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.
Keywords: academic hospitals, community hospitals, critical care, intensive care, randomized controlled trials
KEY POINTS
Question: Did patient characteristics, interventions, clinical outcomes, and trial metrics differ between academic and community hospitals participating in a multicenter, randomized controlled trial of probiotics?
Findings: Patient characteristics, interventions, and clinical outcomes differed between academic and community hospitals. However, trial metrics, including consent rates, enrolment rates, and protocol adherence, were similar.
Meaning: Research conducted exclusively in academic hospitals may not reflect the clinical reality of community hospitals. There is a need for broader engagement of community hospitals in clinical research to ensure the generalizability of study results.
Clinical research, including research in ICUs, has traditionally been conducted in university-affiliated or “academic” hospitals. However, the majority of Canadian patients receive their care in “community” hospitals, which historically have not participated in clinical research (1, 2). A lack of community hospital participation limits the pool of potential patients that can be recruited into clinical research studies. Furthermore, demographic variables and outcomes may differ between patients cared for in academic and community hospitals, thereby limiting the generalizability of research that is conducted exclusively in academic hospitals.
In Canada, there are 57 teaching or “academic” hospitals, which are affiliated with the 17 medical schools. These hospitals are typically located in major urban centers. All other hospitals are considered nonteaching or “community hospitals,” and are typically located in suburban areas or smaller communities. The geographic differences between academic and community hospitals translate into important socioeconomic and cultural differences in patient populations that may impact social determinants of health. For instance, visible minorities and recent immigrants live disproportionately in suburban areas, which are served by community hospitals (3, 4). Although Canada has universal medical coverage, studies have shown that patients living in suburban and rural areas have less access to certain types of specialized care, such as cancer resection and stroke care, which may also impact health outcomes (5, 6). Finally, academic hospitals are teaching institutions staffed by medical trainees and educators. This may impact patterns of care, including adherence to guidelines and resource utilization.
Recently, the Canadian Critical Care Trials Group and its affiliated investigators have encouraged greater community ICU participation in clinical research studies. One such study was the Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT), a randomized controlled trial that compared probiotics to placebo, showing no effect on preventing ventilator-associated pneumonia (VAP) (7). PROSPECT enrolled patients at 41 Canadian hospitals, of which 34 were academic and seven were community hospitals. The objective of this nested observational study was to compare the patients enrolled in PROSPECT from community and academic hospitals with respect to patient demographics, interventions, and outcomes, and to compare trial metrics, including consent rate, enrolment rate, coenrolment rate, protocol adherence, and adverse events, between community and academic sites.
MATERIALS AND METHODS
This is a preplanned observational study nested within the PROSPECT Research Program (7). In PROSPECT, mechanically ventilated patients 18 years old and older were randomized to receive either 1 × 1010 colony forming units of Lactobacillus rhamnosus GG or an identical placebo, twice daily. The primary outcome was VAP. Secondary outcomes were ICU-acquired infections (including Clostridioides difficile), diarrhea (including antibiotic-associated diarrhea), antimicrobial use, ICU and hospital length of stay, and mortality. Trial participation was open to all interested centers.
All Canadian PROSPECT sites were included in this substudy. Community and academic hospital status was determined according to the Canadian Institute for Health Information classification, which differentiates Canadian hospitals by “teaching status” (8). In Canada, there are 17 medical schools, which are affiliated with 57 “teaching” or academic hospitals. For the purposes of this study, “teaching” hospitals were considered “academic,” while “non-teaching” hospitals were considered “community.”
Study outcomes included patient demographics, interventions, and outcomes as well as trial metrics, including consent rate, enrolment rate, coenrolment rate, protocol adherence, and adverse events. Protocol adherence was defined by the percentage of patients who either: 1) received study product or 2) had a legitimate reason not to receive study product on greater than or equal to 90% of ICU days. A protocol deviation was defined as: 1) a patient received at least one dose of wrong study product, 2) at least one dose was not staggered by 4 hours for Lactobacillus-sensitive oral antibiotic, and 3) at least one dose of open-label probiotic was administered.
Statistical Analysis
Data are reported as mean (sd) or median (interquartile range [IQR]) for continuous variables or number of patients (percentage) for categorical variables. Community and academic hospitals were compared using mixed models, which included hospital as a random effect. Continuous variables were analyzed using linear mixed models. Continuous variables that were not normally distributed were log-transformed. Binary variables were analyzed using logistic mixed models. All statistical tests were two-tailed, and statistical significance was defined as p < 0.05. Statistical sample size calculation was not performed a priori, and sample size was equal to the total number of patients enrolled at Canadian sites in PROSPECT. Post hoc subgroup analysis comparing community and academic hospital patients with respect to the effect of probiotics on the primary outcome of VAP was performed using time-to-event analysis. Cox regression was performed adjusting for medical/surgical/trauma diagnosis and with hospital entered as a random effect. Data analysis was performed using the SAS software, Version 9.4 (SAS Institute, Cary, NC).
Ethical Considerations
PROSPECT trial was approved by the Hamilton Integrated Research Ethics Board (15-322). Initial approval date was on July 13, 2015. Informed consent was obtained from all participants. All procedures were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as most recently amended.
RESULTS
Site Characteristics
The PROSPECT trial enrolled patients at 41 sites across Canada, including 34 academic hospitals (82.9%) and seven community hospitals (17.1%). Canadian patient enrollment totaled 2,555 patients, of whom 2,203 (86.2%) were enrolled in academic ICUs and 352 (13.8%) in community ICUs (9). Site characteristics are found in Table 1 and Appendix 1 (http://links.lww.com/CCX/B86). Mean enrollment at academic sites was 57 (sd = 65) and at community sites was 50 (sd = 41).
TABLE 1.
