Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit.

BACKGROUND: Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction. METHODS: In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28. RESULTS: A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event. CONCLUSIONS: In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.).

Intravenous Vitamin C for Patients Hospitalized With COVID-19: Two Harmonized Randomized Clinical Trials.

Importance: The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain. Objective: To determine whether vitamin C improves outcomes for patients with COVID-19. Design, Setting, and Participants: Two prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents. Interventions: Patients were randomized to receive vitamin C administered intravenously or control (placebo or no vitamin C) every 6 hours for 96 hours (maximum of 16 doses). Main Outcomes and Measures: The primary outcome was a composite of organ support-free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from -1 organ support-free days for patients experiencing in-hospital death to 22 organ support-free days for those who survived without needing organ support. The primary analysis used a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented efficacy (improved survival, more organ support-free days, or both), an OR less than 1 represented harm, and an OR less than 1.2 represented futility. Results: Enrollment was terminated after statistical triggers for harm and futility were met. The trials had primary outcome data for 1568 critically ill patients (1037 in the vitamin C group and 531 in the control group; median age, 60 years [IQR, 50-70 years]; 35.9% were female) and 1022 patients who were not critically ill (456 in the vitamin C group and 566 in the control group; median age, 62 years [IQR, 51-72 years]; 39.6% were female). Among critically ill patients, the median number of organ support-free days was 7 (IQR, -1 to 17 days) for the vitamin C group vs 10 (IQR, -1 to 17 days) for the control group (adjusted proportional OR, 0.88 [95% credible interval {CrI}, 0.73 to 1.06]) and the posterior probabilities were 8.6% (efficacy), 91.4% (harm), and 99.9% (futility). Among patients who were not critically ill, the median number of organ support-free days was 22 (IQR, 18 to 22 days) for the vitamin C group vs 22 (IQR, 21 to 22 days) for the control group (adjusted proportional OR, 0.80 [95% CrI, 0.60 to 1.01]) and the posterior probabilities were 2.9% (efficacy), 97.1% (harm), and greater than 99.9% (futility). Among critically ill patients, survival to hospital discharge was 61.9% (642/1037) for the vitamin C group vs 64.6% (343/531) for the control group (adjusted OR, 0.92 [95% CrI, 0.73 to 1.17]) and the posterior probability was 24.0% for efficacy. Among patients who were not critically ill, survival to hospital discharge was 85.1% (388/456) for the vitamin C group vs 86.6% (490/566) for the control group (adjusted OR, 0.86 [95% CrI, 0.61 to 1.17]) and the posterior probability was 17.8% for efficacy. Conclusions and Relevance: In hospitalized patients with COVID-19, vitamin C had low probability of improving the primary composite outcome of organ support-free days and hospital survival. Trial Registration: ClinicalTrials.gov Identifiers: NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP).

The evolution of mean arterial pressure in critically ill patients on vasopressors before and during a trial comparing a specific mean arterial pressure target to usual care.

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.

Promoting vaccination in maternity wards ─ motivational interview technique reduces hesitancy and enhances intention to vaccinate, results from a multicentre non-controlled pre- and post-intervention RCT-nested study, Quebec, March 2014 to February 2015.

BackgroundMany countries are grappling with growing numbers of parents who delay or refuse recommended vaccinations for their children. This has created a need for strategies to address vaccine hesitancy (VH) and better support parental decision-making regarding vaccination.AimTo assess vaccination intention (VI) and VH among parents who received an individual motivational-interview (MI) based intervention on infant immunisation during post-partum stay at a maternity ward between March 2014 and February 2015.MethodsThis non-controlled pre-/post-intervention study was conducted using the results from parents enrolled in the intervention arm of the PromoVaQ randomised control trial (RCT), which was conducted in four maternity wards across the Province of Quebec. Participants (n = 1,223) completed pre- and post-intervention questionnaires on VI and VH using Opel's score. Pre-/post-intervention measures were compared using McNemar's test for categorical variables and Wilcoxon signed-rank test for continuous variables.ResultsPre-intervention: overall VI was 78% and significantly differed across maternity wards (74%, 77%, 84%, 79%, p = 0.02). Post-intervention: VI rose significantly across maternity wards (89%, 85%, 95%, 93%) and the overall increase in VI was 12% (78% vs 90%, p < 0.0001). VH corroborated these observations, pre- vs post-intervention, for each maternity ward (28% vs 16%, 29% vs 21%, 27% vs 17%, 24% vs 13%). Overall, VH was curbed post-intervention by 40% (27% vs 16%; p < 0.0001).ConclusionsCompared with pre-intervention status, participants who received the MI-based intervention on immunisation displayed lower hesitancy and greater intention to vaccinate their infant at 2 months of age.

