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1.  DO IT Trial: vitamin D Outcomes and Interventions in Toddlers – a TARGet Kids! randomized controlled trial 
BMC Pediatrics  2014;14:37.
Vitamin D levels are alarmingly low (<75 nmol/L) in 65-70% of North American children older than 1 year. An increased risk of viral upper respiratory tract infections (URTI), asthma-related hospitalizations and use of anti-inflammatory medication have all been linked with low vitamin D. No study has determined whether wintertime vitamin D supplementation can reduce the risk of URTI and asthma exacerbations, two of the most common and costly illnesses of early childhood. The objectives of this study are: 1) to compare the effect of ‘high dose’ (2000 IU/day) vs. ‘standard dose’ (400 IU/day) vitamin D supplementation in achieving reductions in laboratory confirmed URTI and asthma exacerbations during the winter in preschool-aged Canadian children; and 2) to assess the effect of ‘high dose’ vitamin D supplementation on vitamin D serum levels and specific viruses that cause URTI.
This study is a pragmatic randomized controlled trial. Over 4 successive winters we will recruit 750 healthy children 1–5 years of age. Participating physicians are part of a primary healthcare research network called TARGet Kids!. Children will be randomized to the ‘standard dose’ or ‘high dose’ oral supplemental vitamin D for a minimum of 4 months (200 children per group). Parents will obtain a nasal swab from their child with each URTI, report the number of asthma exacerbations and complete symptom checklists. Unscheduled physician visits for URTIs and asthma exacerbations will be recorded. By May, a blood sample will be drawn to determine vitamin D serum levels. The primary analysis will be a comparison of URTI rate between study groups using a Poisson regression model. Secondary analyses will compare vitamin D serum levels, asthma exacerbations and the frequency of specific viral agents between groups.
Identifying whether vitamin D supplementation of preschoolers can reduce wintertime viral URTIs and asthma exacerbations and what dose is optimal may reduce population wide morbidity and associated health care and societal costs. This information will assist in determining practice and health policy recommendations related to vitamin D supplementation in healthy Canadian preschoolers.
PMCID: PMC3942179  PMID: 24506910
Vitamin D deficiency; Vitamin D supplementation; Infant; Toddler
2.  JURaSSiC 
Neurology  2013;81(5):448-455.
We compared the accuracy of clinicians and a risk score (iScore) to predict observed outcomes following an acute ischemic stroke.
The JURaSSiC (Clinician JUdgment vs Risk Score to predict Stroke outComes) study assigned 111 clinicians with expertise in acute stroke care to predict the probability of outcomes of 5 ischemic stroke case scenarios. Cases (n = 1,415) were selected as being representative of the 10 most common clinical presentations from a pool of more than 12,000 stroke patients admitted to 12 stroke centers. The primary outcome was prediction of death or disability (modified Rankin Scale [mRS] ≥3) at discharge within the 95% confidence interval (CI) of observed outcomes. Secondary outcomes included 30-day mortality and death or institutionalization at discharge.
Clinicians made 1,661 predictions with overall accuracy of 16.9% for death or disability at discharge, 46.9% for 30-day mortality, and 33.1% for death or institutionalization at discharge. In contrast, 90% of the iScore-based estimates were within the 95% CI of observed outcomes. Nearly half (n = 53 of 111; 48%) of participants were unable to accurately predict the probability of the primary outcome in any of the 5 rated cases. Less than 1% (n = 1) provided accurate predictions in 4 of the 5 cases and none accurately predicted all 5 case outcomes. In multivariable analyses, the presence of patient characteristics associated with poor outcomes (mRS ≥3 or death) in previous studies (older age, high NIH Stroke Scale score, and nonlacunar subtype) were associated with more accurate clinician predictions of death at 30 days (odds ratio [OR] 2.40, 95% CI 1.57–3.67) and with a trend for more accurate predictions of death or disability at discharge (OR 1.85, 95% CI 0.99–3.46).
Clinicians with expertise in stroke performed poorly compared to a validated tool in predicting the outcomes of patients with an acute ischemic stroke. Use of the risk stroke outcome tool may be superior for decision-making following an acute ischemic stroke.