Summary of Site Characteristics of Participating Academic and Community Hospitals by Provinces
| Province | Type of Center | N | Census Subdivision Population < 400,000, n (%) | Located in Distant Suburb Zone, n (%) | Antibiotic Stewardship Program | ||
|---|---|---|---|---|---|---|---|
| Mean ICU Beds, n (sd) | Mean Total Enrolment per Sites (sd) | ASP Program (n) | |||||
| British Columbia | Community | 0 | -- | -- | -- | -- | -- |
| Academic | 4 | 2 (50.0) | 2 (50.0) | 22.3 (8.0) | 35.5 (21.7) | 3 | |
| Alberta | Community | 0 | -- | -- | -- | -- | -- |
| Academic | 4 | 0 (0.0) | 0 (0.0) | 27.3 (4.1) | 16.8 (8.2) | 3 | |
| Manitoba | Community | 0 | -- | -- | -- | -- | -- |
| Academic | 2 | 0 (0.0) | 0 (0.0) | 20.0 (9.9) | 7.0 (5.7) | 2 | |
| Ontario | Community | 6 | 4 (66.7) | 2 (33.3) | 18.8 (3.7) | 52.6 (44.4) | 6 |
| Academic | 13 | 1 (7.7) | 1 (7.7) | 25.6 (5.3) | 103.0 (63.3) | 11 | |
| Quebec | Community | 1 | 1 (100.0) | 1 (100.0) | 18 (N/A) | 37 (N/A | 1 |
| Academic | 10 | 1 (10.0) | 1 (10.0) | 34.6 (16.2) | 60.7 (45.5) | 5 | |
| Nova Scotia | Community | 0 | -- | -- | -- | -- | -- |
| Academic | 1 | 0 (0.0) | 0 (0.0) | 21 (N/A) | 36 (N/A) | 1 | |
Patient Characteristics
Patients enrolled in community ICUs were older than those in academic ICUs (mean [sd], 62.7 yr [14.9 yr] vs 59.5 yr [16.4 yr]; p = 0.044), but the proportion of females was similar (40.6% vs 40.2%, respectively; p = 0.925) (Table 2). Admitting diagnostic categories are found in Appendix 2 (http://links.lww.com/CCX/B86). Illness severity at enrollment was similar between community and academic ICUs (Acute Physiology and Chronic Health Evaluation II score, 22.1 [8.6] vs 21.9 [7.7]; p = 0.957); however, patients in community hospitals were more likely to have a medical admission diagnosis (92.3% vs 74.0%; p = 0.007) rather than a surgical or trauma diagnosis (Table 2).
TABLE 2.
Comparison of Baseline Patient Characteristics Between Community and Academic ICUs
| Baseline Patient Characteristics | Community, n = 352 | Academic, n = 2,203 | Total, n = 2,555 | p Adjusted for Center |
|---|---|---|---|---|
| Age, yr, mean (sd) | 62.7 (14.9) | 59.5 (16.4) | 59.9 (16.2) | 0.044 |
| Acute Physiology and Chronic Health Evaluation II, mean (sd) | 22.1 (8.6) | 21.9 (7.7) | 22.0 (7.8) | 0.957 |
| Clinical Frailty Scorea | ||||
| Mean (sd) | 3.7 (1.6) | 3.3 (1.6) | 3.4 (1.6) | 0.230 |
| ≥5, n (%) | 96(27.6) | 350(19.9) | 446 (21.2) | |
| Females, n (%) | 143 (40.6) | 886 (40.2) | 1029 (40.3) | 0.925 |
| Type of patient, number (%)b | ||||
| Medical | 325 (92.3) | 1,631 (74.0) | 1,956 (76.6) | 0.007 |
| Surgical | 26 (7.4) | 242 (11.0) | 268 (10.5) | 0.223 |
| Trauma | 1 (0.3) | 330 (15.0) | 331 (13.0) | 0.017 |
| Days from hospital admission to ICU admission, median (interquartile range) | 0 (0–1) | 0 (0–1) | 0 (0–1) | 0.425c |
aTotal n = 2,103, community sites n = 348 and academic sites n = 1,755.
bp values correspond to medical vs not medical, surgical vs not surgical, and trauma vs not trauma.
cUsing Poisson regression.
Interventions: Life Supports and Medical Therapies
The proportion of patients receiving inotropes or vasopressors (59.1% vs 60.8%; p = 0.402) and renal replacement therapy (7.4% vs 8.3%; p = 0.712) at study enrollment was similar between community and academic ICUs (Table 3). However, the duration of mechanical ventilation was longer in community ICUs (median [IQR], 8 d [4–16 d] vs 7 d [3–12 d]); p = 0.037) (Table 3).
TABLE 3.
Comparison of Interventions Between Community and Academic ICUs
| Interventions | Community, n = 352 | Academic, n = 2,203 | Total, n = 2,555 | p Adjusted for Center |
|---|---|---|---|---|
| On study day 1 | ||||
| Invasive mechanical ventilation, n (%)# | 352 (100.0) | 2,203 (100.0) | 2,555 (100.0) | - |
| Inotropes or vasopressors, n (%) | 208 (59.1) | 1340 (60.8) | 1548 (60.6) | 0.402 |
| Dialysis/renal replacement, n (%) | 26 (7.4) | 183 (8.3) | 209 (8.2) | 0.712 |
| At any time during study enrollment | ||||
| Dialysis/renal replacement, n (%) | 60 (17.0) | 306 (13.9) | 366 (14.3) | 0.178 |
| Duration of mechanical ventilation in days | ||||
| Median (Q1–Q3) | 8 (4–16) | 7 (3–12) | 7 (4–13) | 0.037† |
| Total range | 1–60 | 1–60 | 1–60 | |
#Invasive mechanical ventilation is an inclusion criteria.
†Using the log-transformed variable.