Evolution of metabolic alterations 5 Years after early puberty in a cohort of girls predisposed to polycystic ovary syndrome.

BACKGROUND: We and others have observed that young girls predisposed to polycystic ovary syndrome (PCOS) display defective insulin sensitivity, beta-cell function and non-esterified fatty acids (NEFA) suppressibility during early pubertal years, compared to controls. Our objective is to assess whether these differences in glucose and NEFA metabolisms persist after 5 years in late/post-puberty. METHODS: We conducted a prospective cohort study between 2007 and 2015 with 4-6 years of follow-up in an academic institution research center. We compared 8 daughters and sisters of PCOS women (PCOSr) to 8 age-matched girls unrelated to PCOS (±1.5 years). Girls were assessed initially at 8-14 years old and re-assessed after a median follow-up of 5.4 years, at 13-21 years old. Our main measures were a frequently sampled intravenous glucose tolerance test (FSivGTT)-derived insulin sensitivity (IS) and beta-cell function (disposition index, DIFSivGTT); and indices of NEFA suppression during FSivGTT (logn-linear slope of NEFA and T50 of NEFA suppression). RESULTS: At follow-up, both PCOSr and controls had similar results: IS = 3.2 vs 3.4 (p = 0.88), DIFSivGTT = 1926 vs 1380 (p = 0.44), logn-linear slope = -0.032 vs -0.032 (p = 0.88) and T50NEFA = 18.1 vs 20.8 min (p = 0.57). IS, DIFSivGTT and NEFA suppressibility were stable in PCOSr after 5 years, but decreased significantly in controls (all p < 0.05). CONCLUSIONS: Impaired metabolism observed during early puberty in girls predisposed to PCOS remains stable after 5 years whereas control girls deteriorated their metabolic parameters. Therefore, both groups become comparable in late/post-puberty. Early puberty may thus represent a window during which metabolic alterations are transiently apparent in girls at risk of PCOS.

Higher maternal leptin levels at second trimester are associated with subsequent greater gestational weight gain in late pregnancy.

BACKGROUND: Excessive gestational weight gain (GWG) is associated with adverse pregnancy outcomes. In non-pregnant populations, low leptin levels stimulate positive energy balance. In pregnancy, both the placenta and adipose tissue contribute to circulating leptin levels. We tested whether maternal leptin levels are associated with subsequent GWG and whether this association varies depending on stage of pregnancy and on maternal body mass index (BMI). METHODS: This prospective cohort study included 675 pregnant women followed from 1(st) trimester until delivery. We collected anthropometric measurements, blood samples at 1(st) and 2(nd) trimester, and clinical data until delivery. Maternal leptin was measured by ELISA (Luminex technology). We classified women by BMI measured at 1(st) trimester: BMI < 25 kg/m(2) = normal weight; 25 ≤ BMI < 30 kg/m(2) = overweight; and BMI ≥ 30 kg/m(2) = obese. RESULTS: Women gained a mean of 6.7 ± 3.0 kg between 1(st) and 2(nd) trimester (mid pregnancy GWG) and 5.6 ± 2.5 kg between 2(nd) and the end of 3(rd) trimester (late pregnancy GWG). Higher 1(st) trimester leptin levels were associated with lower mid pregnancy GWG, but the association was no longer significant after adjusting for % body fat (%BF; ß = 0.38 kg per log-leptin; SE = 0.52; P = 0.46). Higher 2(nd) trimester leptin levels were associated with greater late pregnancy GWG and this association remained significant after adjustment for BMI (ß = 2.35; SE = 0.41; P < 0.0001) or %BF (ß = 2.01; SE = 0.42; P < 0.0001). In BMI stratified analyses, higher 2(nd) trimester leptin levels were associated with greater late pregnancy GWG in normal weight women (ß = 1.33; SE = 0.42; P =0.002), and this association was stronger in overweight women (ß = 2.85; SE = 0.94; P = 0.003--P for interaction = 0.05). CONCLUSIONS: Our results suggest that leptin may regulate weight gain differentially at 1(st) versus 2(nd) trimester of pregnancy: at 2(nd) trimester, higher leptin levels were associated with greater subsequent weight gain--the opposite of its physiologic regulation in non-pregnancy--and this association was stronger in overweight women. We suspect the existence of a feed-forward signal from leptin in second half of pregnancy, stimulating a positive energy balance and leading to greater weight gain.

