Acute rheumatic fever in First Nations communities in northwestern Ontario: Social determinants of health "bite the heart".

OBJECTIVE: To document a case series of 8 young First Nations patients diagnosed with acute rheumatic fever (ARF), a preventable disease that resulted in the death of 2 patients, in northwestern Ontario in the context of late diagnosis, overcrowded housing, and inadequate public health response. DESIGN: Retrospective case series over an 18-month period. SETTING: Remote First Nations communities in northwestern Ontario. PARTICIPANTS: Eight patients with ARF. MAIN OUTCOME MEASURES: Incidence, mortality, residual rheumatic heart disease, time to diagnosis, barriers to diagnosis and treatment, housing situation of patients, patient demographic characteristics (age, sex), and investigation results. RESULTS: The incidence of ARF in this population was 21.3 per 100,000, which is 75 times greater than the overall Canadian estimated incidence. The average patient age was 9.4 years. Most cases developed joint findings, and 5 of the surviving patients had rheumatic heart disease when they received echocardiography. The average time to diagnosis was 88 days. Two 4-year-old children died from ARF. Most patients lived in inadequate and crowded housing. CONCLUSION: This rare disease still exists in remote First Nations communities. These communities demonstrate an incidence equal to that in aboriginal communities in Australia and New Zealand, which have among the highest international incidence of ARF. Primordial prevention, including improved on-reserve housing, is urgently needed. Case detection and ongoing surveillance for primary and secondary prophylaxis requires a well resourced regional strategy.

Survey of consent practices in cluster randomized trials: improvements are needed in ethical conduct and reporting.

BACKGROUND: Informed consent procedures in cluster randomized trials (CRTs) are considerably more complicated than in individually randomized trials. In a CRT, the units of randomization, intervention, and observation may differ in a single trial; there can be multiple levels of participants (individual and cluster level); consent may be required separately for intervention and data collection; and there may be practical constraints to seeking informed consent, for example, due to cluster-level interventions or the sheer size of clusters. PURPOSE: We aimed to document consent practices at individual and cluster levels, assess the adequacy of reporting consent in trial publications, and assess associations with two trial characteristics that may influence consent requirements in CRTs: presence or absence of study interventions and presence or absence of data collection procedures at individual and cluster levels. METHODS: We reviewed a random sample of 300 CRTs published during 2000-2008. We sent survey questionnaires to 285 unique authors of these trials to gather detailed information about consent procedures used in each trial. RESULTS: In all, 182 authors (64%) responded. Overall, 93% (95% confidence interval (CI): 88.8%-96.6%) indicated that participant consent had been sought for some aspects of the study. Consent was less frequently sought for a study intervention (70% of respondents) than for data collection (88%). More than half of the respondents (52%) indicated that consent had been sought at both cluster and individual levels. There was strong evidence for under-reporting of consent in trial publications: only 63% of all trial publications reported that informed consent had been sought for some aspect of the study. The odds ratios (ORs) summarizing the association of the two trial characteristics with cluster-level participant consent were weak (OR = 1.17, p = 0.70 for presence of cluster-level study intervention and OR = 1.54, p = 0.29 for data collection); on the other hand, the ORs summarizing the associations with individual-level consent were strong (OR = 6.2, p < 0.0001 for presence of individual-level intervention and OR = 14.7, p < 0.0001 for data collection). LIMITATIONS: In all, 36% of authors did not respond to the survey; to the extent that consent practices in their trials were different than in respondents' trials, our results may be biased. CONCLUSIONS: There is a need for improvements in research practices in CRTs as well as their reporting. There may be a lack of clarity about consent requirements at the cluster level in particular. With the publication of the Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials, researchers and research ethics committees now have access to comprehensive ethics guidelines specific to CRTs.

Research recruitment practices and critically ill patients. A multicenter, cross-sectional study (the Consent Study).

