Effect of spirulina on risk of hospitalization among patients with COVID-19: the TOGETHER randomized trial.

BACKGROUND: Algae-derived nutraceuticals, such as spirulina, have been reported to have biological activities that may minimize clinical consequences to COVID-19 infections. OBJECTIVES: This study aimed to determine whether spirulina is an effective treatment for high-risk patients with early COVID-19 in an outpatient setting. METHODS: The TOGETHER trial is a placebo-controlled, randomized, platform trial conducted in Brazil. Eligible participants were symptomatic adults with a positive rapid test for SARS-CoV-2 older than 50 y or with a known risk factor for disease severity. Patients were randomly assigned to receive placebo or spirulina (1 g twice daily for 14 d). The primary end point was hospitalization defined as either retention in a COVID-19 emergency setting for >6 h or transfer to tertiary hospital owing to COVID-19 at 28 d. Secondary outcomes included time-to-hospitalization, mortality, and adverse drug reactions. We used a Bayesian framework to compare spirulina with placebo. RESULTS: We recruited 1126 participants, 569 randomly assigned to spirulina and 557 to placebo. The median age was 49.0 y, and 65.3% were female. The primary outcome occurred in 11.2% in the spirulina group and 8.1% in the placebo group (odds ratio [OR]: 1.24; 95% credible interval: 0.84, 1.86). There were no differences in emergency department visit (OR: 1.21; 95% credible interval: 0.81, 1.83), nor time to symptom relief (hazard ratio: 0.90; 95% credible interval: 0.79, 1.03). Spirulina also not demonstrate important treatment effects in the prespecified subgroups defined by age, sex, BMI, days since symptom onset, or vaccination status. CONCLUSIONS: Spirulina has no any clinical benefits as an outpatient therapy for COVID-19 compared with placebo with respect to reducing the retention in an emergency setting or COVID-19-related hospitalization. There are no differences between spirulina and placebo for other secondary outcomes. This trial was registered at clinicaltrials.gov as NCT04727424.

Selective early medical treatment of the patent ductus arteriosus in extremely low gestational age infants: a pilot randomised controlled trial protocol (SMART-PDA).

INTRODUCTION: Patent ductus arteriosus (PDA) is the most common cardiovascular problem that develops in extremely preterm infants and is associated with poor clinical outcomes. Uncertainty exists on whether early pharmacotherapeutic treatment of a clinically symptomatic and echocardiography-confirmed haemodynamically significant PDA in extremely preterm infants improves outcomes. Given the wide variation in the approach to PDA treatment in this gestational age (GA) group, a randomised trial design is essential to address the question. Before embarking on a large RCT in this vulnerable population, it is important to establish the feasibility of such a trial. METHODS AND ANALYSIS: Design: a multi-centre, open-labelled, parallel-designed pilot randomised controlled trial. Participants: preterm infants born <26 weeks of gestation with a PDA diagnosed within 72 hours after birth. Intervention (selective early medical treatment (SMART) strategy): selective early pharmacological treatment of a moderate-severe PDA shunt (identified based on pre-defined clinical signs and routine screening echocardiography) within the first 72 postnatal hours with provision for repeat treatment if moderate-severe shunt persists. Comparison (early conservative management strategy): no treatment of PDA in the first postnatal week. Primary outcomes: (1) proportion of eligible infants recruited during the study period; (2) proportion of randomised infants treated outside of protocol-mandated therapy. Sites and sample size: the study is being conducted in seven neonatal intensive care units across Canada and the USA with a target of 100 randomised infants. Analysis: the primary feasibility outcomes will be expressed as proportions. A pre-planned Bayesian analysis will be conducted for secondary clinical outcomes such as mortality, severe intraventricular haemorrhage, procedural PDA closure and chronic lung disease to aid stakeholders including parent representatives decide on the appropriateness of enrolling this vulnerable population in a larger trial if the feasibility of recruitment in the pilot trial is established. ETHICS AND DISSEMINATION: The study has been approved by the IWK Research Ethics Board (#1027298) and six additional participating sites. On the completion of the study, results will be presented at national and international meetings, published in peer-reviewed journals and incorporated into existing systematic reviews. TRIAL REGISTRATION NUMBER: NCT05011149 (WHO Trial Registration Data Set in Appendix A). PROTOCOL VERSION: Ver 7.2 (dated July 19, 2023).

Disparity between statistical and clinical significance in published randomised controlled trials indexed in PubMed: a protocol for a cross-sectional methodological survey.