Timing of Excessive Weight Gain During Pregnancy Modulates Newborn Anthropometry.

OBJECTIVE: Excessive gestational weight gain (GWG) is associated with increased birth weight and neonatal adiposity. However, timing of excessive GWG may have a differential impact on birth outcomes. The objective of this study was to compare the effect of early and mid/late excessive GWG on newborn anthropometry in the context of the Canadian clinical recommendations that are specific for first trimester and for second/third trimesters based on maternal pre-pregnancy BMI. METHODS: We included 607 glucose-tolerant women in our main analyses, after excluding women who had less than the recommended total GWG. Maternal body weight was measured in early pregnancy, mid-pregnancy, and late pregnancy. Maternal and fetal clinical outcomes were collected, including newborn anthropometry. Women were divided into four groups according to the Canadian guidelines for GWG in the first and in the second/third trimesters: (1) "overall non-excessive" (reference group); (2) "early excessive GWG"; (3) "mid/late excessive GWG"; and (4) "overall excessive GWG." Differences in newborn anthropometry were tested across GWG categories. RESULTS: Women had a mean (±SD) pre-pregnancy BMI of 24.7 ± 5.2 kg/m(2) and total GWG of 15.3 ± 4.4 kg. Women with mid/late excessive GWG gave birth to heavier babies (gestational age-adjusted birth weight z-score 0.33 ± 0.91) compared with women in the reference group (0.00 ± 0.77, P = 0.007), whereas women with early excessive GWG gave birth to babies of similar weight (gestational age-adjusted z-score 0.01 ± 0.86) to the reference group (0.00 ± 0.77, P = 0.84). When we stratified our analyses and investigated women who gained within the recommendations for total GWG, mid/late excessive GWG specifically was associated with greater newborn size, similar to our main analyses. CONCLUSION: Excessive GWG in mid/late pregnancy in women who did not gain weight excessively in early pregnancy is associated with increased birth size, even in those who gained within the Canadian recommendations for total GWG.

Expression and role of the angiotensin II AT2 receptor in human prostate tissue: in search of a new therapeutic option for prostate cancer.

BACKGROUND: Evidence shows that angiotensin II type 1 receptor (AT1R) blockers may be associated with improved outcome in prostate cancer patients. It has been proposed that part of this effect could be due to angiotensin II type 2 receptor (AT2R) activation, the only active angiotensin II receptor in this situation. This study aimed to characterize the localization and expression of AT2R in prostate tissues and to assess its role on cell morphology and number in prostatic epithelial cells in primary culture. METHODS: AT2R and its AT2R-interacting protein (ATIP) expression were assessed on non-tumoral and tumoral human prostate using tissue microarray immunohistochemistry, binding assay, and Western blotting. AT2R effect on cell number was measured in primary cultures of epithelial cells from non-tumoral human prostate. RESULTS: AT2R was localized at the level of the acinar epithelial layer and its expression decreased in cancers with a Gleason score 6 or higher. In contrast, ATIP expression increased with cancer progression. Treatment of primary cell cultures from non-tumoral prostate tissues with C21/M024, a selective AT2R agonist, alone or in co-incubation with losartan, an AT1R antagonist, significantly decreased cell number compared to untreated cells. CONCLUSIONS: AT2R and ATIP are present in non-tumoral human prostate tissues and differentially regulated according to Gleason score. The decrease in non-tumoral prostate cell number upon selective AT2R stimulation suggests that AT2R may have a protective role against prostate cancer development. Treatment with a selective AT2R agonist could represent a new approach for prostate cancer prevention or for patients on active surveillance.