Antimicrobial use data were collected for 2,283 patients, totaling 31,059 patient days. Days of therapy per 1,000 patient-days, defined as daily dose per 1,000 patient-days and antimicrobial-free days per 1,000 patient-days, were similar between community and academic ICUs (Table 4). During the trial, antimicrobial stewardship programs were in place in seven of seven (100%) community ICUs and in 25 of 34 (73.5%) academic ICUs (Table 1).
TABLE 4.
Comparison of Antimicrobial Metrics Between Community and Academic ICUs
| Antimicrobial Metrics | Community, n = 352 | Academic, n = 1,931 | Total, n = 2,283 | p Adjusted for Center |
|---|---|---|---|---|
| Antibiotics, antifungals, and antivirals | ||||
| Days of therapy per 1,000 patient-days in ICU | 1,280.6 | 1,287.1 | 1,285.9 | 0.326a |
| Antimicrobial-free days per 1,000 patient-days in ICU | 290.4 | 288.2 | 288.6 | 0.994a |
| Defined daily dose per 1,000 patient-days in ICU | 1,668.4 | 1,806.3 | 1,780.5 | 0.333a |
aUsing the square root transformed variable.
Clinical Outcomes
The median duration of ICU stay was longer for patients enrolled in community ICUs (13 d [8–23 d]) compared with academic ICUs (11 d [7–18 d]); p = 0.012, whereas the median duration of hospital stay was similar. However, mortality was significantly higher in community hospitals, both in the ICU (30.4% [25.8–35.4%] vs 20.5% [18.9–11.3%]; p = 0.002) and in hospital (40.6% [35.6–45.8%] vs 26.1% [24.3–27.9%]; p < 0.001) (Table 5). The incidence of VAP and C. difficile infection was similar between community and academic ICUs (Table 5).
TABLE 5.
Comparison of Clinical Outcomes of Community and Academic ICUs
| Clinical Outcomes | Community, n = 352 | Academic, n = 2,203 | Total, n = 2,555 | p Adjusted for Center |
|---|---|---|---|---|
| Incident of ventilator-associated pneumonia, n (%) | 83 (23.6) | 474 (21.5) | 557 (21.8) | 0.882 |
| Incident of Clostridioides difficile infection, number of patients (%) | 4 (1.1) | 51 (2.3) | 55 (2.2) | 0.231 |
| Duration of ICU stay in days | ||||
| Median (Q1–Q3) | 13 (8–23) | 11 (7–18) | 12 (7–19) | 0.012a |
| Total range | 2–447 | 1–346 | 1–447 | |
| Duration of hospital stay in days | ||||
| Median (Q1–Q3) | 22 (12–42.5) | 22 (13–40) | 22 (13–40) | 0.726a |
| Total range | 3–630 | 1–493 | 1–630 | |
| Death in ICU, n (%), 95% CI | 107 (30.4), 25.8–35.4 | 452 (20.5), 18.9–22.3 | 559 (21.9) | 0.002 |
| Death in hospital, n (%), 95% CI | 143 (40.6), 35.6–45.8 | 574 (26.1), 24.3–27.9 | 717 (28.1) | <0.001 |
| AEs, n (%) | 2 (0.6) | 12 (0.5) | 14 (0.5) | 0.835 |
| SAEs, n (%) | 0 (0.0) | 2 (0.1) | 2 (0.1) | - |
| AE/SAE, n (%) | 2 (0.6) | 14 (0.6) | 16 (0.6) | 0.957 |
AE = adverse event, SAE = serious adverse events.
aUsing the log-transformed variable.
With respect to the primary outcome of the PROSPECT trial, a post hoc subgroup analysis by hospital status showed no difference in the treatment effect of probiotics on VAP between academic and community ICUs (test for interaction p value 0.0.575; Appendix 3, http://links.lww.com/CCX/B86).
Adverse Events and Serious Adverse Events
Adverse events were uncommon in PROSPECT, and no difference was noted between community and academic ICUs (Table 5). Serious adverse events related to isolation of L. rhamnosus GG from a sterile site (or as the predominant organism in a nonsterile site) were found in 0 instances in community ICUs and in two instances (0.1% patients) in academic ICUs (Table 5).
Trial Metrics
The informed consent rate was similar between community ICUs (85.9%) and academic ICUs (76.3%) (p = 0.149) (Table 6). The mean [sd] monthly enrolment rate for this trial (enrolments per month indexed to a 15-bed ICU) was similar in community ICUs (2.1 [1.4]) and academic ICUs (1.1 [0.7]) (p = 0.119). The percentage of patients coenrolled in other studies was similar between (8.0% in community ICUs vs 23.1% in academic ICUs; p = 0.061) (Table 6).
TABLE 6.
Comparisons of Trial Metrics Between Community and Academic ICUs
| Trial Metrics | Community, n = 352 | Academic, n = 2203 | Total, n = 2555 | p Adjusted for Center |
|---|---|---|---|---|
| Total approached for consent, n | 410 | 2,888 | 3,298 | |
| Informed consent obtained, n | 352 | 2203 | 2,555 | |
| Consent rate (%) | 85.9 | 76.3 | 77.5 | 0.149 |
| Monthly enrollment per 15-bed ICU, mean (sd) | 2.1 (1.4) | 1.1 (0.7) | 1.3 (0.9) | 0.119a |
| Coenrolled, n (%) | 28 (8.0) | 508 (23.1) | 536 (21.0) | 0.061 |
| Protocol adherence | ||||
| Either a) received study product or b) had a legitimate reason not to receive study product on ≥90% of ICU days, n (%) | 319 (90.6) | 2,019 (91.6) | 2,338 (91.5) | 0.207 |
| Received at least one dose of study product, n (%) | 348 (98.9) | 2,187 (99.3) | 2,535 (99.2) | 0.422 |
| No protocol violationb, n (%) | 318 (90.3) | 2,052 (93.1) | 2,370 (92.8) | 0.232 |
aCenter is the unit of analysis for month enrollment; therefore, a t test was performed without adjustment for center.
bNo protocol violation refers to patients who experienced none of the following: 1) received dose(s) of wrong study product, 2) received dose(s) not staggered by 4 hr when concurrently receiving a Lactobacillus-sensitive oral antibiotic, and 3) received dose(s) of open label probiotic.
