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3.  Safety and effectiveness of dipeptidyl peptidase-4 inhibitors versus intermediate-acting insulin or placebo for patients with type 2 diabetes failing two oral antihyperglycaemic agents: a systematic review and network meta-analysis 
BMJ Open  2014;4(12):e005752.
Objective
To evaluate the effectiveness and safety of dipeptidyl peptidase-4 (DPP-4) inhibitors versus intermediate-acting insulin for adults with type 2 diabetes mellitus (T2DM) and poor glycaemic control despite treatment with two oral agents.
Setting
Studies were multicentre and multinational.
Participants
Ten studies including 2967 patients with T2DM.
Interventions
Studies that examined DPP-4 inhibitors compared with each other, intermediate-acting insulin, no treatment or placebo in patients with T2DM.
Primary and secondary outcome measures
Primary outcome was glycosylated haemoglobin (HbA1c). Secondary outcomes were healthcare utilisation, body weight, fractures, quality of life, microvascular complications, macrovascular complications, all-cause mortality, harms, cost and cost-effectiveness.
Results
10 randomised clinical trials with 2967 patients were included after screening 5831 titles and abstracts, and 180 full-text articles. DPP-4 inhibitors significantly reduced HbA1c versus placebo in network meta-analysis (NMA; mean difference (MD) −0.62%, 95% CI −0.93% to −0.33%) and meta-analysis (MD −0.61%, 95% CI −0.81% to −0.41%), respectively. Significant differences in HbA1c were not observed for neutral protamine Hagedorn (NPH) insulin versus placebo and DPP-4 inhibitors versus NPH insulin in NMA. In meta-analysis, no significant differences were observed between DPP-4 inhibitors and placebo for severe hypoglycaemia, weight gain, cardiovascular disease, overall harms, treatment-related harms and mortality, although patients receiving DPP-4 inhibitors experienced less infections (relative risk 0.72, 95% CI 0.57 to 0.91).
Conclusions
DPP-4 inhibitors were superior to placebo in reducing HbA1c levels in adults with T2DM taking at least two oral agents. Compared with placebo, no safety signals were detected with DPP-4 inhibitors and there was a reduced risk of infection. There was no significant difference in HbA1c observed between NPH and placebo or NPH and DPP-4 inhibitors.
Trial registration number
PROSPERO # CRD42013003624.
doi:10.1136/bmjopen-2014-005752
PMCID: PMC4275675  PMID: 25537781
systematic review; meta-analysis
4.  Analyzing composite outcomes in cardiovascular studies: traditional Cox proportional hazards versus quality-of-life–adjusted survival approaches 
Open Medicine  2010;4(1):e40-e48.
Background
Composite outcomes that weight each component equally are commonly used to study treatment effects. We hypothesized that each component of a composite outcome would differentially affect patients’ overall health-related quality of life (HRQL).
Methods
We tested our hypothesis using data from 2 published clinical studies of treatment for heart failure, one comparing metformin and sulfonylurea and the other comparing digoxin and placebo. We applied the quality-adjusted survival (QAS) approach, which incorporates HRQL data to accommodate differential weights for 2 components (in this analysis, death or admission to hospital) of a commonly used composite end point. For each of the 2 studies, the composite outcome was partitioned into its components, to which utility weights derived from the literature were assigned. Total QAS time determined for each treatment by the QAS analysis was compared with the results from traditional survival analyses based on Cox proportional hazards regression.
Results
In the observational study of metformin in heart failure, the risk of the composite outcome of death or admission to hospital was lower for those receiving metformin therapy than for those who received sulfonylurea (event rate 160 [77%] v. 658 [85%]; hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.70–0.99). With traditional survival analysis, the net gain was 0.82 years (95% CI 0.26–1.37), whereas the difference in QAS time was less, at 0.54 years (95% CI 0.20–0.89). In the randomized trial of digoxin therapy, the risk of the composite outcome was lower for those receiving the intervention than for those receiving placebo (event rate 1291 [38%] v. 1041 [31%]; HR 0.75, 95% CI 0.69–0.82). With traditional survival analysis, the net gain was 0.06 years (95% CI 0.02–0.16), whereas the difference in QAS time was greater, at 0.11 years (95% CI 0.06–0.16).
Interpretation
Studies that assume equal weights for the components of composite outcomes may overestimate or underestimate treatment effects. By incorporating HRQL into survival analyses, the impact of the various components of the outcome can be assessed more directly.
PMCID: PMC3116673  PMID: 21686293
5.  Macrolide use in the treatment of critically ill patients with pneumonia: Incidence, correlates, timing and outcomes 
BACKGROUND:
Macrolide antibiotics are commonly used to treat pneumonia despite increasing antimicrobial resistance. Evidence suggests that macrolides may also decrease mortality in severe sepsis via immunomodulatory properties.
OBJECTIVE:
To evaluate the incidence, correlates, timing and mortality associated with macrolide-based treatment.
METHODS:
A population-based cohort of critically ill adults with pneumonia at five intensive care units in Edmonton, Alberta, was prospectively followed over two years. Data collected included disease severity (Acute Physiology and Chronic Health Evaluation [APACHE] II score), pneumonia severity (Pneumonia Severity Index score), comorbidities, antibiotic treatments at presentation and time to effective antibiotic. The independent association between macrolide-based treatment and 30-day all-cause mortality was examined using multivariable Cox regression. A secondary exploratory analysis examined time to effective antimicrobial therapy.
