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Abstract Background Understanding site-related factors that influence enrolment within multicenter randomized controlled trials (RCT) may help reduce trial delays and cost over-runs and prevent early trial discontinuation. In this analysis of PROSPECT (Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial), we describe patient enrolment patterns and examine factors influencing site-based monthly enrolment. Design Retrospective analysis of a multicenter RCT. Methods The PROSPECT multicenter RCT enrolled patients in the main trial from July 2015 to March 2019. We documented site characteristics and trial metrics including data from the methods center tracking documents, site-level data at trial initiation, screening logs submitted by research coordinators, and prospectively collected case report forms. In this retrospective analysis of trial data, we analyzed enrolment patterns across sites using negative binomial regression to explore the association between monthly enrolment rate accounting for number of ICU beds, site characteristics, and trial metrics. Results Overall, 41 sites enrolling 2365 patients in the PROSPECT main trial were analyzed. After accounting for number of beds in each ICU, site launch early in the trial was associated with higher monthly enrolment rates, but time to first enrolment and research coordinator experience was not. We observed considerable variability in the number of active screening months and enrolment rates across sites. Conclusion These findings highlight the complexity of recruitment dynamics in critical care RCTs and emphasize the need for tailored approaches to trial planning and execution. Trial registration PROSPECT (Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial): NCT02462590 (registered June 2, 2015).

Introduction Most solid organ transplants originate from donors meeting criteria for death by neurological criteria (DNC). Within the organ donor, physiological responses to brain death increase the risk of ischaemia reperfusion injury and delayed graft function. Donor preconditioning with calcineurin inhibition may reduce this risk.Methods and analysis We designed a multicentre placebo-controlled pilot randomised trial involving nine organ donation hospitals and all 28 transplant programmes in the Canadian provinces of Ontario and Québec. We planned to enrol 90 DNC donors and their approximately 324 organ recipients, totalling 414 participants. Donors receive an intravenous infusion of either tacrolimus 0.02 mg/kg over 4 hours prior to organ retrieval, or a matching placebo, while monitored in an intensive care unit for any haemodynamic changes during the infusion. Among all study organ recipients, we record measures of graft function for the first 7 days in hospital and we will record graft survival after 1 year. We examine the feasibility of this trial with respect to the proportion of all eligible donors enrolled and the proportion of all eligible transplant recipients consenting to receive a CINERGY organ transplant and to allow the use of their health data for study purposes. We will report these feasibility outcomes as proportions with 95% CIs. We also record any barriers encountered in the launch and in the implementation of this trial with detailed source documentation.Ethics and dissemination We will disseminate trial results through publications and presentations at participating sites and conferences. This study has been approved by Health Canada (HC6-24-c241083) and by the Research Ethics Boards of all participating sites and in Québec (MP-31-2020-3348) and Clinical Trials Ontario (Project #3309).Trial registration number NCT05148715.

Dans la foulée de la transition numérique du système scolaire québécois, les directions d’établissement d’enseignement et les gestionnaires scolaires ont reçu le mandat de planifier, de mettre en œuvre et de piloter l’implantation du numérique. Or, les pratiques professionnelles et les stratégies de gestion déployées dans ce cadre relèvent d’un domaine peu investigué en éducation. Cet article présente une partie des résultats de la recherche intitulée Gestion et leadership pédagonumérique (Gravelle et al., 2021), menée en collaboration avec le ministère de l’Éducation du Québec (MEQ) au printemps 2021. L’étude avait comme premier objectif d’alimenter l’état des connaissances actuelles concernant les rôles, les pratiques professionnelles et les stratégies de gestion des directions d’établissement d’enseignement et des gestionnaires scolaires qui ont implanté le numérique; elle avait comme second objectif de favoriser le partage d’expériences entre praticiens. Sur la base d’échanges tenus dans le cadre d’une communauté de pratique, six champs d’action réunissant diverses stratégies de gestion utilisées par les participants ont été dégagés. À la lumière du partage d’expériences et de pratiques professionnelles, l’article interroge la notion de leadership pédagonumérique, qui se révèle comme un moteur d’innovation au service de l’intégration du numérique.

