réalisée à partir de données provenant des Alberta Health Services pour l'année 2018. Les données démographiques et les caractéristiques cliniques de tou·tes les patient·es admis·es aux soins intensifs ont été comparées avec les critères d'éligibilité de dix importantes études multicentriques, randomisées, contrôlées en soins intensifs. Les patient·es des unités de soins intensifs universitaires et communautaires ont tou·tes été évalué·es pour leur éligibilité à chacune des dix études, et des modèles d'arbres décisionnels ont été construits en se basant sur les critères originaux d'inclusion et d'exclusion. RéSULTATS: Le nombre de personnes potentiellement éligibles pour les dix études s'est situé entre 2082 et 10 157. Les patient·es potentiellement admissibles en provenance d'unités de soins intensifs communautaires ont représenté 40,0 % de toutes les personnes potentiellement admissibles. Le recrutement de patient·es en provenance d'unités de soins intensifs communautaires aurait permis une hausse moyenne du recrutement potentiel de 64,0 %. L'inclusion de patient·es des unités de soins intensifs communautaires pourrait également réduire le temps nécessaire à la complétion des études de 14 mois en moyenne (réduction de 43 %). CONCLUSION: L'inclusion de patient·es en provenance d'unités de soins intensifs d'hôpitaux communautaires dans la recherche clinique en soins critiques a le potentiel d'augmenter substantiellement le recrutement et de diminuer le temps nécessaire à la complétion des études.

Small-Volume Blood Collection Tubes to Reduce Transfusions in Intensive Care: The STRATUS Randomized Clinical Trial.

Importance: Blood collection for laboratory testing in intensive care unit (ICU) patients is a modifiable contributor to anemia and red blood cell (RBC) transfusion. Most blood withdrawn is not required for analysis and is discarded. Objective: To determine whether transitioning from standard-volume to small-volume vacuum tubes for blood collection in ICUs reduces RBC transfusion without compromising laboratory testing procedures. Design, Setting, and Participants: Stepped-wedge cluster randomized trial in 25 adult medical-surgical ICUs in Canada (February 5, 2019 to January 21, 2021). Interventions: ICUs were randomized to transition from standard-volume (n = 10 940) to small-volume tubes (n = 10 261) for laboratory testing. Main Outcomes and Measures: The primary outcome was RBC transfusion (units per patient per ICU stay). Secondary outcomes were patients receiving at least 1 RBC transfusion, hemoglobin decrease during ICU stay (adjusted for RBC transfusion), specimens with insufficient volume for testing, length of stay in the ICU and hospital, and mortality in the ICU and hospital. The primary analysis included patients admitted for 48 hours or more, excluding those admitted during a 5.5-month COVID-19-related trial hiatus. Results: In the primary analysis of 21 201 patients (mean age, 63.5 years; 39.9% female), which excluded 6210 patients admitted during the early COVID-19 pandemic, there was no significant difference in RBC units per patient per ICU stay (relative risk [RR], 0.91 [95% CI, 0.79 to 1.05]; P = .19; absolute reduction of 7.24 RBC units/100 patients per ICU stay [95% CI, -3.28 to 19.44]). In a prespecified secondary analysis (n = 27 411 patients), RBC units per patient per ICU stay decreased after transition from standard-volume to small-volume tubes (RR, 0.88 [95% CI, 0.77 to 1.00]; P = .04; absolute reduction of 9.84 RBC units/100 patients per ICU stay [95% CI, 0.24 to 20.76]). Median decrease in transfusion-adjusted hemoglobin was not statistically different in the primary population (mean difference, 0.10 g/dL [95% CI, -0.04 to 0.23]) and lower in the secondary population (mean difference, 0.17 g/dL [95% CI, 0.05 to 0.29]). Specimens with insufficient quantity for analysis were rare (≤0.03%) before and after transition. Conclusions and Relevance: Use of small-volume blood collection tubes in the ICU may decrease RBC transfusions without affecting laboratory analysis. Trial Registration: ClinicalTrials.gov Identifier: NCT03578419.

Characterizing Risk Factors for Hospitalization and Clinical Characteristics in a Cohort of COVID-19 Patients Enrolled in the GENCOV Study.

