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1.  Functional Recovery following Critical Illness in Children: the “Wee-cover” Pilot Study 
To determine the feasibility of conducting a longitudinal prospective study to evaluate functional recovery and predictors of impaired functional recovery in critically ill children.
Prospective pilot study.
Single center Pediatric Intensive Care Unit (PICU) at McMaster Children’s Hospital, Hamilton, Canada.
Children aged 12 months to 17 years, with at least one organ dysfunction, limited mobility or bed-rest during the first 48 hours of PICU admission, and a minimum 48 hour PICU length of stay, were eligible. Patients transferred from a neonatal intensive care unit prior to ever being discharged home, already mobilizing well or at baseline functional status at time of screening, with an English language barrier, and prior enrollment into this study were excluded.
The primary outcome was feasibility, as defined by the ability to screen, enroll eligible patients, and execute the study procedures and measurements on participants. Secondary outcomes included functional status at baseline, 3 and 6 months, PICU morbidity and mortality. Functional status was measured using the Pediatric Evaluation of Disability Inventory (PEDI), and the Participation and Environment Measure for Children and Youth (PEM-CY).
Main results
Thirty-three patients were enrolled between October 2012 and April 2013. Consent rate was 85%, follow-up rates 93% at 3 months, and 71% at 6 months. We were able to execute the study procedures and measurements, demonstrating feasibility of conducting a future longitudinal study. Functional status deteriorated following critical illness. Recovery appears to be influenced by baseline health or functional status, and severity of illness.
Longitudinal research is needed to understand how children recover after a critical illness. Our results suggest factors that may influence the recovery trajectory, and were used to inform the methodology, outcomes of interest, and appropriate sample size of a larger multi-center study evaluating functional recovery in this population.
PMCID: PMC4499478  PMID: 25651047
pediatrics; critical illness; function; recovery
2.  Efficacy of Hospital at Home in Patients with Heart Failure: A Systematic Review and Meta-Analysis 
PLoS ONE  2015;10(6):e0129282.
Heart failure (HF) is the commonest cause of hospitalization in older adults. Compared to routine hospitalization (RH), hospital at home (HaH)—substitutive hospital-level care in the patient’s home—improves outcomes and reduces costs in patients with general medical conditions. The efficacy of HaH in HF is unknown.
Methods and Results
We searched MEDLINE, Embase, CINAHL, and CENTRAL, for publications from January 1990 to October 2014. We included prospective studies comparing substitutive models of hospitalization to RH in HF. At least 2 reviewers independently selected studies, abstracted data, and assessed quality. We meta-analyzed results from 3 RCTs (n = 203) and narratively synthesized results from 3 observational studies (n = 329). Study quality was modest. In RCTs, HaH increased time to first readmission (mean difference (MD) 14.13 days [95% CI 10.36 to 17.91]), and improved health-related quality of life (HrQOL) at both, 6 months (standardized MD (SMD) -0.31 [-0.45 to -0.18]) and 12 months (SMD -0.17 [-0.31 to -0.02]). In RCTs, HaH demonstrated a trend to decreased readmissions (risk ratio (RR) 0.68 [0.42 to 1.09]), and had no effect on all-cause mortality (RR 0.94 [0.67 to 1.32]). HaH decreased costs of index hospitalization in all RCTs. HaH reduced readmissions and emergency department visits per patient in all 3 observational studies.
In the context of a limited number of modest-quality studies, HaH appears to increase time to readmission, reduce index costs, and improve HrQOL among patients requiring hospital-level care for HF. Larger RCTs are necessary to assess the effect of HaH on readmissions, mortality, and long-term costs.
PMCID: PMC4460137  PMID: 26052944
3.  Successful knowledge translation intervention in long-term care: final results from the vitamin D and osteoporosis study (ViDOS) pilot cluster randomized controlled trial 
Trials  2015;16:214.
Few studies have systematically examined whether knowledge translation (KT) strategies can be successfully implemented within the long-term care (LTC) setting. In this study, we examined the effectiveness of a multifaceted, interdisciplinary KT intervention for improving the prescribing of vitamin D, calcium and osteoporosis medications over 12-months.
We conducted a pilot, cluster randomized controlled trial in 40 LTC homes (21 control; 19 intervention) in Ontario, Canada. LTC homes were eligible if they had more than one prescribing physician and received services from a large pharmacy provider. Participants were interdisciplinary care teams (physicians, nurses, consultant pharmacists, and other staff) who met quarterly. Intervention homes participated in three educational meetings over 12 months, including a standardized presentation led by expert opinion leaders, action planning for quality improvement, and audit and feedback review. Control homes did not receive any additional intervention. Resident-level prescribing and clinical outcomes were collected from the pharmacy database; data collectors and analysts were blinded. In addition to feasibility measures, study outcomes were the proportion of residents taking vitamin D (≥800 IU/daily; primary), calcium ≥500 mg/day and osteoporosis medications (high-risk residents) over 12 months. Data were analyzed using the generalized estimating equations technique accounting for clustering within the LTC homes.
At baseline, 5,478 residents, mean age 84.4 (standard deviation (SD) 10.9), 71% female, resided in 40 LTC homes, mean size = 137 beds (SD 76.7). In the intention-to-treat analysis (21 control; 19 intervention clusters), the intervention resulted in a significantly greater increase in prescribing from baseline to 12 months between intervention versus control arms for vitamin D (odds ratio (OR) 1.82, 95% confidence interval (CI): 1.12, 2.96) and calcium (OR 1.33, 95% CI: 1.01, 1.74), but not for osteoporosis medications (OR 1.17, 95% CI: 0.91, 1.51). In secondary analyses, excluding seven nonparticipating intervention homes, ORs were 3.06 (95% CI: 2.18, 4.29), 1.57 (95% CI: 1.12, 2.21), 1.20 (95% CI: 0.90, 1.60) for vitamin D, calcium and osteoporosis medications, respectively.