Neurologically deceased organ donors (NDDs) generally display an immune response involving an intense production of pro-inflammatory cytokines referred to as the cytokine storm. The sudden surge of inflammatory mediators in circulation promotes tissue and organ damages and ultimately leads to poor transplant outcome. As microRNAs (miRNAs) are frequently proposed as key regulators of inflammation and are relatively stable in circulation, changes in their profiles could play a role in the onset of the cytokine storm in NDDs. In this proof-of-concept study, we sought to investigate differentially abundant circulating miRNAs in a temporal manner between neurological death and organ recovery and to assess the association between specific miRNAs and levels of inflammatory cytokines in blood. Plasma samples from five NDDs were obtained at multiple time points between organ donation consent and organ recovery. Using a time-course analysis and miRNA sequencing, we identified 32 plasma miRNAs fluctuating between consent and organ recovery (false discovery rate; q-value < 0.1). Eleven miRNAs relatively abundant (>100 reads) and detected in all samples were selected for further biological pathway analysis (miR-486-3p, miR-103a-3p, miR-106b-3p, miR-182-5p, miR-101-3p, miR-10a-5p, miR-125a-5p, miR-146b-5p, miR-26a-5p, miR-423-5p, miR-92b-3p). These miRNAs targeted genes such as c-JUN (TNF signalling pathway) and eEF2 (AMPK pathway), suggesting a potential role in regulation of inflammation. Our results contribute to a better understanding of the miRNAs dynamic after neurological death in organ donors and could potentially be used to predict the related early cytokine storm.Trial registration: ClinicalTrials.gov ID NCT03786991. Registered December 2018

Abstract Background In randomized clinical controlled trials, the choice of usual care as the comparator may be associated with better clinician uptake of the study protocol and lead to more generalizable results. However, if care processes evolve to resemble the intervention during the course of a trial, differences between the intervention group and usual care control group may narrow. We evaluated the effect on mean arterial pressure of an unblinded trial comparing a lower mean arterial pressure target to reduce vasopressor exposure, vs. a clinician-selected mean arterial pressure target, in critically ill patients at least 65 years old. Methods For this multicenter observational study using data collected both prospectively and retrospectively, patients were recruited from five of the seven trial sites. We compared the mean arterial pressure of patients receiving vasopressors, who met or would have met trial eligibility criteria, from two periods: [1] at least 1 month before the trial started, and [2] during the trial period and randomized to usual care, or not enrolled in the trial. Results We included 200 patients treated before and 229 after trial initiation. There were no differences in age (mean 74.5 vs. 75.2 years; p = 0.28), baseline Acute Physiology and Chronic Health Evaluation II score (median 26 vs. 26; p = 0.47) or history of chronic hypertension (n = 126 [63.0%] vs. n = 153 [66.8%]; p = 0.41). Mean of the mean arterial pressure was similar between the two periods (72.5 vs. 72.4 mmHg; p = 0.76). Conclusions The initiation of a trial of a prescribed lower mean arterial pressure target, compared to a usual clinician-selected target, was not associated with a change in mean arterial pressure, reflecting stability in the net effect of usual clinician practices over time. Comparing prior and concurrent control groups may alleviate concerns regarding drift in usual practices over the course of a trial or permit quantification of any change.

Abstract Background High-dose vitamin C is increasingly used for sepsis and more recently for coronavirus disease 2019 (COVID-19) infections. Proponents argue that the low cost and near perfect safety profile of vitamin C support its early adoption. Yet, adverse events might be underreported and underappreciated. Case presentation We report a 73-year-old non-diabetic white man with end-stage renal disease on peritoneal dialysis admitted to the intensive care unit with septic shock that was suspected to be due to peritonitis. The patient was enrolled in LOVIT (Lessening Organ Dysfunction with VITamin C; ClinicalTrials.gov identifier: NCT03680274), a randomized placebo-controlled trial of high-dose intravenous vitamin C. He developed factitious hyperglycemia, as measured with a point-of-care glucometer, that persisted for 6 days after discontinuation of the study drug, confirmed to be vitamin C after unblinding. He also had short-lived iatrogenic coma because of hypoglycemia secondary to insulin administration. These events triggered a protocol amendment. Conclusions Although factitious hyperglycemia has been reported before using certain glucometers in patients treated with high-dose vitamin C, the persistence of this phenomenon for 6 days after the discontinuation of the therapy is a distinguishing feature. This case highlights the importance of monitoring glucose with a core laboratory assay for up to a week in specific populations, such as patients on peritoneal dialysis.