The GENCOV study aims to identify patient factors which affect COVID-19 severity and outcomes. Here, we aimed to evaluate patient characteristics, acute symptoms and their persistence, and associations with hospitalization. Participants were recruited at hospital sites across the Greater Toronto Area in Ontario, Canada. Patient-reported demographics, medical history, and COVID-19 symptoms and complications were collected through an intake survey. Regression analyses were performed to identify associations with outcomes including hospitalization and COVID-19 symptoms. In total, 966 responses were obtained from 1106 eligible participants (87% response rate) between November 2020 and May 2022. Increasing continuous age (aOR: 1.05 [95%CI: 1.01-1.08]) and BMI (aOR: 1.17 [95%CI: 1.10-1.24]), non-White/European ethnicity (aOR: 2.72 [95%CI: 1.22-6.05]), hypertension (aOR: 2.78 [95%CI: 1.22-6.34]), and infection by viral variants (aOR: 5.43 [95%CI: 1.45-20.34]) were identified as risk factors for hospitalization. Several symptoms including shortness of breath and fever were found to be more common among inpatients and tended to persist for longer durations following acute illness. Sex, age, ethnicity, BMI, vaccination status, viral strain, and underlying health conditions were associated with developing and having persistent symptoms. By improving our understanding of risk factors for severe COVID-19, our findings may guide COVID-19 patient management strategies by enabling more efficient clinical decision making.

Proton pump inhibitors in critically ill mechanically ventilated patients with COVID-19: protocol for a substudy of the Re-EValuating the Inhibition of Stress Erosions (REVISE) Trial.

BACKGROUND: Critically ill patients commonly receive proton pump inhibitors (PPIs) to prevent gastrointestinal (GI) bleeding from stress-induced ulceration. Despite widespread use in the intensive care unit (ICU), observational data suggest that PPIs may be associated with adverse outcomes in patients with COVID-19 infection. This preplanned study is nested within a large randomized trial evaluating pantoprazole versus placebo in invasively ventilated patients. The 3 objectives are as follows: (1) to describe the characteristics of patients with COVID-19 in terms of demographics, biomarkers, venous thromboembolism, tracheostomy incidence and timing, and other clinical outcomes; (2) to evaluate the impact of COVID-19 infection on clinically important GI bleeding, 90-day mortality, and other outcomes compared to a propensity-matched non-infected cohort; and (3) to explore whether pantoprazole has a differential treatment effect on clinically important GI bleeding, 90-day mortality, and other outcomes in patients with and without COVID-19 infection. METHODS: The ongoing trial Re-EValuating the Inhibition of Stress Erosions (REVISE) compares pantoprazole 40 mg IV to placebo on the primary efficacy outcome of clinically important GI bleeding and the primary safety outcome of 90-day mortality. The protocol described in this report is for a substudy focused on patients with COVID-19 infection that was not in the original pre-pandemic trial protocol. We developed a one-page case report form to characterize these patients including data related to biomarkers, venous thromboembolism, COVID-19 therapies, tracheostomy incidence and timing, duration of mechanical ventilation, and ICU and hospital stay. Our analysis will describe the trajectory of patients with COVID-19 infection, a propensity-matched analysis of infected and non-infected patients, and an extended subgroup analysis comparing the effect of PPI among patients with and without COVID-19 infection. DISCUSSION: Prophylactic acid suppression in invasively ventilated critically ill patients with COVID-19 infection has unknown consequences. The results of these investigations will inform practice, guidelines, and future research. TRIAL REGISTRATION: REVISE Trial [NCT03374800 December 15, 2017], COVID-19 Cohort Study [NCT05715567 February 8, 2023].

Time required to initiate a clinical trial in Canada at the onset of the COVID-19 pandemic: an observational research-in-motion study.