Protocol adherence was similar between community and academic ICUs (90.6% vs 91.6%; p = 0.207), and there was no difference in the percentage of patients without protocol violations (318 [90.3%] vs 2,052 [93.1%]; p = 0.232) (Table 6).
Interpretation
In this large, multicenter, randomized controlled trial of probiotics versus placebo for mechanically ventilated patients, we identified key differences between patients enrolled in academic and community ICUs that may affect the generalizability of results when trials were enrolled exclusively in academic hospitals. Patients recruited from community ICUs were, on average, older and more likely to have a medical admission diagnosis. Severity of illness and frequency of life support interventions (vasopressor and renal replacement therapy) were similar; however, the duration of mechanical ventilation, duration of ICU stay, and ICU and hospital mortality were higher among patients enrolled in community ICUs.
These findings have important implications for clinical trials as differences in patient characteristics, and outcomes may affect the efficacy of trial interventions. To ensure that trial results are generalizable, it is essential that enrolled populations resemble as closely as possible the eventual treatment population, by involving as broad a range of practice settings as possible. Depending on the characteristics of the patients and interventions being evaluated, investigators may want to consider subgroup analyses to explore the risk-benefit ratio of tested interventions in academic and community ICU populations.
The mortality difference observed between academic and community hospital patients in the present study is likely multifactorial. All of the community hospital ICUs that participated in PROSPECT were designated level 3 ICUs, caring for mechanically ventilated patients and run by specialist intensivists. Adjudicated rates of VAP and C. difficile infection were similar between academic and community ICUs, two important quality of care markers. However, there may have been differences in care processes between community and academic hospitals that were not adequately captured in this dataset. In addition, there may have been demographic differences between patients in academic and community hospitals that impact health outcomes but that were not captured in this study, including race, ethnicity, and socioeconomic status. For example, visible minority and recent immigrant populations are concentrated in suburban areas in Canada, which are primarily served by community hospitals (3, 4). This is not the first study to report a mortality difference between patients in community and academic hospitals in Canada. A recent study of out-of-hospital cardiac arrest patients reported higher mortality among patients admitted to non-teaching (community) hospitals relative to teaching (academic) hospitals (10). Mortality differences between teaching, minor-teaching and non-teaching hospitals have also been reported in the United States (11) as have mortality differences between hospitals that participate in research and those that do not, even when adjusted for teaching status (12, 13). Further studies will be required to elucidate the reasons for these important outcome differences, which may be complex.
Another key finding of this study was that trial metrics, including informed consent rate and enrollment rate, were similar between community ICUs and academic ICUs. Successful completion of randomized controlled trials depends upon efficiently screening patients and obtaining informed consent. Although community ICUs typically have less research experience than academic ICUs, their research teams were able to achieve similar recruitment rates. The high consent rate also indicates that patients in community ICUs were open to participating in clinical research. Recruitment in community ICUs may also be facilitated by the presence of fewer competing studies, leading to a more focused approach to a consent encounter.
Protocol adherence in PROSPECT was similar between community and academic centers. Protocol nonadherence can increase the risk of bias as well as diminish the feasibility of clinical trials (14, 17). The high level of protocol adherence confirms that community ICU participation is feasible and can augment recruitment without compromising trial quality. Furthermore, we found no difference in the rate of adverse events and serious adverse events between community and academic ICUs, which were very low overall.
The strengths of this study include its preplanned design and large sample size. Data on patient demographics, life supports, and treatments were collected prospectively, as were trial metrics and adverse events. Our analysis is limited by the nested observational design and the potential for ecological fallacy—that is, although differences between patients enrolled in community versus academic ICUs may reflect differences in populations, they could also reflect differences in patient selection for study enrollment in these centers. Moreover, since the number of community ICUs in PROSPECT was relatively small and there was a lack of rural hospital involvement, the results may not be generalizable to all Canadian community ICUs.
Engaging community ICUs in clinical research has the potential to increase study recruitment and improve the generalizability of study results. The Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial in the United Kingdom is an example of what can be achieved with broad engagement of community hospitals in research. RECOVERY harnessed the infrastructure of the National Institute of Health Research Clinical Research Network to recruit 11,000 patients from 176 hospital trusts in just 3 months, resulting in immediate worldwide practice-change for COVID-19 (16). The engagement of so many community hospitals accelerated recruitment and ensured that the study findings were applicable to a broad range of clinical settings. Our results show that community ICUs can conduct high-quality clinical research with excellent recruitment rates and protocol adherence. The differences observed in patient characteristics and outcomes between community and academic ICUs highlight the need for broader engagement of Canadian community ICUs in clinical research to ensure efficient study completion and generalizability of study results.
ACKNOWLEDGMENTS
We thank the patients and families who participated in this trial, as well as the collaborating Research Coordinators and Investigators, and bedside clinicians who supported this work. The trial was designed by the PROSPECT Steering Committee, the PROSPECT Investigators and Research Coordinators, and the Canadian Critical Care Trials Group. We thank other PROSPECT Methods Center staff for their expertise and data management, including Shelley Anderson-White, Alyson Takaoka, France Clarke, Lori Hand, Megan Davis, Melissa Shears, and Kristine Wachmann.