RESULTS:
The cohort included 328 patients with a mean Pneumonia Severity Index score of 116 and a mean APACHE II score of 17; 84% required invasive mechanical ventilation. Ninety-one (28%) patients received macrolide-based treatments, with no significant correlates of treatment except nursing home residence (15% versus 30% for nonresidents [P=0.02]). Overall mortality was 54 of 328 (16%) at 30 days: 14 of 91 (15%) among patients treated with macrolides versus 40 of 237 (17%) for nonmacrolides (adjusted HR 0.93 [95% CI 0.50 to 1.74]; P=0.8). Patients who received effective antibiotics within 4 h of presentation were less likely to die than those whose treatment was delayed (14% versus 17%; adjusted HR 0.50 [95% CI 0.27 to 0.94]; P=0.03).
CONCLUSIONS:
Macrolide-based treatment was not associated with lower 30-day mortality among critically ill patients with pneumonia, although receipt of effective antibiotic within 4 h was strongly predictive of survival. Based on these results, timely effective treatment may be more important than choice of antibiotics.
PMCID: PMC3905010  PMID: 24489569
Critical care; Intensive care; Lung; Macrolides; Mortality; Pneumonia
6.  Hypoglycemia Associated With Hospitalization and Adverse Events in Older People 
Diabetes Care  2013;36(11):3585-3590.
OBJECTIVE
Little is known about the prognostic impact of hypoglycemia associated with hospitalization. We hypothesized that hospitalized hypoglycemia would be associated with increased long-term morbidity and mortality, irrespective of diabetes status.
RESEARCH DESIGN AND METHODS
We undertook a cohort study using linked administrative health care and laboratory databases in Alberta, Canada. From 1 January 2004 to 31 March 2009, we included all outpatients 66 years of age and older who had at least one serum creatinine and one A1C measured. To examine the independent association between hospitalized hypoglycemia and all-cause mortality, we used time-varying Cox proportional hazards (adjusted hazard ratio [aHR]), and for all-cause hospitalizations, we used Poisson regression (adjusted incidence rate ratio [aIRR]).
RESULTS
The cohort included 85,810 patients: mean age 75 years, 51% female, and 50% had diabetes defined by administrative data. Overall, 440 patients (0.5%) had severe hypoglycemia associated with hospitalization and most (93%) had diabetes. During 4 years of follow-up, 16,320 (19%) patients died. Hospitalized hypoglycemia was independently associated with increased mortality (60 vs. 19% mortality for no hypoglycemia; aHR 2.55 [95% CI 2.25–2.88]), and this increased in a dose-dependent manner (aHR no hypoglycemia = 1.0 vs. one episode = 2.49 vs. one or more = 3.78, P trend <0.001). Hospitalized hypoglycemia was also independently associated with subsequent hospitalizations (aIRR no hypoglycemia = 1.0 vs. one episode = 1.90 vs. one or more = 2.61, P trend <0.001) and recurrent hypoglycemia (aHR no hypoglycemia = 1.0 vs. one episode = 2.45 vs. one or more = 9.66, P trend <0.001).
CONCLUSIONS
Older people who have an episode of hospitalized hypoglycemia are easily identified and at substantially increased risk of morbidity and mortality.
doi:10.2337/dc13-0523
PMCID: PMC3816904  PMID: 24089536
7.  Weight loss required by the severely obese to achieve clinically important differences in health-related quality of life: two-year prospective cohort study 
BMC Medicine  2014;12(1):175.
Background
Guidelines and experts describe 5% to 10% reductions in body weight as ‘clinically important’; however, it is not clear if 5% to 10% weight reductions correspond to clinically important improvements in health-related quality of life (HRQL). Our objective was to calculate the amount of weight loss required to attain established minimal clinically important differences (MCIDs) in HRQL, measured using three validated instruments.
Methods
Data from the Alberta Population-based Prospective Evaluation of Quality of Life Outcomes and Economic Impact of Bariatric Surgery (APPLES) study, a population-based, prospective Canadian cohort including 150 wait-listed, 200 medically managed and 150 surgically treated patients were examined. Two-year changes in weight and HRQL measures (Short-Form (SF)-12 physical (PCS; MCID = 5) and mental (MCS; MCID = 5) component summary score, EQ-5D Index (MCID = 0.03) and Visual Analog Scale (VAS; MCID = 10), Impact of Weight on Quality of Life (IWQOL)-Lite total score (MCID = 12)) were calculated. Separate multivariable linear regression models were constructed within medically and surgically treated patients to determine if weight changes achieved HRQL MCIDs. Pooled analysis in all 500 patients was performed to estimate the weight reductions required to achieve the pre-defined MCID for each HRQL instrument.
Results
Mean age was 43.7 (SD 9.6) years, 88% were women, 92% were white, and mean initial body mass index was 47.9 (SD 8.1) kg/m2. In surgically treated patients (two-year weight loss = 16%), HRQL MCIDs were reached for all instruments except the SF-12 MCS. In medically managed patients (two-year weight loss = 3%), MCIDs were attained in the EQ-index but not the other instruments. In all patients, percent weight reductions to achieve MCIDs were: 23% (95% confidence interval (CI): 17.5, 32.5) for PCS, 25% (17.5, 40.2) for MCS, 9% (6.2, 15.0) for EQ-Index, 23% (17.3, 36.1) for EQ-VAS, and 17% (14.1, 20.4) for IWQOL-Lite total score.
Conclusions
Weight reductions to achieve MCIDs for most HRQL instruments are markedly higher than the conventional threshold of 5% to 10%. Surgical, but not medical treatment, consistently led to clinically important improvements in HRQL over two years.
Trial registration
Clinicaltrials.gov NCT00850356.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0175-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-014-0175-5
PMCID: PMC4212133  PMID: 25315502
Health-related quality of life; Weight loss; Minimal clinically important difference; Obesity; Patient reported outcomes; Bariatric care
8.  Impact of a patient decision aid on care among patients with nonvalvular atrial fibrillation: a cluster randomized trial 
Background
Too few patients with nonvalvular atrial fibrillation (NVAF) receive appropriate antithrombotic therapy. We tested the short-term (primary outcome) and long-term (secondary outcome) effect of a patient decision aid on the appropriateness of antithrombotic therapy among patients with NVAF.