INTRODUCTION: The commonly used frequentist paradigm of null hypothesis statistics testing with its reliance on the p-value and the corresponding notion of 'statistical significance' has been under ongoing criticism. Misinterpretation and misuse of the p-value have contributed to publication bias, unreliable studies, frequent false positives, fraud and mistrust in results of scientific studies. While p-values themselves are still useful, part of the problem may be the confusion between statistical and clinical significance. In randomised controlled trials of health interventions, this confusion could lead to erroneous conclusions about treatment efficacy, research waste and compromised patient outcomes. The extent to which clinical and statistical significance of published randomised clinical trials do not match is not known. This is a protocol for a methodological study to understand the extent of the problem of disparities between statistical and clinical significance in published clinical trials, and to identify and assess the factors associated with discrepant results in these studies. METHODS AND ANALYSIS: A methodological survey of published randomised controlled trials is planned. Trials published between 2018 and 2022 and their protocols will be searched and screened for inclusion, with a planned sample size of 500 studies. The reported minimum clinically important difference, the study effect size and confidence intervals will be used to assess clinical importance of trial results. Comparison of statistical significance and clinical importance of the trial results will be used to determine disparity. Data will be analysed to estimate the outcomes, and factors associated with disparate study results will be assessed using logistic regression analysis. ETHICS AND DISSEMINATION: Ethical approval for the study has been granted by Stellenbosch University's Health Research Ethics Committee. This is part of a larger study towards a PhD in Biostatistics and will be disseminated as a thesis, conference abstract and peer-reviewed manuscript.

Long-Term Kidney Outcomes after Pediatric Acute Kidney Injury.

BACKGROUND: Acute kidney injury (AKI) is common in hospitalized children. Pediatric AKI receiving acute kidney replacement therapy (KRT) is associated with long-term chronic kidney disease (CKD), hypertension, and death. We aim to determine the outcomes after AKI in children who did not receive acute KRT, since these remain uncertain. METHODS: Retrospective cohort study of all hospitalized children (0-18 years) surviving AKI without acute KRT between 1996-2020 in Ontario, Canada, identified by validated diagnostic codes in provincial administrative health databases. Children with prior KRT, CKD, or AKI were excluded. Cases were matched with up to four hospitalized comparators without AKI by age, neonatal status, sex, intensive care unit admission, cardiac surgery, malignancy, hypertension, hospitalization era, and a propensity score for AKI. Patients were followed until death, provincial emigration, or censoring in March 2021. The primary outcome was long-term major adverse kidney events (MAKE-LT; a composite of all-cause mortality, long-term KRT, or incident CKD). RESULTS: We matched 4,173 pediatric AKI survivors with 16,337 hospitalized comparators. Baseline covariates were well-balanced following propensity score matching. During median 9.7-year follow-up, 18% of AKI survivors developed MAKE-LT vs. 5% of hospitalized comparators (hazard ratio [HR] 4.0, 95% confidence interval [CI] 3.6-4.4). AKI survivors had higher rates of long-term KRT (2% vs. <1%; HR 11.7, 95%CI 7.5-18.4), incident CKD (16% vs. 2%; HR 7.9, 95%CI 6.9-9.1), incident hypertension (17% vs. 8%; HR 2.3, 95%CI 2.1-2.6), and AKI during subsequent hospitalization (6% vs. 2%; HR 3.7, 95%CI 3.1-4.5), but no difference in all-cause mortality (3% vs. 3%; HR 0.9, 95%CI 0.7-1.1). CONCLUSIONS: Children surviving AKI without acute KRT were at higher long-term risk of CKD, long-term KRT, hypertension, and subsequent AKI vs. hospitalized comparators.

Statistical analysis plan for the SQUEEZE trial: A trial to determine whether septic shock reversal is quicker in pediatric patients randomized to an early goal-directed fluid-sparing strategy vs. usual care (SQUEEZE).

Background: The SQUEEZE trial is a multicentred randomized controlled trial which seeks to determine the optimal approach to fluid resuscitation in paediatric septic shock. SQUEEZE also includes a nested translational study, SQUEEZE-D, investigating the value of plasma cell-free DNA for prediction of clinical outcomes. Objective: To present a pre-specified statistical analysis plan (SAP) for the SQUEEZE trial prior to finalizing the trial data set and prior to commencing data analysis. Design: SQUEEZE is a pragmatic, two-arm, open-label, prospective multicentre randomized controlled trial. Setting: Canadian paediatric tertiary care centres. Participants: Paediatric patients with suspected sepsis and persistent signs of shock in need of ongoing resuscitation. Sample size target: 400 participants. Interventions: The trial is designed to compare a fluid-sparing resuscitation strategy to usual care. Main outcome measures: The primary outcome for the SQUEEZE trial is the time to shock reversal (in hours). The primary outcome analysis will assess the difference in time to shock reversal between the intervention and control groups, reported as point estimate with 95% confidence intervals. The statistical test for the primary analysis will be a two-sided t-test. Secondary outcome measures include clinical outcomes and adverse events including measures of organ dysfunction and mortality outcomes. Results: The SAP presented here is reflective of and where necessary clarifies in detail the analysis plan as presented in the trial protocol. The SAP includes a mock CONSORT diagram, figures and tables. Data collection methods are summarized, primary and secondary outcomes are defined, and outcome analyses are described. Conclusions: We have developed a statistical analysis plan for the SQUEEZE Trial for transparency and to align with best practices. Analysis of SQUEEZE Trial data will adhere to the SAP to reduce the risk of bias. Registration: ClinicalTrials.gov identifiers: Definitive trial NCT03080038; Registered Feb 28, 2017. Pilot Trial NCT01973907; Registered Oct 27, 2013.