Our KT intervention significantly improved the prescribing of vitamin D and calcium and is a model that could potentially be applied to other areas requiring quality improvement.
Trial Registration NCT01398527. Registered: 19 July 2011.
PMCID: PMC4431601  PMID: 25962885
Fracture; long-term care; Vitamin D; prescribing; knowledge translation
4.  Association between body mass index and suicidal behaviors: a systematic review protocol 
Systematic Reviews  2015;4:52.
Suicide is among the leading causes of death worldwide. Suicide attempts and suicidal ideation are more common than completed suicide and are associated with psychological distress. These behaviors are considered risk factors of completed suicide. Considering the psychosocial stigma and medical comorbidities associated with obesity, an accumulating body of studies have investigated body mass index (BMI) as a potential risk factor of suicide. However, several cohort studies have demonstrated an inverse relationship between BMI and completed suicide, suggesting a protective effect of increasing BMI against completed suicide. The association between BMI and attempted suicide is more equivocal, with several studies reporting both positive and negative relationships between BMI and attempted suicide. The primary objective of this study is to systematically review the literature to determine the association between BMI and suicidal behavior (including completed suicide, attempted suicide, suicidal ideation) in an adult population (18 years and older). The secondary objective is to explore whether sex, age, and the method used in suicide modify the relationship between BMI and suicidal behavior.
An electronic search will be conducted using PubMed/MEDLINE, PsycINFO, CINAHL, and EMBASE using a predefined search strategy; databases will be searched from their inception. Two authors (SP and RE) will independently screen articles using predefined inclusion and exclusion criteria and will extract pertinent data using a pilot tested extraction form. At all levels of screening, discrepancies between the two authors will be resolved by consensus, and in the case of disagreement, by consulting a third author (ZS). The primary outcomes include the association between BMI and completed suicide, attempted suicide, and suicidal ideation. If appropriate, a meta-analysis will be conducted. Risk of bias and quality of evidence will be assessed.
The results of this systematic review will inform health care professionals and researchers about whether BMI has a significant role in suicidal behavior and psychological well-being.
Systematic review registration
PROSPERO CRD42014014739.
Electronic supplementary material
The online version of this article (doi:10.1186/s13643-015-0038-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4424510  PMID: 25927506
Suicide; Attempted suicide; Suicidal ideation; Suicidal behavior; Body mass index; BMI; Obesity; Systematic review; Protocol
5.  The impact of chronic pain on opioid addiction treatment: a systematic review protocol 
Systematic Reviews  2015;4:49.
The consequences of opioid relapse among patients being treated with opioid substitution treatment (OST) are serious and can result in abnormal cardiovascular function, overdose, and mortality. Chronic pain is a major risk factor for opioid relapse within the addiction treatment setting. There exist a number of opioid maintenance therapies including methadone, buprenorphine, naltrexone, and levomethadyl acetate (LAAM), of which the mediating effects of pain on treatment attrition, substance use behavior, and social functioning may differ across therapies. We aim to 1) evaluate the impact of pain on the treatment outcomes of addiction patients being managed with OST and 2) identify the most recently published opioid maintenance treatment guidelines from the United States, Canada, and the UK to determine how the evidence is being translated into clinical practice.
The authors will search Medline, EMBASE, PubMed, PsycINFO, Web of Science, Cochrane Database of Systematic Reviews, ProQuest Dissertations and theses Database, Cochrane Central Register of Controlled Trials (CENTRAL), World Health Organization International Clinical Trials Registry Platform Search Portal, and the National Institutes for Health Clinical Trials Registry. We will search and the National Institute for Care and Excellence (NICE) databases to identify the most recently published OST guidelines. All screening and data extraction will be completed in duplicate. Provided the data are suitable, we will perform a multiple treatment comparison using Bayesian meta-analytic methods to produce summary statistics estimating the effect of chronic pain on all OSTs. Our primary outcome is substance use behavior, which includes opioid and non-opioid substance use. We will also evaluate secondary endpoints such as treatment retention, general physical health, intervention adherence, personal and social functioning, as well as psychiatric symptoms.
This review will capture the experience of treatment outcomes for a sub-population of opioid addiction patients and provide an opportunity to distinguish the best quality guidelines for OST. If chronic pain truly does result in negative consequences for opioid addiction patients, it is important we identify which OSTs are most appropriate for chronic pain patients as well as ensure the treatment guidelines incorporate this information.
Systematic review registration
PROSPERO CRD42014014015
PMCID: PMC4403999  PMID: 25927914
Chronic pain; Opioid maintenance; Addiction; Opioid substitution therapies; Opioid dependence; Buprenorphine/naloxone; Methadone; Methadone maintenance therapy; Naltrexone; Systematic review; Network meta-analysis
6.  Comparison between Frailty Index of Deficit Accumulation and Phenotypic Model to Predict Risk of Falls: Data from the Global Longitudinal Study of Osteoporosis in Women (GLOW) Hamilton Cohort 
PLoS ONE  2015;10(3):e0120144.
To compare the predictive accuracy of the frailty index (FI) of deficit accumulation and the phenotypic frailty (PF) model in predicting risks of future falls, fractures and death in women aged ≥55 years.