Methods
We conducted a cluster randomized trial with blinded outcome assessment involving 434 NVAF patients from 102 community-based primary care practices. Patients in the intervention group received a self-administered booklet and audiotape decision aid tailored to their personal stroke risk profile. Patients in the control group received usual care. The primary outcome measure was change in antithrombotic therapy at 3 months. Appropriateness of therapy was defined using the American College of Chest Physicians (ACCP) recommendations.
Results
The mean patient age was 72 years, and the median duration of NVAF was 5 years. In the control group, there was a 3% decrease over 3 months in the number of patients receiving therapy appropriate to their risk of stroke (40% [85/215] at baseline v. 37% [79/215] at 3 months). In the intervention group, the number of patients receiving therapy appropriate to their stroke risk increased by 9% (32% [69/219] at baseline v. 41% [89/219] at 3 months). Although the proportion of patients whose therapy met the ACCP treatment recommendations did not differ between study arms at baseline (p = 0.11) or 3 months (p = 0.44), there was a 12% absolute improvement in the number of patients receiving appropriate care in the intervention group compared with the control group at 3 months (p = 0.03). The beneficial effect of the decision aid did not persist (p = 0.44 for differences between study arms after 12 months).
Interpretation
There was short-term improvement in the appropriateness of antithrombotic care among patients with NVAF who were exposed to a decision aid, but the improvement did not persist.
doi:10.1503/cmaj.050091
PMCID: PMC1188186  PMID: 16129870
9.  Detection Bias and Overestimation of Bladder Cancer Risk in Type 2 Diabetes 
Diabetes Care  2013;36(10):3070-3075.
OBJECTIVE
To investigate whether the risk of bladder cancer in individuals with newly diagnosed type 2 diabetes is influenced by the frequency of physician visits before diagnosis as a measure of detection bias.
RESEARCH DESIGN AND METHODS
With the use of linked administrative databases from 1996 to 2006, we established a cohort of 185,100 adults from British Columbia, Canada, with incident type 2 diabetes matched one to one with nondiabetic individuals on age, sex, and index date. Incidence rates and adjusted hazard ratios (aHRs) for bladder cancer were calculated during annual time windows following the index date. Analyses were stratified by number of physician visits in the 2 years before diabetes diagnosis and adjusted for age, sex, year of cohort entry, and socioeconomic status.
RESULTS
The study population was 54% men and had an average age of 60.7 ± 13.5 years; 1,171 new bladder cancers were diagnosed over a median follow-up of 4 years. In the first year after diabetes diagnosis, bladder cancer incidence in the diabetic cohort was 85.3 (95% CI 72.0–100.4) per 100,000 person-years and 66.1 (54.5–79.4) in the control cohort (aHR 1.30 [1.02–1.67], P = 0.03). This first-year increased bladder cancer risk was limited to those with the fewest physician visits 2 years before the index date (≤12 visits, aHR 2.14 [1.29–3.55], P = 0.003). After the first year, type 2 diabetes was not associated with bladder cancer.
CONCLUSIONS
The results suggest that early detection bias may account for an overestimation in previously reported increased risks of bladder cancer associated with type 2 diabetes.
doi:10.2337/dc13-0045
PMCID: PMC3781560  PMID: 23990517
10.  Case management for blood pressure and lipid level control after minor stroke: PREVENTION randomized controlled trial 
Background:
Optimization of systolic blood pressure and lipid levels are essential for secondary prevention after ischemic stroke, but there are substantial gaps in care, which could be addressed by nurse- or pharmacist-led care. We compared 2 types of case management (active prescribing by pharmacists or nurse-led screening and feedback to primary care physicians) in addition to usual care.
Methods:
We performed a prospective randomized controlled trial involving adults with recent minor ischemic stroke or transient ischemic attack whose systolic blood pressure or lipid levels were above guideline targets. Participants in both groups had a monthly visit for 6 months with either a nurse or pharmacist. Nurses measured cardiovascular risk factors, counselled patients and faxed results to primary care physicians (active control). Pharmacists did all of the above as well as prescribed according to treatment algorithms (intervention).
Results:
Most of the 279 study participants (mean age 67.6 yr, mean systolic blood pressure 134 mm Hg, mean low-density lipoprotein [LDL] cholesterol 3.23 mmol/L) were already receiving treatment at baseline (antihypertensives: 78.1%; statins: 84.6%), but none met guideline targets (systolic blood pressure ≤ 140 mm Hg, fasting LDL cholesterol ≤ 2.0 mmol/L). Substantial improvements were observed in both groups after 6 months: 43.4% of participants in the pharmacist case manager group met both systolic blood pressure and LDL guideline targets compared with 30.9% in the nurse-led group (12.5% absolute difference; number needed to treat = 8, p = 0.03).
Interpretation:
Compared with nurse-led case management (risk factor evaluation, counselling and feedback to primary care providers), active case management by pharmacists substantially improved risk factor control at 6 months among patients who had experienced a stroke. Trial registration: ClinicalTrials.gov, no. NCT00931788
doi:10.1503/cmaj.140053
PMCID: PMC4016053  PMID: 24733770
11.  Medication transitions and polypharmacy in older adults following acute care 
Background/objective
Medication changes at transitions of care and polypharmacy are growing concerns that adversely impact optimal drug use. We aimed to describe transitions and patterns of medication use before and 1 year after older patients were hospitalized for community-acquired pneumonia, the second-most common reason for admission in North America.