BACKGROUND: Randomized controlled trials (RCTs) provide essential evidence to inform practice, but the many necessary steps result in lengthy times to initiation, which is problematic in the case of rapidly emerging infections such as COVID-19. This study aimed to describe the start-up timelines for the Canadian Treatments for COVID-19 (CATCO) RCT. METHODS: We surveyed hospitals participating in CATCO and ethics submission sites using a structured data abstraction form. We measured durations from protocol receipt to site activation and to first patient enrolment, as well as durations of administrative processes, including research ethics board (REB) approval, contract execution and lead times between approvals to site activation. RESULTS: All 48 hospitals (26 academic, 22 community) and 4 ethics submission sites responded. The median time from protocol receipt to trial initiation was 111 days (interquartile range [IQR] 39-189 d, range 15-412 d). The median time between protocol receipt and REB submission was 41 days (IQR 10-56 d, range 4-195 d), from REB submission to approval, 4.5 days (IQR 1-12 d, range 0-169 d), from REB approval to site activation, 35 days (IQR 22-103 d, range 0-169 d), from protocol receipt to contract submission, 42 days (IQR 20-51 d, range 4-237 d), from contract submission to full contract execution, 24 days (IQR 15-58 d, range 5-164 d) and from contract execution to site activation, 10 days (IQR 6-27 d, range 0-216 d). Processes took longer in community hospitals than in academic hospitals. INTERPRETATION: The time required to initiate RCTs in Canada was lengthy and varied among sites. Adoption of template clinical trial agreements, greater harmonization or central coordination of ethics submissions, and long-term funding of platform trials that engage academic and community hospitals are potential solutions to improve trial start-up efficiency.

Public knowledge of SARS-CoV-2 serological and viral lineage laboratory testing and result interpretation: A GENCOV study cross-sectional survey.

OBJECTIVES: Concepts related to SARS-CoV-2 laboratory testing and result interpretation can be challenging to understand. A cross-sectional survey of COVID-19 positive adults residing in Ontario, Canada was conducted to explore how well people understand SARS-CoV-2 laboratory tests and their associated results. DESIGN AND METHODS: Participants were recruited through fliers or by prospective recruitment of outpatients and hospitalized inpatients with COVID-19. Enrolled participants included consenting adults with a positive SARS-CoV-2 polymerase chain reaction test result. An 11-item questionnaire was developed by researchers, nurses, and physicians in the study team and was administered online between April 2021 to May 2022 upon enrolment into the study. RESULTS: Responses were obtained from 940 of 1106 eligible participants (85% participation rate). Most respondents understood 1) that antibody results should not influence adherence to social distancing measures (n = 602/888, 68%), 2) asymptomatic SARS-CoV-2 infection following test positivity (n = 698/888, 79%), 3) serological test sensitivity in relation to post-infection timeline (n = 540/891, 61%), and 4) limitations of experts' knowledge related to SARS-CoV-2 serology (n = 693/887, 78%). Conversely, respondents demonstrated challenges understanding 1) conflicting molecular and serological test results and their relationship with immune protection (n = 162/893, 18%) and 2) the impact of SARS-CoV-2 variants on vaccine effectiveness (n = 235/891, 26%). Analysis of responses stratified by sociodemographic variables identified that respondents who were either: 1) female, 2) more educated, 3) aged 18-44, 4) from a high-income household, or 5) healthcare workers responded expectedly more often. CONCLUSIONS: We have highlighted concepts related to SARS-CoV-2 laboratory tests and associated results which may be challenging to understand. The findings of this study enable us to identify 1) misconceptions related to various SARS-CoV-2 test results, 2) groups of individuals at risk, and 3) strategies to improve people's understanding of their test results.

Measuring healthy ageing: current and future tools.

Human ageing is a complex, multifactorial process characterised by physiological damage, increased risk of age-related diseases and inevitable functional deterioration. As the population of the world grows older, placing significant strain on social and healthcare resources, there is a growing need to identify reliable and easy-to-employ markers of healthy ageing for early detection of ageing trajectories and disease risk. Such markers would allow for the targeted implementation of strategies or treatments that can lessen suffering, disability, and dependence in old age. In this review, we summarise the healthy ageing scores reported in the literature, with a focus on the past 5 years, and compare and contrast the variables employed. The use of approaches to determine biological age, molecular biomarkers, ageing trajectories, and multi-omics ageing scores are reviewed. We conclude that the ideal healthy ageing score is multisystemic and able to encompass all of the potential alterations associated with ageing. It should also be longitudinal and able to accurately predict ageing complications at an early stage in order to maximize the chances of successful early intervention.