Based on the data from the Global Longitudinal Study of Osteoporosis in Women (GLOW) 3-year Hamilton cohort (n = 3,985), we compared the predictive accuracy of the FI and PF in risks of falls, fractures and death using three strategies: (1) investigated the relationship with adverse health outcomes by increasing per one-fifth (i.e., 20%) of the FI and PF; (2) trichotomized the FI based on the overlap in the density distribution of the FI by the three groups (robust, pre-frail and frail) which were defined by the PF; (3) categorized the women according to a predicted probability function of falls during the third year of follow-up predicted by the FI. Logistic regression models were used for falls and death, while survival analyses were conducted for fractures.
The FI and PF agreed with each other at a good level of consensus (correlation coefficients ≥ 0.56) in all the three strategies. Both the FI and PF approaches predicted adverse health outcomes significantly. The FI quantified the risks of future falls, fractures and death more precisely than the PF. Both the FI and PF discriminated risks of adverse outcomes in multivariable models with acceptable and comparable area under the curve (AUCs) for falls (AUCs ≥ 0.68) and death (AUCs ≥ 0.79), and c-indices for fractures (c-indices ≥ 0.69) respectively.
The FI is comparable with the PF in predicting risks of adverse health outcomes. These findings may indicate the flexibility in the choice of frailty model for the elderly in the population-based settings.
PMCID: PMC4357575  PMID: 25764521
7.  Hip fracture evaluation with alternatives of total hip arthroplasty versus hemiarthroplasty (HEALTH): protocol for a multicentre randomised trial 
BMJ Open  2015;5(2):e006263.
Hip fractures are a leading cause of mortality and disability worldwide, and the number of hip fractures is expected to rise to over 6 million per year by 2050. The optimal approach for the surgical management of displaced femoral neck fractures remains unknown. Current evidence suggests the use of arthroplasty; however, there is lack of evidence regarding whether patients with displaced femoral neck fractures experience better outcomes with total hip arthroplasty (THA) or hemiarthroplasty (HA). The HEALTH trial compares outcomes following THA versus HA in patients 50 years of age or older with displaced femoral neck fractures.
Methods and analysis
HEALTH is a multicentre, randomised controlled trial where 1434 patients, 50 years of age or older, with displaced femoral neck fractures from international sites are randomised to receive either THA or HA. Exclusion criteria include associated major injuries of the lower extremity, hip infection(s) and a history of frank dementia. The primary outcome is unplanned secondary procedures and the secondary outcomes include functional outcomes, patient quality of life, mortality and hip-related complications—both within 2 years of the initial surgery. We are using minimisation to ensure balance between intervention groups for the following factors: age, prefracture living, prefracture functional status, American Society for Anesthesiologists (ASA) Class and centre number. Data analysts and the HEALTH Steering Committee are blinded to the surgical allocation throughout the trial. Outcome analysis will be performed using a χ2 test (or Fisher's exact test) and Cox proportional hazards modelling estimate. All results will be presented with 95% CIs.
Ethics and dissemination
The HEALTH trial has received local and McMaster University Research Ethics Board (REB) approval (REB#: 06-151).
Outcomes from the primary manuscript will be disseminated through publications in academic journals and presentations at relevant orthopaedic conferences. We will communicate trial results to all participating sites. Participating sites will communicate results with patients who have indicated an interest in knowing the results.
Trial registration number
The HEALTH trial is registered with (NCT00556842).
PMCID: PMC4330331  PMID: 25681312
8.  Reanalysis of morphine consumption from two randomized controlled trials of gabapentin using longitudinal statistical methods 
Journal of Pain Research  2015;8:79-85.
Postoperative pain management in total joint replacement surgery remains ineffective in up to 50% of patients and has an overwhelming impact in terms of patient well-being and health care burden. We present here an empirical analysis of two randomized controlled trials assessing whether addition of gabapentin to a multimodal perioperative analgesia regimen can reduce morphine consumption or improve analgesia for patients following total joint arthroplasty (the MOBILE trials).
Morphine consumption, measured for four time periods in patients undergoing total hip or total knee arthroplasty, was analyzed using a linear mixed-effects model to provide a longitudinal estimate of the treatment effect. Repeated-measures analysis of variance and generalized estimating equations were used in a sensitivity analysis to compare the robustness of the methods.
There was no statistically significant difference in morphine consumption between the treatment group and a control group (mean effect size estimate 1.0, 95% confidence interval −4.7, 6.7, P=0.73). The results remained robust across different longitudinal methods.
The results of the current reanalysis of morphine consumption align with those of the MOBILE trials. Gabapentin did not significantly reduce morphine consumption in patients undergoing major replacement surgeries. The results remain consistent across longitudinal methods. More work in the area of postoperative pain is required to provide adequate management for this patient population.
PMCID: PMC4332293  PMID: 25709496
postoperative morphine consumption; randomized controlled trials; gabapentin; reanalysis
9.  The Relationship between Intramuscular Adipose Tissue, Functional Mobility, and Strength in Postmenopausal Women with and without Type 2 Diabetes 
Journal of Aging Research  2015;2015:872726.