Materials and methods
This was an analysis of a population-based clinical registry of patients treated in any of the six hospitals or seven emergency departments in Edmonton, Alberta, Canada, comprising 2,105 patients 65 years and older with community-acquired pneumonia who had survived at least 1 year. The prevalence of polypharmacy (five or more unique prescription drugs), as well as new use and persistence of common drug classes were assessed.
Results
The mean age was 78 years (standard deviation 8 years), 50% were female, 62% were hospitalized, and 58% had severe pneumonia. Among the 2,105 patients, 949 (45%) were using five or more medications prior to hospitalization, increasing to 1,559 (74%) within 90 days postdischarge and remaining over 70% at 1 year. Overall, 1,690 (80%) patients newly started and 1,553 (74%) patients stopped at least one medication in the first 90 days of follow-up. The prevalence of the most common drug classes (ie, cardiovascular, alimentary/metabolism) remained stable, with the exception of anti-infective agents, whereby 25% of patients were dispensed an anti-infective agent 3 months to 1 year after hospitalization.
Conclusion
Most older patients with pneumonia are subject to polypharmacy, and almost every patient had a medication started or stopped during 1-year follow-up, with 25% using antibiotics again. The period following an episode of pneumonia represents an opportunity potentially to optimize pharmacotherapy.
Video abstract
doi:10.2147/TCRM.S58707
PMCID: PMC3964163  PMID: 24672243
polypharmacy; drug utilization; elderly; community-acquired pneumonia; pharmacoepidemiology
12.  Health Literacy and Health Outcomes in Diabetes: A Systematic Review 
ABSTRACT
BACKGROUND
Low health literacy is considered a potential barrier to improving health outcomes in people with diabetes and other chronic conditions, although the evidence has not been previously systematically reviewed.
OBJECTIVE
To identify, appraise, and synthesize research evidence on the relationships between health literacy (functional, interactive, and critical) or numeracy and health outcomes (i.e., knowledge, behavioral and clinical) in people with diabetes.
METHODS
English-language articles that addressed the relationship between health literacy or numeracy and at least one health outcome in people with diabetes were identified by two reviewers through searching six scientific databases, and hand-searching journals and reference lists.
FINDINGS
Seven hundred twenty-three citations were identified and screened, 196 were considered, and 34 publications reporting data from 24 studies met the inclusion criteria and were included in this review. Consistent and sufficient evidence showed a positive association between health literacy and diabetes knowledge (eight studies). There was a lack of consistent evidence on the relationship between health literacy or numeracy and clinical outcomes, e.g., A1C (13 studies), self-reported complications (two studies), and achievement of clinical goals (one study); behavioral outcomes, e.g., self-monitoring of blood glucose (one study), self-efficacy (five studies); or patient-provider interactions (i.e., patient-physician communication, information exchange, decision-making, and trust), and other outcomes. The majority of the studies were from US primary care setting (87.5 %), and there were no randomized or other trials to improve health literacy.
CONCLUSIONS
Low health literacy is consistently associated with poorer diabetes knowledge. However, there is little sufficient or consistent evidence suggesting that it is independently associated with processes or outcomes of diabetes-related care. Based on these findings, it may be premature to routinely screen for low health literacy as a means for improving diabetes-related health-related outcomes.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-012-2241-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s11606-012-2241-z
PMCID: PMC3579965  PMID: 23065575
health literacy; numeracy; diabetes; health outcomes
13.  Association between frailty and short- and long-term outcomes among critically ill patients: a multicentre prospective cohort study 
Background:
Frailty is a multidimensional syndrome characterized by loss of physiologic and cognitive reserves that confers vulnerability to adverse outcomes. We determined the prevalence, correlates and outcomes associated with frailty among adults admitted to intensive care.
Methods:
We prospectively enrolled 421 critically ill adults aged 50 or more at 6 hospitals across the province of Alberta. The primary exposure was frailty, defined by a score greater than 4 on the Clinical Frailty Scale. The primary outcome measure was in-hospital mortality. Secondary outcome measures included adverse events, 1-year mortality and quality of life.
Results:
The prevalence of frailty was 32.8% (95% confidence interval [CI] 28.3%–37.5%). Frail patients were older, were more likely to be female, and had more comorbidities and greater functional dependence than those who were not frail. In-hospital mortality was higher among frail patients than among non-frail patients (32% v. 16%; adjusted odds ratio [OR] 1.81, 95% CI 1.09–3.01) and remained higher at 1 year (48% v. 25%; adjusted hazard ratio 1.82, 95% CI 1.28–2.60). Major adverse events were more common among frail patients (39% v. 29%; OR 1.54, 95% CI 1.01–2.37). Compared with nonfrail survivors, frail survivors were more likely to become functionally dependent (71% v. 52%; OR 2.25, 95% CI 1.03–4.89), had significantly lower quality of life and were more often readmitted to hospital (56% v. 39%; OR 1.98, 95% CI 1.22–3.23) in the 12 months following enrolment.
Interpretation:
Frailty was common among critically ill adults aged 50 and older and identified a population at increased risk of adverse events, morbidity and mortality. Diagnosis of frailty could improve prognostication and identify a vulnerable population that might benefit from follow-up and intervention.
doi:10.1503/cmaj.130639
PMCID: PMC3903764  PMID: 24277703
14.  Prioritization and willingness to pay for bariatric surgery: the patient perspective 
Canadian Journal of Surgery  2014;57(1):33-39.
Background
Access to publicly funded bariatric surgery is limited, potential candidates face lengthy waits, and no universally accepted prioritization criteria exist. We examined patients’ perspectives regarding prioritization for surgery.
