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1.  Comparison of sampling methods for hard-to-reach francophone populations: yield and adequacy of advertisement and respondent-driven sampling 
Open Medicine  2014;8(4):e120-e129.
Francophones who live outside the primarily French-speaking province of Quebec, Canada, risk being excluded from research by lack of a sampling frame. We examined the adequacy of random sampling, advertising, and respondent-driven sampling for recruitment of francophones for survey research.
We recruited francophones residing in the city of Calgary, Alberta, through advertising and respondentdriven sampling. These 2 samples were then compared with a random subsample of Calgary francophones derived from the 2006 Canadian Community Health Survey (CCHS). We assessed the effectiveness of advertising and respondent-driven sampling in relation to the CCHS sample by comparing demographic characteristics and selected items from the CCHS (specifically self-reported general health status, perceived weight, and having a family doctor).
We recruited 120 francophones through advertising and 145 through respondent-driven sampling; the random sample from the CCHS consisted of 259 records. The samples derived from advertising and respondentdriven sampling differed from the CCHS in terms of age (mean ages 41.0, 37.6, and 42.5 years, respectively), sex (proportion of males 26.1%, 40.6%, and 56.6%, respectively), education (college or higher 86.7% , 77.9% , and 59.1%, respectively), place of birth (immigrants accounting for 45.8%, 55.2%, and 3.7%, respectively), and not having a regular medical doctor (16.7%, 34.5%, and 16.6%, respectively). Differences were not tested statistically because of limitations on the analysis of CCHS data imposed by Statistics Canada.
The samples generated exclusively through advertising and respondent-driven sampling were not representative of the gold standard sample from the CCHS. Use of such biased samples for research studies could generate misleading results.
PMCID: PMC4242789  PMID: 25426180
2.  Association between First Nations ethnicity and progression to kidney failure by presence and severity of albuminuria 
Despite a low prevalence of chronic kidney disease (estimated glomerular filtration rate [GFR] < 60 mL/min per 1.73 m2), First Nations people have high rates of kidney failure requiring chronic dialysis or kidney transplantation. We sought to examine whether the presence and severity of albuminuria contributes to the progression of chronic kidney disease to kidney failure among First Nations people.
We identified all adult residents of Alberta (age ≥ 18 yr) for whom an outpatient serum creatinine measurement was available from May 1, 2002, to Mar. 31, 2008. We determined albuminuria using urine dipsticks and categorized results as normal (i.e., no albuminuria), mild, heavy or unmeasured. Our primary outcome was progression to kidney failure (defined as the need for chronic dialysis or kidney transplantation, or a sustained doubling of serum creatinine levels). We calculated rates of progression to kidney failure by First Nations status, by estimated GFR and by albuminuria category. We determined the relative hazard of progression to kidney failure for First Nations compared with non–First Nations participants by level of albuminuria and estimated GFR.
Of the 1 816 824 participants we identified, 48 669 (2.7%) were First Nations. First Nations people were less likely to have normal albuminuria compared with non–First Nations people (38.7% v. 56.4%). Rates of progression to kidney failure were consistently 2- to 3-fold higher among First Nations people than among non–First Nations people, across all levels of albuminuria and estimated GFRs. Compared with non–First Nations people, First Nations people with an estimated GFR of 15.0–29.9 mL/min per 1.73 m2 had the highest risk of progression to kidney failure, with similar hazard ratios for those with normal and heavy albuminuria.
Albuminuria confers a similar risk of progression to kidney failure for First Nations and non–First Nations people.
PMCID: PMC3903763  PMID: 24295865
4.  Regional variations in not treating diagnosed hypertension in Canada 
Improvements in the diagnosis and treatment of hypertension have been documented in Canada following implementation of a national program to improve hypertension management.
To determine whether there are regional variations in not treating diagnosed hypertension with drugs in Canada.
Using data from the Canadian Community Health Survey (CCHS) cycle 3.1 (2005), regional variation in drug treatment of diagnosed hypertension was examined. Also, national drug data from the Intercontinental Medical Statistics CompuScript database were analyzed to determine regional trends in total antihypertensive prescriptions in the period before and following the CCHS cycle 3.1.
The overall rate of untreated hypertension among those diagnosed with hypertension in Canada was 12.7%. The highest untreated rate among those diagnosed with hypertension was in the Northern region (29.2%) and the lowest was in the Atlantic region (8.8%). Alberta (16.5%) and British Columbia (BC) (15.4%) also had higher untreated rates, while Ontario (13.2%) was similar to Canada overall. Younger age, single/never married status, larger household size, lack of access to a family physician and daily smoking were all associated with a higher likelihood of not receiving antihypertensive treatment. Adjusting for demographic characteristics, diagnosed hypertensive patients in Alberta (adjusted OR 1.35 [95% CI 1.14 to 1.61]) and BC (adjusted OR 1.64 [95% CI 1.40 to 1.91]) were more likely to be untreated than those in Ontario. The largest overall percentage increase in total antihypertensive prescriptions following the CCHS (ie, 2006) occurred in BC and Ontario. In Alberta, it remained almost unchanged and declined in Manitoba.