Objectives. To determine (1) whether intramuscular adipose tissue (IntraMAT) differs between women with and without type 2 diabetes and (2) the association between IntraMAT and mobility and strength. Methods. 59 women ≥ 65 years with and without type 2 diabetes were included. A 1-Tesla MRI was used to acquire images of the leg. Timed-up-and-go (TUG) and grip strength were measured. Regression was used to determine associations between the following: (1) type 2 diabetes and IntraMAT (covariates: age, ethnicity, BMI, waist : hip ratio, and energy expenditure), (2) IntraMAT and TUG (covariates: diabetes, age, BMI, and energy expenditure), and (3) IntraMAT and grip strength (covariates: diabetes, age, height, and lean mass). Results. Women with diabetes had more IntraMAT. After adjustment, IntraMAT was similar between groups (diabetes mean [SD] = 13.2 [1.4]%, controls 11.8 [1.3]%, P = 0.515). IntraMAT was related to TUG and grip strength, but the relationships became nonsignificant after adjustment for covariates (difference/percent IntraMAT [95% CI]: TUG = 0.041 seconds [−0.079–0.161], P = 0.498, grip strength = −0.144 kg [−0.335–0.066], P = 0.175). Conclusions. IntraMAT alone may not be a clinically important predictor of functional mobility and strength; however, whether losses in functional mobility and strength are promoted by IntraMAT accumulation should be explored.
PMCID: PMC4322662  PMID: 25692042
10.  Mobile phone text messaging interventions for HIV and other chronic diseases: an overview of systematic reviews and framework for evidence transfer 
Strong international commitment and the widespread use of antiretroviral therapy have led to higher longevity for people living with human immune deficiency virus (HIV). Text messaging interventions have been shown to improve health outcomes in people living with HIV. The objectives of this overview were to: map the state of the evidence of text messaging interventions, identify knowledge gaps, and develop a framework for the transfer of evidence to other chronic diseases.
We conducted a systematic review of systematic reviews on text messaging interventions to improve health or health related outcomes. We conducted a comprehensive search of PubMed, EMBASE (Exerpta Medica Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, Web of Science (WoS) and the Cochrane Library on the 17th April 2014. Screening, data extraction and assessment of methodological quality were done in duplicate. Our findings were used to develop a conceptual framework for transfer.
Our search identified 135 potential systematic reviews of which nine were included, reporting on 37 source studies, conducted in 19 different countries. Seven of nine (77.7%) of these reviews were high quality. There was some evidence for text messaging as a tool to improve adherence to antiretroviral therapy. Text messages also improved attendance at appointments and behaviour change outcomes. The findings were inconclusive for self-management of illness, treatment of tuberculosis and communicating results of medical investigations. The geographical distribution of text messaging research was limited to specific regions of the world. Prominent knowledge gaps included the absence of data on long term outcomes, patient satisfaction, and economic evaluations. The included reviews also identified methodological limitations in many of the primary studies.
Global evidence supports the use of text messaging as a tool to improve adherence to medication and attendance at scheduled appointments. Given the similarities between HIV and other chronic diseases (long-term medications, life-long care, strong link to behaviour and the need for home-based support) evidence from HIV may be transferred to these diseases using our proposed framework by integration of HIV and chronic disease services or direct transfer.
PMCID: PMC4308847  PMID: 25609559
Text message; HIV chronic disease; Evidence transfer; Overview
11.  Management of chronic neuropathic pain: a protocol for a multiple treatment comparison meta-analysis of randomised controlled trials 
BMJ Open  2014;4(11):e006112.
Chronic neuropathic pain is associated with reduced health-related quality of life and substantial socioeconomic costs. Current research addressing management of chronic neuropathic pain is limited. No review has evaluated all interventional studies for chronic neuropathic pain, which limits attempts to make inferences regarding the relative effectiveness of treatments.
Methods and analysis
We will conduct a systematic review of all randomised controlled trials evaluating therapies for chronic neuropathic pain. We will identify eligible trials, in any language, by a systematic search of CINAHL, EMBASE, MEDLINE, AMED, HealthSTAR, DARE, PsychINFO and the Cochrane Central Registry of Controlled Trials. Eligible trials will be: (1) enrol patients presenting with chronic neuropathic pain, and (2) randomise patients to alternative interventions (pharmacological or non-pharmacological) or an intervention and a control arm. Pairs of reviewers will, independently and in duplicate, screen titles and abstracts of identified citations, review the full texts of potentially eligible trials and extract information from eligible trials. We will use a modified Cochrane instrument to evaluate risk of bias of eligible studies, recommendations from the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) to inform the outcomes we will collect, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to evaluate our confidence in treatment effects. When possible, we will conduct: (1) in direct comparisons, a random-effects meta-analysis to establish the effect of reported therapies on patient-important outcomes; and (2) a multiple treatment comparison meta-analysis within a Bayesian framework to assess the relative effects of treatments. We will define a priori hypotheses to explain heterogeneity between studies, and conduct meta-regression and subgroup analyses consistent with the current best practices.
Ethics and Dissemination
We do not require ethics approval for our proposed review. We will disseminate our findings through peer-reviewed publications and conference presentations.
Trial registration number
PROSPERO (CRD42014009212).
PMCID: PMC4244486  PMID: 25412864
12.  Evaluation of clinical and inflammatory profile in opioid addiction patients with comorbid pain: results from a multicenter investigation 
Chronic pain is the most commonly reported comorbidity among patients with opioid addiction receiving methadone maintenance treatment (MMT), with an estimated prevalence ranging between 30% and 55%. Evidence suggests that patients with comorbid pain are at high risk for poor treatment response, including continued illicit substance use. Due to the important relationship between the presence of pain and illicit substance abuse within the MMT setting, it is imperative that we target our efforts toward understanding the characteristics of this patient population.