RATIONALE: Limited cross-sectional data exist to characterize the challenges of enrolling critically ill patients into research studies. OBJECTIVES: We aimed to describe recruitment practices, document factors that impact recruitment, and identify factors that may enhance future research feasibility. METHODS: We conducted a prospective, observational study of all critically ill adults eligible to participate in research studies at 23 Canadian intensive care units. We characterized eligibility events into one of five consent outcomes, identified reasons why opportunities to recruit were missed or infeasible, and documented decision maker's rationale for providing or declining consent. MEASUREMENTS AND MAIN RESULTS: Patients made decisions for themselves in 8.9% of encounters. In 452 eligibility events, consent was not required in 14 (3.1%), missed in 130 (28.8%), infeasible due to operational reasons in 129 (28.5%), obtained in 140 (31.0%), and declined in 39 (8.6%). More than half (57.3%) of all opportunities to recruit patients were missed or infeasible, largely because of research team workload, limited availability, narrow time windows for inclusion, difficulties in contacting families, nonexistent substitute decision makers (SDMs), physician refusals, and protocols prohibiting coenrollment. The rationale for providing consent differed between patients and SDMs. Greater research coordinator experience and site research volume and broader time windows for inclusion were significant predictors of fewer declined consents. CONCLUSIONS: A large gap exists between eligibility and the frequency with which consent encounters occur in intensive care unit research. Recruitment is susceptible to design and procedural inefficiencies that hinder recruitment and to personnel availability, given the need to interact with SDMs. Current enrollment practices may underrepresent potential study populations.

What makes public health studies ethical? Dissolving the boundary between research and practice.

BACKGROUND: The generation of evidence is integral to the work of public health and health service providers. Traditionally, ethics has been addressed differently in research projects, compared with other forms of evidence generation, such as quality improvement, program evaluation, and surveillance, with review of non-research activities falling outside the purview of the research ethics board. However, the boundaries between research and these other evaluative activities are not distinct. Efforts to delineate a boundary - whether on grounds of primary purpose, temporality, underlying legal authority, departure from usual practice, or direct benefits to participants - have been unsatisfactory.Public Health Ontario has eschewed this distinction between research and other evaluative activities, choosing to adopt a common framework and process to guide ethical reflection on all public health evaluative projects throughout their lifecycle - from initial planning through to knowledge exchange. DISCUSSION: The Public Health Ontario framework was developed by a working group of public health and ethics professionals and scholars, in consultation with individuals representing a wide range of public health roles. The first part of the framework interprets the existing Canadian research ethics policy statement (commonly known as the TCPS 2) through a public health lens. The second part consists of ten questions that guide the investigator in the application of the core ethical principles to public health initiatives.The framework is intended for use by those designing and executing public health evaluations, as well as those charged with ethics review of projects. The goal is to move toward a culture of ethical integrity among investigators, reviewers and decision-makers, rather than mere compliance with rules. The framework is consonant with the perspective of the learning organization and is generalizable to other public health organizations, to health services organizations, and beyond. SUMMARY: Public Health Ontario has developed an ethics framework that is applicable to any evidence-generating activity, regardless of whether it is labelled research. While developed in a public health context, it is readily adaptable to other health services organizations and beyond.

Clinical and serological predictors of post COVID-19 condition-findings from a Canadian prospective cohort study.

Introduction: More than 3 years into the pandemic, there is persisting uncertainty as to the etiology, biomarkers, and risk factors of Post COVID-19 Condition (PCC). Serological research data remain a largely untapped resource. Few studies have investigated the potential relationships between post-acute serology and PCC, while accounting for clinical covariates. Methods: We compared clinical and serological predictors among COVID-19 survivors with (n = 102 cases) and without (n = 122 controls) persistent symptoms ≥12 weeks post-infection. We selected four primary serological predictors (anti-nucleocapsid (N), anti-Spike, and anti-receptor binding domain (RBD) IgG titres, and neutralization efficiency), and specified clinical covariates a priori. Results: Similar proportions of PCC-cases (66.7%, n = 68) and infected-controls (71.3%, n = 87) tested positive for anti-N IgG. More cases tested positive for anti-Spike (94.1%, n = 96) and anti-RBD (95.1%, n = 97) IgG, as compared with controls (anti-Spike: 89.3%, n = 109; anti-RBD: 84.4%, n = 103). Similar trends were observed among unvaccinated participants. Effects of IgG titres on PCC status were non-significant in univariate and multivariate analyses. Adjusting for age and sex, PCC-cases were more likely to be efficient neutralizers (OR 2.2, 95% CI 1.11-4.49), and odds was further increased among cases to report deterioration in quality of life (OR 3.4, 95% CI 1.64-7.31). Clinical covariates found to be significantly related to PCC included obesity (OR 2.3, p = 0.02), number of months post COVID-19 (OR 1.1, p < 0.01), allergies (OR 1.8, p = 0.04), and need for medical support (OR 4.1, p < 0.01). Conclusion: Despite past COVID-19 infection, approximately one third of PCC-cases and infected-controls were seronegative for anti-N IgG. Findings suggest higher neutralization efficiency among cases as compared with controls, and that this relationship is stronger among cases with more severe PCC. Cases also required more medical support for COVID-19 symptoms, and described complex, ongoing health sequelae. More data from larger cohorts are needed to substantiate results, permit subgroup analyses of IgG titres, and explore for differences between clusters of PCC symptoms. Future assessment of IgG subtypes may also elucidate new findings.