Impact of maternal use of asthma-controller therapy on perinatal outcomes.

BACKGROUND: Asthma during pregnancy usually requires treatment with controller medications about which more safety information is needed. The objectives are to assess the impact of the use of long-acting ß2-agonists (LABAs) and the dose of inhaled corticosteroids (ICSs) during pregnancy on the prevalence of low birth weight (LBW), preterm birth (PB) and small for gestational age (SGA). METHODS: A cohort of women with asthma giving birth from 1998 to 2008 was constructed from Québec (Canada) administrative databases. LBW was defined as weight <2500 g, PB as delivery before 37 weeks' gestation and SGA as a birth weight below the 10th percentile. The impact of the use of LABAs and the dose of ICSs during pregnancy on the outcomes was determined with generalised-estimating-equation models. RESULTS: The cohort included 7376 pregnancies: 8.8% exposed to LABAs and 56.9% exposed to ICSs. All LABA users also received ICSs. The prevalence of LBW, PB and SGA was 7.7%, 9.5% and 13.5%, respectively. LABA use was not found to be associated with increased prevalence of LBW (OR 0.81; 95% CI 0.58 to 1.12), PB (OR 0.84; 95% CI 0.61 to 1.15) or SGA (OR 0.92; 95% CI 0.70 to 1.20). Mean ICSs doses >125 µg/day (fluticasone-equivalent) were associated with a non-significant trend of increased LBW, PB and SGA. CONCLUSIONS: Despite the possibility of residual confounding due to uncontrolled or more severe asthma or smoking status, the use of LABA and low to moderate doses of ICSs were not associated with increased prevalence of perinatal outcomes. Additional research on higher ICSs doses is required to better evaluate their safety during pregnancy.

Program of Uncontrolled Donation After Circulatory Death as Potential Solution to the Shortage of Organs: A Canadian Single-Center Retrospective Cohort Study.

Purpose: Worldwide, the number of patients waiting for organ transplantation exceeds the number of organs available. Program for uncontrolled donation after circulatory death (uDCD) implemented in Europe has resulted in a 10-15% expansion of the donor pool. We aimed to describe the number of patients eligible for an uDCD program in a regional tertiary care center. Methods: We conducted a retrospective cohort study in a Canadian tertiary academic center located in a rural area including all adults who received cardiopulmonary resuscitation in 2016 and died in the emergency department (ED) or during their hospitalization. The primary outcome was the number of patients eligible for uDCD defined as aged between 18 and 60 years old whose collapse was witnessed and where the time between cardiac arrest to cardiopulmonary resuscitation and ED arrival was, respectively, less than 30 and 120 minutes. As a secondary outcome, we determined the number of patients eligible for controlled donation after circulatory death. Results: Of the 130 patients included, 84 did not return to spontaneous circulation. We identified 15 potential uDCD candidates, with a mean age of 46.6 (95% Confidence Interval [CI] 41.3 to 52) years. Twelve had an out-of-hospital cardiac arrest with a mean time between collapse and arrival to the ED of 43.2 (29.8 to 56.6) minutes. Among the 46 patients who died after a return of spontaneous circulation, 10 (21.7%) were eligible for organ donation after circulatory death. Conclusion: Implementing an uDCD program in a tertiary hospital covering a rural area could increase the number of donors.

Time-course full profiling of circulating miRNAs in neurologically deceased organ donors: a proof of concept study to understand the onset of the cytokine storm.

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.

Training Intervention and Program of Support for Fostering the Adoption of Family-Centered Telehealth in Pediatric Rehabilitation: Protocol for a Multimethod, Prospective, Hybrid Type 3 Implementation-Effectiveness Study.