The primary objective of this study was to explore the clinical and inflammatory profile of MMT patients reporting comorbid pain. This multicenter study enrolled patients (n=235) on MMT for the treatment of opioid dependence. Clinical history and blood and urine data were collected. Blood samples were obtained for estimating the serum levels of inflammatory markers (tumor necrosis factor [TNF]-α, interleukin-1 receptor antagonist [IL-1ra], IL-6, IL-8, IL-10, interferon [IFN]-γ and chemokine (C–C motif) ligand 2 [CCL2]). The study objectives were addressed using a descriptive statistical summary and a multivariable logistic regression model constructed in STATA version 12.
Among the participants eligible for inclusion (n=235), serum IFN-γ level and substance abuse behavior proved to be important delineating characteristics for the detection of comorbid pain. Analysis of inflammatory profile showed IFN-γ to be significantly elevated among patients reporting comorbid pain (odds ratio [OR]: 2.02; 95% confidence interval [CI]: 1.17, 3.50; P=0.01). Patients reporting comorbid pain were also found to have an increase in positive opioid urine screens (OR: 1.02; 95% CI: 1.00, 1.03; P=0.01), indicating an increase in illicit opioid consumption.
MMT patients with comorbid pain were shown to have elevated IFN-γ and higher rates of continued opioid abuse. The ability to objectively distinguish between patients with comorbid pain may help to both improve the prediction of poor responders to MMT as well as identify treatment approaches such as anti-inflammatory medications as safe alternatives for MMT patients with comorbid pain.
PMCID: PMC4242695  PMID: 25429222
methadone maintenance treatment; inflammatory markers; TNF-α; IFN-γ; interleukins; CCL2; Brief Pain Inventory; opioid dependence
13.  Continuous venovenous hemofiltration versus continuous venovenous hemodiafiltration in critically ill patients: A retrospective cohort study from a Canadian tertiary centre 
Critically ill patients who develop acute kidney injury are at an increased risk for death. Several trials have compared therapeutic methods and have reported superior survival benefits for some. Although there is variation in practice worldwide, it is unknown whether the methods investigated in this particular study differ with regard to patient outcomes.
Studies comparing continuous renal replacement therapy modalities are lacking. Theoretically, continuous venovenous hemofiltration (CVVH) could be more effective than continuous venovenous hemodiafiltration (CVVHDF), and may be associated with fewer complications; however, there are no published data to support this hypothesis.
To examine the effect of CVVH on mortality and other clinically important outcomes compared with CVVHDF in the intensive care unit (ICU) setting.
Using a log of all continuous renal replacement therapy performed at a Canadian tertiary centre between 2007 and 2010, the records of patients meeting the inclusion criteria of being admitted to the ICU, and receiving either CVVH or CVVHDF for management of acute renal failure, were reviewed. The information retrieved included demographic data, death events, and hospital and ICU length of stay.
Data from 153 patients were included in the present study. Hospital and 30-day mortality were similar in the CVVH and CVVHDF groups (OR 0.85 [95% CI 0.38 to 1.89]; P=0.69 and OR 1.35 [95% CI 0.62 to 2.95]; P=0.45, respectively). There was no difference in hospital length of stay (mean difference −34.14 [95% CI −72.92 to 4.65]; P=0.08).
The present retrospective review suggests that the use of CVVH does not reduce mortality or hospital length of stay when compared with CVVHDF. Future randomized trials should control for different patient populations and continue to evaluate the removal of small molecules such as hormones.
PMCID: PMC4128463  PMID: 24712012
Acute renal failure; Cohort study; Continuous renal replacement therapy; Critically ill patients
14.  Treatment crossovers in time-to-event non-inferiority randomised trials of radiotherapy in patients with breast cancer 
BMJ Open  2014;4(10):e006531.
In non-inferiority trials of radiotherapy in patients with early stage breast cancer, it is inevitable that some patients will cross over from the experimental arm to the standard arm prior to initiation of any treatment due to complexities in treatment planning or subject preference. Although the intention-to-treat (ITT) analysis is the preferred approach for superiority trials, its role in non-inferiority trials is still under debate. This has led to the use of alternative approaches such as the per-protocol (PP) analysis or the as-treated (AT) analysis, despite the inherent biases of such approaches.
Using simulations, we investigate the effect of 2%, 5% and 10% random and non-random crossovers prior to radiotherapy initiation on the ITT, PP, AT and the combination of ITT and PP analyses with respect to type I error in trials with time-to-event outcomes. We also evaluate bias and SE of the estimates from the ITT, PP and AT approaches.
The AT approach had the best performance in terms of type I error, but was anticonservative as non-random crossover increased. The ITT and PP approaches were anticonservative under all percentages of random and non-random crossover. Similarly, lowest bias was seen with the AT approach; however, bias increased as the percentage of non-random crossover increased. The ITT and PP had poor performance in terms of bias as crossovers increased.
If minimal crossovers were to occur, we have shown that the AT approach has the lowest type I error rates and smallest opportunity for bias. Results of trials with a high number of crossovers should be interpreted with caution, especially when crossover is non-random. Attempts to prevent crossovers should be maximised.
PMCID: PMC4212183  PMID: 25344487
15.  Training Cameroonian researchers on pragmatic knowledge translation trials: a workshop report 
Limited health research capacity in one of the factors that prevents developing countries from attaining optimal health outcomes and achieving the Millennium Development Goals. We report here, the details of a workshop on pragmatic knowledge translation trials for Cameroonian researchers, the material covered and additional resources to support capacity development. At the end of this workshop, knowledge gains were noted and participants were able to initiate proposals for funding. These proposals were aimed at improving the clinical management of diabetes, hypertension and malaria.