PARTICIPATING CENTERS
Canada: Alberta—Foothills Medical Centre, University of Calgary, Calgary, AB: Dr. Tom Stelfox (Lead); Dr. Philippe Couillard, Dr. Christopher Doig, and Dr. Ken Parhar (Co-Investigators); Joshua Booth, Cassidy Codan, and Stacy Ruddell (Research Coordinators); Candice Cameron, Rhonda Edison, Anne Martin, and Breanna Mina (Pharmacy). Peter Lougheed Hospital, University of Calgary, Calgary, AB: Dr. Dan Niven (Lead); Dr. Luc Berthiaume and Dr. Jonathan Gaudet (Co-Investigators); Joshua Booth, Cassidy Codan, Gina Fleming, Katie Ross, and Stacy Ruddell (Research Coordinators); and Candice Cameron, Rhonda Edison, Anne Martin, and Breanna Mina (Pharmacy). Royal Alexandra Hospital, Edmonton, AB: Dr. Jim Kutsiogiannis (Lead), Dr. Raiyan Chowdhury, Dr. Jon Davidow, Dr. Curt Johnston, Dr. Richard Johnston, Dr. Kim Macala, Dr. Sam Marcushamer, Dr. Darren Markland, Dr. Doug Matheson, Dr. Damian Paton-Gay, and Dr. David Zygun (Co-Investigators); Nadine Grant, Tayne Hewer, and Pat Thompson (Research Coordinators); Maggie Ge, Janny Hall, and Sharon Matenchuk (Pharmacy). University of Alberta Hospital, Edmonton, AB: Dr. Wendy Sligl (Lead), Dr. Sean Bagshaw (Co-Investigator); Nadia Baig and Lorena McCoshen (Research Coordinators); Katrina Alexandropoulos, Sherri Bain, Michelle Brandt, Cathy Constable, Kari Douglas, Shaleen Maharaj, and Sabrina Travers (Pharmacy). British Columbia—Royal Columbian Hospital, New Westminster, BC: Dr. Steve Reynolds (Lead); Suzette Willems (Research Coordinator); and Tina Sekhon (Pharmacy). St Paul’s Hospital, Vancouver BC: Dr. Peter Dodek (Lead); Dr. Najib Ayas (Co-Investigator); Maria Agda, Victoria Alcuaz, Betty Jean Ashley, Kelsey Brewer, and Janice Palmer (Research Coordinators); and Glen Brown and Mara Pavan (Pharmacy). Vancouver General Hospital, Vancouver, BC: Dr. Bill Henderson (Lead); Dr. Donald Griesdale, and Dr. Mypinder Sekhon (Co-Investigators); Denise Foster and Suzie Logie (Research Coordinators); and Judy Yip (Pharmacy). Vancouver Island Health Authority, Victoria, BC: Dr. Gordon Wood (Lead); Dr. Daniel Ovakim (Co-Investigator); Fiona Auld, Gayle Camey, Ralph Fleming, Jennifer Good, and Mandeep Manhas (Research Coordinators); and Karin Boyd and Jane Dheere (Pharmacy). Manitoba—Health Sciences Centre Winnipeg, Winnipeg, MB: Dr. Ryan Zarychanski (Lead); Dr. Bojan Paunovic (Co-Investigator); Justin Lys and Nicole Marten (Research Coordinators); Audrey Bhairo, Halyna Ferenes, Beata Kozak, Debra Kubin, Dawn-Lee McLaughlin, and Maria Valente (Pharmacy). St Boniface Hospital, Winnipeg, MB: Dr. Ryan Zarychanski (Lead); Dr. Marcus Blouw, Dr. Kendiss Olafson, Dr. Bojan Paunovic, and Dr. Heather Smith (Co-Investigators); Oliver Gutieror; Justin Lys, Nicole Marten, and Sherri Lynn Wingfield (Research Coordinators); Marnie Boyle, Halyna Ferens, Debbie Hrabi, Beata Kozak, Chantal MacDonald, and Julie Muise (Pharmacy). Nova Scotia—Nova Scotia Health Authority QEII, Halifax, NS: Dr. Osama Loubani (Lead); Dr. Rick Hall, and Dr. Robert Green (Co-Investigators); Diana Gillis, Lisa Julien, Laura Lee Magennis, and Tamara Mitterer (Research Coordinators); Joanna Arsenault, Kim Bruce-Payne, and Patti Gallant (Pharmacy). Ontario—Brantford General Hospital, Brantford, ON: Dr. Brenda Reeve (Lead); Karen Bento, Megan Davis, William Dechert, Krista Gallo, Barbara Longo, Courtney Mullen, Elysia Skrzypek, and Laurenne Wierenga (Research Coordinators); Wesam Abuzaiter, Lynda Amorim, Rosemarie Bauer, Rachel Damota, Thoa Ho, Nicole Macdougall, Mary Thornewell, Lara Pe, and Jennifer Visocchi (Pharmacy). Grand River Hospital, Kitchener, ON: Dr. Paul Hosek (Lead); Dr. Bill Plaxton (Co-Investigator); Catherine Armstrong, Rhonda Barber, William Dechert, Janelle Ellis, Kayla Fisk, Melissa Gabnouri, Emilie Gordon, Rebecca Haegens, Lisa Halford, Brooklynn Hillis, Rebecca Jesso, Jenn McLaren, Elliot McMillan, Mariska Pelkmans, Matthew Rekman, Sylvia Sinkovitis, Monica Truong, and Michelle White (Research Coordinators); Noah Bates, Susan Bryden-Cromwell, Lisa Cha, Colleen Cameron, Aminah Deen, Sheri DiGiovanni, Anders Foss, Esther Lee, Heidi MacGregor, Esther Galbraith Robyn McArthur, Julie McGregor, Keith Miller, Sharon Morris, Shelley Parker, Candice Smith, Joanna Stoglow, Jennifer Tung, and Melissa