Limb salvage with endoprosthetic reconstruction is the standard of care for the management of lower-extremity bone tumours in skeletally mature patients. The risk of deep postoperative infection in these procedures is high and the outcomes can be devastating. The most effective prophylactic antibiotic regimen remains unknown, and current clinical practice is highly varied. This trial will evaluate the effect of varying postoperative prophylactic antibiotic regimens on the incidence of deep infection following surgical excision and endoprosthetic reconstruction of lower-extremity bone tumours.
Methods and analysis
This is a multicentre, blinded, randomised controlled trial, using a parallel two-arm design. 920 patients 15 years of age or older from 12 tertiary care centres across Canada and the USA who are undergoing surgical excision and endoprosthetic reconstruction of a primary bone tumour will receive either short (24 h) or long (5 days) duration postoperative antibiotics. Exclusion criteria include prior surgery or infection within the planned operative field, known colonisation with methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus at enrolment, or allergy to the study antibiotics. The primary outcome will be rates of deep postoperative infections in each arm. Secondary outcomes will include type and frequency of antibiotic-related adverse events, patient functional outcomes and quality-of-life scores, reoperation and mortality. Randomisation will be blocked, with block sizes known only to the methods centre responsible for randomisation, and stratified by location of tumour and study centre. Patients, care givers and a Central Adjudication Committee will be blinded to treatment allocation. The analysis to compare groups will be performed using Cox regression and log-rank tests to compare survival functions at α=0.05.
Ethics and dissemination
This study has ethics approval from the McMaster University/Hamilton Health Sciences Research Ethics Board (REB# 12-009). Successful completion will significantly impact on clinical practice and enhance patients’ lives. More broadly, this trial will develop a network of collaboration from which further high-quality trials in Orthopaedic Oncology will follow.
To model variables influencing the dissemination of evidence-based practices to addiction service providers and administrators.
A discrete–choice conjoint experiment. We systematically varied combinations of 16 dissemination variables that might influence the adoption of evidence-based practices. Participants chose between sets of variables.
Canadian agencies (n=333) providing addiction services to women.
Service providers and administrators (n=1379).
We estimated the relative importance and optimal level of each dissemination variable. We used Latent Class analysis to identify subsets of participants with different preferences and simulated the conditions under which participants would use more demanding professional development options..
Three subsets of participants were identified: outcome sensitive (52%), process sensitive (29.6%) and demand sensitive (18.2%). Across all participants, the number of clients who were expected to benefit from an evidence-based practice exerted the most influence on dissemination choices. If a practice was seen as feasible, co-worker and administrative support influenced decisions. Client benefits were most important to outcome-sensitive participants; type of dissemination process (e.g. active versus passive learning) was more important to process-sensitive participants. Brief options with little follow-up were preferred by demand-sensitive participants. Simulations predicted that initiatives selected and endorsed by government funders would reduce participation.
Clinicians and administrators are more likely to adopt evidence-based addiction practices if the practice is seen as helpful to clients, and if it is supported by co-workers and program administration.
PMID: 22296280 CAMSID: cams3708
addiction; conjoint analysis; discrete choice conjoint experiment; dissemination; implementation; reactance
There are few treatment options for patients with severe atopic asthma. Antagonism of IgE is an effective strategy. We investigated, by utilizing serum samples from a clinical trial of Rituximab in patients with Idiopathic Thrombocytopenic Purpura, if B cell depletion would decrease serum IgE and therefore be a potential therapeutic option.
In a placebo-controlled randomized clinical trial of Rituximab, an anti-CD20 molecule, there were no significant differences in serum levels of IgE or BAFF levels between the two treatment groups at 3 or 6 months irrespective of the baseline serum IgE levels.
Since Rituximab did not significantly decrease serum IgE levels, this proof of concept study suggests that Rituximab may not be a useful treatment strategy for patients with severe IgE mediated disease.
Anti-CD20; Rituximab; Immunoglobulin E; BAFF; Asthma
The value of integrated care through comprehensive, coordinated, and family-centered services has been increasingly recognized for improving health outcomes of children with special health care needs (CSHCN). In a randomized controlled trial (RCT), the integrated care provided through the Children’s Treatment Network (CTN) was compared with usual care in improving the psychosocial health of target CSHCN. In this paper, we aimed to estimate the effect of CTN care by conducting multiple analyses to handle noncompliance in the trial.
The trial recruited target children in Simcoe County and York Region, ON, Canada. Children were randomized to receive CTN or usual care and were followed for 2 years. The CTN group received integrated services through multiple providers to address their specific needs while the usual care group continued to receive care directed by their parents. The outcome was change in psychosocial quality of life at 2 years. We conducted intention-to-treat, as-treated, per-protocol, and instrumental variable analyses to analyze the outcome.