Enrollment of Black, Indigenous and People of Color (BIPOC) and female participants in the US diabetes trials spanning 2000 to 2020: A chronological survey.

AIMS: Little is known about the enrollment practice of both Black, Indigenous and People of Color (BIPOC) and females in the US diabetes trials. We aimed to perform a chronological survey to evaluate the enrollment of BIPOC and female participants in the US diabetes randomized controlled trials (RCTs) over the past two decades. METHODS: We searched databases to systematically include the US diabetes RCTs from 2000 January 1st to 2020 December 31st. Primary outcome was the adequate enrollment of both BIPOC and females, defined by the participation to prevalence ratio (PPR) > 0.8. We tested the temporal trend in adequate enrollment over time and used logistic regression analysis to explore the relationship between adequate enrollment and trial characteristics. RESULTS: A total of 69 US diabetes trials were included for analyses, with a median BIPOC and female enrollment percentage of 29.0 % and 45.4 % respectively. There were 22 (31.9 %) trials with adequate enrollment of both BIPOC and females. No significant trend of adequate enrollment percentage of BIPOC and females over time was observed (P = 0.16). Of trial types, those with medication interventions were significantly related to decreased odds of adequate enrollment, when compared to trials with non-drug interventions (odds ratio = 0.29, 95 % confidence interval: 0.11-0.84). CONCLUSIONS: Less than one third of the US diabetes trials adequately enrolled both BIPOC and females over the past two decades, and no temporal improvement in BIPOC and female participant enrollment was observed. These results highlight the need for more endeavors to mitigate inadequate representation regarding BIPOC and female enrollment in diabetes trials.

Association between Complications and Death within 30 days after General Surgery: A Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) substudy.

OBJECTIVE: To determine the epidemiology of post-operative complications among general surgery patients, inform their relationships with 30-day mortality, and determine the attributable fraction of death of each postoperative complication. BACKGROUND: The contemporary causes of post-operative mortality among general surgery patients are not well characterized. METHODS: VISION is a prospective cohort study of adult non-cardiac surgery patients across 28 centres in 14 countries, who were followed for 30 days after surgery. For the subset of general surgery patients, a cox proportional hazards model was used to determine associations between various surgical complications and post-operative mortality. The analyses were adjusted for preoperative and surgical variables. Results were reported in adjusted hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Among 7950 patients included in the study, 240 (3.0%) patients died within 30 days of surgery. Five post-operative complications (myocardial injury after non-cardiac surgery [MINS], major bleeding, sepsis, stroke, and acute kidney injury resulting in dialysis) were independently associated with death. Complications associated with the largest attributable fraction (AF) of post-operative mortality (i.e., percentage of deaths in the cohort that can be attributed to each complication, if causality were established) were major bleeding (n=1454, 18.3%, HR 2.49 95%CI 1.87-3.33, P<0.001, AF 21.2%), sepsis (n=783, 9.9%, HR 6.52, 95%CI 4.72-9.01, P<0.001, AF 15.6%), and MINS (n=980, 12.3%, HR 2.00, 95%CI 1.50-2.67, P<0.001, AF 14.4%). CONCLUSION: The complications most associated with 30-day mortality following general surgery are major bleeding, sepsis, and MINS. These findings may guide the development of mitigating strategies, including prophylaxis for perioperative bleeding.

Hip fracture rate and osteoporosis treatment in Ontario: A population-based retrospective cohort study.