BACKGROUND: Children with disability face long wait times for rehabilitation services. Before the COVID-19 pandemic, telehealth adoption was low across pediatric rehabilitation. Owing to the COVID-19 pandemic restrictions, pediatric therapists were asked to rapidly shift to telehealth, often with minimal training. To facilitate the behavior changes necessary for telehealth adoption, provision of appropriate evidence-based training and support is required. However, evidence to support the effective implementation of such training is lacking. The successful real-world implementation of a training intervention and program of support (TIPS) targeting pediatric therapists to enhance the adoption of family-centered telerehabilitation (FCT) requires the evaluation of both implementation and effectiveness. OBJECTIVE: This study aimed to evaluate TIPS implementation in different pediatric rehabilitation settings and assess TIPS effectiveness, as it relates to therapists' adoption, service wait times, families' perception of service quality, and costs. METHODS: This 4-year, pan-Canadian study involves managers, pediatric occupational therapists, physiotherapists, speech-language pathologists, and families from 20 sites in 8 provincial jurisdictions. It will use a multimethod, prospective, hybrid type 3 implementation-effectiveness design. An interrupted time series will assess TIPS implementation. TIPS will comprise a 1-month training intervention with self-paced learning modules and a webinar, followed by an 11-month support program, including monthly site meetings and access to a virtual community of practice. Longitudinal mixed modeling will be used to analyze indicators of therapists' adoption of and fidelity to FCT collected at 10 time points. To identify barriers and facilitators to adoption and fidelity, qualitative data will be collected during implementation and analyzed using a deductive-inductive thematic approach. To evaluate effectiveness, a quasi-experimental pretest-posttest design will use questionnaires to evaluate TIPS effectiveness at service, therapist, and family levels. Generalized linear mixed effects models will be used in data analysis. Manager, therapist, and family interviews will be conducted after implementation and analyzed using reflective thematic analysis. Finally, cost data will be gathered to calculate public system and societal costs. RESULTS: Ethics approval has been obtained from 2 jurisdictions (February 2022 and July 2022); approval is pending in the others. In total, 20 sites have been recruited, and data collection is anticipated to start in September 2022 and is projected to be completed by September 2024. Data analysis will occur concurrently with data collection, with results disseminated throughout the study period. CONCLUSIONS: This study will generate knowledge about the effectiveness of TIPS targeting pediatric therapists to enhance FCT adoption in pediatric rehabilitation settings, identify facilitators for and barriers to adoption, and document the impact of telehealth adoption on therapists, services, and families. The study knowledge gained will refine the training intervention, enhance intervention uptake, and support the integration of telehealth as a consistent pediatric rehabilitation service option for families of children with disabilities. TRIAL REGISTRATION: ClinicalTrials.gov NCT05312827; https://clinicaltrials.gov/ct2/show/NCT05312827. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/40218.

Lessening Organ Dysfunction With Vitamin C (LOVIT) Trial: Statistical Analysis Plan.

BACKGROUND: The 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. OBJECTIVE: We aim to describe a prespecified statistical analysis plan (SAP) for the LOVIT trial prior to unblinding and locking of the trial database. METHODS: The 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. RESULTS: The 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. CONCLUSIONS: We 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.

The Canadian Pediatric Cardiology Research Network: A Model National Data-Sharing Organization to Facilitate the Study of Pediatric Heart Diseases.

BACKGROUND: Common hurdles to pediatric cardiology research include the heterogeneity and relative rarity of specific cardiac malformations, the potential for effect of residual lesions occurring decades after repair, and the scarcity of objective and easily measurable outcomes such as death and transplantation. METHODS: To help meet these challenges, the Canadian Pediatric Cardiology Research Network (CPCRN) was founded by the Canadian Pediatric Cardiology Association to link Canadian academic institutions to promote and facilitate multicollaborations for the benefit of pediatric and congenital cardiology research. The overarching goal of the CPCRN is to build a national framework that harnesses the strong desire for collaboration within the pediatric cardiology community and to identify solutions to barriers that impede multicentre partnerships. RESULTS: In this report, the authors describe the approach and the components of the CPCRN. Specifically, we detail the rolling out of a pan-Canadian master agreement that covers current and future studies, the systematic banking of all project data, and the mechanisms developed to facilitate secondary use of data. CONCLUSIONS: This experience could help guide the formation of other national research groups, particularly those focused on congenital or rare diseases.