Vos (Pharmacy). Hamilton General Hospital, Hamilton Health Science, Hamilton, ON: Dr. Maureen Meade (Lead); Dr. Emilie Belley-Cote (Co-Investigator) Katrina Fimiani, Lori Hand, Dr. Harjot Jagdey, Lisa Klotz, Alexandra Sabev, and Nevena Savija (Research Coordinators); Deanne Cosentino, Diane Lourenco, Julie Misina, and Gita Sobhi (Pharmacy). Joseph Brant Hospital, Burlington, ON: Dr. Paul Lysecki (Lead); Dr. Joseph Berlingieri, Dr. Sameer Shaikh, and Dr. Steven Skitch (Co-Investigators); Tracy Campbell (Research Coordinator); and Hala Basheer, Kathy Bruder, Jane Cheng, Kaiser Qureshi, and Celeste Thibault (Pharmacy). Juravinski Hospital Hamilton Health Science Centre, Hamilton, ON: Dr. Timothy Karachi (Lead); Dr. Bram Rochwerg (Co-Investigator); Mashari Alghuroba, Alia Khaled, Lauren Locco, Tina Millen, and Ryan Vaisler (Research Coordinators); and Maya Biljan, Deanne Cosentino, Brittany Marriott, and Gita Sobhi (Pharmacy). Kingston General Hospital, Kingston, ON: Dr. John Muscedere (Lead); Dr. Gord Boyd, Dr. Christine D’Arsigny, Dr. John Drover, Dr. Jason Erb, Dr. David Maslove, Dr. Chris Parker, and Dr. Stephanie Sibley (Co-Investigators); Tracy Boyd, Ilinca Georgescu, Miranda Hunt, and Danielle Muscedere (Research Coordinators); and Cathy Baker, Jennifer Engel, Jennifer Fleming, Lisa Roderick, Shelley Silk, Marcy Spencer, and Michelle Tryon (Pharmacy). London Health Sciences Centre—University Hospital, London, ON: Dr. Dave Nagpal (Lead); Dr. Ian Ball (Co-Investigator); Tracey Bentall, and Jessica Sturt-Smith (Research Coordinators); and Michelle Alexander, Tammy Ellis, Mindy Muylaert, and Cindy Paczkowski (Pharmacy). London Health Sciences Centre—Victoria Hospital, London, ON: Dr. Ian Ball (Lead); Eileen Campbell, Susie Imerovski, Athena Ovsenek, and Rebecca Rondinelli (Research Coordinators); and Teresa Longfield, Amy Moyer, Faith Norris, Janice Sumpton, and Karina Teterycz (Pharmacy). Mount Sinai Hospital, Toronto, ON: Dr. Geeta Mehta (Lead); Dr. Stephen Lapinsky and Dr. Laveena Munshi; Maedean Brown, Brittany Giacomino, Marnie Jakab, Alan Kraguljac, Sumesh Shah, Erik Tamberg, and Laura Vergeer (Research Coordinators); Doret Cheng, Gagan Grewal, Andrew Han, Holly Leung, Ioanna Mantas, Hilary Rodrigues, and Andrew Wyllie (Pharmacy). Niagara Health, St Catharines, ON: Dr. Jennifer Ly Tsang (Lead); Dr. Erick Duan (Co-Investigator); Mercedes Carmargo and Beverly Hoekstra (Research Coordinators); and Rita Caporuscio, Rachel Kressner Falvo, Dimitra Fleming, Carmelina Maxwell, and Karmen Plantic (Pharmacy). Ottawa Civic Hospital, Ottawa, ON: Dr. Lauralyn McIntyre (Lead); Dr. Joe Pagilarello (Co-Investigator); Pierre Cardinal, Gianni D’Egidio, Shane English, Mike Hartwick, Jonathon Hooper, Gwynne Jones, John Kim, Dal Kubelik, Kwadwo Kyeremanteng, Hilary Meggison, Sherissa Microys, Dave Neiliovitz, Guiseppe Pagliarello, Rakesh Patel, Jo Po, Peter Reardon, Erin Rosenberg, Aimee Sarti, and Andrew Seely (Co-Investigators); Shelley Acres, Brigette Gomes, Heather Langlois, Liane Leclair, Sydney Miezitis, Kaitlyn Montroy, Rebecca Porteous, Shawna Reddie, and Irene Watpool (Research Coordinators); Wendy Aikens, Marianne Cox, Ann-Marie Dugal, Susan Fetzer, Kathy Fraser, Jennifer Kuhn, Rob MacLeod, Susanne Richard, Dawn Rose, and Sherry Weir (Pharmacy). Ottawa General Hospital, Ottawa, ON: Dr. Lauralyn McIntyre (Lead); Dr. Pierre Cardinal, Dr. Gianni D’Egidio, Dr. Shane English, Dr. Mike Hartwick, Dr. Jonathon Hooper, Dr. Gwynne Jones, Dr. John Kim, Dr. Dal Kubelik, Dr. Kwadwo Kyeremanteng, Dr. Hilary Meggison, Dr. Sherissa Microys, Dr. Dave Neiliovitz, Dr. Guiseppe Pagliarello, Dr. Rakesh Patel, Dr. Jo Po, Dr. Peter Reardon, Dr. Erin Rosenberg, Dr. Aimee Sarti, and Dr. Andrew Seely (Co-Investigators); Shelley Acres, Heather Langlois, Liane Leclair, Sydney Miezitis, Kaitlyn Montroy, Rebecca Porteous, Shawna Reddie, Amanda Van Beinum, Allyshia Van Tol, and Irene Watpool (Research Coordinators); and Wendy Aikens, Anne-Marie Dugal, Susan Fetzer, and Sherry Weir (Pharmacy). St Joseph’s Healthcare, Hamilton, ON: Dr. Deborah Cook (Lead); Dr. Erick Duan and Dr. Mark Soth, (Co-Investigators); France Clarke, Mary Copland; Neala Hoad, Marnie Jakab, Melissa Shears, Alyson Takaoka, and Nicole Zytaruk (Research Coordinators); and Christa