This population-based study analyzes hip fracture and osteoporosis treatment rates among older adults, stratified by place of residence prior to fracture. Hip fracture rates were higher among older adults living in the community and discharged to long-term care (LTC) after fracture, compared to LTC residents and older adults living in the community. Only 23% of LTC residents at high fracture risk received osteoporosis treatment. PURPOSE: This population-based study examines hip fracture rate and osteoporosis management among long-term care (LTC) residents > 65 years of age compared to community-dwelling older adults at the time of fracture and admitted to LTC after fracture, in Ontario, Canada. METHODS: Healthcare utilization and administrative databases were linked using unique, encoded identifiers from the ICES Data Repository to estimate hip fractures (identified using the Public Health Agency of Canada algorithm and International Classification of Diseases (ICD)-10 codes) and osteoporosis management (pharmacotherapy) among adults > 66 years from April 1, 2014 to March 31, 2018. Sex-specific and age-standardized rates were compared by pre-fracture residency and discharge location (i.e., LTC to LTC, community to LTC, or community to community). Fracture risk was determined using the Fracture Risk Scale (FRS). RESULTS: At baseline (2014/15), the overall age-standardized hip fracture rate among LTC residents was 223 per 10,000 person-years (173 per 10,000 females and 157 per 10,000 males), 509 per 10,000 person-years (468 per 10,000 females and 320 per 10,000 males) among the community to LTC cohort, and 31.5 per 10,000 person-years (43.1 per 10,000 females and 25.6 per 10,000 males). During the 5-year observation period, the overall annual average percent change (APC) for hip fracture increased significantly in LTC (AAPC = + 8.6 (95% CI 5.0 to 12.3; p = 0.004) compared to the community to LTC group (AAPC = + 2.5 (95% CI - 3.0 to 8.2; p = 0.248)) and the community-to-community cohort (AAPC - 3.8 (95% CI - 6.7 to - 0.7; p = 030)). However, hip fracture rate remained higher in the community to LTC group over the study period. There were 33,594 LTC residents identified as high risk of fracture (FRS score 4 +), of which 7777 were on treatment (23.3%). CONCLUSION: Overall, hip fracture rates have increased in LTC and among community-dwelling adults admitted to LTC after fracture. However, hip fracture rates among community-dwelling adults have decreased over time. A non-significant increase in osteoporosis treatment rates was observed among LTC residents at high risk of fracture (FRS4 +). Residents in LTC are at very high risk for fracture and require individualized based on goals of care and life expectancy.

Journal requirement for data sharing statements in clinical trials: a cross-sectional study.

OBJECTIVES: Data sharing statements are considered routine in clinical trial reporting and represent a step toward data transparency. The International Committee of Medical Journal Editors (ICMJE) required clinical trials to publish data sharing statements. We aimed to assess the requirement for data sharing statements of individual participant data by biomedical journals and explore associations between journal characteristics and journal requirements for data sharing statements. STUDY DESIGN AND SETTING: In this cross-sectional study, we included all biomedical journals that published clinical trials from January 1, 2019, to December 31, 2022, and that were indexed by the Journal Citation Reports. The study outcome was the journal requirement for data sharing statements. Multivariable logistic regression analysis was used to assess the relationship between journal characteristics and requirement for data sharing statements. RESULTS: Of the 3229 biomedical journals included in the analysis, 2345 (72.6%) required authors to include data sharing statements. Journals published in the UK (OR, 3.19 [95% CI, 2.43-4.22]) and endorsing the Consolidated Standards of Reporting Trials (OR, 3.30 [95% CI, 2.78-3.92]) had greater odds of requiring data sharing statements. Journals that were open access, non-English language, in the Journal Citation Reports group of clinical medicine, and on the ICMJE list had lower odds of requiring data sharing statements, with ORs ranging from 0.18 to 0.81. CONCLUSION: Despite ICMJE recommendations, more than 27% of the biomedical journals that published clinical trials did not require clinical trials to include data sharing statements, highlighting room for improved transparency.

Early In-Bed Cycle Ergometry in Mechanically Ventilated Patients.

BACKGROUND: Critical illness requiring invasive mechanical ventilation can precipitate important functional disability, contributing to multidimensional morbidity following admission to an intensive care unit (ICU). Early in-bed cycle ergometry added to usual physiotherapy may mitigate ICU-acquired physical function impairment. METHODS: We randomly assigned 360 adult ICU patients undergoing invasive mechanical ventilation to receive 30 minutes of early in-bed Cycling + Usual physiotherapy (n=178) or Usual physiotherapy alone (n=182). The primary outcome was the Physical Function ICU Test-scored (PFIT-s) at 3 days after discharge from the ICU (the score ranges from 0 to 10, with higher scores indicating better function). RESULTS: Cycling began within a median (interquartile range) of 2 (1 to 3) days of starting mechanical ventilation; patients received 3 (2 to 5) cycling sessions for a mean (±standard deviation) of 27.2 ± 6.6 minutes. In both groups, patients started Usual physiotherapy within 2 (2 to 4) days of mechanical ventilation and received 4 (2 to 7) Usual physiotherapy sessions. The duration of Usual physiotherapy was 23.7 ± 15.1 minutes in the Cycling + Usual physiotherapy group and 29.1 ± 13.2 minutes in the Usual physiotherapy group. No serious adverse events occurred in either group. Among survivors, the PFIT-s at 3 days after discharge from the ICU was 7.7 ± 1.7 in the Cycling + Usual physiotherapy group and 7.5 ± 1.7 in the Usual physiotherapy group (absolute difference, 0.23 points; 95% confidence interval, -0.19 to 0.65; P=0.29). CONCLUSIONS: Among adults receiving mechanical ventilation in the ICU, adding early in-bed Cycling to usual physiotherapy did not improve physical function at 3 days after discharge from the ICU compared with Usual physiotherapy alone. Cycling did not cause any serious adverse events. (Funded by the Canadian Institutes of Health Research and others; ClinicalTrials.gov numbers, NCT03471247 [full randomized clinical trial] and NCT02377830 [CYCLE Vanguard 46-patient internal pilot].).