Methods
We surveyed consecutively recruited patients awaiting bariatric surgery about 9 hypothetical scenarios describing patients waiting for surgery. Respondents were asked to rank the priority of these hypothetical patients on the wait list relative to their own. Scenarios examined variations in age, clinical severity, functional impairment, social dependence and socioeconomic status. Willingness to pay for faster access was assessed using a 5-point ordinal scale and analyzed using multivariable logistic regression.
Results
The 99 respondents had mean age of 44.7 ± 9.9 years, 76% were women, and the mean body mass index was 47.3 ± SD 7.6. The mean wait for surgery was 34.4 ± 9.4 months. Respondents assigned similar priority to hypothetical patients with characteristics identical to theirs (p = 0.22) and higher priority (greater urgency) to those exhibiting greater clinical severity (p < 0.001) and functional impairment (p = 0.003). Lower priority was assigned to patients at the extremes of age (p = 0.006), on social assistance (p < 0.001) and of high socioeconomic status (p < 0.001). Most (85%) respondents disagreed with payment to expedite access, although participants earning more than $80 000/year were less likely to disagree.
Conclusion
Most patients waiting for bariatric surgery consider greater clinical severity and functional impairments related to obesity to be important prioritization indicators and disagreed with paying for faster access. These findings may help inform future efforts to develop acceptable prioritization strategies for publicly funded bariatric surgery.
doi:10.1503/cjs.021212
PMCID: PMC3908993  PMID: 24461224
15.  Safety, effectiveness, and cost of long-acting versus intermediate-acting insulin for type 1 diabetes: Protocol for a systematic review and network meta-analysis 
Systematic Reviews  2013;2:73.
Background
Type 1 diabetes mellitus (T1DM) causes progressive destruction of pancreatic beta cells leading to absolute insulin deficiency. Treatment of T1DM requires insulin, and some evidence suggests that longer acting insulin analogues might have a higher effectiveness and greater safety profile compared to intermediate-acting insulin. Our objective is to evaluate the comparative effectiveness, safety, and cost of long-acting insulin versus intermediate-acting insulin through a systematic review and network meta-analysis.
Design/methods
Studies examining long-acting versus intermediate-acting insulin or placebo preparations for adult T1DM patients will be included. The primary outcome is glycosylated hemoglobin (A1C), and secondary outcomes include emergency department and physician visits, hospital admissions, weight gain, quality of life, microvascular complications (e.g., retinopathy), macrovascular complications (e.g., cardiovascular disease), all-cause mortality, incident cancers, and cost. We will include experimental [randomized clinical trials (RCTs), quasi-RCTs, non-RCTs], quasi-experimental (controlled before-after, interrupted time series), observational (cohort), and cost studies, of any duration of follow-up, conducted during all time periods, and disseminated in any language.
We will conduct comprehensive searches of electronic databases from inception onwards, including MEDLINE, Cochrane Central Register of Controlled Trials, and EMBASE. We will also search for difficult to locate and unpublished literature by searching dissertation databases, public health organization websites, and trial registries. After a calibration exercise using our eligibility criteria and data abstraction forms, two reviewers will screen all citations, full-text articles, and abstract data in duplicate. Conflicts will be resolved by team discussion. Using a similar process, the Cochrane Effective Practice and Organization of Care Risk of Bias tool will be used to appraise the risk of bias of experimental and quasi-experimental studies, while the Newcastle Ottawa Scale will be used to assess the methodological quality of cohort studies. If feasible and appropriate, we will conduct a random effects meta-analysis, as well as a network meta-analysis.
Discussion
Our systematic review will be of utility to healthcare providers, policy-makers, T1DM patients and family members regarding treatment options of long-acting versus intermediate-acting insulin preparations.
Trial registration
PROSPERO registry number: CRD42013003610
doi:10.1186/2046-4053-2-73
PMCID: PMC3847127  PMID: 24020869
16.  The evaluating self-management and educational support in severely obese patients awaiting multidisciplinary bariatric care (EVOLUTION) trial: rationale and design 
Background
In Canada, demand for multidisciplinary bariatric (obesity) care far outstrips capacity. Consequently, prolonged wait times exist and contribute to substantial health impairments.
A supportive, educational intervention (with in-person and web-based versions) designed to enhance the self-management skills of patients wait-listed for multidisciplinary bariatric medical and surgical care has been variably implemented across Alberta, Canada. However, its effectiveness has not been evaluated. Our objectives were: 1. To determine if this program improves clinical and humanistic outcomes and is cost-effective compared to a control intervention; and 2. To compare the effectiveness and cost-effectiveness of in-person group-based versus web-based care. We hypothesize that both the web-based and in-person programs will reduce body weight and improve outcomes compared to the control group. Furthermore, we hypothesize that the in-person version will be more effective but more costly than the web-based version.
Methods/Design
This pragmatic, prospective controlled trial will enrol 660 wait-listed subjects (220 per study arm) from regional bariatric programs in Alberta and randomly assign them to: 1. an in-person, group-based intervention (9 modules delivered over 10 sessions); 2. a web-based intervention (13 modules); and 3. controls who will receive mailed literature. Subjects will have three months to review the content assigned to them (the intervention period) after which they will immediately enter the weight management clinic. Data will be collected at baseline and every 3 months for 9 months (study end), including: 1. Clinical [5% weight loss responders (primary outcome), absolute and % weight losses, changes in obesity-related comorbidities]; 2. Humanistic (health related quality of life, patient satisfaction, depression, and self-efficacy); and 3. Economic (incremental costs and utilities and cost per change in BMI assessed from the third party health care payor perspective) outcomes. Covariate-adjusted baseline-to-nine-month change-scores will be compared between groups for each outcome using linear regression for continuous outcomes and logistic regression for dichotomous ones.
Discussion
Our findings will determine whether this intervention is effective and cost-effective compared to controls and if online or in-person care delivery is preferred. This information will be useful for clinicians, health-service providers and policy makers and should be generalizable to similar publically-funded bariatric care programs.