Challenges in the research ethics review of cluster randomized trials: international survey of investigators.

BACKGROUND: Cluster randomized trials (CRTs) complicate the interpretation of standard research ethics guidelines for several reasons. For one, the units of allocation, intervention, and observation often may differ within a single trial. In the absence of tailored and internationally accepted ethics guidelines for CRTs, researchers and research ethics committees have no common standard by which to judge ethically appropriate practices in CRTs. Moreover, lack of familiarity with and consideration of the unique features of the CRT design by research ethics committees may cause difficulties in the research ethics review process, and amplify problems such as variability in the requirements and decisions reached by different research ethics committees. PURPOSE: We aimed to characterize research ethics review of CRTs, examine investigator experiences with the ethics review process, and assess the need for ethics guidelines for CRTs. METHODS: An electronic search strategy implemented in MEDLINE was used to identify and randomly sample 300 CRTs published in English language journals from 2000 to 2008. A web-based survey with closed- and open-ended questions was administered to corresponding authors in a series of six contacts. RESULTS: The survey response rate was 64%. Among 182 of 285 eligible respondents, 91% indicated that they had sought research ethics approval for the identified CRT, although only 70% respondents reported research ethics approval in the published article. Nearly one-third (31%) indicated that they have had to meet with ethics committees to explain aspects of their trials, nearly half (46%) experienced variability in the ethics review process in multijurisdictional trials, and 38% experienced negative impacts of the ethics review process on their trials, including delays in trial initiation (28%), increased costs (10%), compromised ability to recruit participants (16%), and compromised methodological quality (9%). Most respondents (74%; 95% confidence interval (CI): 67%-80%) agreed or strongly agreed that there is a need to develop ethics guidelines for CRTs, and (70%; 95% CI: 63%-77%) that ethics committees could be better informed about distinct ethical issues surrounding CRTs. LIMITATIONS: Thirty-six percent of authors did not respond to the survey. Due to the absence of comparable results from a representative sample of authors of individually randomized trials, it is unclear to what extent the reported challenges result from the CRT design. CONCLUSIONS: CRT investigators are experiencing challenges in the research ethics review of their trials, including excessive delays, variability in process and outcome, and imposed requirements that can have negative consequences for study conduct. Investigators identified a clear need for ethics guidelines for CRTs and education of research ethics committees about distinct ethical issues in CRTs.

Community-associated methicillin-resistant Staphylococcus aureus in northwest Ontario: A five-year report of incidence and antibiotic resistance.

BACKGROUND: The incidence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is traditionally high in remote areas of Canada with large Aboriginal populations. Northwestern Ontario is home to 28,000 First Nations people in more than 30 remote communities; rates of CA-MRSA are unknown. OBJECTIVE: To determine the CA-MRSA rates and antibiotic susceptibilities in this region. METHODS: A five-year review of laboratory and patient CA-MRSA data and antibiotic susceptibility was undertaken. RESULTS: In 2012, 56% of S aureus isolates were CA-MRSA strains, an increase from 31% in 2008 (P=0.06). Reinfection rates have been increasing faster than new cases and, currrently, 25% of infections are reinfections. CA-MRSA isolates continue to be susceptible to many common antibiotics (nearly 100%), particularly trimethoprim/sulfamethoxazole, clindamycin and tetracycline. Erythromycin susceptibility stands at 58%. DISCUSSION: Rates of CA-MRSA, as a percentage of all S aureus isolates, were higher than those reported in other primary care series. The infection rate per 100,000 is one the highest reported in Canada. Antibiotic susceptibilities were unchanged during the study period; the 99% susceptibility rate to clindamycin differs from a 2010 Vancouver (British Columbia) study that reported only a 79% susceptibility to this antibiotic. CONCLUSION: There are very high rates of CA-MRSA infections in northwestern Ontario. Disease surveillance and ongoing attention to antibiotic resistance is important in understanding the changing profile of MRSA infections. Social determinants of health, specifically improved housing and sanitation, remain important regional issues.

