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Abstract Background In Canada, academic hospitals are the principal drivers of research and medical education, while community hospitals provide patient care to a majority of the population. Benefits of increasing community hospital research include improved patient outcomes and access to research, enhanced staff satisfaction and retention and increased research efficiency and generalizability. While the resources required to build Canadian community hospital research capacity have been identified, strategies for strengthening organizational research culture in these settings are not well defined. This study aimed to understand how research culture is experienced and shaped in Canadian community hospitals to provide strategies for strengthening research culture in these settings. Methods This qualitative descriptive study, as part of a larger study, explored the underlying dimensions of research culture. Participants were purposefully sampled and included healthcare providers, research staff or hospital administrators from community hospitals across Canada, with non-existent, emerging or established research programs. Data were collected via virtual semi-structured interviews and a demographic questionnaire. Interview transcripts were analyzed using reflexive thematic analysis and Schein’s Model of Organizational Culture as a sensitizing framework. Demographic data were analyzed using descriptive statistics. Results A total of 38 participants from 20 Canadian community hospitals described their experiences of research culture illustrating three key themes. As community hospital research programs matured, participants described a shift in research culture whereby research became more embedded in “the way things are done” within the community hospital. Recommended strategies to achieve an embedded culture of research involve: communications; relationship building; mentorship, training and education opportunities; selecting locally relevant studies; and systems-level support. A top-down approach to embedding research culture was contrasted with a bottom-up approach. Conclusions This study described the underlying dimensions of community hospital research culture and targeted strategies for strengthening research culture at different levels of research program maturity. Community hospitals without pre-existing research infrastructure were able to foster a culture of research from the bottom-up by emphasizing the value of embedding research in clinical practice. Although challenging, fostering a culture of research from the bottom-up may be necessary to propel research forward and initiate the process to build research capacity within a community hospital.

Abstract Background Most Canadians receive their care in community hospitals, yet most clinical research is conducted in academic hospitals. This study aims to compare patients with community acquired pneumonia (CAP) treated in academic and community hospitals with respect to their demographics, clinical characteristics, treatments and outcomes. Methods This nested observational cohort substudy of the Community Acquired Pneumonia: Toward InnoVAtive Treatment (CAPTIVATE) trial included 1,329 hospitalized adults with CAP recruited between March 1st, 2018 and September 31st, 2023 from 15 Canadian hospitals. Unadjusted and adjusted analyses for age, sex and co-morbidities using logistic, Cox and censored quantile regressions were conducted. Results Patients in community hospitals were older (mean [SD] 75.0 [15.7] years vs. 68.3 [16.2] years; p

Abstract Background Community hospitals provide the majority of patient care in Canada but traditionally do not participate in clinical research. The disconnect between where most patients receive their health care and where health research is conducted leads to decreased study recruitment, reduced generalizability of study results, and inequitable patient access to novel therapies. A scoping review of the research activities of Ontario’s large community hospitals (LCHs) between 2013 and 2015 reported an annualized output of 266 publications. In the last decade, efforts have been made to engage more community hospitals in research. In this updated scoping review, we provide a snapshot of the research activities of Ontario’s LCHs between 2016 and 2022, describing the number and type of research publications as well as the frequency of collaboration within and between LCHs. Methods Three medical databases (PubMed, Embase, and CINAHL) were searched for publications that included at least one author affiliated with one of Ontario’s 47 LCHs, and for which the topic was hospital or health related. Screening and extraction occurred concurrently. Results We identified 3,719 publications from 2016 to 22 with at least one Ontario LCH-affiliated author, representing an annualized output of 531 publications. The most frequent publication type was observational study (n = 1,654; 45%), quality improvement (n = 355; 10%), systematic reviews (n = 352; 9%) and randomized controlled trials (n = 325; 9%). The most common disciplines were outpatient care (n = 1,144; 31%), health systems research (n = 806; 22%), inpatient care (n = 437; 12%) and surgery (n = 403; 11%). LCH-affiliated first authors were identified in 997 (27%) publications, representing 755 unique authors, while LCH-affiliated senior authors were identified in 962 (26%) publications, representing 583 unique authors. Among the 1,565 studies with an LCH-affiliated first or senior author, 574 (37%) included collaborators from the same LCH and 86 (5%) included collaborators from other Ontario LCHs. Conclusions Health research by LCH-affiliated clinicians and researchers increased significantly in 2016–2022 relative to 2013–2015. Participation in randomized controlled trials however, remains low, suggesting that further efforts are required to build clinical research infrastructure in LCHs.

Abstract 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].

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.

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.

Abstract 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.

OBJECTIVES:. 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.

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.

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.