PMCID: PMC4369305  PMID: 25821533
Pragmatic trials; knowledge translation; capacity building; Cameroon; workshop
16.  Patients’ values and preferences of the expected efficacy of hip arthroscopy for osteoarthritis: a protocol for a multinational structured interview-based study combined with a randomised survey on the optimal amount of information to elicit preferences 
BMJ Open  2014;4(10):e005536.
Symptomatic hip osteoarthritis (OA) is a disabling condition with up to a 25% cumulative lifetime risk. Total hip arthroplasty (THA) is effective in relieving patients’ symptoms and improving function. It is, however, associated with substantial risk of complications, pain and major functional limitation before patients can return to full function. In contrast, hip arthroscopy (HA) is less invasive and can postpone THA. However, there is no evidence regarding the delay in the need for THA that patients would find acceptable to undergoing HA. Knowing patients’ values and preferences (VP) on this expected delay is critical when making recommendations regarding the advisability of HA. Furthermore, little is known on the optimal amount of information regarding interventions and outcomes needed to present in order to optimally elicit patients’ VP.
Methods and analysis
We will perform a multinational, structured interview-based survey of preference in delay time for THA among patients with non-advanced OA who failed to respond to conservative therapy. We will combine these interviews with a randomised trial addressing the optimal amount of information regarding the interventions and outcomes required to elicit preferences. Eligible patients will be randomly assigned (1 : 1) to either a short or a long format of health scenarios of THA and HA. We will determine each patient's VP using a trade-off and anticipated regret exercises. Our primary outcomes for the combined surveys will be: (1) the minimal delay time in the need for THA surgery that patients would find acceptable to undertaking HA, (2) patients’ satisfaction with the amount of information provided in the health scenarios used to elicit their VPs.
Ethics and dissemination
The protocol has been approved by the Hamilton Integrated Research Ethics Board (HIREB13-506). We will disseminate our study findings through peer-reviewed publications and conference presentations, and make them available to guideline makers issuing recommendations addressing HA and THA.
PMCID: PMC4202002  PMID: 25326208
Patients' values and preference; Total Hip Arthroplasty; Hip Arthroscopy; Patient Written Information; Decision Making
17.  Evaluating the test re-test reliability and inter-subject variability of health care provider manual fluid resuscitation performance 
BMC Research Notes  2014;7:724.
Health Care Providers (HCPs) report that manual techniques of intravascular fluid resuscitation are commonly used during pediatric shock management. The optimal pediatric fluid resuscitation technique is currently unknown. We sought to determine HCP test-retest reliability (repeatability) and inter-subject variability of fluid resuscitation performance outcomes to inform the design of future studies.
Fifteen consenting HCPs from McMaster Children’s Hospital, in Hamilton, Canada participated in this single-arm interventional trial. Participants were oriented to a non-clinical model representing a 15 kg toddler, which incorporated a 22-gauge IV catheter. Following a standardization procedure, participants administered 600 mL (40 mL/kg) of saline to the simulated child under emergency conditions using prefilled 60-mL syringes. Each participant completed 5 testing trials. All testing was video recorded, with fluid administration time outcome data (in seconds) extracted from trial videos by two blinded outcome assessors. Data describing catheter dislodgement events, volume of saline effectively delivered, and participant demographics were also collected. The primary outcome of fluid administration time test-retest reliability was analyzed by one-way analysis of variance (ANOVA) and intra-class correlation (ICC), with good reliability defined as ICC > 0.70.
Differences in HCP fluid administration times are attributable to inter-subject variability rather than intra-subject variability based on one-way ANOVA analysis, F (14,60) = 43.125; p < 0.001. Test-retest reliability of subjects was excellent with ICC = 0.97 (95% CI: 0.95-0.99); p < 0.001.
Findings demonstrate excellent test-retest reliability of HCP fluid resuscitation performance in a setting involving a non-clinical model. Investigators can justify a single evaluation of HCP performance in future studies.
Electronic supplementary material
The online version of this article (doi:10.1186/1756-0500-7-724) contains supplementary material, which is available to authorized users.
PMCID: PMC4210565  PMID: 25315062
Research methods; Resuscitation; Shock; Fluid therapy; Pediatrics
18.  Factors associated with development of gastrointestinal problems in patients with scleroderma: a protocol for a systematic review 
Systematic Reviews  2014;3:115.
Scleroderma affects the gastrointestinal (GI) tract in 90% of all cases. Malnutrition, diarrhea, and constipation are some GI complications that can stem from scleroderma, and they contribute considerably to impairment in quality of life. Reports of haphazard clusters of high prevalence suggest that environmental exposure is a risk factor for scleroderma. However, it is largely uncertain whether the GI involvement secondary to scleroderma is influenced by these environmental factors. This study will review the association between GI involvement (unintentional weight loss, choking, early satiety, etc.) and environmental exposure in patients with scleroderma.
Any available observational studies that report GI problems in patients with scleroderma along with the associated risk factors will be selected. We will search CINAHL, EMBASE, LILACS, MEDLINE, and Web of Science for relevant articles written in English from June 1884 to May 2014. Identified articles will be screened in duplicate, and full text for selected articles will be retrieved. Data extraction will be done in duplicate on sociodemographic characteristics of participants, diagnosis of scleroderma, diagnosis of risk of GI problem, risk factors reported, etc. Discrepancies will be resolved by consensus or by consulting a third author. We will assess the participants, methods, and intervention effects of included studies for heterogeneity. Any identified clinical or statistical heterogeneity will be explored visually or using the chi-square test. Data will be pooled statistically using the DerSimmonian and Laird random effects method if we have a measure of relative risk and its precision. Our findings will be reported according to the Meta-Analyses and Systematic Review of Observational Studies (MOOSE) guideline.