HISTORIQUE: L'incidence de Staphylococcus aureus résistant à la méthicilline d'origine non nosocomiale (SARM-ONN) est généralement élevée dans les régions éloignées du Canada aux fortes populations autochtones. Ainsi, 28 000 membres des Premières nations habitent dans plus de 30 communautés éloignées du nord-ouest de l'Ontario. On n'y connaît pas le taux de SARM-ONN. OBJECTIF: Déterminer le taux de SARM-ONN et les susceptibilités aux antibiotiques dans cette région. MÉTHODOLOGIE: Les chercheurs ont effectué une analyse quinquennale des données de laboratoire et des données des patients à l'égard du SARM-ONN ainsi que de leur susceptibilité aux antibiotiques. RÉSULTATS: En 2012, 56 % des isolats de S aureus étaient des souches de SARM-ONN, soit une augmentation par rapport aux 31 % de 2008 (P=0,06). Le taux de réinfection augmentait plus rapidement que le taux de nouveaux cas : 25 % des infections sont désormais des réinfections. Les isolats de SARM-ONN continuent d'être susceptibles à de nombreux antibiotiques courants (près de 100 %), notamment le triméthoprim-sulfaméthoxazole, la clindamycine et la tétracycline. La susceptibilité à l'érythromycine est de 58 %. EXPOSÉ: Le taux de SAMR-ONN, à titre de pourcentage de tous les isolats de S aureus, était plus élevé que celui déclaré dans d'autres séries de soins de première ligne. Le taux d'infection sur 100 000 habitants est l'un des plus élevés à être signalé au Canada. Les susceptibilités aux antibiotiques demeuraient inchangées pendant la période de l'étude. Le taux de susceptibilité de 99 % à la clindamycine diffère de celui de seulement 79 % obtenu dans une étude de 2010 menée à Vancouver, en Colombie-Britannique. CONCLUSION: Les chercheurs ont constaté un taux très élevé d'infections par le SARM-ONN au nord-ouest de l'Ontario. Il est important de surveiller la maladie et de demeurer attentif à l'antibiorésistance pour comprendre l'évolution du profil des infections par le SARM. Les déterminants sociaux de la santé, particulièrement l'amélioration des logements et des mesures d'assainissement, continuent de représenter d'importants problèmes régionaux.

What do we talk about when we talk about "equipoise"? Stakeholder interviews assessing the use of equipoise in clinical research ethics.

INTRODUCTION: Equipoise, generally defined as uncertainty about the relative effects of the treatments being compared in a trial, is frequently referenced as an ethical standard for the conduct of randomized clinical trials. However, it seems to be defined in several different ways and may be used differently by different individuals. We explored how clinical researchers, chairs of research ethics boards, and philosophers of science define and reason with this term. METHODS: We completed semi-structured interviews about clinical trial ethics with 15 clinical researchers, 15 research ethics board chairs, and 15 philosophers of science/bioethicists. Each participant was asked a standardized set of 10 questions, 4 of which were specifically about equipoise. All interviews were conducted telephonically and transcribed. Responses were grouped and analysed via a modified grounded theory method. RESULTS: Forty-three respondents defined equipoise in 7 logically distinct ways, and 2 respondents could not explicitly define it. The most common definition, offered by 14 respondents (31%), defined "equipoise" as a disagreement at the level of a community of physicians. There was significant variability in definitions offered between and within groups. When asked how they would "operationalize" equipoise - i.e. check or test for its presence - respondents provided 7 alternatives, the most common being in relation to a literature review (15/45, 33%). The vast majority of respondents (35/45, 78%) felt the concept was helpful, though many acknowledged that the lack of a clear definition or operationalization was problematic. CONCLUSION: There is significant variation in definitions of equipoise offered by respondents, suggesting that parties within groups and between groups may be referring to different concepts when they reference "equipoise". This non-uniformity may impact fairness and transparency and opens the door to potential ethical problems in the evaluation of clinical trials - for instance, a patient may understand equipoise very differently than the researchers enrolling her in a trial, which could cause her agreement to participate to be based upon false premises.

No time for complacency: The CoVaRR-Net Biobank is an essential element of laboratory preparedness for infectious disease outbreaks.