The trial randomized 445 children, with 229 in the intervention group and 216 in the control group. During follow-up, 52% of children in the intervention group did not receive complete CTN care for various reasons. At 2 years, we did not find a significant improvement in psychosocial quality of life among the children receiving CTN care compared with usual care (intention-to-treat mean difference 1.50, 95% confidence interval −1.49 to 4.50; P = 0.32). Other methods of analysis yielded similar results.
Although the effect of CTN care was not significant, there was evidence showing benefits of integrated care for CSHCN. More RCTs are needed to demonstrate the magnitude of such an effect. The CTN study highlights the key challenges in RCTs when assessing interventions involving integrated care, and informs further RCTs including similar evaluations.
children with special health care needs; chronically ill; family-centered care; randomized controlled trial; noncompliance
Most HIV prevention strategies assume beneficiaries can act on their prevention decisions. But some people are unable to do so. They are ‘choice-disabled’. Economic and educational interventions can reduce sexual violence, but there is less evidence that they can reduce HIV. There is little research on complex interventions in HIV prevention, yet all countries in southern Africa implement combination prevention programmes.
The primary objective is to reduce HIV infections among women aged 15 to 29 years. Secondary objectives are reduction in gender violence and improvement in HIV-related knowledge, attitudes and practices among youth aged 15 to 29 years.
A random sample of 77 census enumeration areas in three countries (Botswana, Namibia and Swaziland) was allocated randomly to three interventions, alone or in combination, in a factorial design stratified by country, HIV rates (above or below average for country), and urban/rural location. A baseline survey of youth aged 15 to 29 years provided cluster specific rates of HIV. All clusters continue existing prevention efforts and have a baseline and follow-up survey. Cluster is the unit of allocation, intervention and analysis, using generalised estimating equations, on an intention-to-treat basis.
One intervention discusses evidence about choice disability with local HIV prevention services, to help them to serve the choice-disabled. Another discusses an eight-episode audio-docudrama with community groups, of all ages and both sexes, to generate endogenous strategies to reduce gender violence and develop an enabling environment. A third supports groups of women aged 18 to 25 years to build self-esteem and life skills and to set up small enterprises to generate income.
A survey in all clusters after 3 years will measure outcomes, with interviewers unaware of group assignment of the clusters. The primary outcome is HIV infection in women aged 15 to 29 years. Secondary outcomes in youth aged 15 to 29 years are gender violence and protective knowledge, attitudes, subjective norms, intention to change, agency, discussion of prevention and practices related to HIV and gender violence.
Trial registration number: ISRCTN28557578
HIV prevention; Gender violence; Southern Africa; Cluster randomised controlled trial
Physical activity is known to benefit many physiological processes, including bone turnover. There are; however, currently no clinical guidelines regarding the most appropriate type, intensity and duration of activity to prevent bone loss.
To help address this gap in the literature, we performed a retrospective analysis of data from the Canadian Multicentre Osteoporosis Study (CaMos), a prospective cohort of 9423 adult patients, to determine the relationship between the amount of regular daily physical activity performed and bone mineral density. A total of 1169 female participants aged 75 and over provided information regarding their daily activity levels, including the amount of time spent each week performing physical activity at varying levels of intensity. Multiple and linear regression analyses were used to determine the effect of increasing amounts of this regular physical activity on bone mineral density.
The results indicate that a step increase in the amount of physical activity performed each day resulted in a positive effect on bone mineral density at the hip, Ward’s triangle, trochanter and femoral neck (B = 0.006 to 0.008, p < 0.05). Possible confounding factors such as the use of anti-resorptive therapy, body mass index and age were included in the analysis and suggested that age had a negative effect on bone density while body mass index had a positive effect. Anti-resorptive therapy provided a protective effect against loss of bone density.
The data indicate that a step increase in the amount of daily activity, using simple, daily performed tasks, can help prevent decreases in post-menopausal bone mineral density.
Osteoporosis; Physical activity; Bone mineral density; Post-menopausal
Multiple sclerosis (MS) is a chronic neurodegenerative disease of the CNS. Recently a controversial vascular hypothesis for MS, termed chronic cerebrospinal venous insufficiency (CCSVI), has been advanced. The objective of this study was to evaluate the relative prevalence of the venous abnormalities that define CCSVI.
A case-control study was conducted in which 100 MS patients aged between 18–65 y meeting the revised McDonald criteria were randomly selected and stratified into one of four MS subtypes: relapsing/remitting, secondary progressive, primary progressive and benign. Control subjects (16–70 y) with no known history of MS or other neurological condition were matched with the MS cases. All cases and controls underwent ultrasound imaging of the veins of the neck plus the deep cerebral veins, and magnetic resonance imaging of the neck veins and brain. These procedures were performed on each participant on the same day.