CONTEXTE: Les obstacles courants dans le domaine de la recherche en cardiologie pédiatrique comprennent l'hétérogénéité et la rareté des malformations cardiaques, le fait que des lésions résiduelles aient des répercussions qui se manifesteront des décennies après une intervention, et la rareté des issues cliniques objectives et facilement mesurables comme les décès et les transplantations. MÉTHODOLOGIE: Pour remédier à ces obstacles, le Réseau canadien de recherche en cardiologie pédiatrique (CPCRN) a été fondé par la l'Association canadienne de cardiologie pédiatrique afin de mettre en relation les établissements universitaires canadiens et de promouvoir ainsi des collaborations multiples qui bénéficieront à la recherche en cardiologie pédiatrique et congénitale. L'objectif principal du CPCRN est de mettre sur pied une structure nationale qui tire profit de l'important désir de collaboration dans le domaine de la cardiologie pédiatrique et de trouver des solutions aux obstacles qui nuisent aux partenariats entre les différents établissements. RÉSULTATS: Dans cet article, les auteurs décrivent l'approche et les composantes du CPCRN. Ils passent en revue les détails du déploiement d'une entente-cadre pancanadienne concernant les études en cours et à venir, la mise en banque systématique de toutes les données de recherche et les mécanismes mis au point pour permettre l'utilisation secondaire de ces données. CONCLUSIONS: Cette expérience pourrait permettre de guider la formation d'autres groupes de recherche nationaux, plus particulièrement dans les domaines des maladies rares ou congénitales.

Patient-partner engagement at the Centre de recherche du CHUS in the Province of Québec, Canada: from an intuitive methodology to outreach after three years of implementation.

BACKGROUND: Medical societies and funding agencies strongly recommend that patients be included as partners in research publications and grant applications. Although this "top-down" approach is certainly efficient at forcing this new and desirable type of collaboration, our past experience demonstrated that it often results in an ambiguous relationship as not yet well integrated into the cultures of either patients' or the researchers'. The question our group raised from this observation was: "How to generate a cultural shift toward a fruitful and long-lasting collaboration between patients and researchers? A "bottom-up" approach was key to our stakeholders. The overall objective was to build a trusting and bidirectional-ecosystem between patients and researchers. The specific objectives were to document: 1) the steps that led to the development of the first patient-partner strategic committee within a research center in the Province of Québec; 2) the committee's achievements after 3 years. METHODS: Eighteen volunteer members, 12 patient-partners and 6 clinician/institutional representatives, were invited to represent the six research themes of the Centre de recherche du CHU de Sherbrooke (CRCHUS) (Quebec, Canada). Information on the services offered by Committee was disseminated internally and to external partners. Committee members satisfaction was evaluated. RESULTS: From May 2017 to April 2020, members attended 29 scheduled and 6 ad hoc meetings and contributed to activities requiring over 1000 h of volunteer time in 2018-2019 and 1907 h in the 2019-2020 period. The Committee's implication spanned governance, expertise, and knowledge transfer in research. Participation in these activities increased annually at local, provincial, national and international levels. The Patient-Partner Committee collaborated with various local (n = 7), provincial (n = 6) and national (n = 4) partners. Member satisfaction with the Committee's mandate and format was 100%. CONCLUSIONS: The CRCHUS co-constructed a Patient-Partner Strategic Committee which resulted in meaningful bilateral, trusting and fruitful collaborations between patients, researchers and partners. The "bottom-up" approach - envisioned and implemented by the Committee, where the expertise and the needs of patients complemented those of researchers, foundations, networks and decision-makers - is key to the success of a cultural shift. The CRCHUS Committee created a hub to develop the relevant intrinsic potential aimed at changing the socio-cultural environment of science.

Inhibition of DHCR24/seladin-1 impairs cellular homeostasis in prostate cancer.