The SARS-CoV-2 pandemic highlighted the need for rapid, collaborative, and population-centric research to define health impact, develop health care policies and establish reliable diagnostic and surveillance tests. Critical for these objectives were in-depth clinical data collected in standardized fashion and large numbers of various types of human samples prior and post-viral encounter. As the pandemic evolved with the emergence of new variants of concern (VOCs), access to samples and data from infected and vaccinated individuals were needed to monitor immune durability, the possibility of increased transmissibility and virulence, and vaccine protection against new and emerging VOCs. Therefore, essential to the pandemic response is a strong laboratory and data research component, supported by effective biobanking and data sharing. Critically important to the speed of the research response is the rapid access to biobanked samples. To address critical challenges brought to light by the pandemic, the Coronavirus Variants Rapid Response Network (CoVaRR-Net), funded by the Canadian Institutes of Health Research, was established to coordinate research efforts to provide rapid evidence-based responses to emerging VOCs. The purpose of this paper is to introduce the CoVaRR-Net Biobank and define its contribution to pandemic preparedness.

La pandémie de SRAS-CoV-2 a fait ressortir la nécessité de réaliser des recherches rapides, coopératives et populationnelles pour en définir les effets sur la santé, promulguer des politiques sanitaires et établir des tests diagnostiques et des tests de surveillance fiables. Pour réaliser ces objectifs, il était essentiel de colliger des données cliniques approfondies d'une manière standardisée et d'amasser un grand nombre de divers types d'échantillons humains avant et après le contact viral. Lorsque la pandémie a évolué par l'émergence de nouveaux variants préoccupants (VOC), il est devenu nécessaire d'accéder à des échantillons et à des données de personnes infectées et vaccinées pour surveiller la durabilité de l'immunité, la possibilité d'une transmissibilité et d'une virulence accrues et la protection conférée par les vaccins contre les VOC nouveaux et émergents. Ainsi, il est essentiel de disposer d'un vigoureux volet de recherches de laboratoire et de recherches à partir de données pour répondre à la pandémie, soutenu par une mise en biobanque et un partage des données efficaces. Pour assurer une réponse rapide par la recherche, il est tout aussi important d'accéder rapidement aux échantillons mis en biobanque. Afin de relever les défis cruciaux soulevés par la pandémie, le Coronavirus Variants Rapid Response Network (réseau de réponse rapide aux variants du coronavirus; CoVaRR-Net), financé par les Instituts de recherche en santé du Canada, a été créé pour coordonner les efforts de recherche afin de fournir des réponses rapides fondées sur des données probantes aux VOC en émergence. Le présent article vise à présenter la Biobanque CoVaRR-Net et à en définir la contribution à la préparation aux pandémies.

Results of the Stop the Spread Ottawa (SSO) cohort study: a Canadian urban-based prospective evaluation of antibody responses and neutralisation efficiency to SARS-CoV-2 infection and vaccination.

BACKGROUND: Predictors of COVID-19 vaccine immunogenicity and the influence of prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection require elucidation. METHODS: Stop the Spread Ottawa is a prospective cohort of individuals at-risk for or who have been infected with SARS-CoV-2, initially enrolled for 10 months beginning October 2020. This cohort was enriched for public-facing workers. This analysis focuses on safety and immunogenicity of the initial two doses of COVID-19 vaccine. RESULTS: Post-vaccination data with blood specimens were available for 930 participants. 22.8% were SARS-CoV2 infected prior to the first vaccine dose. Cohort characteristics include: median age 44 (IQR: 22-56), 66.6% women, 89.0% white, 83.2% employed. 38.1% reported two or more comorbidities and 30.8% reported immune compromising condition(s). Over 95% had detectable IgG levels against the spike and receptor binding domain (RBD) 3 months post second vaccine dose. By multivariable analysis, increasing age and high-level immune compromise predicted diminishing IgG spike and RBD titres at month 3 post second dose. IgG spike and RBD titres were higher immediately post vaccination in those with SARS-CoV-2 infection prior to first vaccination and spike titres were higher at 6 months in those with wider time intervals between dose 1 and 2. IgG spike and RBD titres and neutralisation were generally similar by sex, weight and whether receiving homogeneous or heterogeneous combinations of vaccines. Common symptoms post dose 1 vaccine included fatigue (64.7%), injection site pain (47.5%), headache (27.2%), fever/chills (26.2%) and body aches (25.3%). These symptoms were similar with subsequent doses. CONCLUSION: The initial two COVID-19 vaccine doses are safe, well-tolerated and highly immunogenic across a broad spectrum of vaccine recipients including those working in public facing environments.

FLUID trial: a hospital-wide open-label cluster cross-over pragmatic comparative effectiveness randomised pilot trial comparing normal saline to Ringer's lactate.