Trial registration
Trial Identifier: NCT01860131
doi:10.1186/1472-6963-13-321
PMCID: PMC3751526  PMID: 24059346
Bariatric care; Wait list; Severe obesity; Randomized controlled trial; Self management
17.  Safety, effectiveness, and cost of dipeptidyl peptidase-4 inhibitors versus intermediate acting insulin for type 2 diabetes: protocol for a systematic review and network meta-analysis 
Systematic Reviews  2013;2:47.
Background
Type 2 diabetes mellitus (T2DM) results from insulin resistance and relative insulin deficiency. T2DM treatment is a step-wise approach beginning with lifestyle modifications (for example, diet, exercise), followed by the addition of oral hypoglycemic agents (for example, metformin). Patients who do not respond to first-line therapy are offered second-line therapy (for example, sulfonylureas). Third-line therapy may include insulin and/or dipeptidyl peptidase-4 (DPP-4) inhibitors.
It is unclear whether DPP-4 inhibitors are safer and more effective than intermediate acting insulin for third-line management of T2DM. As such, our objective is to evaluate the comparative effectiveness, safety and cost-effectiveness of DPP-4 inhibitors versus intermediate acting insulin for T2DM patients who have failed both first- and second-line diabetes treatments.
Design/Methods
Electronic searches of MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, and grey literature (for example, trial registries, public health websites) will be conducted to identify studies examining DPP-4 inhibitors compared with each other, intermediate acting insulin, no treatment, or placebo for adults with T2DM. The outcomes of interest include glycosylated hemoglobin (A1C) (primary outcome), as well as emergency department visits, physician visits, hospital admissions, weight gain, quality of life, microvascular complications, macrovascular complications, all-cause mortality, and cost (secondary outcomes). Randomized clinical trials (RCTs), quasi-RCTs, non-RCTs, controlled before-after, interrupted time series, cohort studies, and cost studies reporting data on these outcomes will be included. Eligibility will not be restricted by publication status, language of dissemination, duration of study follow-up, or time period of study conduct.
Two reviewers will screen the titles and abstracts resulting from the literature search, as well as potentially relevant full-text articles, in duplicate. Data will be abstracted and quality will be appraised by two team members independently. Conflicts at all levels of screening and abstraction will be resolved through team discussion.
Our results will be described narratively. Random effects meta-analysis and network meta-analysis will be conducted, if feasible and appropriate.
Discussion
Our systematic review results can be used to determine the most effective, safe and cost-effective third-line strategies for managing T2DM. This information will be of great use to health policy-makers and clinicians, as well as patients living with T2DM and their families.
Trial registration
PROSPERO registry number: CRD42013003624
doi:10.1186/2046-4053-2-47
PMCID: PMC3702520  PMID: 23810103
Systematic review; Type 2 diabetes; Dipeptidyl peptidase-4; Intermediate-acting insulin; Glycosolated hemoglobin
18.  Prevalence and Predictors of Self-Reported Sexual Abuse in Severely Obese Patients in a Population-Based Bariatric Program 
Journal of Obesity  2013;2013:374050.
Background. Sexual abuse may be associated with poorer weight loss outcomes following bariatric treatment. Identifying predictors of abuse would enable focused screening and may increase weight management success. Methods. We analyzed data from 500 consecutively recruited obese subjects from a population-based, regional bariatric program. The prevalence of self-reported sexual abuse was ascertained using a single interview question. Health status was measured using a visual analogue scale (VAS). Multivariable logistic regression was performed to identify sexual abuse predictors. Results. The mean age was 43.7 y (SD 9.6), 441 (88.2%) were females, 458 (91.8%) were white, and the mean body mass index (BMI) was 47.9 kg/m2 (SD 8.1). The self-reported prevalence of past abuse was 21.8% (95% CI 18.4–25.4%). Abused subjects had worse health status (VAS score 53.1 (SD 21.2) versus 58.0 (SD 20.1), P = 0.03). BMI was not associated with abuse (P > 0.5). Age, sex, BMI, and covariate-adjusted independent predictors of abuse included alcohol addiction (adjusted odds ratio 15.8; 95% CI 4.0–62.8), posttraumatic stress disorder (4.9; 2.5–9.5), borderline personality (3.8; 1.0–13.8), depression (2.4; 1.3–4.3), and lower household income (3.4; 1.6–7.0). Conclusions. Abuse was common amongst obese patients managed in a population-based bariatric program; alcohol addiction, psychiatric comorbidities, and low-income status were highly associated with sexual abuse.
doi:10.1155/2013/374050
PMCID: PMC3705987  PMID: 23864941
19.  Efficacy of falls prevention interventions: protocol for a systematic review and network meta-analysis 
Systematic Reviews  2013;2:38.
Background
Falls are a leading cause of morbidity and mortality in older adults. Although numerous trials of falls prevention interventions have been completed, there is extensive variation in their intervention components and clinical context, such that the key elements of an effective falls prevention program remain unclear to patients, clinicians, and policy-makers. Our objective is to identify the most effective interventions and combinations of interventions that prevent falls though a systematic review and meta-analysis, including a network meta-analysis.
Methods/Design
We will search for published (e.g., MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Ageline) and unpublished (e.g., trial registries, dissertations) randomised clinical trials (RCTs) in all languages examining interventions to prevent falls compared to usual care or other falls prevention interventions among adults aged ≥65 years from all settings (e.g., community, acute care, long-term care, and rehabilitation). The primary outcomes are number of injurious falls and number of hospitalizations due to falls. Secondary outcomes include falls rate, number of fallers, number of emergency room visits due to falls, number of physician visits due to falls, number of fractures, costs, and number of intervention-related harms (e.g., muscle soreness related to exercise).