On ultrasound we found no evidence of reflux, stenosis or blockage in the internal jugular veins (IJV) or vertebral veins (VV) in any study participant. Similarly, there was no evidence of either reflux or cessation of flow in the deep cerebral veins in any subject. Flow was detected in the IJV and VV in all study participants. Amongst 199 participants there was one MS subject who fulfilled the minimum two ultrasound criteria for CCSVI. Using MRI we found no significant differences in either the intra- or extra-cranial venous flow velocity or venous architecture between cases and controls.
This case-control study provides compelling evidence against the involvement of CCSVI in multiple sclerosis.
Advances in pediatric care have not provided the interdisciplinary support services required by those young adults with pediatric life-threatening conditions (pedLTCs) who live beyond childhood but have limited expectations to live past early adulthood. These young adults, the first generation to live into adulthood, face multiple challenges transitioning from a plethora of pediatric palliative services to scant adult health services. In a case study, using an innovative bulletin board focus group, we describe the complex interplay of the health, education, and social service sectors in this transition. Our descriptions include system deficits and strengths and the young adults' resilience and coping strategies to overcome those deficits and move forward with their lives. Young adults with pedLTC need knowledgeable providers, coordinated and accessible services, being respected and valued, and services and supports that promote independence. We recommend implementation of multidisciplinary solutions that are focused on young adult priorities to ensure seamless access to resources to support these young adults' health, educational, vocational, and social goals. The input and voice of young adults in the development of these services are imperative to ensure that multisystem services support their needs and life goals.
The role of vitamin D in management of depression is unclear. Results from observational and emerging randomized controlled trials (RCTs) investigating the efficacy of vitamin D in depression lack consistency - with some suggesting a positive association while others show a negative or inconclusive association.
The primary aim of this study is to conduct a systematic review of RCTs to assess the effect of oral vitamin D supplementation versus placebo on depression symptoms measured by scales and the proportion of patients with symptomatic improvement according to the authors’ original definition. Secondary aims include assessing the change in quality of life, adverse events and treatment discontinuation. We will conduct the systematic review and meta-analysis according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions. We will search the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1966 to present), EMBASE (1980 to present), CINAHL (1982 to present), PsychINFO (1967 to present) and ClinicalTrials.gov. Unpublished work will be identified by searching two major conferences: the International Vitamin Conference, the Anxiety Disorders and Depression Conference, while grey literature will be acquired by contacting authors of included studies. We will use the random-effects meta-analysis to synthesize the data by pooling the results of included studies.
The results of this systematic review will be helpful in clarifying the efficacy of vitamin D supplementation and providing evidence to establish guidelines for implementation of vitamin D for depression in general practice and other relevant settings.
Unique identifier: CRD42013003849.
Vitamin D; Depression; Randomized controlled trial; Adults; Efficacy; Systematic review protocol
Goal-directed therapy guidelines for pediatric septic shock resuscitation recommend fluid delivery at speeds in excess of that possible through use of regular fluid infusion pumps. In our experience, syringes are commonly used by health care providers (HCPs) to achieve rapid fluid resuscitation in a pediatric fluid resuscitation scenario. At present, it is unclear which syringe size health care providers should use when performing fluid resuscitation to achieve maximal fluid resuscitation efficiency. The objective of this study was therefore to determine if an optimal syringe size exists for conducting manual pediatric fluid resuscitation.
This 48-participant parallel group randomized controlled trial included 4 study arms (10, 20, 30, 60 mL syringe size groups). Eligible participants were HCPs from McMaster Children’s Hospital, Hamilton, Canada blinded to the purpose of the trial. Consenting participants were randomized using a third party technique. Following a standardization procedure, participants administered 900 mL (60 mL/kg) of isotonic saline to a simulated 15 kg child using prefilled provided syringes of the allocated size in rapid sequence. Primary outcome was total time to administer the 900 mL and this data was collected through video review by two blinded outcome assessors. Sample size was predetermined based upon a primary outcome analysis using one-way ANOVA.
12 participants were randomized to each group (n=48) and all completed trial protocol to analysis. Analysis was conducted according to intention to treat principles. A significant difference in fluid resuscitation time (in seconds) was found between syringe size group means: 10 mL, 563s [95% CI 521; 606]; 20 mL, 506s [95% CI 64; 548]; 30 mL, 454s [95% CI 412; 596]; 60 mL, 455s [95% CI 413; 497] (p<0.001).
The syringe size used when performing manual pediatric fluid resuscitation has a significant impact on fluid resuscitation speed, in a setting where fluid filled syringes are continuously available. Greatest efficiency was achieved with 30 or 60 mL syringes.