A prospective cohort study of chronic postsurgical pain after ambulatory surgeries.

OBJECTIVE: The incidence and factors associated with chronic postsurgical pain (CPSP) after ambulatory surgeries have not been well studied. Our primary objective was to determine the incidence of CPSP and secondary objectives included assessment of intensity of CPSP, incidence of moderate-to-severe CPSP, and exploration of factors associated with CPSP. METHODS: This is a prospective cohort study of ambulatory surgery patients having procedures with a potential to cause moderate-to-severe postoperative pain. All patients had participated in a randomized controlled trial (RCT) showing no difference in achieving satisfactory analgesia in a recovery unit with either morphine or hydromorphone. CPSP was defined as chronic pain that developed or increased in intensity after the surgical procedure and is localized to the surgical field or within the innervation territory of a nerve in the surgical field, and has persisted for 3 months post-surgery, with the exclusion of other causes of pain. Incidences of CPSP were reported as rate (%) with 95% CI, and intensity using a 0-10 numerical rating scale (95% CI). We used logistic regression to explore factors associated with CPSP adjusting for baseline catastrophizing and depression. RESULTS: Among 402 RCT patients, 208 provided data for the 3-month outcome. Incidence of CPSP was 18.8% (39/208), 95% CI = 13.7%-24.7% and 78% (28/39) of them had moderate-to-severe CPSP. Average CPSP intensity was 5.5, 95% CI = 4.7-6.4. Every unit increase in pain over the first 24 h was significantly associated with increased odds of moderate-to-severe CPSP at 3 months; odds ratio = 1.28, 95% CI = 1.04-1.58. CONCLUSIONS: Nearly one in five patients develop CPSP after ambulatory surgeries with the majority of them having moderate-to-severe pain. Considering that acute pain after discharge is associated with CPSP and that there are no formal care pathways to address this need, studies need to focus on evaluating feasible strategies to provide continuing care.

Sex and gender-based analysis and diversity metric reporting in acute care trials published in high-impact journals: a systematic review.

OBJECTIVE: To characterise sex and gender-based analysis (SGBA) and diversity metric reporting, representation of female/women participants in acute care trials and temporal changes in reporting before and after publication of the 2016 Sex and Gender Equity in Research guideline. DESIGN: Systematic review. DATA SOURCES: We searched MEDLINE for trials published in five leading medical journals in 2014, 2018 and 2020. STUDY SELECTION: Trials that enrolled acutely ill adults, compared two or more interventions and reported at least one clinical outcome. DATA ABSTRACTION AND SYNTHESIS: 4 reviewers screened citations and 22 reviewers abstracted data, in duplicate. We compared reporting differences between intensive care unit (ICU) and cardiology trials. RESULTS: We included 88 trials (75 (85.2%) ICU and 13 (14.8%) cardiology) (n=111 428; 38 140 (34.2%) females/women). Of 23 (26.1%) trials that reported an SGBA, most used a forest plot (22 (95.7%)), were prespecified (21 (91.3%)) and reported a sex-by-intervention interaction with a significance test (19 (82.6%)). Discordant sex and gender terminology were found between headings and subheadings within baseline characteristics tables (17/32 (53.1%)) and between baseline characteristics tables and SGBA (4/23 (17.4%)). Only 25 acute care trials (28.4%) reported race or ethnicity. Participants were predominantly white (78.8%) and male/men (65.8%). No trial reported gendered-social factors. SGBA reporting and female/women representation did not improve temporally. Compared with ICU trials, cardiology trials reported significantly more SGBA (15/75 (20%) vs 8/13 (61.5%) p=0.005). CONCLUSIONS: Acute care trials in leading medical journals infrequently included SGBA, female/women and non-white trial participants, reported race or ethnicity and never reported gender-related factors. Substantial opportunity exists to improve SGBA and diversity metric reporting and recruitment of female/women participants in acute care trials. PROSPERO REGISTRATION NUMBER: CRD42022282565.

Long-Term Cardiovascular Outcomes in Children and Adolescents With Hypertension.