OBJECTIVES: Normal saline (NS) and Ringer's lactate (RL) are the most common crystalloids used for fluid therapy. Despite evidence of possible harm associated with NS (eg, hyperchloremic metabolic acidosis, impaired kidney function and death), few large multi-centre randomised trials have evaluated the effect of these fluids on clinically important outcomes. We conducted a pilot trial to explore the feasibility of a large trial powered for clinically important outcomes. DESIGN: FLUID was a pragmatic pilot cluster randomised cross-over trial. SETTING: Four hospitals in the province of Ontario, Canada PARTICIPANTS: All hospitalised adult and paediatric patients with an incident admission to the hospital over the course of each study period. INTERVENTIONS: A hospital wide policy/strategy which stocked either NS or RL throughout the hospital for 12 weeks before crossing over to the alternate fluid for the subsequent 12 weeks. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary feasibility outcome was study fluid protocol adherence. Secondary feasibility outcomes included time to Research Ethics Board (REB) approval and trial initiation. Primary (composite of death or re-admission to hospital in first 90 days of index hospitalisation) and secondary clinical outcomes were analysed descriptively. RESULTS: Among 24 905 included patients, mean age 59.1 (SD 20.5); 13 977 (56.1%) were female and 21 150 (85.0%) had medical or surgical admitting diagnoses. Overall, 96 821 L were administered in the NS arm, and 78 348 L in the RL arm. Study fluid adherence to NS and RL was 93.7% (site range: 91.6%-98.0%) and 79.8% (site range: 72.5%-83.9%), respectively. Time to REB approval ranged from 2 to 48 days and readiness for trial initiation from 51 to 331 days. 5544 (22.3%) patients died or required hospital re-admission in the first 90 days. CONCLUSIONS: The future large trial is feasible. Anticipating and addressing logistical challenges during the planning stages will be imperative. TRIAL REGISTRATION NUMBER: NCT02721485.

A Hospital-Wide Open-Label Cluster Crossover Pragmatic Comparative Effectiveness Randomized Trial Comparing Normal Saline to Ringer's Lactate: Protocol and Statistical Analysis Plan of The FLUID Trial.

BACKGROUND: Normal saline (NS) and Ringer's lactate (RL) are the most common crystalloids given to hospitalized patients. Despite concern about possible harm associated with NS (eg, hyperchloremic metabolic acidosis, impaired kidney function, and death), few large multicenter randomized trials focused on critically ill patients have compared these fluids. Uncertainty exists about the effects of these fluids on clinically important outcomes across all hospitalized patients. OBJECTIVE: The FLUID trial is a pragmatic, multicenter, 2×2 cluster crossover comparative effectiveness randomized trial that aims to evaluate the effectiveness of a hospital-wide policy that stocks either NS or RL as the main crystalloid fluid in 16 hospitals across Ontario, Canada. METHODS: All hospitalized adult and pediatric patients (anticipated sample size 144,000 patients) with an incident admission to the hospital over the course of each study period will be included. Either NS or RL will be preferentially stocked throughout the hospital for 12 weeks before crossing to the alternate fluid for the subsequent 12 weeks. The primary outcome is a composite of death and hospital readmission within 90 days of hospitalization. Secondary outcomes include death, hospital readmission, dialysis, reoperation, postoperative reintubation, length of hospital stay, emergency department visits, and discharge to a facility other than home. All outcomes will be obtained from health administrative data, eliminating the need for individual case reports. The primary analysis will use cluster-level summaries to estimate cluster-average treatment effects. RESULTS: The statistical analysis plan has been prepared "a priori" in advance of receipt of the trial data set from ICES and any analyses. CONCLUSIONS: We describe the protocol and statistical analysis plan for the evaluation of primary and secondary outcomes for the FLUID trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04512950; https://classic.clinicaltrials.gov/ct2/show/NCT04512950. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51783.

How are randomized clinical trials ethically justified? A systematic scoping review and thematic analysis of reasons that ethically justify randomized clinical trials.