Fluid therapy; Resuscitation; Shock; Pediatrics
Sensitivity analyses play a crucial role in assessing the robustness of the findings or conclusions based on primary analyses of data in clinical trials. They are a critical way to assess the impact, effect or influence of key assumptions or variations—such as different methods of analysis, definitions of outcomes, protocol deviations, missing data, and outliers—on the overall conclusions of a study.
The current paper is the second in a series of tutorial-type manuscripts intended to discuss and clarify aspects related to key methodological issues in the design and analysis of clinical trials.
In this paper we will provide a detailed exploration of the key aspects of sensitivity analyses including: 1) what sensitivity analyses are, why they are needed, and how often they are used in practice; 2) the different types of sensitivity analyses that one can do, with examples from the literature; 3) some frequently asked questions about sensitivity analyses; and 4) some suggestions on how to report the results of sensitivity analyses in clinical trials.
When reporting on a clinical trial, we recommend including planned or posthoc sensitivity analyses, the corresponding rationale and results along with the discussion of the consequences of these analyses on the overall findings of the study.
Sensitivity analysis; Clinical trials; Robustness
Tuberculosis (TB) disease affects survival among HIV co-infected patients on antiretroviral therapy (ART). Yet, the magnitude of TB disease on mortality is poorly understood.
Using a prospective cohort of 22,477 adult patients who initiated ART between August 2000 and June 2009 in Uganda, we assessed the effect of active pulmonary TB disease at the initiation of ART on all-cause mortality using a Cox proportional hazards model. Propensity score (PS) matching was used to control for potential confounding. Stratification and covariate adjustment for PS and not PS-based multivariable Cox models were also performed.
A total of 1,609 (7.52%) patients had active pulmonary TB at the start of ART. TB patients had higher proportions of being male, suffering from AIDS-defining illnesses, having World Health Organization (WHO) disease stage III or IV, and having lower CD4 cell counts at baseline (p < 0.001). The percentages of death during follow-up were 10.47% and 6.38% for patients with and without TB, respectively. The hazard ratio (HR) for mortality comparing TB to non-TB patients using 1,686 PS-matched pairs was 1.37 (95% confidence interval [CI]: 1.08 – 1.75), less marked than the crude estimate (HR = 1.74, 95% CI: 1.49 – 2.04). The other PS-based methods and not PS-based multivariable Cox model produced similar results.
After controlling for important confounding variables, HIV patients who had TB at the initiation of ART in Uganda had an approximate 37% increased hazard of overall mortality relative to non-TB patients.
Antiretroviral therapy; HIV; Tuberculosis; Propensity score methods; Uganda; Prospective cohort study
Mobile phone ownership and use are growing fastest in sub-Saharan Africa, and there is evidence that mobile phone text messages can be used successfully to significantly improve adherence to antiretroviral therapy and reduce treatment interruptions. However, the effects of many mobile health interventions are often reduced by human resource shortages within health facilities. Also, research projects generating evidence for health interventions in developing countries are most often conducted using external funding sources, with limited sustainability and adoption by local governments following completion of the projects. Strong community participation driven by active outreach programmes and mobilisation of community resources are the key to successful adoption and long-term sustainability of effective interventions. Our aim was to develop a framework for community ownership of a text messaging programme to improve adherence to antiretroviral therapy; improve communication between patients and doctors and act as a reminder for appointments.
Methods and analysis
We will use the exploratory sequential mixed methods approach. The first qualitative phase will entail focus group discussions with people living with HIV at the Yaoundé Central Hospital in Yaoundé, Cameroon (6–10 participants/group). The second quantitative phase will involve a cross-sectional survey (n=402). In this study, binary logistic regression techniques will be used to determine the factors associated with community readiness and acceptability of ownership. Data from both phases will be merged.
Ethics and dissemination
This study has been approved by the Yaoundé Central Hospital Institutional Review Board. The results of this paper will be disseminated as peer-reviewed publications at conferences and as part of a doctoral thesis.
Childhood obesity has reached epidemic proportions and is impacting children's health globally. In adults, obesity is associated with chronic low-grade inflammation that leads to insulin resistance, which is one of the important mechanisms through which dysregulation of metabolism occurs. There is limited information available about the contribution of inflammation to metabolic health in obese children, and how individual and lifestyle factors impact this risk. One of the paediatric groups at risk of higher rates of obesity includes the survivors of childhood brain tumours. The aim of this study was to evaluate the mechanisms that contribute to inflammation in obese survivors of childhood brain tumours.