Importance: Hypertension affects 6% of all children, and its prevalence is increasing. Childhood hypertension tracks into adulthood and is associated with subclinical cardiovascular disease; however, there is a lack of evidence linking childhood hypertension to cardiovascular outcomes, which may contribute to underdiagnosis and undertreatment. Objective: To determine the long-term associated risk of major adverse cardiac events (MACE) among children diagnosed with hypertension. Design, Setting, and Participants: This was a population-based, retrospective, matched cohort study conducted from 1996 to 2022. The study included all children (aged 3-18 years) alive in Ontario, Canada, from 1996 to 2021, who were identified using provincial administrative health databases. Children with prior kidney replacement therapy were excluded. Exposure: Incident hypertension diagnosis, identified by validated case definitions using diagnostic and physician billing claims. Each case was matched with 5 controls without hypertension by age, sex, birth weight, maternal gestational hypertension, prior comorbidities (chronic kidney disease, diabetes, cardiovascular surgery), and a propensity score for hypertension. Main Outcomes and Measures: The primary outcome was MACE (a composite of cardiovascular death, stroke, hospitalization for myocardial infarction or unstable angina, or coronary intervention). Time to MACE was evaluated using the Kaplan-Meier method and Cox proportional hazards regression. Results: A total of 25 605 children (median [IQR] age, 15 [11-17] years; 14 743 male [57.6%]) with hypertension were matched to 128 025 controls without hypertension. Baseline covariates were balanced after propensity score matching, and prior comorbidities were uncommon (hypertension vs control cohort: malignancy, 1451 [5.7%] vs 7908 [6.2%]; congenital heart disease, 1089 [4.3%] vs 5408 [4.2%]; diabetes, 482 [1.9%] vs 2410 [1.9%]). During a median (IQR) of 13.6 (7.8-19.5) years of follow-up, incidence of MACE was 4.6 per 1000 person-years in children with hypertension vs 2.2 per 1000 person-years in controls (hazard ratio, 2.1; 95% CI, 1.9-2.2). Children with hypertension were at higher associated risk of stroke, hospitalization for myocardial infarction or unstable angina, coronary intervention, and congestive heart failure, but not cardiovascular death, compared with nonhypertensive controls. Conclusions and Relevance: Children diagnosed with hypertension had a higher associated long-term risk of MACE compared with controls without hypertension. Improved detection, follow-up, and control of pediatric hypertension may reduce the risk of adult cardiovascular disease.

Coordination of oral anticoagulant care at hospital discharge (COACHeD): pilot randomised controlled trial.

OBJECTIVES: To evaluate whether a focused, expert medication management intervention is feasible and potentially effective in preventing anticoagulation-related adverse events for patients transitioning from hospital to home. DESIGN: Randomised, parallel design. SETTING: Medical wards at six hospital sites in southern Ontario, Canada. PARTICIPANTS: Adults 18 years of age or older being discharged to home on an oral anticoagulant (OAC) to be taken for at least 4 weeks. INTERVENTIONS: Clinical pharmacologist-led intervention, including a detailed discharge medication management plan, a circle of care handover and early postdischarge virtual check-up visits to 1 month with 3-month follow-up. The control group received the usual care. OUTCOMES MEASURES: Primary outcomes were study feasibility outcomes (recruitment, retention and cost per patient). Secondary outcomes included adverse anticoagulant safety events composite, quality of transitional care, quality of life, anticoagulant knowledge, satisfaction with care, problems with medications and health resource utilisation. RESULTS: Extensive periods of restriction of recruitment plus difficulties accessing patients at the time of discharge negatively impacted feasibility, especially cost per patient recruited. Of 845 patients screened, 167 were eligible and 56 were randomised. The mean age (±SD) was 71.2±12.5 years, 42.9% females, with two lost to follow-up. Intervention patients were more likely to rate their ability to manage their OAC as improved (17/27 (63.0%) vs 7/22 (31.8%), OR 3.6 (95% CI 1.1 to 12.0)) and their continuity of care as improved (21/27 (77.8%) vs 2/22 (9.1%), OR 35.0 (95% CI 6.3 to 194.2)). Fewer intervention patients were taking one or more inappropriate medications (7 (22.5%) vs 15 (60%), OR 0.19 (95% CI 0.06 to 0.62)). CONCLUSION: This pilot randomised controlled trial suggests that a transitional care intervention at hospital discharge for older adults taking OACs was well received and potentially effective for some surrogate outcomes, but overly costly to proceed to a definitive large trial. TRIAL REGISTRATION NUMBER: NCT02777047.

Youth not engaged in education, employment, or training: a discrete choice experiment of service preferences in Canada.