Introduction There is considerable variability in symptoms and severity of COVID-19 among patients infected by the SARS-CoV-2 virus. Linking host and virus genome sequence information to antibody response and biological information may identify patient or viral characteristics associated with poor and favourable outcomes. This study aims to (1) identify characteristics of the antibody response that result in maintained immune response and better outcomes, (2) determine the impact of genetic differences on infection severity and immune response, (3) determine the impact of viral lineage on antibody response and patient outcomes and (4) evaluate patient-reported outcomes of receiving host genome, antibody and viral lineage results.Methods and analysis A prospective, observational cohort study is being conducted among adult patients with COVID-19 in the Greater Toronto Area. Blood samples are collected at baseline (during infection) and 1, 6 and 12 months after diagnosis. Serial antibody titres, isotype, antigen target and viral neutralisation will be assessed. Clinical data will be collected from chart reviews and patient surveys. Host genomes and T-cell and B-cell receptors will be sequenced. Viral genomes will be sequenced to identify viral lineage. Regression models will be used to test associations between antibody response, physiological response, genetic markers and patient outcomes. Pathogenic genomic variants related to disease severity, or negative outcomes will be identified and genome wide association will be conducted. Immune repertoire diversity during infection will be correlated with severity of COVID-19 symptoms and human leucocyte antigen-type associated with SARS-CoV-2 infection. Participants can learn their genome sequencing, antibody and viral sequencing results; patient-reported outcomes of receiving this information will be assessed through surveys and qualitative interviews.Ethics and dissemination This study was approved by Clinical Trials Ontario Streamlined Ethics Review System (CTO Project ID: 3302) and the research ethics boards at participating hospitals. Study findings will be disseminated through peer-reviewed publications, conference presentations and end-users.

Abstract Background Breast cancer is a highly heterogeneous disease resulting in diverse clinical behaviours and therapeutic responses. DNA methylation is a major epigenetic alteration that is commonly perturbed in cancers. The aim of this study is to characterize the relationship between DNA methylation and aberrant gene expression in breast cancer. Methods We analysed DNA methylation and gene expression profiles from breast cancer tissue and matched normal tissue in The Cancer Genome Atlas (TCGA). Genome-wide differential methylation analysis and methylation-gene expression correlation was performed. Gene expression changes were subsequently validated in the METABRIC dataset. The Oncoscore tool was used to identify genes that had previously been associated with cancer in the literature. A subset of genes that had not previously been studied in cancer was chosen for further analysis. Results We identified 368 CpGs that were differentially methylated between tumor and normal breast tissue (∆β > 0.4). Hypermethylated CpGs were overrepresented in tumor tissue and were found predominantly (56%) in upstream promoter regions. Conversely, hypomethylated CpG sites were found primarily in the gene body (66%). Expression analysis revealed that 209 of the differentially-methylated CpGs were located in 169 genes that were differently expressed between normal and breast tumor tissue. Methylation-expression correlations were predominantly negative (70%) for promoter CpG sites and positive (74%) for gene body CpG sites. Among these differentially-methylated and differentially-expressed genes, we identified 7 that had not previously been studied in any form of cancer. Three of these, TDRD10, PRAC2 and TMEM132C, contained CpG sites that showed diagnostic and prognostic value in breast cancer, particularly in estrogen-receptor (ER)-positive samples. A pan-cancer analysis confirmed differential expression of these genes together with diagnostic and prognostic value of their respective CpG sites in multiple cancer types. Conclusion We have identified 368 DNA methylation changes that characterize breast cancer tumor tissue, of which 209 are associated with genes that are differentially-expressed in the same samples. Novel DNA methylation markers were identified, of which cg12374721 (PRAC2), cg18081940 (TDRD10) and cg04475027 (TMEM132C) show promise as diagnostic and prognostic markers in breast cancer as well as other cancer types.

Intensive care unit healthcare workers (ICU HCW) are at risk of mental health issues during emerging disease outbreaks. A study of ICU HCW from France revealed symptoms of anxiety and depression in 50.4% and 30.4% of workers at the peak of the first wave of the pandemic. The level of COVID-19 exposure of these ICU HCW was very high. In Canada, ICU HCW experienced variable exposure to COVID-19 during the first wave of the pandemic, with some hospitals seeing large numbers of patients while others saw few or none. In this study we examined the relationship between COVID-19 exposure and mental health in Canadian ICU HCW. We conducted a cross-sectional cohort study of Canadian ICU HCW in April 2020, during the acceleration phase of the first wave of the pandemic. Psychosocial distress was assessed using the 12-item General Health Questionnaire (GHQ-12). Participants were asked about sources of stress as well as about exposure to COVID-19 patients and availability of personal protective equipment (PPE). Factors associated with clinically-relevant psychosocial distress were identified. Responses were received from 310 Canadian ICU HCW affiliated with more than 30 institutions. Of these, 64.5% scored ≥ 3 points on the GHQ-12 questionnaire, indicating clinically-relevant psychosocial distress. The frequency of psychosocial distress was highest amongst registered nurses (75.7%) and lowest amongst physicians (49.4%). It was also higher amongst females (64.9%) than males (47.6%). Although PPE availability was good (> 80% of participants reported adequate availability), there was significant anxiety with respect to PPE availability, with respect to the risk of being infected with COVID-19, and with respect to the risk of transmitting COVID-19 to others. In multivariable regression analysis, Anxiety with respect to being infected with COVID-19 (OR 1.53, CI 1.31-1.81) was the strongest positive predictor of clinically-relevant psychosocial distress while the Number of shifts with COVID-19 exposure (OR 0.86, CI 0.75-0.95) was the strongest negative predictor. In summary, clinically-relevant psychosocial distress was identified amongst a majority of ICU HCW during the acceleration phase of the first wave of the COVID-19 pandemic, including those with minimal or no exposure to COVID-19. Strategies to support mental health amongst ICU HCW are required across the entire healthcare system.