Among adult Canadians diagnosed with hypertension, there were regional variations in the likelihood of not receiving antihypertensive therapy. Further research is required to understand the reasons for these variations to regionally target interventions and improve hypertension management in Canada.
PMCID: PMC2954533  PMID: 20931092
Canada; Hypertension; Regional variation; Treatment
5.  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.
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.
Studies were multicentre and multinational.
Ten studies including 2967 patients with T2DM.
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.
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).
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.
PMCID: PMC4275675  PMID: 25537781
systematic review; meta-analysis
6.  Trends in antihypertensive drug prescriptions and physician visits in Canada between 1996 and 2006 
In 1999, the Canadian Hypertension Education Program (CHEP) was launched to develop and implement evidence-based hypertension guidelines.
To determine temporal trends in antihypertensive drug prescribing and physician visits for hypertension in Canada, and correlate these trends with CHEP recommendations.
Longitudinal drug data (Intercontinental Medical Statistics [IMS] CompuScript database; IMS Health Canada) were used to examine prescriptions over an 11-year period (1996 to 2006) for five major cardiovascular drug classes. The IMS Canadian Disease and Therapeutic Index database was used to determine trends in physician office visits for hypertension.
Prescriptions for antihypertensive agents increased significantly over the 11-year period (4054% for angiotensin receptor blockers, 127% for thiazide diuretics, 108% for angiotensin-converting enzyme inhibitors, 87% for beta-blockers and 55% for calcium channel blockers). Time series analyses demonstrated increases in the growth rate for all drug classes, with the greatest annual change in prescriptions occurring during the 1999 to 2002 time period (except in angiotensin receptor blockers). An increase in prescriptions for fixed-dose combination products occurred, which was temporally related to the change in CHEP recommendations encouraging their use in 2001. The proportion of physician office visits for hypertension increased significantly from 4.9% in 1995 to 6.8% in 2005 (P<0.001).
The largest increase in antihypertensive drug prescribing occurred in the period immediately following implementation of CHEP (1999 to 2002). Although prescribing rates are still increasing, the rate of change has decreased, suggesting that the treatment market for hypertension may be becoming saturated. The impact of these changes on blood pressure control and clinical outcomes remains to be determined.
PMCID: PMC2643197  PMID: 18548150
Drug therapy; Hypertension
7.  Hypoglycemia Associated With Hospitalization and Adverse Events in Older People 
Diabetes Care  2013;36(11):3585-3590.
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.
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]).
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).
Older people who have an episode of hospitalized hypoglycemia are easily identified and at substantially increased risk of morbidity and mortality.
PMCID: PMC3816904  PMID: 24089536
8.  The 2006 Canadian Hypertension Education Program recommendations for the management of hypertension: Part I – Blood pressure measurement, diagnosis and assessment of risk 
To provide updated, evidence-based recommendations for the diagnosis and assessment of adults with high blood pressure.
For persons in whom a high blood pressure value is recorded, a diagnosis of hypertension is dependent on the appropriate measurement of blood pressure, the level of the blood pressure elevation, the approach used to monitor blood pressure (office, ambulatory or home/self), and the duration of follow-up. In addition, the presence of cardiovascular risk factors and target organ damage should be assessed to determine the urgency, intensity and type of treatment. For persons diagnosed as having hypertension, estimating the overall risk of adverse cardiovascular outcomes requires an assessment for other vascular risk factors and hypertensive target organ damage.
MEDLINE searches were conducted from November 2004 to October 2005 to update the 2005 recommendations. Reference lists were scanned, experts were polled, and the personal files of the authors and subgroup members were used to identify other studies. Identified articles were reviewed and appraised using pre-specified levels of evidence by content and methodological experts. As per previous years, the authors only included studies that had been published in the peer-reviewed literature and did not include evidence from abstracts, conference presentations or unpublished personal communications.
The present document contains recommendations for blood pressure measurement, diagnosis of hypertension, and assessment of cardiovascular risk for adults with high blood pressure. These include the accurate measurement of blood pressure, criteria for the diagnosis of hypertension and recommendations for follow-up, assessment of overall cardiovascular risk, routine and optional laboratory testing, assessment for renovascular and endocrine causes, home and ambulatory blood pressure monitoring, and the role of echocardiography for those with hypertension. Key features of the 2006 recommendations include continued emphasis on an expedited diagnosis of hypertension, an in-depth review of the role of global risk assessment in hypertension therapy, and the use of home/self blood pressure monitoring for patients with masked hypertension (subjects with hypertension who have a blood pressure that is normal in clinic but elevated on home/self measurement).
All recommendations were graded according to the strength of the evidence and were voted on by the 45 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported herein received at least 95% consensus. These guidelines will continue to be updated annually.
PMCID: PMC2560864  PMID: 16755312
Blood pressure; Diagnosis; Guidelines; High blood pressure; Hypertension; Risk factors
9.  Age modification of diabetes-related hospitalization among First Nations adults in Alberta, Canada 
We sought to determine the modifying effects of age and multimorbidity on the association between First Nations status and hospitalizations for diabetes-specific ambulatory care sensitive conditions (ACSC).