PMCID: PMC3776534  PMID: 23897872
4.  Optimal Mode of clearance in critically ill patients with Acute Kidney Injury (OMAKI) - a pilot randomized controlled trial of hemofiltration versus hemodialysis: a Canadian Critical Care Trials Group project 
Critical Care  2012;16(5):R205.
Among critically ill patients with acute kidney injury (AKI) needing continuous renal replacement therapy (CRRT), the effect of convective (via continuous venovenous hemofiltration [CVVH]) versus diffusive (via continuous venovenous hemodialysis [CVVHD]) solute clearance on clinical outcomes is unclear. Our objective was to evaluate the feasibility of comparing these two modes in a randomized trial.
This was a multicenter open-label parallel-group pilot randomized trial of CVVH versus CVVHD. Using concealed allocation, we randomized critically ill adults with AKI and hemodynamic instability to CVVH or CVVHD, with a prescribed small solute clearance of 35 mL/kg/hour in both arms. The primary outcome was trial feasibility, defined by randomization of >25% of eligible patients, delivery of >75% of the prescribed CRRT dose, and follow-up of >95% of patients to 60 days. A secondary analysis using a mixed-effects model examined the impact of therapy on illness severity, defined by sequential organ failure assessment (SOFA) score, over the first week.
We randomized 78 patients (mean age 61.5 years; 39% women; 23% with chronic kidney disease; 82% with sepsis). Baseline SOFA scores (mean 15.9, SD 3.2) were similar between groups. We recruited 55% of eligible patients, delivered >80% of the prescribed dose in each arm, and achieved 100% follow-up. SOFA tended to decline more over the first week in CVVH recipients (-0.8, 95% CI -2.1, +0.5) driven by a reduction in vasopressor requirements. Mortality (54% CVVH; 55% CVVHD) and dialysis dependence in survivors (24% CVVH; 19% CVVHD) at 60 days were similar.
Our results suggest that a large trial comparing CVVH to CVVHD would be feasible. There is a trend toward improved vasopressor requirements among CVVH-treated patients over the first week of treatment.
Trial Registration NCT00675818
PMCID: PMC3682309  PMID: 23095370
5.  Effectiveness guidance document (EGD) for acupuncture research - a consensus document for conducting trials 
There is a need for more Comparative Effectiveness Research (CER) to strengthen the evidence base for clinical and policy decision-making. Effectiveness Guidance Documents (EGD) are targeted to clinical researchers. The aim of this EGD is to provide specific recommendations for the design of prospective acupuncture studies to support optimal use of resources for generating evidence that will inform stakeholder decision-making.
Document development based on multiple systematic consensus procedures (written Delphi rounds, interactive consensus workshop, international expert review). To balance aspects of internal and external validity, multiple stakeholders including patients, clinicians and payers were involved.
Recommendations focused mainly on randomized studies and were developed for the following areas: overall research strategy, treatment protocol, expertise and setting, outcomes, study design and statistical analyses, economic evaluation, and publication.
The present EGD, based on an international consensus developed with multiple stakeholder involvement, provides the first systematic methodological guidance for future CER on acupuncture.
PMCID: PMC3495216  PMID: 22953730
Comparative effectiveness research; Effectiveness guidance document; Acupuncture
6.  Prevalence and predictors of low vitamin D concentrations in urban Canadian toddlers 
Paediatrics & Child Health  2011;16(2):e11-e15.
To determine the prevalence of low vitamin D concentrations in a cohort of healthy two-year-old children living in a large Canadian city, and to explore whether body mass index (BMI) and cow’s milk intake are associated with low vitamin D concentrations.
A cross-sectional study was performed on healthy two-year-old children attending a well-child visit in Toronto, Ontario (latitude 43.4°N). Dietary exposures were measured by questionnaire. The primary outcome was the prevalence of low vitamin D concentrations (25-hydroxyvitamin D concentration of lower than 50 nmol/L or lower than 75 nmol/L).
A total of 91 healthy children 24 to 30 months of age were recruited between November 2007 and May 2008. The prevalence of low vitamin D concentrations (lower than 50 nmol/L) was 32% (29 of 92, 95% CI 22% to 42%) and the prevalence of vitamin D concentrations of lower than 75 nmol/L was 82% (75 of 91, 95% CI 73% to 89%). Using multivariable logistic regression, the odds of vitamin D concentrations being lower than 50 nmol/L decreased by 0.44 (95% CI 0.2 to 0.96) for each additional cup of cow’s milk intake per day and increased by 1.2 to 2.6 per unit BMI depending on BMI level (P=0.07).