Connolly, Denise Davis, Catherine Eaton, Tracy Gallinas, Jean Lee-Yoo, Connie Lukinuk, Leia Musielak, Nancy Pavunkovic, Joy Pelayo, Kaitlyn Phillips, Catherine Pracsovics, Julia Raimondo, Vida Stankus, Christine Wallace, Angela Wright, and Crystal (Pharmacy). Unity Health—St Joseph’s Health Care, Toronto, ON: Dr. Rob Cirone (Lead); Dr. Jennie Johnstone (Co-Investigator); Kanthi Kavikondala, Axelle Pellerin, Laura Tomat (Research Coordinators); and Jeff Carter, Jiten Jani, and Brendan Yeats (Pharmacy). Unity Health—St Michael’s Hospital, Toronto, ON: Dr. John Marshall (Lead); Dr. Jan Friedrich (Co-Investigator); Jennifer Hodder, Imrana Khalid, Julie Lee, Yoon Lee, Pragma Roy, Kurtis Salway, Gyan Sandhu, Marlene Santos, Orla Smith, and Melissa Wang (Research Coordinators); and Norman Dewhurst, Ann Dowbenka, Ann Kosinski, Terri Norrie, Ranjit Parhar, Laura Parsons, Johanna Proceviat, Gitana Ramonas, and Mae Yuen (Pharmacy). Sunnybrook Health Sciences Centre, Toronto, ON: Dr. Neill Adhikari (Lead); Dr. Andre Amaral, Dr. Andre Carlos, Dr. Brian Cuthbertson, Dr. Rob Fowler, and Dr. Damon Scales (Co-Investigators); Navjot Kaur, Nicole Marinoff, Adic Perez, and Jane Wang (Research Coordinators); and Katrina Hatzifilalithis, John Iazzetta, Chrys Kolos, and Ingrid Quinton (Pharmacy). University Health Network, Toronto Western Hospital, Toronto, ON: Dr. Margaret Herridge (Lead); Dr. Alberto Goffi, Dr. Eyal Golan, Dr. John Granton, Dr. Victoria McCredie, Dr. Elizabeth Wilcox (Co-Investigators); Jaimie Archer, Daniel Chen, Paulina Farias, Brooke Fraser, Cheryl Geen-Smith, Barbara Kosky, Andrea Matte, Christina Pugliese, Priscila Robles, Lia Stenyk, Cristian Urrea, and Karolina Walczak (Research Coordinators); and Kyung Ae, Jane Ascroft, Fatima Haji, Rajvinder Kaur, Jane Lui, Sophia Mateo, Nga Pham, Tam Pham, Matthew Suen, and Jennifer Teng (Pharmacy). William Osler Health System—Brampton Civic Hospital Brampton, ON: Dr. Sebastien Trop (Lead); Dr. Alexandra Binnie and Dr. Ronald Heslegrave, (Co-Investigator); Kim Sharman and Zaynab Panchbhaya (Research Coordinators); and Rakhi Goel, Kim Kozluk, Julianne Labelle, Hina Marsonia, and Cecillia Scott (Pharmacy). Québec—Centre hospitalier de l’Université de Montréal, Montréal, QC (3 sites): Dr. Martin Girard (Lead); Dr. Pierre Aslanian, Dr. Sylvain Belisle, Dr. François-Martin Carrier, Dr. Michaël Chassé, Dr. André Denault, Dr. Jean-Gilles Guimond, Dr. Antoine Halwagi, Dr. Paul Hébert, Dr. Christopher Kolan, Dr. Jordi Mancebo, Dr. Nicholas Robillard (Site Co-Investigator); Fatna Benettaib, Dounia Boumahni, Casey Bourdeau Caporuscio, Marie-Ève Cantin, Virginy Côté-Gravel, Ali Ghamraoui, Martine Lebrasseur, Lancelot Legendre Courville, Stéphanie Lorio, Maria Trinidad Madrid, Nicole Poitras, Romain Rigal, Maya Salame, Valérie Tran (Research Coordinators); Katie Bacon, Nathalie Boudreau, Cecilia Carvajal, Lyne Gauthier, Julie Gendron, Karine Jean, Louise Laforest, Antonietta Lembo, Sothun Lim, Jennifer Morrissette, France Pagé, Lucie Pelletier, Marie-Christine Rodrigue (Pharmacy). Centre intégré de santé et de services sociaux de Chaudière-Appalaches (Hôtel-Dieu de Lévis), Lévis, QC: Dr. Patrick Archambault (Lead); Dr. Jean-François Bellemare, Dr. Simon Bordeleau, Dr. Christine Drouin, Dr. Benoît Duhaime, Dr. Ann Laberge, and Dr. Philippe Lachance (Co-Investigators); Mélanie Constantin (Assistant Head Nurse), Robin Roy (Head Nurse), Isabelle Michel (Nurse Educator), Estel Deblois, Maude Dionne, Lise Lavoie, Alexandre Pépin, and Sandrine Poulin (Research Coordinators); and Sarah Anctil, Amélie Chouinard, and Louis-Étienne Marchand (Pharmacy). Centre intégré universitaire de santé et de services sociaux de l’Estrie—Centre hospitalier universitaire de Sherbrooke, Sherbrooke, QC: Dr. François Lamontagne (Lead); Dr. Frédérick D’Aragon, Dr. Charles St-Arnaud, and Dr. Hector Quiroz (Co-Investigator); Virginie Bolduc, Elaine Carbonneau, Joannie Marchand, and Marie-Hélène Masse (Research Coordinators); Sylvie Cloutier, Marianne Guay, Line Morin, Jessie Nicolson, Isabelle Paquette, Patricia Roy, and France Théberge (Pharmacy). Centre intégré universitaire de santé et de services sociaux du Nord-de-l’Île-de-Montréal (Hôpital du Sacré-Cœur de Montréal), Montréal, QC: Dr. Emmanuel Charbonney (Lead); Dr. Yoan Lamarche, Dr. Soazig Leguillan, Dr. Karim Serri, Dr. Colin Verdant, Dr. Yanick Beaulieu, Dr. Patrick Bellemare, Dr. Philippe Bernard, Dr. Marc Giasson, Dr. Véronique Brunette, Dr. Alexandros Cavayas, and Dr. Émilie Lévesque (Co-Investigators); Halina Labikova, Julia Lainer Palacios, Marie-Ève Langlois, and Virginie Williams (Research Coordinators); Thuy Anh Nguyen, Valérie Phaneuf, and Dr. David Williamson (Pharmacy). Centre intégré universitaire de santé et de services sociaux de l’Est-de-l’Île-de-Montréal (Hôpital Maisonneuve-Rosemont), Montréal, QC: Dr. François Marquis (Lead); Dr. Han Tin Wang, Dr. Francis Toupin, Dr. Stephane Ahern, Dr. Brian Laufer, and Dr. Marc Brosseau (Co-Investigators); Pauline Dul, Johanne Harvey, Lotthida Inthanavong, and Danae Tassy (Research Coordinators); Helen Assayag, Maude Bachand, Marysa Betournay, Karine Daoust, Kristine Goyette, Ariane Lessard, and Marceline Quach (Pharmacy). CHU de Québec-Université Laval (Hôpital de l’Enfant-Jésus), Québec City, QC: Dr. François Lauzier (Lead); Dr. Alexis Turgeon (Co-Investigator); Danny Barriault, David Bellemare, Anick Boivin, Sarah-Judith Breton, Ève Cloutier, Marjorie Daigle, Charles Delisle-Thibeault, Panagiota Giannakouros, Stéphanie Grenier, Gabrielle Guilbault, Caroline Léger, Catherine Ouellet, and Marie-Claude Tremblay (Research Coordinators); and Élisabeth Gagne, Julie Gaudreau, Claire Grégoire, Véronique Labbé, Ariane Laprise-Rochette, Caroline Ouellet, Mélanie Samson, Marie-David Simoneau, Virginie Turcotte, and Tuong-Vi Tran (Pharmacy). Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC: Dr. François Lellouche (Lead), Dr. Ying Tung Sia, and Dr. Mathieu Simon (Co-Investigators); Pierre-Alexandre Bouchard and Patricia Lizotte (Research Coordinators); and Nathalie Chateauvert and Thérèse Grenier (Pharmacy). McGill University Health Centre (Montréal General Hospital), Montréal, QC: Dr. Kosar Khwaja (Lead), Dr. Dan Deckelbaum, Dr. Jeremy Grushka, Dr. Ash Gursahaney, Dr. David Hornstein, Dr. Dev Jayaraman, Dr. Tarek Razek, Dr. Robert Salasidis, and Dr. Patrizia Zanelli (Co-Investigators); Norine Alam and Laura Garcia (Research Coordinators); and Tonia Doerksen, Ariane Lessard, Gilbert Matte, and Marie-France Robert (Pharmacy). McGill University Health Centre (Royal Victoria Hospital, Glen Site), Montréal, QC: Dr. Arnold S. Kristof (Lead), Dr. Peter Goldberg, Dr. Roupen Hatzakorzian, Dr. Sheldon Magder, Dr. Jason Shahin, and Dr. Salman Qureshi (Co-Investigators); Josie Campisi (Research Coordinator); and Vasilica Botan, Anissa Capilnean, Alyssa Corey, Annick Gagné, Jasmine Mian, and Kathleen Normandin (Pharmacy). United States—Mayo Clinic, Rochester, MN Dr. Rodrigo Cartin-Ceba (Lead) and Dr. Richard Oeckler (Co-Investigator); Brenda Anderson, Lavonne Liedl, Laurie Meade, and Sueanne Weist (Research Coordinators); and Anna Bartoo, Debbie Bauer, Vince Brickley, Shaun Bridges, Greg Brunn, Jennifer Eickstaedt, Jill Randolph, Sandy Showalter, Erin Stern, and Melissa Wendling (Pharmacy). St John’s Mercy Medical Center, St Louis, MO: Dr. Robert Taylor (Lead); Margaret Cytron, Kim Fowler, Katie Krause, Jackie O’Brien, and Marianne Tow (Research Coordinators); and John Ma and Kaitlin Stassi (Pharmacy). Saudi Arabia—King Abdulaziz Medical Center, Riyadh, Saudi Arabia: Dr. Yaseen Arabi (Lead), Dr. Abdulaziz Al-Dawood, Dr. Haytham Tlayjeh, Dr. Alaaeldien Ghanem, Dr. Ahmad Hassanien, Dr. Mohamed Hegazy, Dr. Ashraf El Sharkawi (Co-Investigators); Felwa Bin Humaid, Hala Alanizi, Nadyah Alanizy, and Njoud Al Bogami, (Research Coordinators); Dr. Mohammed Muhaidib, Dr. Jawaher Gramish, Randa Alsomali, Nora Devera, and Marjane Villafranca (Pharmacy).
Supplementary Material
Footnotes
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccejournal).
The Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial Trial was funded by the Canadian Institutes of Health Research Research Grant. Dr. Tsang is supported by a Mid-Career Research Award of the McMaster University Department of Medicine. Dr. Cook is supported by a Canada Research Chair of the Canadian Institutes for Health Research. The remaining authors have disclosed that they do not have any potential conflicts of interest.
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