We identified 183,654 adults with diabetes from Alberta Canada, and followed them for one year for the outcome of hospitalization or emergency department (ED) visit for a diabetes-specific ACSC. We used logistic regression to determine the association between First Nations status and the outcome, assessing for effect modification by age and multimorbidity with interaction terms. In a model adjusting for age, age2, baseline A1c, duration of diabetes, and multimorbidity, First Nations people were at greater risk than non-First Nations to experience a diabetes-specific hospitalization or ED visit (unadjusted odds ratio [OR] 3.74; 95% confidence interval [CI]: 3.45-4.07). After adjustment for relevant covariates, this association varied by age (interaction: p = 0.018): adjusted OR 3.94 (95% CI: 3.11-4.99) and 5.74 (95% CI: 3.36-9.80) for First Nations compared to non-First Nations at ages 30 and 80 years, respectively.
Compared with non-First Nations, older First Nations patients with diabetes are at greater risk for diabetes-specific hospitalizations. Older First Nations patients with diabetes should be given priority access to primary care services as they are at greatest risk for requiring hospitalization for stabilization of their condition.
PMCID: PMC4192759  PMID: 25309626
American indian; First Nations; Hospitalization; Diabetes mellitus; Risk adjustment
11.  Sociodemographic correlates of 25-hydroxyvitamin D test utilization in Calgary, Alberta 
Increasing laboratory test utilization is a major challenge facing clinical laboratories.
However, in most instances we lack population level information on the patient groups to which increased testing is directed. Much recent work has been published on the sociodemographic correlates of 25-hydroxyvitamin D deficiency. An unanswered question, however, is whether testing is preferentially directed towards individuals with a higher likelihood of deficiency. In this paper we examine this question by combining laboratory information system data on testing rates with Census Canada data.
We examined 1,436 census dissemination areas within the city of Calgary, Alberta, Canada. For each census dissemination area we determined age and sex-specific 25-hydroxyvitamin D testing rates over a one year period. We then compared these testing rates with the following sociodemographic variables obtained from Census Canada: first nations status, education level, household income, visible minority status, and recent immigrant status.
Overall, 6.9% of males in the city of Calgary were tested during the study period. Females were 1.7 times more likely to be tested than males. Testing rate increased with increasing age, with 16.8% of individuals 66 years and over tested during the one-year study period.
Individuals having at least some university education were less likely to be tested (RR = 0.60;
p < 0.0001). Interestingly, although visible minorities were over twice as likely to be tested as compared to non-visual minorities (RR = 2.25; p < 0.0001), recent immigrants, a group known to exhibit low 25 hydroxyvitamin D levels, were significantly less likely to be tested than non-recent immigrants (RR = 0.72; p = 0.0174). While median household income was modestly associated with increased testing (RR = 1.02; p < 0.0001), First Nations status and non-English speaking were not significant predictors of 25-hydroxyvitamin D testing.
Testing for 25-hydroxyvitamin D is in part directed toward populations at higher risk of deficiency (visible minorities) and at higher risk of osteoporosis (older females), but a particularly high risk group (recent immigrants) is being tested at a lower rate than other patient groups.
PMCID: PMC4132197  PMID: 25106954
Vitamin D; Laboratory utilization; Canada census data
12.  The VITAH Trial Vitamin D supplementation and cardiac autonomic tone in hemodialysis: a blinded, randomized controlled trial 
BMC Nephrology  2014;15:129.
Patients with end-stage kidney disease (ESKD) have a high rate of mortality and specifically an increased risk of sudden cardiac death (SCD). Impaired cardiac autonomic tone is associated with elevated risk of SCD. Moreover, patients with ESKD are often vitamin D deficient, which we have shown may be linked to autonomic dysfunction in humans. To date, it is not known whether vitamin D supplementation normalizes cardiac autonomic function in the high-risk ESKD population. The VITamin D supplementation and cardiac Autonomic tone in Hemodialysis (VITAH) randomized trial will determine whether intensive vitamin D supplementation therapies improve cardiac autonomic tone to a greater extent than conventional vitamin D supplementation regimens in ESKD patients requiring chronic hemodialysis.
A total of 60 subjects with ESKD requiring thrice weekly chronic hemodialysis will be enrolled in this 2x2 crossover, blinded, randomized controlled trial. Following a 4-week washout period from any prior vitamin D therapy, subjects are randomized 1:1 to intensive versus standard vitamin D therapy for 6 weeks, followed by a 12-week washout period, and finally the remaining treatment arm for 6 weeks. Intensive vitamin D treatment includes alfacalcidiol (activated vitamin D) 0.25mcg orally with each dialysis session combined with ergocalciferol (nutritional vitamin D) 50 000 IU orally once per week and placebo the remaining two dialysis days for 6 weeks. The standard vitamin D treatment includes alfacalcidiol 0.25mcg orally combined with placebo each dialysis session per week for 6 weeks. Cardiac autonomic tone is measured via 24 h Holter monitor assessments on the first dialysis day of the week every 6 weeks throughout the study period. The primary outcome is change in the low frequency: high frequency heart rate variability (HRV) ratio during the first 12 h of the Holter recording at 6 weeks versus baseline. Secondary outcomes include additional measures of HRV. The safety of intensive versus conventional vitamin D supplementation is also assessed.