A total of 30% to 80% of toddlers in the present study’s urban Canadian setting demonstrated low vitamin D concentrations – the highest prevalence of low vitamin D in toddlers outside of Alaska. Modifiable factors associated with low vitamin D were lower cow’s milk intake and higher BMI. The vitamin D status of toddlers in urban Canada may require specific attention.
PMCID: PMC3043048  PMID: 22294872
Obesity; Primary care; Toddlers; Vitamin D
7.  Association between chronic cerebrospinal venous insufficiency and multiple sclerosis: a meta-analysis 
It has been proposed by Zamboni and colleagues that multiple sclerosis is caused by chronic cerebrospinal venous insufficiency, a term used to describe ultrasound-detectable abnormalities in the anatomy and flow of intra- and extracerebral veins. We conducted a meta-analysis of studies that reported the frequency of chronic cerebrospinal venous insufficiency among patients with and those without multiple sclerosis.
We searched MEDLINE and EMBASE as well as bibliographies of relevant articles for eligible studies. We included studies if they used ultrasound to diagnose chronic cerebrospinal venous insufficiency and compared the frequency of the venous abnormalities among patients with and those without multiple sclerosis.
We identified eight eligible studies: all included healthy controls, and four of them also included a control group of patients with neurologic diseases other than multiple sclerosis. Chronic cerebrospinal venous insufficiency was more frequent among patients with multiple sclerosis than among the healthy controls (odds ratio [OR] 13.5, 95% confidence interval [CI] 2.6–71.4), but there was extensive unexplained heterogeneity among the studies. The association remained significant in the most conservative sensitivity analysis (OR 3.7, 95% CI 1.2–11.0), in which we removed the initial study by Zamboni and colleagues and added a study that did not find chronic cerebrospinal venous insufficiency in any patient. Although chronic cerebrospinal venous insufficiency was also more frequent among patients with multiple sclerosis than among controls with other neurologic diseases (OR 32.5, 95% CI 0.6–1775.7), the association was not statistically significant, the 95% CI was wide, and the OR was less extreme after removal of the study by Zamboni and colleagues (OR 3.5, 95% 0.8–15.8).
Our findings showed a positive association between chronic cerebrospinal venous insufficiency and multiple sclerosis. However, poor reporting of the success of blinding and marked heterogeneity among the studies included in our review precluded definitive conclusions.
PMCID: PMC3216446  PMID: 21969411
8.  Evaluation of a clinical decision support tool for osteoporosis disease management: protocol for an interrupted time series design 
Osteoporosis affects over 200 million people worldwide at a high cost to healthcare systems. Although guidelines on assessing and managing osteoporosis are available, many patients are not receiving appropriate diagnostic testing or treatment. Findings from a systematic review of osteoporosis interventions, a series of mixed-methods studies, and advice from experts in osteoporosis and human-factors engineering were used collectively to develop a multicomponent tool (targeted to family physicians and patients at risk for osteoporosis) that may support clinical decision making in osteoporosis disease management at the point of care.
A three-phased approach will be used to evaluate the osteoporosis tool. In phase 1, the tool will be implemented in three family practices. It will involve ensuring optimal functioning of the tool while minimizing disruption to usual practice. In phase 2, the tool will be pilot tested in a quasi-experimental interrupted time series (ITS) design to determine if it can improve osteoporosis disease management at the point of care. Phase 3 will involve conducting a qualitative postintervention follow-up study to better understand participants' experiences and perceived utility of the tool and readiness to adopt the tool at the point of care.
The osteoporosis tool has the potential to make several contributions to the development and evaluation of complex, chronic disease interventions, such as the inclusion of an implementation strategy prior to conducting an evaluation study. Anticipated benefits of the tool may be to increase awareness for patients about osteoporosis and its associated risks and provide an opportunity to discuss a management plan with their physician, which may all facilitate patient self-management.
PMCID: PMC3152529  PMID: 21781318
9.  Inhaled nitric oxide for the adjunctive therapy of severe malaria: Protocol for a randomized controlled trial 
Trials  2011;12:176.