How can we modulate aging through nutrition and physical exercise? An epigenetic approach.

The World Health Organization predicts that by 2050, 2.1 billion people worldwide will be over 60 years old, a drastic increase from only 1 billion in 2019. Considering these numbers, strategies to ensure an extended "healthspan" or healthy longevity are urgently needed. The present study approaches the promotion of healthspan from an epigenetic perspective. Epigenetic phenomena are modifiable in response to an individual's environmental exposures, and therefore link an individual's environment to their gene expression pattern. Epigenetic studies demonstrate that aging is associated with decondensation of the chromatin, leading to an altered heterochromatin structure, which promotes the accumulation of errors. In this review, we describe how aging impacts epigenetics and how nutrition and physical exercise can positively impact the aging process, from an epigenetic point of view. Canonical histones are replaced by histone variants, concomitant with an increase in histone post-translational modifications. A slight increase in DNA methylation at promoters has been observed, which represses transcription of previously active genes, in parallel with global genome hypomethylation. Aging is also associated with deregulation of gene expression - usually provided by non-coding RNAs - leading to both the repression of previously transcribed genes and to the transcription of previously repressed genes. Age-associated epigenetic events are less common in individuals with a healthy lifestyle, including balanced nutrition, caloric restriction and physical exercise. Healthy aging is associated with more tightly condensed chromatin, fewer PTMs and greater regulation by ncRNAs.

Genome screening, reporting, and genetic counseling for healthy populations.

Rapid advancements of genome sequencing (GS) technologies have enhanced our understanding of the relationship between genes and human disease. To incorporate genomic information into the practice of medicine, new processes for the analysis, reporting, and communication of GS data are needed. Blood samples were collected from adults with a PCR-confirmed SARS-CoV-2 (COVID-19) diagnosis (target N = 1500). GS was performed. Data were filtered and analyzed using custom pipelines and gene panels. We developed unique patient-facing materials, including an online intake survey, group counseling presentation, and consultation letters in addition to a comprehensive GS report. The final report includes results generated from GS data: (1) monogenic disease risks; (2) carrier status; (3) pharmacogenomic variants; (4) polygenic risk scores for common conditions; (5) HLA genotype; (6) genetic ancestry; (7) blood group; and, (8) COVID-19 viral lineage. Participants complete pre-test genetic counseling and confirm preferences for secondary findings before receiving results. Counseling and referrals are initiated for clinically significant findings. We developed a genetic counseling, reporting, and return of results framework that integrates GS information across multiple areas of human health, presenting possibilities for the clinical application of comprehensive GS data in healthy individuals.

Academic and Community ICUs Participating in a Critical Care Randomized Trial: A Comparison of Patient Characteristics and Trial Metrics.

Clinical research in Canada is conducted primarily in "academic" hospitals, whereas most clinical care is provided in "community" hospitals. The objective of this nested observational study was to compare patient characteristics, outcomes, process-of-care variables, and trial metrics for patients enrolled in a large randomized controlled trial who were admitted to academic and community hospitals in Canada. DESIGN: We conducted a preplanned observational study nested within the Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT, a randomized controlled trial comparing probiotics to placebo in mechanically ventilated patients) Research Program. SETTING: ICUs. PATIENTS: Mechanically ventilated patients. MEASUREMENTS: We compared patient characteristics, interventions, outcomes, and trial metrics between patients enrolled in PROSPECT from academic and community hospitals. MAIN RESULTS: Participating centers included 34 (82.9%) academic and seven (17.1%) community hospitals, which enrolled 2,203 (86.2%) and 352 (13.8%) patients, respectively. Compared with academic hospitals, patients enrolled in community hospitals were older (mean [sd] 62.7 yr [14.9 yr] vs 59.5 yr [16.4 yr]; p = 0.044), had longer ICU stays (median [interquartile range {IQR}], 13 d [8-23 d] vs 11 d [7-8 d]; p = 0.012) and higher mortality (percentage, [95% CI] in the ICU, 30.4% [25.8-35.4%]vs 20.5% [18.9-11.3%]; p = 0.002) and hospital (40.6% [35.6-45.8%] vs 26.1% [24.3-27.9%]; p < 0.001). Trial metrics, including informed consent rate (85.9% vs 76.3%; p = 0.149), mean (sd) monthly enrolment rate (2.1 [1.4] vs 1.1 [0.7]; p = 0.119), and protocol adherence (90.6% vs 91.6%; p = 0.207), were similar between community and academic ICUs. CONCLUSIONS: Community hospitals can conduct high-quality research, with similar trial metrics to academic hospitals. Patient characteristics differed between community and academic hospitals, highlighting the need for broader engagement of community hospitals in clinical research to ensure generalizability of study results.