Our findings may help patients with scleroderma and health care professionals in preventing GI morbidity. Knowing that the cost of care for patients with scleroderma increases with more organ involvement, study findings can inform policy developers to identify ways to curb health care costs.
Systematic review registration
PROSPERO: CRD42014010707
PMCID: PMC4201836  PMID: 25312976
Systematic review; Scleroderma; Gastrointestinal; Risk factor
19.  Accounting for center in the Early External Cephalic Version trials: an empirical comparison of statistical methods to adjust for center in a multicenter trial with binary outcomes 
Trials  2014;15:377.
Clustering of outcomes at centers involved in multicenter trials is a type of center effect. The Consolidated Standards of Reporting Trials Statement recommends that multicenter randomized controlled trials (RCTs) should account for center effects in their analysis, however most do not. The Early External Cephalic Version (EECV) trials published in 2003 and 2011 stratified by center at randomization, but did not account for center in the analyses, and due to the nature of the intervention and number of centers, may have been prone to center effects. Using data from the EECV trials, we undertook an empirical study to compare various statistical approaches to account for center effect while estimating the impact of external cephalic version timing (early or delayed) on the outcomes of cesarean section, preterm birth, and non-cephalic presentation at the time of birth.
The data from the EECV pilot trial and the EECV2 trial were merged into one dataset. Fisher’s exact method was used to test the overall effect of external cephalic version timing unadjusted for center effects. Seven statistical models that accounted for center effects were applied to the data. The models included: i) the Mantel-Haenszel test, ii) logistic regression with fixed center effect and fixed treatment effect, iii) center-size weighted and iv) un-weighted logistic regression with fixed center effect and fixed treatment-by-center interaction, iv) logistic regression with random center effect and fixed treatment effect, v) logistic regression with random center effect and random treatment-by-center interaction, and vi) generalized estimating equations.
For each of the three outcomes of interest approaches to account for center effect did not alter the overall findings of the trial. The results were similar for the majority of the methods used to adjust for center, illustrating the robustness of the findings.
Despite literature that suggests center effect can change the estimate of effect in multicenter trials, this empirical study does not show a difference in the outcomes of the EECV trials when accounting for center effect.
Trial registration
The EECV2 trial was registered on 30 July 30 2005 with Current Controlled Trials: ISRCTN%2056498577.
PMCID: PMC4192344  PMID: 25257928
Randomized controlled trials; Center effect; Multicenter trials; Trial design; Trial analysis; Random effect; Mixed-effects; Generalized estimating equations; Generalized linear mixed model
20.  A framework for community ownership of a text messaging programme to improve adherence to antiretroviral therapy and client-provider communication: a mixed methods study 
Mobile phone text messaging has been shown to improve adherence to antiretroviral therapy and to improve communication between patients and health care workers. It is unclear which strategies are most appropriate for scaling up text messaging programmes. We sought to investigate acceptability and readiness for ownership (community members designing, sending and receiving text messages) of a text message programme among a community of clients living with human immunodeficiency virus (HIV) in Yaoundé, Cameroon and to develop a framework for implementation.
We used the mixed-methods sequential exploratory design. In the qualitative strand we conducted 7 focus group discussions (57 participants) to elicit themes related to acceptability and readiness. In the quantitative strand we explored the generalizability of these themes in a survey of 420 clients. Qualitative and quantitative data were merged to generate meta-inferences.
Both qualitative and quantitative strands showed high levels of acceptability and readiness despite low rates of participation in other community-led projects. In the qualitative strand, compared to the quantitative strand, more potential service users were willing to pay for a text messaging service, preferred participation of health personnel in managing the project and preferred that the project be based in the hospital rather than in the community. Some of the limitations identified to implementing a community-owned project were lack of management skills in the community, financial, technical and literacy challenges. Participants who were willing to pay were more likely to find the project acceptable and expressed positive feelings about community readiness to own a text messaging project.
Community ownership of a text messaging programme is acceptable to the community of clients at the Yaoundé Central Hospital. Our framework for implementation includes components for community members who take on roles as services users (demonstrating clear benefits, allowing a trial period and ensuring high levels of confidentiality) or service providers (training in project management and securing sustainable funding). Such a project can be evaluated using participation rate, clinical outcomes, satisfaction with the service, cost and feedback from users.
Electronic supplementary material
The online version of this article (doi:10.1186/1472-6963-14-441) contains supplementary material, which is available to authorized users.
PMCID: PMC4263054  PMID: 25258249
Text messaging; Community ownership; HIV; Mixed methods; Cameroon
21.  The effectiveness of opioid substitution treatments for patients with opioid dependence: a systematic review and multiple treatment comparison protocol 
Systematic Reviews  2014;3:105.
Opioids are psychoactive analgesic drugs prescribed for pain relief and palliative care. Due to their addictive potential, effort and vigilance in controlling prescriptions is needed to avoid misuse and dependence. Despite the effort, the prevalence of opioid use disorder continues to rise. Opioid substitution therapies are commonly used to treat opioid dependence; however, there is minimal consensus as to which therapy is most effective. Available treatments include methadone, heroin, buprenorphine, as well as naltrexone. This systematic review aims to assess and compare the effect of all available opioid substitution therapies on the treatment of opioid dependence.
The authors will search Medline, EMBASE, PubMed, PsycINFO, Web of Science, Cochrane Library, Cochrane Clinical Trials Registry, World Health Organization International Clinical Trials Registry Platform Search Portal, and the National Institutes for Health Clinical Trials Registry. The title, abstract, and full-text screening will be completed in duplicate. When appropriate, multiple treatment comparison Bayesian meta-analytic methods will be performed to deduce summary statistics estimating the effectiveness of all opioid substitution therapies in terms of retention and response to treatment (as measured through continued opioid abuse).