Severe malaria remains a major cause of global morbidity and mortality. Despite the use of potent anti-parasitic agents, the mortality rate in severe malaria remains high. Adjunctive therapies that target the underlying pathophysiology of severe malaria may further reduce morbidity and mortality. Endothelial activation plays a central role in the pathogenesis of severe malaria, of which angiopoietin-2 (Ang-2) has recently been shown to function as a key regulator. Nitric oxide (NO) is a major inhibitor of Ang-2 release from endothelium and has been shown to decrease endothelial inflammation and reduce the adhesion of parasitized erythrocytes. Low-flow inhaled nitric oxide (iNO) gas is a US FDA-approved treatment for hypoxic respiratory failure in neonates.
This prospective, parallel arm, randomized, placebo-controlled, blinded clinical trial compares adjunctive continuous inhaled nitric oxide at 80 ppm to placebo (both arms receiving standard anti-malarial therapy), among Ugandan children aged 1-10 years of age with severe malaria. The primary endpoint is the longitudinal change in Ang-2, an objective and quantitative biomarker of malaria severity, which will be analysed using a mixed-effects linear model. Secondary endpoints include mortality, recovery time, parasite clearance and neurocognitive sequelae.
Noteworthy aspects of this trial design include its efficient sample size supported by a computer simulation study to evaluate statistical power, meticulous attention to complex ethical issues in a cross-cultural setting, and innovative strategies for safety monitoring and blinding to treatment allocation in a resource-constrained setting in sub-Saharan Africa.
Trial Registration Identifier: NCT01255215
PMCID: PMC3151218  PMID: 21752262
10.  Limitations in the current screening practice of assessing left ventricular ejection fraction for a primary prophylactic implantable defibrillator in southern Ontario 
The Canadian Journal of Cardiology  2010;26(3):e118-e124.
Screening echocardiography (ECHO) is commonly performed to determine whether the patient’s left ventricular ejection fraction (LVEF) is appropriate for primary prophylactic implantable cardiac defibrillator (ICD) referral. However, radionuclide ventriculography (RNA) is used by many implantation centres for decision making.
To determine whether current screening ECHO techniques are effective in identifying patients suitable for primary prophylactic ICD referral.
Correlation, sensitivity, specificity and likelihood ratios (LRs) of semiquantitative and numerical quantitative ECHO LVEFs were calculated for predicting RNA LVEFs that met implantation criteria (LVEF less than 30% and less than 35%).
Among 193 patients, the LRs for a semiquantitative ECHO predicting an RNA LVEF of less than 30% (negative LR was 0.21 to 0.69 and positive LR was 1.22 to 2.83) or RNA LVEF of less than 35% (negative LR was 0.24 to 0.73 and positive LR was 1.33 to 3.46) demonstrated that current screening ECHO techniques are ineffective. However, the positive predictive value of grade 4 ECHO was 93.0%, suggesting that these patients may not require further LVEF investigation before implantation. Among 102 patients, current quantitative ECHO techniques did not improve the screening characteristics.
Current screening ECHO techniques may not be adequate for screening patients for consideration of a primary prophylactic ICD, but a grade 4 ECHO finding has a high positive predictive value in meeting implantation LVEF criteria. Improved screening standards should increase the number of patients referred with appropriate LVEF for primary prophylactic ICD implantation.
PMCID: PMC2851474  PMID: 20352140
ECHO; LVEF; Primary prophylactic ICD; RNA; Screening; Sudden cardiac death
11.  A knowledge translation collaborative to improve the use of therapeutic hypothermia in post-cardiac arrest patients: protocol for a stepped wedge randomized trial 
Advances in resuscitation science have dramatically improved survival rates following cardiac arrest. However, about 60% of adults that regain spontaneous circulation die before leaving the hospital. Recently it has been shown that inducing hypothermia in cardiac arrest survivors immediately following their arrival in hospital can dramatically improve both overall survival and neurological outcomes. Despite the strong evidence for its efficacy and the apparent simplicity of this intervention, recent surveys show that therapeutic hypothermia is delivered inconsistently, incompletely, and often with delay.