BACKGROUND: Prior research has showed the importance of providing integrated support services to prevent and reduce youth not in education, employment, or training (NEET) related challenges. There is limited evidence on NEET youth's perspectives and preferences for employment, education, and training services. The objective of this study was to identify employment, education and training service preferences of NEET youth. We acknowledge the deficit-based lens associated with the term NEET and use 'upcoming youth' to refer to this population group. METHODS: Canadian youth (14-29 years) who reported Upcoming status or at-risk of Upcoming status were recruited to the study. We used a discrete choice experiment (DCE) survey, which included ten attributes with three levels each indicating service characteristics. Sawtooth software was used to design and administer the DCE. Participants also provided demographic information and completed the Global Appraisal of Individual Needs-Short Screener. We analyzed the data using hierarchical Bayesian methods to determine service attribute importance and latent class analyses to identify groups of participants with similar service preferences. RESULTS: A total of n=503 youth participated in the study. 51% of participants were 24-29 years of age; 18.7% identified as having Upcoming status; 41.1% were from rural areas; and 36.0% of youth stated that they met basic needs with a little left. Participants strongly preferred services that promoted life skills, mentorship, basic income, and securing a work or educational placement. Three latent classes were identified and included: (i) job and educational services (38.9%), or services that include career counseling and securing a work or educational placement; (ii) mental health and wellness services (34.9%), or services that offer support for mental health and wellness in the workplace and free mental health and substance use services; and (iii) holistic skills building services (26.1%), or services that endorsed skills for school and job success, and life skills. CONCLUSIONS: This study identified employment, education, and training service preferences among Upcoming youth. The findings indicate a need to create a service model that supports holistic skills building, mental health and wellness, and long-term school and job opportunities.

Protocol implementation during the COVID-19 pandemic: experiences from a randomized trial of stress ulcer prophylaxis.

BACKGROUND: During the COVID-19 pandemic, many intensive care units (ICUs) halted research to focus on COVID-19-specific studies. OBJECTIVE: To describe the conduct of an international randomized trial of stress ulcer prophylaxis (Re-Evaluating the Inhibition of Stress Erosions in the ICU [REVISE]) during the pandemic, addressing enrolment patterns, center engagement, informed consent processes, data collection, a COVID-specific substudy, patient transfers, and data monitoring. METHODS: REVISE is a randomized trial among mechanically ventilated patients, comparing pantoprazole 40 mg IV to placebo on the primary efficacy outcome of clinically important upper gastrointestinal bleeding and the primary safety outcome of 90-day mortality. We documented protocol implementation status from March 11th 2020-August 30th 2022. RESULTS: The Steering Committee did not change the scientific protocol. From the first enrolment on July 9th 2019 to March 10th 2020 (8 months preceding the pandemic), 267 patients were enrolled in 18 centers. From March 11th 2020-August 30th 2022 (30 months thereafter), 41 new centers joined; 59 were participating by August 30th 2022 which enrolled 2961 patients. During a total of 1235 enrolment-months in the pandemic phase, enrolment paused for 106 (8.6%) months in aggregate (median 3 months, interquartile range 2;6). Protocol implementation involved a shift from the a priori consent model pre-pandemic (188, 58.8%) to the consent to continue model (1615, 54.1%, p < 0.01). In one new center, an opt-out model was approved. The informed consent rate increased slightly (80.7% to 85.0%, p = 0.05). Telephone consent encounters increased (16.6% to 68.2%, p < 0.001). Surge capacity necessitated intra-institutional transfers; receiving centers continued protocol implementation whenever possible. We developed a nested COVID-19 substudy. The Methods Centers continued central statistical monitoring of trial metrics. Site monitoring was initially remote, then in-person when restrictions lifted. CONCLUSION: Protocol implementation adaptations during the pandemic included a shift in the consent model, a sustained high consent rate, and launch of a COVID-19 substudy. Recruitment increased as new centers joined, patient transfers were optimized, and monitoring methods were adapted.

Reporting quality of heart failure randomized controlled trials 2000-2020: Temporal trends in adherence to CONSORT criteria.