BackgroundThe LOVIT (Lessening Organ Dysfunction with Vitamin C) trial is a blinded multicenter randomized clinical trial comparing high-dose intravenous vitamin C to placebo in patients admitted to the intensive care unit with proven or suspected infection as the main diagnosis and receiving a vasopressor. ObjectiveWe aim to describe a prespecified statistical analysis plan (SAP) for the LOVIT trial prior to unblinding and locking of the trial database. MethodsThe SAP was designed by the LOVIT principal investigators and statisticians, and approved by the steering committee and coinvestigators. The SAP defines the primary and secondary outcomes, and describes the planned primary, secondary, and subgroup analyses. ResultsThe SAP includes a draft participant flow diagram, tables, and planned figures. The primary outcome is a composite of mortality and persistent organ dysfunction (receipt of mechanical ventilation, vasopressors, or new renal replacement therapy) at 28 days, where day 1 is the day of randomization. All analyses will use a frequentist statistical framework. The analysis of the primary outcome will estimate the risk ratio and 95% CI in a generalized linear mixed model with binomial distribution and log link, with site as a random effect. We will perform a secondary analysis adjusting for prespecified baseline clinical variables. Subgroup analyses will include age, sex, frailty, severity of illness, Sepsis-3 definition of septic shock, baseline ascorbic acid level, and COVID-19 status. ConclusionsWe have developed an SAP for the LOVIT trial and will adhere to it in the analysis phase. International Registered Report Identifier (IRRID)DERR1-10.2196/36261

Abstract Background Sepsis is a health problem of global importance; treatments focus on controlling infection and supporting failing organs. Recent clinical research suggests that intravenous vitamin C may decrease mortality in sepsis. We have designed a randomized controlled trial (RCT) to ascertain the effect of vitamin C on the composite endpoint of death or persistent organ dysfunction at 28 days in patients with sepsis. Methods LOVIT (Lessening Organ dysfunction with VITamin C) is a multicenter, parallel-group, blinded (participants, clinicians, study personnel, Steering Committee members, data analysts), superiority RCT (minimum n = 800). Eligible patients have sepsis as the diagnosis for admission to the intensive care unit (ICU) and are receiving vasopressors. Those admitted to the ICU for more than 24 h are excluded. Eligible patients are randomized to high-dose intravenous vitamin C (50 mg/kg every 6 h for 96 h) or placebo. The primary outcome is a composite of death or persistent organ dysfunction (need for vasopressors, invasive mechanical ventilation, or new and persisting renal replacement therapy) at day 28. Secondary outcomes include persistent organ dysfunction-free days to day 28, mortality and health-related quality of life at 6 months, biomarkers of dysoxia, inflammation, infection, endothelial function, and adverse effects (hemolysis, acute kidney injury, and hypoglycemia). Six subgroup analyses are planned. Discussion This RCT will provide evidence of the effect of high-dose intravenous vitamin C on patient-important outcomes in patients with sepsis. Trial registration clinicaltrials.gov, NCT03680274, first posted 21 September 2018.

Introduction Vasodilatory hypotension is common among intensive care unit (ICU) patients; vasopressors are considered standard of care. However, optimal mean arterial pressure (MAP) targets for vasopressor titration are unknown. The objective of the Optimal VAsopressor TitraTION in patients 65 years and older (OVATION-65) trial is to ascertain the effect of permissive hypotension (vasopressor titration to achieve MAP 60–65 mm Hg) versus usual care on biomarkers of organ injury in hypotensive patients aged ≥65 years.Methods and analysis OVATION-65 is an allocation-concealed randomised trial in 7 Canadian hospitals. Eligible patients are ≥65 years of age, in an ICU with vasodilatory hypotension, receiving vasopressors for ≤12 hours to maintain MAP ≥65 mm Hg during or after adequate fluid resuscitation, and expected to receive vasopressors for ≥6 additional hours. Patients are excluded for any of the following: active treatment for spinal cord or acute brain injury; vasopressors given solely for bleeding, ventricular failure or postcardiopulmonary bypass vasoplegia; withdrawal of life-sustaining treatments expected within 48 hours; death perceived as imminent; previous enrolment in OVATION-65; organ transplant within the last year; receiving extracorporeal life support or lack of physician equipoise. Patients are randomised to permissive hypotension versus usual care for up to 28 days. The primary outcome is high-sensitivity troponin T, a biomarker of cardiac injury, on day 3. Secondary outcomes include biomarkers of injury to other organs (brain, liver, intestine, skeletal muscle); lactate (a biomarker of global tissue dysoxia); resource utilisation; adverse events; mortality (90 days and 6 months) and cognitive function (6 months). Assessors of biomarkers, mortality and cognitive function are blinded to allocation.Ethics and dissemination This protocol has been approved at all sites. Consent is obtained from the eligible patient, the substitute decision-maker if the patient is incapable, or in a deferred fashion where permitted. End-of-grant dissemination plans include presentations, publications and social media platforms and discussion forums.Trial registration number NCT03431181.