VITAH will determine whether an intensive vitamin D supplementation regimen will improve cardiac autonomic tone compared to conventional vitamin D supplementation and will assess the safety of these two supplementation regimens in ESKD patients receiving chronic hemodialysis.
Trial registration, NCT01774812
PMCID: PMC4130113  PMID: 25098377
Chronic kidney disease; Vitamin D; Ergocalciferol; Alfacalcidiol; Autonomic nervous system; Cardiovascular risk; Clinical trial
13.  A population-based study on care and clinical outcomes in remote dwellers with heavy proteinuria 
Kidney International Supplements  2013;3(2):254-258.
Patients with proteinuria are at high risk of cardiovascular and renal complications. Since this risk can be reduced by appropriate interventions, we hypothesized that remote dwellers, who are known to have lower access to health care, might have a higher risk of complications. Using a database of all adults with at least one measure of urine protein between May 2002 and March 2009, we examined the frequency of heavy proteinuria, quality of care delivery, and rates of adverse clinical outcomes across travel distance categories to the nearest nephrologist. Heavy proteinuria was defined by an albumin:creatinine ratio ⩾60 mg/mmol, protein:creatinine ratio ⩾100 mg/mmol, or protein ⩾2+ on dipstick urinalysis. Of 1,359,330 subjects in the study, 262,209 were remote dwellers. The overall prevalence of proteinuria was 2.3%, 2.9%, and 2.5% in those who live >200, 100.1–200, and 50.1–100 km, respectively, as compared to 1.5% in those who live within 50 km of the nearest nephrologist (P<0.001). Similarly, the prevalence of heavy proteinuria was increased among remote dwellers compared to urban dwellers (P=0.001 for trend). There were no differences in markers of good-quality care or the rate of adverse outcomes (all-cause mortality, heart failure, and renal outcomes) across distance categories. However, the rates of hospitalizations and stroke were significantly higher with increased distance from the nearest nephrologist (P<0.001and 0.02, respectively). In conclusion, heavy proteinuria was common in Alberta residents, especially in remote dwellers. Care seemed similar across distance categories of travel, but with higher risk of hospitalizations and stroke among remote dwellers. Further work is needed to understand the basis for the increased risk of hospitalizations and stroke.
PMCID: PMC4089650  PMID: 25018993
adverse clinical outcomes; population; proteinuria; quality of care; remote dwellers
14.  Likelihood of coronary angiography among First Nations patients with acute myocardial infarction 
Morbidity due to cardiovascular disease is high among First Nations people. The extent to which this may be related to the likelihood of coronary angiography is unclear. We examined the likelihood of coronary angiography after acute myocardial infarction (MI) among First Nations and non–First Nations patients.
Our study included adults with incident acute MI between 1997 and 2008 in Alberta. We determined the likelihood of angiography among First Nations and non–First Nations patients, adjusted for important confounders, using the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) database.
Of the 46 764 people with acute MI, 1043 (2.2%) were First Nations. First Nations patients were less likely to receive angiography within 1 day after acute MI (adjusted odds ratio [OR] 0.73, 95% confidence interval [CI] 0.62–0.87). Among First Nations and non–First Nations patients who underwent angiography (64.9%), there was no difference in the likelihood of percutaneous coronary intervention (PCI) (adjusted hazard ratio [HR] 0.92, 95% CI 0.83–1.02) or coronary artery bypass grafting (CABG) (adjusted HR 1.03, 95% CI 0.85–1.25). First Nations people had worse survival if they received medical management alone (adjusted HR 1.38, 95% CI 1.07–1.77) or if they underwent PCI (adjusted HR 1.38, 95% CI 1.06–1.80), whereas survival was similar among First Nations and non–First Nations patients who received CABG.
First Nations people were less likely to undergo angiography after acute MI and experienced worse long-term survival compared with non–First Nations people. Efforts to improve access to angiography for First Nations people may improve outcomes.
PMCID: PMC4081235  PMID: 24847149
15.  Comparative safety of anti-epileptic drugs among infants and children exposed in utero or during breastfeeding: protocol for a systematic review and network meta-analysis 
Systematic Reviews  2014;3:68.
Epilepsy affects about 1% of the general population. Anti-epileptic drugs (AEDs) prevent or terminate seizures in individuals with epilepsy. Pregnant women with epilepsy may continue taking AEDs. Many of these agents cross the placenta and increase the risk of major congenital malformations, early cognitive and developmental delays, and infant mortality. We aim to evaluate the comparative safety of AEDs approved for chronic use in Canada when administered to pregnant and breastfeeding women and the effects on their infants and children through a systematic review and network meta-analysis.