Methods and analysis
This is a prospective cohort study. We will recruit lean and obese survivors of childhood brain tumours, and a control group composed of lean and obese children with no history of tumours. We will measure circulating and urinary cytokine levels and cytokine gene expression in monocytes. In addition, the methylation patterns of cytokine genes and that of toll-like receptor genes will be evaluated. These will be correlated with individual and lifestyle factors including age, sex, ethnicity, puberty, body mass index, fasting lipid levels, insulin sensitivity, diet, exercise, sleep, stress and built environment. The sample size calculation showed that we need 25 participants per arm
Ethics and dissemination
This study has received ethics approval from the institutional review board. Once completed, we will publish this work in peer-reviewed journals and share the findings in presentations and posters in meetings.
This study will permit the interrogation of inflammation as a contributor to obesity and its complications in obese survivors of childhood brain tumours and compare them with lean survivors and lean and obese controls with no history of tumours, which may help identify therapeutic and preventative interventions to combat the rising tide of obesity.
Interventions to improve retention in care after HIV diagnosis are necessary to optimise the timely initiation of antiretroviral therapy (ART) and HIV/AIDS control outcomes. Widespread mobile phone use presents new opportunities to engage patients in care. A randomised controlled trial (RCT), WelTel Kenya1, demonstrated that weekly text messages led to improved ART adherence and viral load suppression among those initiating ART. The aim of this study was to determine whether the WelTel intervention is an effective and cost-effective method of improving retention in care in the first year of care following HIV diagnosis.
Methods and analysis
WelTel Retain is an open, parallel group RCT that will be conducted at the Kibera Community Health Centre in Nairobi, Kenya. Over a 1-year period, we aim to recruit 686 individuals newly diagnosed with HIV who will be randomly allocated to an intervention or control arm (standard care) at a 1:1 ratio. Intervention arm participants will receive the weekly WelTel SMS ‘check-in’ to which they will be instructed to respond within 48 h. An HIV clinician will follow-up and triage any problems that are identified. Participants will be followed for 1 year, with a primary endpoint of retention in care at 12 months. Secondary outcomes include retention in stage 1 HIV care (patients return to the clinic to receive their first CD4 results) and timely ART initiation. Cost-effectiveness will be analysed through decision-analytic modelling.
Ethics and dissemination
Ethical approval has been obtained from the University of British Columbia and the African Medical and Research Foundation. This trial will test the effectiveness and cost-effectiveness of the WelTel intervention to engage patients during the first year of HIV care. Trial results and economic evaluation will help inform policy and practice on the use of WelTel in the early stages of HIV care.
Health Economics; Public Health
Mobile phone text messaging is emerging as an important tool in the care of people living with HIV; however, reports diverge on its efficacy in improving adherence to antiretroviral therapy (ART), and little is known about which patient groups may benefit most from phone-based adherence interventions. We will conduct an individual patient data meta-analysis to investigate the overall and subgroup effects of text messaging in three recently published text-messaging randomised controlled trials.
Methods and analysis
Data from two Kenyan and one Cameroonian trial will be verified, reformatted and merged. We will determine pooled effect sizes for text messaging versus standard care for improving adherence to ART using individual patient random-effects meta-analysis. We will test for the interaction effects of age, gender, level of education and duration on ART. Sensitivity analyses will be conducted with regard to thresholds for adherence, methods of handling missing data and fixed-effects meta-analysis. Only anonymised data will be collected from the individual studies.
Ethics and dissemination
Ethical approval was obtained for the individual studies. The results of this paper will be disseminated as peer-reviewed publications, at conferences and as part of a doctoral thesis. This individual patient data meta-analysis may provide important insights into the effects of text messaging on ART adherence in different subpopulations, with important implications for programme implementation involving such interventions and future research.
Statistics & Research Methods
Reporting guidelines have been available for the past 17 years since the inception of the Consolidated Standards of Reporting Trials statement in 1996. These guidelines were developed to improve the quality of reporting of studies in medical literature. Despite the widespread availability of these guidelines, the quality of reporting of medical literature remained suboptimal. In this study, we assess the current adherence practice to reporting guidelines; determine key factors associated with better adherence to these guidelines; and provide recommendations to enhance adherence to reporting guidelines for future studies.
We undertook a systematic scoping review of systematic reviews of adherence to reporting guidelines across different clinical areas and study designs. We searched four electronic databases (Cumulative Index to Nursing and Allied Health Literature, Web of Science, Embase, and Medline) from January 1996 to September 2012. Studies were included if they addressed adherence to one of the following guidelines: Consolidated Standards of Reporting Trials (CONSORT), Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), Quality of Reporting of Meta-analysis (QUOROM), Transparent Reporting of Evaluations with Nonrandomized Designs (TREND), Meta-analysis Of Observational Studies in Epidemiology (MOOSE) and Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). A protocol for this study was devised. A literature search, data extraction, and quality assessment were performed independently by two authors in duplicate. This study reporting follows the PRISMA guidelines.