We will calibrate our eligibility criteria amongst the team and two independent team members will screen the literature search results in duplicate. Conflicts will be resolved through team discussion. A similar process will be used for data abstraction and quality appraisal with the Cochrane risk of bias tool.
Our results will be synthesized descriptively and a random effects meta-analysis will be conducted if the studies are deemed methodologically, clinically, and statistically (e.g., I2<60%) similar. If appropriate, a network meta-analysis will be conducted, which will allow the comparison of interventions that have not been compared in head-to-head RCTs, as well as the effectiveness of interventions.
Discussion
We will identify the most effective interventions and combinations of interventions that prevent falls in older people. Our results will be used to optimize falls prevention strategies, and our goal is to ultimately improve the health of seniors internationally.
Trial registration
PROSPERO registry number: CRD42013004151
doi:10.1186/2046-4053-2-38
PMCID: PMC3683540  PMID: 23738619
Falls prevention; Systematic review; Network meta-analysis; Elderly
21.  Applying the RE-AIM framework to the Alberta's Caring for Diabetes Project: a protocol for a comprehensive evaluation of primary care quality improvement interventions 
BMJ Open  2012;2(5):e002099.
Introduction
Diabetes represents a major public health and health system burden. As part of the Alberta's Caring for Diabetes (ABCD) Project, two quality-improvement interventions are being piloted in four Primary Care Networks in Alberta. Gaps between health research, policy and practice have been documented and the need to evaluate the impact of public health interventions in real-world settings to inform decision-making and clinical practice is paramount. In this article, we describe the application of the RE-AIM framework to evaluate the interventions beyond effectiveness.
Methods and analysis
Two quality-improvement interventions were implemented, based on previously proven effective models of care and are directed at improving the physical and mental health of patients with type-2 diabetes. Our goal is to adapt and apply the RE-AIM framework, using a mixed-methods approach, to understand the impact of the interventions to inform policy and clinical decision-making. We present the proposed measures, data sources and data management and analysis strategies used to evaluate the interventions by RE-AIM dimension.
Ethics and dissemination
Ethics approval for the ABCD Project has been granted from the Health Research Ethics Board (HREB #PRO00012663) at the University of Alberta. The RE-AIM framework will be used to structure our dissemination activities by dimension.
Results
It will be presented at relevant conferences and prepared for publication in peer-reviewed journals. Various products, such as presentations, briefing reports and webinars, will be developed to inform key stakeholders of the findings. Presentation of findings by RE-AIM dimension will facilitate discussion regarding the public health impact of the two interventions within the primary care context of Alberta and lessons learned to be used in programme planning and care delivery for patients with type-2 diabetes. It will also promote the application of evaluation models to better assess the impact of community-based primary healthcare interventions through our dissemination activities.
doi:10.1136/bmjopen-2012-002099
PMCID: PMC3488740  PMID: 23103609
Primary Care
22.  Characteristics of the population eligible for and receiving publicly funded bariatric surgery in Canada 
Background
Bariatric surgery is the most effective current treatment for severe obesity. Capacity to perform surgery within Canada’s public health system is limited and potential candidates face protracted wait times. A better understanding of the gaps between demand for surgery and the capacity to provide it is required. The purpose of this study was to quantify and characterize the bariatric surgery-eligible population in Canada in comparison to surgery-ineligible subjects and surgical recipients.
Methods
Data from adult (age > 20) respondents of the 2007–09 nationally representative Canadian Health Measures Survey (CHMS) were analyzed to estimate the prevalence and characteristics of the surgery-eligible and ineligible populations. Federally mandated administrative healthcare data (2007–08) were used to characterize surgical recipients.
Results
In 2007–09, an estimated 1.5 million obese Canadian adults met eligibility criteria for bariatric surgery. 19.2 million were surgery-ineligible (3.4 million obese and 15.8 million non-obese). Surgery-eligible Canadians had a mean BMI of 40.1 kg/m2 (95% CI 39.3 to 40.9 kg/m2) and, compared to the surgery-ineligible obese population, were more likely to be female (62 vs. 44%), 40–59 years old (55 vs. 48%), less educated (43 vs. 35%), in the lowest socioeconomic tertile (41 vs. 34%), and inactive (73 vs. 59%). Self-rated mental health and quality of life were lower and comorbidity was higher in surgery-eligible respondents compared with the ineligible populations. The annual proportion of Canadians eligible for surgery that actually underwent a publicly funded bariatric surgery between 2007–09 was 0.1%. Surgical recipients (n = 847) had a mean age of 43.6 years (SD 11.1) and 82% were female. With the exception of type 2 diabetes, obesity-related comorbidity prevalence was much lower in surgical recipients compared to those eligible for surgery.
Conclusions
The proportion of bariatric surgery-eligible Canadians that undergo publicly funded bariatric surgery is very low. There are notable differences in sociodemographic profiles and prevalence of comorbidities between surgery-eligible subjects and surgical recipients.
doi:10.1186/1475-9276-11-54
PMCID: PMC3495843  PMID: 22984790
Canada; Bariatric surgery; Health services research; Population health; Access
23.  Use of thiazolidinediones and the risk of bladder cancer among people with type 2 diabetes: a meta-analysis 
Background:
Patients with type 2 diabetes have a 40% increased risk of bladder cancer. Thiazolidinediones, especially pioglitazone, may increase the risk. We conducted a systematic review and meta-analysis to evaluate the risk of bladder cancer among adults with type 2 diabetes taking thiazolidinediones.