Methods and design
This study will evaluate a multi-faceted knowledge translation strategy designed to increase the utilization rate of induced hypothermia in survivors of cardiac arrest across a network of 37 hospitals in Southwestern Ontario, Canada. The study is designed as a stepped wedge randomized trial lasting two years. Individual hospitals will be randomly assigned to four different wedges that will receive the active knowledge translation strategy according to a sequential rollout over a number of time periods. By the end of the study, all hospitals will have received the intervention. The primary aim is to measure the effectiveness of a multifaceted knowledge translation plan involving education, reminders, and audit-feedback for improving the use of induced hypothermia in survivors of cardiac arrest presenting to the emergency department. The primary outcome is the proportion of eligible OHCA patients that are cooled to a body temperature of 32 to 34°C within six hours of arrival in the hospital. Secondary outcomes will include process of care measures and clinical outcomes.
Inducing hypothermia in cardiac arrest survivors immediately following their arrival to hospital has been shown to dramatically improve both overall survival and neurological outcomes. However, this lifesaving treatment is frequently not applied in practice. If this trial is positive, our results will have broad implications by showing that a knowledge translation strategy shared across a collaborative network of hospitals can increase the number of patients that receive this lifesaving intervention in a timely manner.
Trial Registration Trial Identifier: NCT00683683
PMCID: PMC3031244  PMID: 21235799
12.  Decision aid on radioactive iodine treatment for early stage papillary thyroid cancer - a randomized controlled trial 
Trials  2010;11:81.
Patients with early stage papillary thyroid carcinoma (PTC), are faced with the decision to either to accept or reject adjuvant radioactive iodine (RAI) treatment after thryroidectomy. This decision is often difficult because of conflicting reports of RAI treatment benefit and medical evidence uncertainty due to the lack of long-term randomized controlled trials.
We report the protocol for a parallel, 2-arm, randomized trial comparing an intervention group exposed to a computerized decision aid (DA) relative to a control group receiving usual care. The DA explains the options of adjuvant radioactive iodine or no adjuvant radioactive iodine, as well as associated potential benefits, risks, and follow-up implications. Potentially eligible adult PTC patient participants will include: English-speaking individuals who have had recent thyroidectomy, and whose primary tumor was 1 to 4 cm in diameter, with no known metastases to lymph nodes or distant sites, with no other worrisome features, and who have not received RAI treatment for thyroid cancer. We will measure the effect of the DA on the following patient outcomes: a) knowledge about PTC and RAI treatment, b) decisional conflict, c) decisional regret, d) client satisfaction with information received about RAI treatment, and e) the final decision to accept or reject adjuvant RAI treatment and rationale.
This trial will provide evidence of feasibility and efficacy of the use of a computerized DA in explaining complex issues relating to decision making about adjuvant RAI treatment in early stage PTC.
Trial registration
Clinical Identifier: NCT01083550
PMCID: PMC2917435  PMID: 20659341
14.  Comparing Administration of Questionnaires via the Internet to Pen-and-Paper in Patients with Heart Failure: Randomized Controlled Trial 
The use of the Internet to administer questionnaires has many potential advantages over the use of pen-and-paper administration. Yet it is important to validate Internet administration, as most questionnaires were initially developed and validated for pen-and-paper delivery. While some have been validated for use over the Internet, these questionnaires have predominately been used amongst the healthy general population. To date, information is lacking on the validity of questionnaires administered over the Internet in patients with chronic diseases such as heart failure.
To determine the validity of three heart failure questionnaires administered over the Internet compared to pen-and-paper administration in patients with heart failure.
We conducted a prospective randomized study using test-retest design comparing administration via the Internet to pen-and-paper administration for three heart failure questionnaires provided to patients recruited from a heart failure clinic in Toronto, Ontario, Canada: the Kansas City Cardiomyopathy Questionnaire (KCCQ), the Minnesota Living with Heart Failure Questionnaire (MLHFQ), and the Self-Care Heart Failure Index (SCHFI).
Of the 58 subjects enrolled, 34 completed all three questionnaires. The mean difference and confidence intervals for the summary scores of the KCCQ, MLHFQ, and SCHFI were 1.2 (CI -1.5 to 4.0, scale from 0 to 100), 4.0 (CI -1.98 to 10.04, scale from 0 to 105), and 10.1 (CI 1.18 to 19.07, scale from 66.7 to 300), respectively.