Our search retrieved 5159 titles, of which 50 were eligible. Overall, 86.0% of studies reported suboptimal levels of adherence to reporting guidelines. Factors associated with better adherence included journal impact factor and endorsement of guidelines, publication date, funding source, multisite studies, pharmacological interventions and larger studies.
Reporting guidelines in the clinical literature are important to improve the standards of reporting of clinical studies; however, adherence to these guidelines remains suboptimal. Action is therefore needed to enhance the adherence to these standards. Strategies to enhance adherence include journal editorial policies endorsing these guidelines.
scoping; systematic; review; adherence; reporting; guidelines
Using two-way mobile phone text messages to improve adherence to antiretroviral medication enhances communication between patients and health workers. We describe the implications of participants’ responses to text messages in the Cameroon Mobile Phone SMS (CAMPS) trial.
This is a cross-sectional analysis of data from the intervention arm of the CAMPS trial. CAMPS was a randomized controlled trial of motivational text messaging versus usual care to improve adherence to antiretroviral medication among people living with HIV in Yaounde, Cameroon (n = 200) over a 6 month period. Participants in the intervention arm (n = 101) were given a contact phone number, but were not required to respond to their reminder messages. If they did, their responses were noted and reported as counts and percentages. We received 99 phone calls and 55 text messages (154 responses) from 48 participants during the study period. The median number of responses was 1 (first quartile [Q1]: 1; third quartile [Q3]: 3). Half (n = 79, 51.1%) of them were expressions of gratitude. The rest included requests for logistical (n = 21, 13.6%), medical (n = 20, 12.9%) and financial (n = 11, 7.1%) support.
Initiating two-way mobile communication opens more channels for people living with HIV to express unmet needs. Researchers, policy makers and clinicians should be ready to respond to the needs expressed by patients who respond to text messages.
Pan-African Clinical Trials Registry: PACTR201011000261458;
Text messaging; SMS; HIV; Adherence; Antiretroviral therapy; Communication; Cameroon; CAMPS trial
Obesity is a global epidemic that is impacting children around the world. Obesity is a chronic inflammatory state with enhanced production of multiple cytokines and chemokines. Chemokine (C-C motif) Ligand 2 (CCL2) is produced by immune and metabolic cells and attracts immune cells into liver, muscle and adipose tissue, resulting in initiation and propagation of the inflammatory response in obesity. How obesity and fitness affect the production of this chemokine in children is unknown.
This study tested the hypotheses that CCL2 levels are higher in obese children when compared to lean controls, and that fitness modulates CCL2 levels allowing its use as a biomarker of fitness.
This was a cross sectional case–control study conducted in a Pediatric Tertiary care center in Hamilton, Ontario, Canada. Controls were recruited from the community. This study recruited overweight/obese children (BMI ≥ 85th percentile, n = 18, 9 female, mean age 14.0 ± 2.6 years) and lean controls (BMI < 85th percentile, n = 18, 8 female, mean age 14.0 ± 2.6 years) matched for age, sex and biological maturation.
Aerobic fitness test was done using a cycle ergometer performing the McMaster All-Out Progressive Continuous Cycling test to exhaustion to determine peak oxygen uptake. Fasting CCL2 samples were taken prior to test. Categorical variables including subject categorization into different aerobic fitness levels in overweight/obese and lean children was reported based on the median split in each group.
Obese participants had significantly higher CCL2 levels when compared to lean group (150.4 ± 61.85 pg/ml versus 112.7 ± 38 pg/ml, p-value 0.034).
To establish if CCL2 is a biomarker of fitness, we divided the groups based on their fitness levels. There was a main effect for group (F (3,32) = 3.2, p = 0.036). Obese high fitness group were similar to lean unfit and fit participants. Post-hoc analysis revealed that the overweight/obese low fitness group had significantly higher level of CCL2 compared to the lean low fitness group when adjusted to age, sex and maturity offset (F (3,29) = 3.1, p = 0.04).
CCL2 serves a dual role as a potential biomarker of inflammation and fitness in obese children.
Childhood obesity; Immunometabolism; Inflammation; Chemokine C-C Ligand 2; Fitness
Subjects with breast cancer enrolled in trials may experience multiple events such as local recurrence, distant recurrence or death. These events are not independent; the occurrence of one may increase the risk of another, or prevent another from occurring. The most commonly used Cox proportional hazards (Cox-PH) model ignores the relationships between events, resulting in a potential impact on the treatment effect and conclusions. The use of statistical methods to analyze multiple time-to-event events has mainly been focused on superiority trials. However, their application to non-inferiority trials is limited. We evaluate four statistical methods for multiple time-to-event endpoints in the context of a non-inferiority trial.