Introduction Ventilator-associated pneumonia (VAP) is a common healthcare-associated infection in the intensive care unit (ICU). Probiotics are defined as live microorganisms that may confer health benefits when ingested. Prior randomised trials suggest that probiotics may prevent infections such as VAP and Clostridioides difficile–associated diarrhoea (CDAD). PROSPECT (Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial) is a multicentre, double-blinded, randomised controlled trial comparing the efficacy of the probiotic Lactobacillus rhamnosus GG with usual care versus usual care without probiotics in preventing VAP and other clinically important outcomes in critically ill patients admitted to the ICU.Methods and analysis The objective of E-PROSPECT is to determine the incremental cost-effectiveness of L. rhamnosus GG plus usual care versus usual care without probiotics in critically ill patients. E-PROSPECT will be performed from the public healthcare payer’s perspective over a time horizon from ICU admission to hospital discharge.We will determine probabilities of in-ICU and in-hospital events from all patients alongside PROSPECT. We will retrieve unit costs for each resource use item using jurisdiction-specific public databases, supplemented by individual site unit costs if such databases are unavailable. Direct costs will include medications, personnel costs, radiology/laboratory testing, operative/non-operative procedures and per-day hospital ‘hoteling’ costs not otherwise encompassed. The primary outcome is the incremental cost per VAP prevented between the two treatment groups. Other clinical events such as CDAD, antibiotic-associated diarrhoea and in-hospital mortality will be included as secondary outcomes. We will perform pre-specified subgroup analyses (medical/surgical/trauma; age; frailty status; antibiotic use; prevalent vs no prevalent pneumonia) and probabilistic sensitivity analyses for VAP, then generate confidence intervals using the non-parametric bootstrapping approach.Ethics and dissemination Study approval for E-PROSPECT was granted by the Hamilton Integrated Research Ethics Board of McMaster University on 29 July 2019. Informed consent was obtained from the patient or substitute decision-maker in PROSPECT. The findings of this study will be published in peer-reviewed journals.Trial registration number NCT01782755; Pre-results.

This article seeks to expose the day-to-day implementation of neutrality among teachers in a Quebec context. Its objectives serve first of all to highlight the principles that underlie one of the professional competencies expected of teachers, particularly charged with the question of teacher neutrality, and then observe how it is concretely fulfilled in teaching practice. Finally, we propose to observe the concrete manifestations of the application of neutrality in the light of Jürgen Habermas, inscribed in his Theory of Communicative Action, a particularly fertile theoretical framework for considering how is executed teachers’ practice of neutrality at the "grassroots level". Thus, how does neutrality appear in teachers daily practices ? What are the issues raised by this particular requirement that underlies both prescriptive and communicative dimensions ? These are some of the questions that are discussed in this article.

This article aims to understand the phenomenon of teaching difficulties and suffering from a theoretical point of view, through the sociological and philosophical perspectives of Frankfurt School’s first generation theorists Max Horkheimer and Theodor Adorno. Its main goal is to highlight the possible relation between the microsociological manifestations of suffering experienced in teaching work (adaptation problems, stress, disenchantment vis-à-vis the profession, professional and personal identity changes) and the concept of the instrumental rationalization of the educational systems. What are the possible impacts of this process of rationalization, central to Horkheimer and Adorno’s theories, on the different manifestations of teacher suffering? More specifically, how does the concept of suffering in the two philosopher’s theories allow us to better comprehend the difficulties facing teachers in their work? These are some of the questions that this article aims to answer.