Internet administration of the KCCQ appears to be equivalent to pen-and-paper administration. For the MLHFQ and SCHFI, we were unable to demonstrate equivalence. Further research is necessary to determine if the administration methods are equivalent for these instruments.
PMCID: PMC2762767  PMID: 19275979
Heart failure; Internet; questionnaires; validation
15.  Factors associated with the subspecialty choices of internal medicine residents in Canada 
Currently, there are more residents enrolled in cardiology training programs in Canada than in immunology, pharmacology, rheumatology, infectious diseases, geriatrics and endocrinology combined. There is no published data regarding the proportion of Canadian internal medicine residents applying to the various subspecialties, or the factors that residents consider important when deciding which subspecialty to pursue. To address the concern about physician imbalances in internal medicine subspecialties, we need to examine the factors that motivate residents when making career decisions.
In this two-phase study, Canadian internal medicine residents participating in the post graduate year 4 (PGY4) subspecialty match were invited to participate in a web-based survey and focus group discussions. The focus group discussions were based on issues identified from the survey results. Analysis of focus group transcripts grew on grounded theory.
110 PGY3 residents participating in the PGY4 subspecialty match from 10 participating Canadian universities participated in the web-based survey (54% response rate). 22 residents from 3 different training programs participated in 4 focus groups held across Canada. Our study found that residents are choosing careers that provide intellectual stimulation, are consistent with their personality, and that provide a challenge in diagnosis. From our focus group discussions it appears that lifestyle, role models, mentorship and the experience of the resident with the specialty appear to be equally important in career decisions. Males are more likely to choose procedure based specialties and are more concerned with the reputation of the specialty as well as the anticipated salary. In contrast, residents choosing non-procedure based specialties are more concerned with issues related to lifestyle, including work-related stress, work hours and time for leisure as well as the patient populations they are treating.
This study suggests that internal medicine trainees, and particularly males, are increasingly choosing procedure-based specialties while non-procedure based specialties, and in particular general internal medicine, are losing appeal. We need to implement strategies to ensure positive rotation experiences, exposure to role models, improved lifestyle and job satisfaction as well as payment schedules that are equitable between disciplines in order to attract residents to less popular career choices.
PMCID: PMC2446387  PMID: 18582381
16.  Structuring communication relationships for interprofessional teamwork (SCRIPT): a cluster randomized controlled trial 
Trials  2007;8:23.
Despite a burgeoning interest in using interprofessional approaches to promote effective collaboration in health care, systematic reviews find scant evidence of benefit. This protocol describes the first cluster randomized controlled trial (RCT) to design and evaluate an intervention intended to improve interprofessional collaborative communication and patient-centred care.
The objective is to evaluate the effects of a four-component, hospital-based staff communication protocol designed to promote collaborative communication between healthcare professionals and enhance patient-centred care.
The study is a multi-centre mixed-methods cluster randomized controlled trial involving twenty clinical teaching teams (CTTs) in general internal medicine (GIM) divisions of five Toronto tertiary-care hospitals. CTTs will be randomly assigned either to receive an intervention designed to improve interprofessional collaborative communication, or to continue usual communication practices.
Non-participant naturalistic observation, shadowing, and semi-structured, qualitative interviews were conducted to explore existing patterns of interprofessional collaboration in the CTTs, and to support intervention development. Interviews and shadowing will continue during intervention delivery in order to document interactions between the intervention settings and adopters, and changes in interprofessional communication.
The primary outcome is the rate of unplanned hospital readmission. Secondary outcomes are length of stay (LOS); adherence to evidence-based prescription drug therapy; patients' satisfaction with care; self-report surveys of CTT staff perceptions of interprofessional collaboration; and frequency of calls to paging devices. Outcomes will be compared on an intention-to-treat basis using adjustment methods appropriate for data from a cluster randomized design.
Pre-intervention qualitative analysis revealed that a substantial amount of interprofessional interaction lacks key core elements of collaborative communication such as self-introduction, description of professional role, and solicitation of other professional perspectives. Incorporating these findings, a four-component intervention was designed with a goal of creating a culture of communication in which the fundamentals of collaboration become a routine part of interprofessional interactions during unstructured work periods on GIM wards.
Trial registration
Registered with National Institutes of Health as NCT00466297.
PMCID: PMC2045094  PMID: 17877830

Results 1-16 (16)