Three methods for analyzing multiple events data, namely, i) the competing risks (CR) model, ii) the marginal model, and iii) the frailty model were compared with the Cox-PH model using data from a previously-reported non-inferiority trial comparing hypofractionated radiotherapy with conventional radiotherapy for the prevention of local recurrence in patients with early stage breast cancer who had undergone breast conserving surgery. These methods were also compared using two simulated examples, scenario A where the hazards for distant recurrence and death were higher in the control group, and scenario B. where the hazards of distant recurrence and death were higher in the experimental group. Both scenarios were designed to have a non-inferiority margin of 1.50.
In the breast cancer trial, the methods produced primary outcome results similar to those using the Cox-PH model: namely, a local recurrence hazard ratio (HR) of 0.95 and a 95% confidence interval (CI) of 0.62 to 1.46. In Scenario A, non-inferiority was observed with the Cox-PH model (HR = 1.04; CI of 0.80 to 1.35), but not with the CR model (HR = 1.37; CI of 1.06 to 1.79), and the average marginal and frailty model showed a positive effect of the experimental treatment. The results in Scenario A contrasted with Scenario B with non-inferiority being observed with the CR model (HR = 1.10; CI of 0.87 to 1.39), but not with the Cox-PH model (HR = 1.46; CI of 1.15 to 1.85), and the marginal and frailty model showed a negative effect of the experimental treatment.
When subjects are at risk for multiple events in non-inferiority trials, researchers need to consider using the CR, marginal and frailty models in addition to the Cox-PH model in order to provide additional information in describing the disease process and to assess the robustness of the results. In the presence of competing risks, the Cox-PH model is appropriate for investigating the biologic effect of treatment, whereas the CR models yields the actual effect of treatment in the study.
Non-inferiority; Cox model; Correlation; Marginal model; Frailty model; Competing risks
Paediatric shock is a life-threatening condition with many possible causes and a global impact. Current resuscitation guidelines require rapid fluid administration as a cornerstone of paediatric shock management. However, little evidence is available to inform clinicians how to most effectively perform rapid fluid administration where this is clinically required, resulting in suboptimal knowledge translation of current resuscitation guidelines into clinical practice.
This study aims to determine which of the two commonly used techniques for paediatric fluid resuscitation (disconnect–reconnect technique and push–pull technique) yields a higher fluid administration rate in a simulated clinical scenario. Secondary objectives include determination of catheter dislodgement rates, subjective and objective measures of provider fatiguability and descriptive information regarding any technical issues encountered with performance of each method under the study.
Methods and analysis
This study will utilise a randomised crossover trial design. Participants will include consenting healthcare providers from McMaster Children's Hospital. Each participant will administer 900 ml (60 ml/kg) of normal saline to a simulated 15 kg infant as quickly as possible on two separate occasions using the manual fluid administration techniques under the study. The primary outcome, rate of fluid administration, will be evaluated using a paired two-tailed Student t test.
Ethics and dissemination
This protocol has been approved by the Hamilton Health Sciences Research Ethics Board.
These will be published in a peer-reviewed scientific journal and presented at one or more scientific conferences.
Protocol Registered on ClinicalTrials.gov NCT01774214
Statistics & Research Methods
The objective of this simulation study is to compare the accuracy and efficiency of population-averaged (i.e. generalized estimating equations (GEE)) and cluster-specific (i.e. random-effects logistic regression (RELR)) models for analyzing data from cluster randomized trials (CRTs) with missing binary responses.
In this simulation study, clustered responses were generated from a beta-binomial distribution. The number of clusters per trial arm, the number of subjects per cluster, intra-cluster correlation coefficient, and the percentage of missing data were allowed to vary. Under the assumption of covariate dependent missingness, missing outcomes were handled by complete case analysis, standard multiple imputation (MI) and within-cluster MI strategies. Data were analyzed using GEE and RELR. Performance of the methods was assessed using standardized bias, empirical standard error, root mean squared error (RMSE), and coverage probability.
GEE performs well on all four measures — provided the downward bias of the standard error (when the number of clusters per arm is small) is adjusted appropriately — under the following scenarios: complete case analysis for CRTs with a small amount of missing data; standard MI for CRTs with variance inflation factor (VIF) <3; within-cluster MI for CRTs with VIF≥3 and cluster size>50. RELR performs well only when a small amount of data was missing, and complete case analysis was applied.
GEE performs well as long as appropriate missing data strategies are adopted based on the design of CRTs and the percentage of missing data. In contrast, RELR does not perform well when either standard or within-cluster MI strategy is applied prior to the analysis.