Studies examining the effects of AEDs administered to pregnant and breastfeeding women regardless of indication (e.g., epilepsy, migraine, pain, psychiatric disorders) on their infants and children will be included. We will include randomized clinical trials (RCTs), quasi-RCTs, non-RCTs, controlled before-after, interrupted time series, cohort, registry, and case-control studies. The main literature search will be executed in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. We will seek unpublished literature through searches of trial protocol registries and conference abstracts. The literature search results screening, data abstraction, and risk of bias appraisal will be performed by two individuals, independently. Conflicts will be resolved through discussion. The risk of bias of experimental and quasi-experimental studies will be appraised using the Cochrane Effective Practice and Organization of Care Risk-of-Bias tool, methodological quality of observational studies will be appraised using the Newcastle-Ottawa Scale, and quality of reporting of safety outcomes will be conducted using the McMaster Quality Assessment Scale of Harms (McHarm) tool. If feasible and appropriate, we will conduct random effects meta-analysis. Network meta-analysis will be considered for outcomes that fulfill network meta-analysis assumptions.
The primary outcome is major congenital malformations (overall and by specific types), while secondary outcomes include fetal loss/miscarriage, minor congenital malformations (overall and by specific types), cognitive development, psychomotor development, small for gestational age, preterm delivery, and neonatal seizures.
Our systematic review will address safety concerns regarding the use of AEDs during pregnancy and breastfeeding. Our results will be useful to healthcare providers, policy-makers, and women of childbearing age who are taking anti-epileptic medications.
Systematic review registration
PROSPERO CRD42014008925.
PMCID: PMC4086277  PMID: 24964932
Anti-epileptic drug; Breastfeeding; Comparative safety; Congenital malformation; Epilepsy; Fetus; Infant; Network meta-analysis; Pregnancy; Systematic review
16.  Effect of fish oil supplementation on graft patency and cardiovascular events among patients with new synthetic arteriovenous hemodialysis grafts: A randomized trial 
Arteriovenous grafts, an important option for hemodialysis vascular access, are prone to recurrent stenosis and thrombosis.
To determine the effect of fish oil on arteriovenous graft patency and cardiovascular events.
Design, Setting and Patients
Randomized, double-blind, controlled clinical trial (FISH Study) conducted at 15 North American dialysis centres from November 2003-December 2010 enrolled 201 participants with stage 5 chronic kidney disease (50% female, 63% Caucasian, 53% diabetic) and followed them for 12 months after graft creation
Random allocation to daily fish oil capsules (4×1 gram) or matching placebo on day 7 after graft creation.
Main Outcome Measure
The proportion of participants experiencing a graft thrombosis or radiological or surgical intervention during 12 months follow-up.
The risk of the primary outcome did not differ between fish oil and placebo recipients (48/99 [48%] versus 60/97 [62%]; relative risk 0.78 [95% CI, 0.60–1.03; P = 0.064]). However, the rate of graft failure was lower in the fish oil group (3.43 versus 5.95 per 1,000 access days; incidence rate ratio (IRR) 0.58 [95% CI, 0.44–0.75; P < 0.001). In the fish oil group, there were half as many thrombosis events (1.71 versus 3.41 per 1,000 access days; IRR 0.50 [95% CI, 0.35–0.72; P < 0.001); fewer corrective interventions (2.89 versus 4.92 per 1,000 access days; IRR 0.59 [95% CI, 0.44–0.78; P < 0.001), improved cardiovascular event-free survival; hazard ratio 0.43 [95% CI, 0.19–0.96; P=0.035) and lower systolic blood pressure by 12 months (average −3.61 versus + 4.49 mmHg [95% CI −15.4–−0.85]; P=0.014).
Conclusions: D
aily fish oil ingestion did not reduce the proportion of patients with loss of native patency within 12 months of graft creation; however, it did reduce the rate and time to thrombosis, the need for corrective interventions to maintain patency, and was associated with improved cardiovascular outcomes.
Trial registration Identifier: ISRCTN 15838383
PMCID: PMC4046844  PMID: 22550196
17.  Safety and effectiveness of antiretroviral therapies for HIV-infected women and their infants and children: protocol for a systematic review and network meta-analysis 
Systematic Reviews  2014;3:51.
Antiretroviral therapy reduces mother-to-child transmission of human immunodeficiency virus (HIV) during pregnancy, delivery, and breastfeeding. However, these agents have been associated with preterm birth, anemia and low birth weight. We aim to evaluate the comparative safety and effectiveness of the use of antiretroviral drugs among HIV-infected women and the effects on their infants and children through a systematic review and network meta-analysis.
Studies examining the effects of six antiretroviral drug classes (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, fusion inhibitors, co-receptor inhibitors) administered to HIV-infected pregnant women will be included. We will include randomized clinical trials (RCTs), quasi-RCTs, non-RCTs, controlled before-after, interrupted time series, cohort, registry, and case–control studies. No limitations will be imposed on publication status (that is, unpublished studies are eligible for inclusion), duration of follow-up, study conduct period, and language of dissemination. Comprehensive literature searches will be conducted in major electronic databases, including MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. Gray literature will be identified through searching dissertation databases, trial protocol registries, and conference abstracts.