Wellness and Coping of Physicians Who Worked in ICUs During the Pandemic: A Multicenter Cross-Sectional North American Survey.

OBJECTIVES: Few surveys have focused on physician moral distress, burnout, and professional fulfilment. We assessed physician wellness and coping during the COVID-19 pandemic. DESIGN: Cross-sectional survey using four validated instruments. SETTING: Sixty-two sites in Canada and the United States. SUBJECTS: Attending physicians (adult, pediatric; intensivist, nonintensivist) who worked in North American ICUs. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We analysed 431 questionnaires (43.3% response rate) from 25 states and eight provinces. Respondents were predominantly male (229 [55.6%]) and in practice for 11.8 ± 9.8 years. Compared with prepandemic, respondents reported significant intrapandemic increases in days worked/mo, ICU bed occupancy, and self-reported moral distress (240 [56.9%]) and burnout (259 [63.8%]). Of the 10 top-ranked items that incited moral distress, most pertained to regulatory/organizational ( n = 6) or local/institutional ( n = 2) issues or both ( n = 2). Average moral distress (95.6 ± 66.9), professional fulfilment (6.5 ± 2.1), and burnout scores (3.6 ± 2.0) were moderate with 227 physicians (54.6%) meeting burnout criteria. A significant dose-response existed between COVID-19 patient volume and moral distress scores. Physicians who worked more days/mo and more scheduled in-house nightshifts, especially combined with more unscheduled in-house nightshifts, experienced significantly more moral distress. One in five physicians used at least one maladaptive coping strategy. We identified four coping profiles (active/social, avoidant, mixed/ambivalent, infrequent) that were associated with significant differences across all wellness measures. CONCLUSIONS: Despite moderate intrapandemic moral distress and burnout, physicians experienced moderate professional fulfilment. However, one in five physicians used at least one maladaptive coping strategy. We highlight potentially modifiable factors at individual, institutional, and regulatory levels to enhance physician wellness.

The impact of small-group virtual patient simulator training on perceptions of individual learning process and curricular integration: a multicentre cohort study of nursing and medical students.

BACKGROUND: The COVID-19 pandemic has precipitated rapid changes in medical education to protect students and patients from the risk of infection. Virtual Patient Simulators (VPS) provide a simulated clinical environment in which students can interview and examine a patient, order tests and exams, prioritize interventions, and observe response to therapy, all with minimal risk to themselves and their patients. Like high-fidelity simulators (HFS), VPS are a tool to improve curricular integration. Unlike HFS, VPS require limited infrastructure investment and can be used in low-resource settings. Few studies have examined the impact of VPS training on clinical education. This international, multicenter cohort study was designed to assess the impact of small-group VPS training on individual learning process and curricular integration from the perspective of nursing and medical students. METHODS: We conducted a multi-centre, international cohort study of nursing and medical students. Baseline perceptions of individual learning process and curricular integration were assessed using a 27-item pre-session questionnaire. Students subsequently participated in small-group VPS training sessions lead by a clinical tutor and then completed a 32-item post-session questionnaire, including 25 paired items. Pre- and post-session responses were compared to determine the impact of the small-group VPS experience. RESULTS: Participants included 617 nursing and medical students from 11 institutions in 8 countries. At baseline, nursing students reported greater curricular integration and more clinical and simulation experience than did medical students. After exposure to small-group VPS training, participants reported significant improvements in 5/6 items relating to individual learning process and 7/7 items relating to curricular integration. The impact of the VPS experience was similar amongst nursing and medical students. CONCLUSIONS: In this multi-centre study, perceptions of individual learning process and curricular integration improved after exposure to small-group VPS training. Nursing and medical students showed similar impact. Small-group VPS training is an accessible, low-risk educational strategy that can improve student perceptions of individual learning process and curricular integration.