Marginal model; Population-averaged model; Cluster-specific model; Multiple imputation; Cluster randomized trial; Covariate dependent missingness; Generalized estimating equations; Random-effects logistic regression
Many reports point to the beneficial effect of male partner involvement in programs for the prevention of mother-to-child-transmission (PMTCT) of HIV in curbing pediatric HIV infections. This paper summarizes the barriers and facilitators of male involvement in prevention programs of mother-to-child-transmission of HIV.
We searched PubMed, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials (CENTRAL) for studies published in English from 1998 to March 2012. We included studies conducted in a context of antenatal care or PMTCT of HIV reporting male actions that affected female uptake of PMTCT services. We did not target any specific interventions for this review.
We identified 24 studies from peer-reviewed journals; 21 from sub-Saharan Africa, 2 from Asia and 1 from Europe. Barriers to male PMTCT involvement were mainly at the level of the society, the health system and the individual. The most pertinent was the societal perception of antenatal care and PMTCT as a woman’s activity, and it was unacceptable for men to be involved. Health system factors such as long waiting times at the antenatal care clinic and the male unfriendliness of PMTCT services were also identified. The lack of communication within the couple, the reluctance of men to learn their HIV status, the misconception by men that their spouse’s HIV status was a proxy of theirs, and the unwillingness of women to get their partners involved due to fear of domestic violence, stigmatization or divorce were among the individual factors.
Actions shown to facilitate male PMTCT involvement were either health system actions or factors directly tied to the individuals. Inviting men to the hospital for voluntary counseling and HIV testing and offering of PMTCT services to men at sites other than antenatal care were key health system facilitators. Prior knowledge of HIV and prior male HIV testing facilitated their involvement. Financial dependence of women was key to facilitating spousal involvement.
There is need for health system amendments and context-specific adaptations of public policy on PMTCT services to break down the barriers to and facilitate male PMTCT involvement.
The protocol for this review was registered with the International prospective register of systematic reviews (PROSPERO) record CRD42011001703.
Male; Partner; Involvement; HIV; PMTCT; Barriers; Facilitators
Multiple treatment comparison (MTC) meta-analyses are commonly modeled in a Bayesian framework, and weakly informative priors are typically preferred to mirror familiar data driven frequentist approaches. Random-effects MTCs have commonly modeled heterogeneity under the assumption that the between-trial variance for all involved treatment comparisons are equal (i.e., the ‘common variance’ assumption). This approach ‘borrows strength’ for heterogeneity estimation across treatment comparisons, and thus, ads valuable precision when data is sparse. The homogeneous variance assumption, however, is unrealistic and can severely bias variance estimates. Consequently 95% credible intervals may not retain nominal coverage, and treatment rank probabilities may become distorted. Relaxing the homogeneous variance assumption may be equally problematic due to reduced precision. To regain good precision, moderately informative variance priors or additional mathematical assumptions may be necessary.
In this paper we describe four novel approaches to modeling heterogeneity variance - two novel model structures, and two approaches for use of moderately informative variance priors. We examine the relative performance of all approaches in two illustrative MTC data sets. We particularly compare between-study heterogeneity estimates and model fits, treatment effect estimates and 95% credible intervals, and treatment rank probabilities.
In both data sets, use of moderately informative variance priors constructed from the pair wise meta-analysis data yielded the best model fit and narrower credible intervals. Imposing consistency equations on variance estimates, assuming variances to be exchangeable, or using empirically informed variance priors also yielded good model fits and narrow credible intervals. The homogeneous variance model yielded high precision at all times, but overall inadequate estimates of between-trial variances. Lastly, treatment rankings were similar among the novel approaches, but considerably different when compared with the homogenous variance approach.
MTC models using a homogenous variance structure appear to perform sub-optimally when between-trial variances vary between comparisons. Using informative variance priors, assuming exchangeability or imposing consistency between heterogeneity variances can all ensure sufficiently reliable and realistic heterogeneity estimation, and thus more reliable MTC inferences. All four approaches should be viable candidates for replacing or supplementing the conventional homogeneous variance MTC model, which is currently the most widely used in practice.
Mentoring plays an important role in learning and career development. Mentored researchers are more productive and more likely to publish their work. However, mentorship programs are not universally used in most settings or disciplines. Furthermore, successful and mutually beneficial mentoring relationships are not always easy to arrange. Long-distance mentoring relationships are even more difficult to handle and may break down for a wide variety of reasons. Drawing from our experiences with the first Canadian Institutes of Health Research – Canadian HIV Trials Network international postdoctoral fellowship program, we describe the roles of the context, the key mentor and the mentee attributes; goals and expectations; environments, local support, a communication plan, funding, face-to-face contact, multidisciplinary collaboration, co-mentoring, and evaluation as they apply to the successful implementation of a long-distance mentoring program.
long distance; mentoring; framework; Canada; Cameroon