Two team members will independently screen all citations, full-text articles, and abstract data; conflicts will be resolved through discussion. The risk of bias and methodological quality will be appraised using appropriate tools (for example, Cochrane Collaboration’s tool for assessing risk of bias, Newcastle-Ottawa Scale, and McMaster Quality Assessment Scale of Harms). If feasible and appropriate, we will conduct random effects meta-analysis. Network meta-analysis will be considered for outcomes with the greatest number of treatment comparisons available that fulfill network meta-analysis assumptions (for example, consistency of evidence between direct and indirect data, and low statistical heterogeneity between included studies).
The primary effectiveness outcome is mother-to-child transmission of HIV, and the primary safety outcome is major congenital malformation (overall and specific types) among newborns of HIV-infected women. Secondary safety outcomes include stillbirths, infant/child death, preterm delivery, overall and specific minor congenital malformations, and small for gestational age infants.
Our systematic review will be of utility to healthcare providers, policy-makers, and HIV-positive women regarding the use of antiretroviral drugs.
Trial registration
PROSPERO registry number: CRD42014009071.
PMCID: PMC4039063  PMID: 24887455
antiretroviral therapy; breastfeeding; congenital malformation; human immunodeficiency virus; fetus; mother-to-child-transmission; pregnancy
18.  The Association of Income with Health Behavior Change and Disease Monitoring among Patients with Chronic Disease 
PLoS ONE  2014;9(4):e94007.
Management of chronic diseases requires patients to adhere to recommended health behavior change and complete tests for monitoring. While studies have shown an association between low income and lack of adherence, the reasons why people with low income may be less likely to adhere are unclear. We sought to determine the association between household income and receipt of health behavior change advice, adherence to advice, receipt of recommended monitoring tests, and self-reported reasons for non-adherence/non-receipt.
We conducted a population-weighted survey, with 1849 respondents with cardiovascular-related chronic diseases (heart disease, hypertension, diabetes, stroke) from Western Canada (n = 1849). We used log-binomial regression to examine the association between household income and the outcome variables of interest: receipt of advice for and adherence to health behavior change (sodium reduction, dietary improvement, increased physical activity, smoking cessation, weight loss), reasons for non-adherence, receipt of recommended monitoring tests (cholesterol, blood glucose, blood pressure), and reasons for non-receipt of tests.
Behavior change advice was received equally by both low and high income respondents. Low income respondents were more likely than those with high income to not adhere to recommendations regarding smoking cessation (adjusted prevalence rate ratio (PRR): 1.55, 95%CI: 1.09–2.20), and more likely to not receive measurements of blood cholesterol (PRR: 1.72, 95%CI 1.24–2.40) or glucose (PRR: 1.80, 95%CI: 1.26–2.58). Those with low income were less likely to state that non-adherence/non-receipt was due to personal choice, and more likely to state that it was due to an extrinsic factor, such as cost or lack of accessibility.
There are important income-related differences in the patterns of health behavior change and disease monitoring, as well as reasons for non-adherence or non-receipt. Among those with low income, adherence to health behavior change and monitoring may be improved by addressing modifiable barriers such as cost and access.
PMCID: PMC3983092  PMID: 24722618
19.  Access to primary care and other health care use among western Canadians with chronic conditions: a population-based survey 
CMAJ Open  2014;2(1):E27-E34.
For adults with chronic conditions, access to primary care, including multidisciplinary care, is associated with better outcomes. Few studies have assessed barriers to such care. We sought to describe barriers to primary care, including care from allied health professionals, for adults with chronic conditions.
We surveyed western Canadians aged 40 years or older who had hypertension, diabetes, heart disease or stroke about access to primary care and other use of health care. Using log binomial regression, we determined the association between sociodemographic variables and several indicators of access to primary care and care from allied health professionals.
Of the 2316 people who were approached, 1849 (79.8%) completed the survey. Most of the respondents (95.1%) had a regular medical doctor, but two-thirds (68.1%) did not have after-hours access. Only 6.1% indicated that allied health professionals were involved in their care, although most respondents (87.3%) indicated they would be willing to see a nurse practitioner if their primary care physician was not available. Respondents who were obese or less than 65 years of age were less likely to have a regular medical doctor. Individuals who had diabetes, lived in a rural area, were residents of Alberta or had poorer health were more likely to have allied health professionals involved in their care.
The survey results identified barriers to accessing primary care for people with chronic conditions. Opportunities for improving access to primary care may include greater involvement by allied health professionals, such as nurse practitioners.
PMCID: PMC3985957  PMID: 25077122
20.  Comparison of risk prediction using the CKD-EPI equation and the MDRD Study equation for estimated glomerular filtration rate 
JAMA : the journal of the American Medical Association  2012;307(18):10.1001/jama.2012.3954.
The CKD-EPI equation more accurately estimates glomerular filtration rate (eGFR) than the MDRD Study equation using the same variables, especially at higher GFR, but definitive evidence of its risk implications in diverse settings is lacking.
To evaluate risk implications of eGFRCKD-EPI compared to eGFRMDRD in populations with a broad range of demographic and clinical characteristics.