OBJECTIVES: We set out to identify and count the types of reasons that are used in contemporary scholarship about the ethical permissibility of randomized trials, with the goal of developing a finer grained taxonomy of reasons than what is currently used by most participants in this literature. Because of its central role in justifying normative conclusions about randomized clinical trials (RCTs), we paid particular attention to both uses of the keyword "equipoise" and to the different concepts associated with it. METHODS: We conducted a scoping review to identify articles that included arguments that were likely to express reasons justifying RCTs. Text excerpts that expressed reasoning about the ethical permissibility of RCTs were extracted from relevant papers, and our data were generated by coding these excerpts using a mixed-methods protocol that fused elements of a grounded analysis and thematic coding. In our study, each theme corresponded to a specific type of reason that was contentful and stable when applied to our corpus of text extracts. RESULTS: Our search, screening, and text extraction process yielded 1,335 unique text excerpts, which then formed the basis of our coding. Although we found that 16 themes were sufficient to saturate this corpus, slightly less than 100% of our excerpts were covered by just 10 themes. We also tracked uses of 16 keywords in the text excerpts to explore whether there was any relationship between the keywords and our themes and found that keywords frequently did not cooccur with the presence of our themes. CONCLUSIONS: Our data and analysis support the conclusion that there is significant diversity in the types of reasons offered to justify RCTs; 10 themes effectively captured all the text excerpts we analyzed, and these themes cannot be reduced to the occurrence of relevant keywords. This result highlights how individuals and organizations may use different reasons to consider randomized trials to be justified and even when they use similar language the concepts they are referencing may not be consistent.

Cohort profile: Stop the Spread Ottawa (SSO)-a community-based prospective cohort study on antibody responses, antibody neutralisation efficiency and cellular immunity to SARS-CoV-2 infection and vaccination.

PURPOSE: To investigate the robustness and longevity of SARS-CoV-2 immune responses conferred by natural infection and vaccination among priority populations such as immunocompromised individuals and people with post-acute sequelae of COVID-19 in a prospective cohort study (Stop the Spread Ottawa-SSO) in adults living in the Ottawa region. In this paper, we describe the study design, ongoing data collection and baseline characteristics of participants. PARTICIPANTS: Since October 2020, participants who tested positive for COVID-19 (convalescents) or at high risk of exposure to the virus (under surveillance) have provided monthly blood and saliva samples over a 10-month period. As of 2 November 2021, 1026 adults had completed the baseline survey and 976 had attended baseline bloodwork. 300 participants will continue to provide bimonthly blood samples for 24 additional months (ie, total follow-up of 34 months). FINDINGS TO DATE: The median age of the baseline sample was 44 (IQR 23, range: 18-79) and just over two-thirds (n=688; 67.1%) were female. 255 participants (24.9%) had a history of COVID-19 infection confirmed by PCR and/or serology. Over 600 participants (60.0%) work in high-risk occupations (eg, healthcare, teaching and transportation). 108 participants (10.5%) reported immunocompromising conditions or treatments at baseline (eg, cancer, HIV, other immune deficiency, and/or use of immunosuppressants). FUTURE PLANS: SSO continues to yield rich research potential, given the collection of pre-vaccine baseline data and samples from the majority of participants, recruitment of diverse subgroups of interest, and a high level of participant retention and compliance with monthly sampling. The 24-month study extension will maximise opportunities to track SARS-CoV-2 immunity and vaccine efficacy, detect and characterise emerging variants, and compare subgroup humoral and cellular response robustness and persistence.

Rheumatic heart disease in Indigenous young peoples.

Indigenous children and young peoples live with an inequitable burden of acute rheumatic fever and rheumatic heart disease. In this Review, we focus on the epidemiological burden and lived experience of these conditions for Indigenous young peoples in Australia, New Zealand, and Canada. We outline the direct and indirect drivers of rheumatic heart disease risk and their mitigation. Specifically, we identify the opportunities and limitations of predominantly biomedical approaches to the primary, secondary, and tertiary prevention of disease among Indigenous peoples. We explain why these biomedical approaches must be coupled with decolonising approaches to address the underlying cause of disease. Initiatives underway to reduce acute rheumatic fever and rheumatic heart disease in Australia, New Zealand, and Canada are reviewed to identify how an Indigenous rights-based approach could contribute to elimination of rheumatic heart disease and global disease control goals.

Research ethics and infection control.

The Keystone study of prevention of catheter-related infections in intensive care units raised important issues regarding infection control and research ethics. Infection control is an area common to public health and quality improvement. The performance of surveillance, the reporting of infection control data, and the response to complaints are all obligations raised by the international health regulations. The regulatory system around research ethics focuses on the individual subject in research and is not designed around areas such as infection control. Scientific methods are common to both infection control and research; both may result in "generalizable knowledge." Infection control physicians should work with their institutional review boards to try to streamline the process of ethics review. Regulatory change may be desirable to define and limit what infection control activities are construed as research.

Protocol for a systematic scoping review of reasons given to justify the performance of randomised controlled trials.