BACKGROUND: Seladin-1 belongs to a subgroup of androgen-dependent genes associated with anti-proliferative, pro-differentiation, and pro-apoptotic functions and plays a protective role against oncogenic stress. The present study aims to investigate the localization and expression of Seladin-1 protein in normal and tumoral human prostatic tissues as well as to explore its role in proliferation and steroid secretion in androgen-dependent (LnCaP) and androgen-independent (DU145) cell lines and in human prostate primary cell culture. METHODS: Seladin-1 protein localization and expression were assessed on whole tissue sections by tissue array/immunohistochemistry and following immunofluorescence and Western blotting. Proliferation (Ki67 fluorescence labeling and cell counts) and steroid secretion (ELISA) were assessed in cell lines and primary epithelial cell cultures. RESULTS: In human prostatic tissue and cells, Seladin-1 was mostly localized within epithelial and rarely within stromal cells and primarily present in secretory luminal cells of normal and tumoral prostate cells. Its expression was increased in low-risk prostate cancer but reduced in advanced prostate cancers when compared to normal tissues. Seladin-1 was highly expressed in LnCaP, whereas its expression level was lower in DU145 cells. Seladin-1 inhibition by treatment with its specific inhibitor, U18666A (75 nM), increased proliferation in LnCaP and primary cell culture, as well as testosterone and dihydrotestosterone levels in both LnCaP and DU145 cell lines. CONCLUSIONS: Seladin-1 involvement in proliferation and secretion suggests that its downregulation may be a major mechanism causing prostate cancer evolution. Seladin-1 may thus potentially decrease cell growth and steroid dependency in low-grade prostate cancer.

Fetal adrenal gland alterations in a rat model of adverse intrauterine environment.

By feeding a low-sodium diet to dams over the last third of gestation, we have developed an animal model of intrauterine growth restriction (IUGR). Given that fetal adrenal development and maturation occur during late gestation in rats, the aim of this study was to evaluate the expression of proteins and enzymes involved in steroidogenesis and catecholamine synthesis in adrenal glands from IUGR fetuses. A gene microarray was performed to investigate for alteration in the pathways participating in hormone production. Results show that increased aldosterone serum concentrations in IUGR fetuses were associated with higher mRNA adrenal levels of angiotensin II receptor type 1 (AT(1)R) and cytochrome P450 aldosterone synthase in response to decreased serum sodium content. Conversely, reduced serum corticosterone concentrations in these fetuses appear to result from alterations in gene expression involved in cholesterol metabolism, such as the augmented apolipoprotein E levels, and in steroidogenesis, like the decreased levels of cytochrome P45011beta-hydroxylase. Furthermore, increased AT(2)R expression and the presence of hypoxia and oxidative stress may, in turn, explain the higher adrenal mRNA levels of enzymes involved in catecholamine synthesis. Despite this increase, catecholamine adrenal content was reduced in males and was similar in females compared with sex-matched controls, suggesting higher catecholamine secretion. This could be associated with the induction of genes involved in inflammation-related, acute-phase response in IUGR fetuses. All of these alterations could have long-lasting health effects and may, hence, be implicated in the pathogenesis of increased blood pressure and cardiac hypertrophy observed in IUGR adult animals from this model.

Optimal VAsopressor TitraTION in patients 65 years and older (OVATION-65): protocol and statistical analysis plan for a randomised clinical trial.

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.

Lessening Organ dysfunction with VITamin C (LOVIT): protocol for a randomized controlled trial.

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.

Drug-induced sleep endoscopy compared with systematic adenotonsillectomy in the management of obstructive sleep apnoea in children: a systematic review and meta-analysis protocol.

INTRODUCTION: Obstructive sleep apnoea affects up to 6% of children worldwide. Although current guidelines recommend systematic tonsillectomy and adenoidectomy, many children do not benefit from these interventions. Drug-induced sleep endoscopy (DISE) allows the dynamic evaluation of patients' airways to identify the specific anatomic sites of obstruction. This intervention can potentially guide subsequent invasive procedures to optimise outcomes and minimise the number of children exposed to unnecessary operations. METHODS AND ANALYSIS: We will identify randomised controlled trials and controlled observational studies comparing DISE-directed interventions to systematic tonsillectomy and adenoidectomy in paediatric populations. We will search MEDLINE, EMBASE, CINAHL, CENTRAL as well as clinical trial registries and conference proceedings (initial electronic search date 9 October 2018). Screening, data extraction and risk of bias assessments will be performed in duplicate by independent reviewers. We will use the Grading of Recommendations Assessment, Development and Evaluation approach to assess the overall quality of evidence and present our results. ETHICS AND DISSEMINATION: Ethics approval is not required for this systematic review of published data. This review will be presented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We will present our findings at otorhinolaryngology conferences and publish a report in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42018085370.