Design, Setting, and Participants
Meta-analyses based on data from 1,130,472 adults (aged 18 years or older) from 25 general population, 7 high-risk (of vascular disease), and 13 chronic kidney disease (CKD) cohorts. Data transfer and analyses were conducted between March 2011 and March 2012.
Main Outcome Measures
All-cause mortality (84,482 deaths from 40 cohorts), cardiovascular mortality (22,176 events from 28 cohorts), and end-stage renal disease (ESRD) (7,644 events from 21 cohorts) during 9.4 million person-years of follow-up (median of mean follow-up time across cohorts was 7.4 years).
eGFR was classified into six categories (≥90, 60-89, 45-59, 30-44, 15-29, and <15 ml/min/1.73m2) by both equations. Compared to eGFRMDRD, 24.4% and 0.6% of participants from general population cohorts were reclassified to a higher and lower eGFR category by the CKD-EPI equation, respectively, and the prevalence of CKD stage 3-5 (eGFR <60 ml/min/1.73m2) was reduced from 8.7% to 6.3%. 34.7% of participants with eGFRMDRD 45-59 were reclassified to eGFRCKD-EPI 60-89 and had lower incidence rates (per 1,000 person-years) of outcomes compared to those not reclassified (9.9 vs. 34.5 for all-cause mortality, 2.7 vs. 13.0 for cardiovascular mortality, and 0.5 vs. 0.8 for ESRD). The corresponding adjusted hazard ratios were 0.80 (95% confidence interval, 0.74 to 0.86) for all-cause mortality, 0.73 (0.65 to 0.82) for cardiovascular mortality, and 0.49 (0.27 to 0.88) for ESRD. Similar findings were observed in other eGFRMDRD categories. Net reclassification improvement (NRI) based on eGFR categories was significantly positive for all outcomes (range from 0.06 to 0.13, all P<0.001). NRI was similarly positive in most subgroups defined by age (< and ≥65 years), sex, race/ethnicity (white, Asian, and black), and presence or absence of diabetes and hypertension. The results in high-risk and CKD cohorts were largely consistent with the general population cohorts.
The CKD-EPI equation classified fewer individuals as CKD and more accurately categorized the risk for mortality and ESRD than did the MDRD Study equation across a broad range of populations.
PMCID: PMC3837430  PMID: 22570462
21.  Patterns of engagement with the health care system and risk of subsequent hospitalization amongst patients with diabetes 
Re-hospitalization is common among patients with diabetes, and may be related to aspects of health care use. We sought to determine the association between patterns of health care engagement and risk of subsequent hospitalization within one year of discharge for patients with diabetes.
We identified adults with incident diabetes in Alberta, Canada, who had at least one hospitalization following their diabetes diagnosis between January 1, 2004 and March 31, 2011. We used Cox regression to estimate the association between factors related to health care engagement (prior emergency department use, primary care visits, and discharge disposition (i.e. whether the patient left against medical advice)) and the risk of subsequent all-cause hospitalization within one year.
Of the 33811 adults with diabetes and at least one hospitalization, 11095 (32.8%) experienced a subsequent all-cause hospitalization within a mean (standard deviation) follow-up time of 0.68 (0.3) years. Compared to patients with no emergency department visits, there was a 4 percent increased risk of a subsequent hospitalization for every emergency department visit occurring prior to the index hospitalization (adjusted Hazard Ratio [HR]: 1.04; 95% CI: 1.03–1.05). Limited and increased use of primary care was also associated with increased risk of a subsequent hospitalization. Compared to patients with 1–4 visits, patients with no visits to a primary care physician (adjusted HR: 1.11; 95% CI: 0.99–1.25) and those with 5–9 visits (adjusted HR: 1.06; 95% CI: 1.00–1.12) were more likely to experience a subsequent hospitalization. Finally, compared to patients discharged home, those leaving against medical advice were more likely to have a subsequent hospitalization (adjusted HR: 1.74; 95% CI: 1.50–2.02) and almost 3 times more likely to have a diabetes-specific subsequent event (adjusted HR: 2.86; 95% CI: 1.82–4.49).
Patterns of health care use and the circumstances surrounding hospital discharge are associated with an increased risk of subsequent hospitalization among patients with diabetes. Whether these patterns are related to the health care systems ability to manage complex patients within a primary care setting, or to access to primary care services, remains to be determined.
PMCID: PMC3851786  PMID: 24103159
Diabetes; Administrative data; Hospitalization
Hypertension  2011;57(5):891-897.