INTRODUCTION: Randomised controlled trials (RCTs) are widely viewed to generate the most reliable medical knowledge. However, RCTs are not always scientifically necessary and therefore not always ethical. Unfortunately, it is not clear when an RCT is not necessary or how this should be established. This study seeks to systematically catalogue justifications offered throughout the medical and ethics literature for performing randomisation within clinical trials. METHODS AND ANALYSIS: We will systematically search electronic databases of the medical literature including MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Clinical Trials Register, Web of Science Proceedings, ClinicalTrials.gov; databases of philosophical literature including Philosopher's Index, Phil Papers, JSTOR, Periodicals Archive Online, Project MUSE, National Reference Centre for Bioethics; the library catalogue at the University of Ottawa; bibliographies of retrieved papers; and the grey literature. We will also pursue suggestions from experts in the fields of medical ethics, philosophy and clinical trial methodology. Article screening, selection and data extraction will be performed by two independent reviewers based on prespecified inclusion/exclusion criteria. A third reviewer will be consulted to resolve any discrepancies. We will then extract the reasons given to justify randomisation using methodology established to extract data in a defensible, systematic manner. We will track the reasons given, their frequency of use and changes over time. Finally, using grounded theory, we will combine the reasons into broader themes. These themes will form the foundation of our subsequent analysis from qualitative and quantitative perspectives. This review will map existing arguments that clinicians, ethicists and philosophers use to ethically justify randomisation in clinical trials. ETHICS AND DISSEMINATION: No research ethics board approval is necessary because we are not examining patient-level data. This protocol complies with the reported guidance for conducting systematic scoping reviews. The findings of this paper will be disseminated via presentations and academic publication. In a subsequent phase of this research, we hope to engage with stakeholders and translate any recommendations derived from our findings into operational guidelines.

Staphylococcus aureus bacteraemia of unknown primary source: where do we stand?

There is no generally held definition of Staphylococcus aureus bacteraemia (SAB) of unknown source. For this paper, we consider it to occur when one or more positive blood cultures obtained from a patient grows S. aureus and the origin of the bacteraemia is uncertain after history, physical examination, chest radiography and any further investigations provoked by clinical findings. The incidence of SAB appears to be rising, particularly community-acquired (CA), but also hospital- or healthcare-acquired (HA). Major drivers appear to be intravenous drug use and increasing use of indwelling intravascular devices. There is an increasing prevalence of meticillin-resistant S. aureus (MRSA), both CA and HA. There is increasing hospital acquisition of MRSA that is phenotypically like CA strains, and there is increasing community-based treatment of HA infection. Metastatic infection is a risk of SAB. Infective endocarditis (IE) is a longstanding dreaded concern of SAB. Transoesophageal echocardiography appears to be a superior modality of recognising IE in the context of SAB and can guide the duration of therapy. Prosthetic joints and heart valves are at particular risk of haematogenous seeding from SAB. Implications of the rise of CA-MRSA in terms of metastatic infection warrant further study.

Home-based intermediate care program vs hospitalization: Cost comparison study.

OBJECTIVE: To explore whether a home-based intermediate care program in a large Canadian city lowers the cost of care and to look at whether such home-based programs could be a solution to the increasing demands on Canadian hospitals. DESIGN: Single-arm study with historical controls. SETTING: Department of Family Medicine at the Ottawa Hospital (Civic campus) in Ontario. PARTICIPANTS: Patients requiring hospitalization for acute care. Participants were matched with historical controls based on case-mix, most responsible diagnosis, and level of complexity. INTERVENTIONS: Placement in the home-based intermediate care program. Daily home visits from the nurse practitioner and 24-hour access to care by telephone. MAIN OUTCOME MEASURES: Multivariate regression models were used to estimate the effect of the program on 5 outcomes: length of stay in hospital, cost of care substituted for hospitalization (Canadian dollars), readmission for a related diagnosis, readmission for any diagnosis, and costs incurred by community home-care services for patients following discharge from hospital. RESULTS: The outcomes of 43 hospital admissions were matched with those of 363 controls. Patients enrolled in the program stayed longer in hospital (coefficient 3.3 days, P < .001), used more community care services following discharge (coefficient $729, P = .007), and were more likely to be readmitted to hospital within 3 months of discharge (coefficient 17%, P = .012) than patients treated in hospital. Total substituted costs of home-based care were not significantly different from the costs of hospitalization (coefficient -$501, P = .11). CONCLUSION: While estimated cost savings were not statistically significant, the limitations of our study suggest that we underestimated these savings. In particular, the economic inefficiencies of a small immature program and the inability to control for certain factors when selecting historical controls affected our results. Further research is needed to determine the economic effect of mature home-based programs.