Using evidence gained from this systematic review, we anticipate disseminating an objective review of the current available literature on the effectiveness of all opioid substitution therapies for the treatment of opioid use disorder. The results of this systematic review are imperative to the further enhancement of clinical practice in addiction medicine.
Systematic review registration
PROSPERO CRD42013006507.
PMCID: PMC4171401  PMID: 25239213
Opioid substitution therapies; Opioid dependence; Methadone; Buprenorphine/naloxone; Naltrexone; Heroin; Systematic review; Network meta-analysis
22.  CIHR canadian HIV trials network HIV workshop: ethical research through community participation and strengthening scientific validity 
The CIHR canadian HIV trials network mandate includes strengthening capacity to conduct and apply clinical research through training and mentoring initiatives of HIV researchers by building strong networks and partnerships on the African continent. At the17th International Conference on AIDS and Sexually Transmitted Infections in Africa (ICASA), the CTN facilitated a two-day workshop to address ethical issues in the conduct of HIV research, and career enhancing strategies for young African HIV researchers. Conference attendees were allowed to attend whichever session was of interest to them. We report on the topics covered, readings shared and participants’ evaluation of the workshop. The scientific aspects of ethical research in HIV and career enhancement strategies are relevant issues to conference attendees.
PMCID: PMC4315477  PMID: 25667706
Capacity building; ethics; HIV research; South Africa
23.  Methadone induces testosterone suppression in patients with opioid addiction 
Scientific Reports  2014;4:6189.
Sex hormones may have a role in the pathophysiology of substance use disorders, as demonstrated by the association between testosterone and addictive behaviour in opioid dependence. Although opioid use has been found to suppress testosterone levels in men and women, the extent of this effect and how it relates to methadone treatment for opioid dependence is unclear. The present multi-centre cross-sectional study consecutively recruited 231 patients with opioid dependence from methadone clinics across Ontario, Canada between June and December of 2011. We obtained demographic details, substance use, psychiatric history, and blood and urine samples from enrolled subjects. The control group included 783 non-opioid using adults recruited from a primary care setting in Ontario, Canada. Average testosterone level in men receiving methadone treatment was significantly lower than controls. No effect of opioids including methadone on testosterone level in women was found and testosterone did not fluctuate significantly between menstrual cycle phases. In methadone patients, testosterone level was significantly associated with methadone dose in men only. We recommend that testosterone levels be checked in men prior and during methadone and other opioid therapy, in order to detect and treat testosterone deficiency associated with opioids and lead to successful methadone treatment outcomes.
PMCID: PMC4143768  PMID: 25155550
24.  Genetic influence on methadone treatment outcomes in patients undergoing methadone maintenance treatment for opioid addiction: a pilot study 
Treatment of opioid addiction with methadone is effective; however, it is known to produce interindividual variability. This may be influenced in part by genetic variants, which can increase the initial risk of developing opioid addiction as well as explain differences in response to treatment. This pilot study aimed to assess the feasibility of conducting a full-scale genetic analysis to identify genes that predict methadone treatment outcomes in this population.
This was a cross-sectional observational study of patients admitted to a methadone maintenance treatment program for opioid addiction. We obtained demographic and clinical characteristics in addition to blood and urine samples, for the assessment of treatment outcomes.
The recruitment process yielded 252 patients, representing a 20% recruitment rate. We conducted genetic testing based on a 99.6% rate of provision of DNA samples. The average retention in treatment was 3.4 years, and >50% of the participants reported psychiatric and medical comorbidities. BDNF rs6265 and DRD2 rs1799978 were the common single nucleotide polymorphisms (SNPs) selected for the feasibility study.
This study met our predetermined feasibility criteria; recruitment, response rates, and genetic testing were feasible; treatment duration was sufficient for follow up; and the prevalence of comorbid conditions indicated the need for reliable psychiatric and chronic pain measures. The study strengths included effective collaboration with clinics and the generalizability of sample population. Key learning points show the need for assessment of treatment outcomes on multiple domains, implementation of follow up, and the development of standardized training for the study clinical staff.
PMCID: PMC4149396  PMID: 25187714
genetics; substitute opioid therapy; treatment response; risk factors
25.  Design, implementation, and evaluation of a pediatric and adolescent type 2 diabetes management program at a tertiary pediatric center 
Global rates of type 2 diabetes in children and adolescents have increased significantly over the past three decades. Type 2 diabetes is a relatively new disease in this age group, and there is a dearth of information about how to structure treatment programs to manage its comorbidities and complications. In this paper, we describe the design and implementation of a personalized multidisciplinary, family-centered, pediatric and adolescent type 2 diabetes program at a tertiary pediatric center in Hamilton, Ontario, Canada. We report the process of designing and implementing such a program, and show that this multidisciplinary program led to improvement in glycated hemoglobin (n=17, 8% at baseline versus 6.4% at 1 year, 95% confidence interval (0.1–0.28), P-value <0.0001) and stabilized body mass index, with lowered C-peptide and no change in fitness or metabolic biomarkers of lipid metabolism and liver function. As type 2 diabetes becomes more prevalent in youth, the need for programs that successfully address the complex nature of this disease is central to its management and to mitigate its long-term adverse outcomes.
PMCID: PMC4124128  PMID: 25114539
type 2 diabetes; pediatric; adolescents; program design; multidisciplinary

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