Motivating factors, barriers and facilitators of participation in COVID-19 clinical research: A cross-sectional survey of Canadian community intensive care units.

Only a small proportion of COVID-19 patients in Canada have been recruited into clinical research studies. One reason is that few community intensive care units (ICUs) in Canada participate in research. The objective of this study was to examine the motivating factors, barriers and facilitators to research participation amongst Canadian community ICU stakeholders. A cross-sectional online survey was distributed between May and November 2020. The survey focused on 6 domains: participant demographics, ICU characteristics, ICU research infrastructure, motivating factors, perceived barriers, and perceived facilitators. Responses were received from 73 community ICU stakeholders, representing 18 ICUs. 7/18 ICUs had a clinical research program. Participants rated their interest in pandemic research at a mean of 5.2 (Standard Deviation [SD] = 1.9) on a 7-point Likert scale from 'not interested' to 'very interested'. The strongest motivating factor for research participation was the belief that research improves clinical care and outcomes. The most significant facilitators of research involvement were the availability of an experienced research coordinator and dedicated external funding to cover start-up costs, while the most significant barriers to research involvement were a lack of start-up funding for a research coordinator and a lack of ICU research experience. Canadian Community ICU stakeholders are interested in participating in pandemic research but lack basic infrastructure, research personnel, research experience and start-up funding. Evolution of a research support model at community hospitals, where most patients receive acute care, may increase research participation and improve the generalizability of funded research in Canada.

Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: a randomized controlled trial.

BACKGROUND: The role of remdesivir in the treatment of patients in hospital with COVID-19 remains ill defined in a global context. The World Health Organization Solidarity randomized controlled trial (RCT) evaluated remdesivir in patients across many countries, with Canada enrolling patients using an expanded data collection format in the Canadian Treatments for COVID-19 (CATCO) trial. We report on the Canadian findings, with additional demographics, characteristics and clinical outcomes, to explore the potential for differential effects across different health care systems. METHODS: We performed an open-label, pragmatic RCT in Canadian hospitals, in conjunction with the Solidarity trial. We randomized patients to 10 days of remdesivir (200 mg intravenously [IV] on day 0, followed by 100 mg IV daily), plus standard care, or standard care alone. The primary outcome was in-hospital mortality. Secondary outcomes included changes in clinical severity, oxygen- and ventilator-free days (at 28 d), incidence of new oxygen or mechanical ventilation use, duration of hospital stay, and adverse event rates. We performed a priori subgroup analyses according to duration of symptoms before enrolment, age, sex and severity of symptoms on presentation. RESULTS: Across 52 Canadian hospitals, we randomized 1282 patients between Aug. 14, 2020, and Apr. 1, 2021, to remdesivir (n = 634) or standard of care (n = 648). Of these, 15 withdrew consent or were still in hospital, for a total sample of 1267 patients. Among patients assigned to receive remdesivir, in-hospital mortality was 18.7%, compared with 22.6% in the standard-of-care arm (relative risk [RR] 0.83 (95% confidence interval [CI] 0.67 to 1.03), and 60-day mortality was 24.8% and 28.2%, respectively (95% CI 0.72 to 1.07). For patients not mechanically ventilated at baseline, the need for mechanical ventilation was 8.0% in those assigned remdesivir, and 15.0% in those receiving standard of care (RR 0.53, 95% CI 0.38 to 0.75). Mean oxygen-free and ventilator-free days at day 28 were 15.9 (± standard deviation [SD] 10.5) and 21.4 (± SD 11.3) in those receiving remdesivir and 14.2 (± SD 11) and 19.5 (± SD 12.3) in those receiving standard of care (p = 0.006 and 0.007, respectively). There was no difference in safety events of new dialysis, change in creatinine, or new hepatic dysfunction between the 2 groups. INTERPRETATION: Remdesivir, when compared with standard of care, has a modest but significant effect on outcomes important to patients and health systems, such as the need for mechanical ventilation. Trial registration: ClinicalTrials.gov, no. NCT04330690.