Methods:
We searched key biomedical databases (including MEDLINE, Embase and Scopus) and sources of grey literature from inception through March 2012 for published and unpublished studies, without language restrictions. We included randomized controlled trials (RCTs), cohort studies and case–control studies that reported incident bladder cancer among people with type 2 diabetes who ever (v. never) were exposed to pioglitazone (main outcome), rosiglitazone or any thiazolidinedione.
Results:
Of the 1787 studies identified, we selected 4 RCTs, 5 cohort studies and 1 case–control study. The total number of patients was 2 657 365, of whom 3643 had newly diagnosed bladder cancer, for an overall incidence of 53.1 per 100 000 person-years. The one RCT that reported on pioglitazone use found no significant association with bladder cancer (risk ratio [RR] 2.36, 95% confidence interval [CI] 0.91–6.13). The cohort studies of thiazolidinediones (pooled RR 1.15, 95% CI 1.04–1.26; I2 = 0%) and of pioglitazone specifically (pooled RR 1.22, 95% CI 1.07–1.39; I2 = 0%) showed significant associations with bladder cancer. No significant association with bladder cancer was observed in the two RCTs that evaluated rosiglitazone use (pooled RR 0.87, 95% CI 0.34–2.23; I2 = 0%).
Interpretation:
The limited evidence available supports the hypothesis that thiazolidinediones, particularly pioglitazone, are associated with an increased risk of bladder cancer among adults with type 2 diabetes.
doi:10.1503/cmaj.112102
PMCID: PMC3447078  PMID: 22761478
24.  Controlled trial of a collaborative primary care team model for patients with diabetes and depression: Rationale and design for a comprehensive evaluation 
Background
When depression accompanies diabetes, it complicates treatment, portends worse outcomes and increases health care costs. A collaborative care case-management model, previously tested in an urban managed care organization in the US, achieved significant reduction of depressive symptoms, improved diabetes disease control and patient-reported outcomes, and saved money. While impressive, these findings need to be replicated and extended to other healthcare settings. Our objective is to comprehensively evaluate a collaborative care model for comorbid depression and type 2 diabetes within a Canadian primary care setting.
Methods/design
We initiated the TeamCare model in four Primary Care Networks in Northern Alberta. The intervention involves a nurse care manager guiding patient-centered care with family physicians and consultant physician specialists to monitor progress and develop tailored care plans. Patients eligible for the intervention will be identified using the Patient Health Questionnaire-9 as a screen for depressive symptoms. Care managers will then guide patients through three phases: 1) improving depressive symptoms, 2) improving blood glucose, blood pressure and cholesterol, and 3) improving lifestyle behaviors. We will employ the RE-AIM framework for a comprehensive and mixed-methods approach to our evaluation. Effectiveness will be assessed using a controlled “on-off” trial design, whereby eligible patients would be alternately enrolled in the TeamCare intervention or usual care on a monthly basis. All patients will be assessed at baseline, 6 and 12 months. Our primary analyses will be based on changes in two outcomes: depressive symptoms, and a multivariable, scaled marginal model for the combined outcome of global disease control (i.e., A1c, systolic blood pressure, LDL cholesterol). Our planned enrolment of 168 patients will provide greater than 80% power to observe clinically important improvements in all measured outcomes. Direct costing of all intervention components and measurement of all health care utilization using linked administrative databases will be used to determine the cost-effectiveness of the intervention relative to usual care.
Discussion
Our comprehensive evaluation will generate evidence to reliability, effectiveness and sustainability of this collaborative care model for patients with chronic diseases and depression.
Trials registration
Clintrials.gov Identifier: NCT01328639
doi:10.1186/1472-6963-12-258
PMCID: PMC3445824  PMID: 22897901
Primary care; Collaborative; Diabetes; Depression; Controlled trial; Health services research
25.  Efficacy of cognitive enhancers for Alzheimer’s disease: protocol for a systematic review and network meta-analysis 
Systematic Reviews  2012;1:31.
Background
Approximately 35 million people world-wide have Alzheimer’s disease and this is projected to nearly double by 2030. Cognitive enhancers, including cholinesterase inhibitors (for example, donepezil, galantamine and rivastigmine) and memantine (N-methyl-D-aspartic acid (NMDA) receptor antagonist) have been approved for the treatment of Alzheimer’s disease in many countries. Our objective is to evaluate the comparative effectiveness, safety, and cost of cognitive enhancers for Alzheimer’s disease through a systematic review.
Methods/design
Studies examining the efficacy, safety, and cost of cognitive enhancers compared to placebo, supportive care, and other cognitive enhancers for Alzheimer’s patients will be included. The primary outcome is cognition and secondary outcomes include function, behavior, quality of life, safety, and cost. Experimental studies (randomized controlled trials, quasi-randomized controlled trials, controlled clinical trials), quasi-experimental studies (controlled before-after, interrupted time series), and observational studies (cohort, case–control studies) will be eligible for inclusion. Inclusion will not be limited by publication status, time period or language of dissemination.
We will search electronic databases (for example, MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, CINAHL, Ageline) from inception onwards. The electronic database search will be supplemented by searching for grey literature (for example, conference proceedings, searches in Google and relevant organization websites). Two reviewers will independently screen the studies for inclusion using the eligibility criteria established a priori and independently extract data. Risk of bias will be assessed using the Cochrane Risk of Bias tool for experimental and quasi-experimental studies and the Newcastle Ottawa Scale for observational studies. If deemed appropriate, meta-analysis and network (that is, indirect comparisons) meta-analysis will be conducted.
Discussion
Our systematic review will inform the decision of healthcare providers, policy-makers, Alzheimer’s patients and family members about the use of cognitive enhancers, by improving their understanding of the costs, benefits and harms that are associated with these agents.
PROSPERO registry number
CRD42012001948
doi:10.1186/2046-4053-1-31
PMCID: PMC3407718  PMID: 22742585

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