AIM: Heart failure (HF) is a major cause of morbidity and mortality in older adults. Randomized controlled trials (RCTs) inform HF policy and practice, but the accurate interpretation of results is contingent on clear and transparent reporting. The CONsolidated Standards Of Reporting Trials (CONSORT) statement serves as a guide to RCT reporting. We evaluated the quality of reporting in HF RCTs in high-impact journals by assessing their adherence to CONSORT. METHODS AND RESULTS: We searched MEDLINE, EMBASE and CINAHL for HF RCTs published in high-impact journals 2000-2020. We assessed the proportion of CONSORT criteria that individual HF RCTs adhered to, and used the Jonckheere-Terpstra test to examine temporal trends in adherence. Multivariable linear regression explored the association between trial characteristics and adherence to CONSORT. Primary analysis assessed adherence to CONSORT 2010 update. A sensitivity analysis assessed adherence to the original (1996) CONSORT criteria. Among 221 RCTs analysed, the mean (standard deviation [SD]) adherence was suboptimal overall (mean [SD] adherence 69.7 [11.5]%) (5513/7913 criteria), with a temporal increase in adherence over the 20-year period (p < 0.001). Factors associated with adherence included publication after versus during/before 2010 (ß = 10.17, 95% confidence interval [CI] 7.64-12.70; p < 0.001); two-group parallel individual-level randomization versus other (including multi-group or cluster randomization) (ß = 5.81, 95% CI 2.88-8.73; p < 0.001); and multicentre versus single-centre trials (ß = 7.26, 95% CI 3.25-11.27; p < 0.001). There was no difference in trial adherence to the updated CONSORT (2010) versus the original (1996) CONSORT criteria, and temporal trends in adherence to both sets of criteria were similar, likely due to overlap between the two sets of criteria. Trials with greater adherence to CONSORT were published in higher impact factor journals, with a positive correlation (r = 0.312; p < 0.001). CONCLUSION: The quality of reporting in HF RCTs, as measured by CONSORT adherence, has improved over time but remains suboptimal.

Computerized clinical decision support to improve stroke prevention therapy in primary care management of atrial fibrillation: a cluster randomized trial.

BACKGROUND: Despite guidelines supporting antithrombotic therapy use in atrial fibrillation (AF), under-prescribing persists. We assessed whether computerized clinical decision support (CDS) would enable guideline-based antithrombotic therapy for AF patients in primary care. METHODS: This cluster randomized trial of CDS versus usual care (UC) recruited participants from primary care practices across Nova Scotia, following them for 12 months. The CDS tool calculated bleeding and stroke risk scores and provided recommendations for using oral anticoagulants (OAC) per Canadian guidelines. RESULTS: From June 14, 2014 to December 15, 2016, 203 primary care providers (99 UC, 104 CDS) with access to high-speed Internet were recruited, enrolling 1,145 eligible patients (543 UC, 590 CDS) assigned to the same treatment arm as their provider. Patient mean age was 72.3 years; most were male (350, 64.5% UC, 351, 59.5% CDS) and from a rural area (298, 54.9% UC, 315, 53.4% CDS). At baseline, a higher than anticipated proportion of patients were receiving guideline-based OAC therapy (373, 68.7% UC, 442, 74.9% CDS; relative risk [RR] 0.97 (95% confidence interval [CI], 0.87-1.07; P = .511)). At 12 months, prescription data were available for 538 usual care and 570 CDS patients, and significantly more CDS patients were managed according to guidelines (415, 77.1% UC, 479, 84.0% CDS; RR 1.08 (95% CI, 1.01-1.15; P = .024)). CONCLUSION: Notwithstanding high baseline rates, primary care provider access to the CDS over 12 months further optimized the prescribing of OAC therapy per national guidelines to AF patients potentially eligible to receive it. This suggests that CDS can be effective in improving clinical process of care. TRIAL REGISTRATION: Clinical Trials NCT01927367. https://clinicaltrials.gov/ct2/show/NCT01927367?term=NCT01927367&draw=2&rank=1.

Adjudication of a primary trial outcome: Results of a calibration exercise and protocol for a large international trial.

Background: Ascertainment of the severity of the primary outcome of upper gastrointestinal (GI) bleeding is integral to stress ulcer prophylaxis trials. This protocol outlines the adjudication process for GI bleeding events in an international trial comparing pantoprazole to placebo in critically ill patients (REVISE: Re-Evaluating the Inhibition of Stress Erosions). The primary objective of the adjudication process is to assess episodes submitted by participating sites to determine which fulfil the definition of the primary efficacy outcome of clinically important upper GI bleeding. Secondary objectives are to categorize the bleeding severity if deemed not clinically important, and adjudicate the bleeding site, timing, investigations, and treatments. Methods: Research coordinators follow patients daily for any suspected clinically important upper GI bleeding, and submit case report forms, doctors' and nurses' notes, laboratory, imaging, and procedural reports to the methods center. An international central adjudication committee reflecting diverse specialty backgrounds conducted an initial calibration exercise to delineate the scope of the adjudication process, review components of the definition, and agree on how each criterion will be considered fulfilled. Henceforth, bleeding events will be stratified by study drug, and randomly assigned to adjudicator pairs (blinded to treatment allocation, and study center). Results: Crude agreement, chance-corrected agreement, or chance-independent agreement if data have a skewed distribution will be calculated. Conclusions: Focusing on consistency and accuracy, central independent blinded duplicate adjudication of suspected clinically important upper GI bleeding events will determine which events fulfil the definition of the primary efficacy outcome for this stress ulcer prophylaxis trial. Registration: NCT03374800 (REVISE: Re-Evaluating the Inhibition of Stress Erosions).