We designed this study to explore to what extent the excess risk of cardiovascular events in diabetic individuals is attributable to hypertension. We retrospectively analyzed prospectively collected data from the Framingham Original and Offspring cohorts. Of the 1145 Framingham subjects newly diagnosed with diabetes who did not have a prior history of cardiovascular events, 663 (58%) had hypertension at the time diabetes was diagnosed. During 4154 person-years of follow-up, 125 died and 204 suffered a cardiovascular event. Framingham participants with hypertension at the time of diabetes diagnosis exhibited higher rates of all cause mortality (32 versus 20 per 1000 person years, p<0.001) and cardiovascular events (52 versus 31 per 1000 person years, p<0.001) compared with normotensive subjects with diabetes. After adjustment for demographic and clinical covariates, hypertension was associated with a 72% increase in the risk of all cause death and a 57% increase in the risk of any cardiovascular event in individuals with diabetes. The population attributable risk from hypertension in individuals with diabetes was 30% for all-cause death and 25% for any cardiovascular event (increasing to 44% and 41% respectively if the 110 normotensive subjects who developed hypertension during follow-up were excluded from the analysis). In comparison, after adjustment for concurrent hypertension, the population attributable risk from diabetes in Framingham subjects was 7% for all cause mortality and 9% for any CVD event. While diabetes is associated with increased risks of death and cardiovascular events in Framingham subjects, much of this excess risk is attributable to coexistent hypertension.
PMCID: PMC3785072  PMID: 21403089
diabetes; hypertension; Framingham; population attributable risk
23.  Recommendations for optimal ICD codes to study neurologic conditions 
Neurology  2012;79(10):1049-1055.
Administrative health data are frequently used for large population-based studies. However, the validity of these data for identifying neurologic conditions is uncertain.
This article systematically reviews the literature to assess the validity of administrative data for identifying patients with neurologic conditions. Two reviewers independently assessed for eligibility all abstracts and full-text articles identified through a systematic search of Medline and Embase. Study data were abstracted on a standardized abstraction form to identify ICD code–based case definitions and corresponding sensitivity, specificity, positive predictive values (PPVs), and negative predictive values (NPVs).
Thirty full-text articles met the eligibility criteria. These included 8 studies for Alzheimer disease/dementia (sensitivity: 8–86.5, specificity: 56.3–100, PPV: 60–97.9, NPV: 68.0–98.9), 2 for brain tumor (sensitivity: 54.0–100, specificity: 97.0–99.0, PPV: 91.0–98.0), 4 for epilepsy (sensitivity: 98.8, specificity: 69.6, PPV: 62.0–100, NPV: 89.5–99.1), 4 for motor neuron disease (sensitivity: 78.9–93.0, specificity: 99.0–99.9, PPV: 38.0–90.0, NPV: 99), 2 for multiple sclerosis (sensitivity: 85–92.4, specificity: 55.9–92.6, PPV: 74.5–92.7, NPV: 70.8–91.9), 4 for Parkinson disease/parkinsonism (sensitivity: 18.7–100, specificity: 0–99.9, PPV: 38.6–81.0, NPV: 46.0), 3 for spinal cord injury (sensitivity: 0.9–90.6, specificity: 31.9–100, PPV: 27.3–100), and 3 for traumatic brain injury (sensitivity: 45.9–78.0 specificity: 97.8, PPV: 23.7–98.0, NPV: 99.2). No studies met eligibility criteria for cerebral palsy, dystonia, Huntington disease, hydrocephalus, muscular dystrophy, spina bifida, or Tourette syndrome.
To ensure the accurate interpretation of population-based studies with use of administrative health data, the accuracy of case definitions for neurologic conditions needs to be taken into consideration.
PMCID: PMC3430709  PMID: 22914826
24.  Vitamin D Levels Are Associated with Cardiac Autonomic Activity in Healthy Humans 
Nutrients  2013;5(6):2114-2127.
Vitamin D deficiency (≤50nmol/L 25-hydroxy vitamin D) is a cardiovascular (CV) risk factor that affects approximately one billion people worldwide, particularly those affected by chronic kidney disease (CKD). Individuals with CKD demonstrate abnormal cardiac autonomic nervous system activity, which has been linked to the significant rates of CV-related mortality in this population. Whether vitamin D deficiency has a direct association with regulation of cardiac autonomic activity has never been explored in humans. Methods: Thirty-four (34) healthy, normotensive subjects were studied and categorized based on 25-hydroxy vitamin D deficiency (deficient vs. non-deficient, n = 7 vs. 27), as well as 1,25-dihydroxy vitamin D levels (above vs. below 25th percentile, n = 8 vs. 26). Power spectral analysis of electrocardiogram recordings provided measures of cardiac autonomic activity across low frequency (LF) and high frequency (HF, representative of vagal contribution) bands, representative of the sympathetic and vagal limbs of the autonomic nervous system when transformed to normalized units (nu), respectively, as well as overall cardiosympathovagal balance (LF:HF) during graded angiotensin II (AngII) challenge (3 ng/kg/min × 30 min, 6 ng/kg/min × 30 min). Results: At baseline, significant suppression of sympathovagal balance was observed in the 25-hydroxy vitamin D-deficient participants (LF:HF, p = 0.02 vs. non-deficient), although no other differences were observed throughout AngII challenge. Participants in the lowest 1,25-dihydroxy VD quartile experienced significant withdrawal of inhibitory vagal control, as well as altered overall sympathovagal balance throughout AngII challenge (HF, mean difference = −6.98 ± 3 nu, p = 0.05; LF:HF, mean difference = 0.34 ± 0.1, p = 0.043 vs. above 25th percentile). Conclusions: Vitamin D deficiency is associated with suppression of resting cardiac autonomic activity, while low 1,25-dihydroxy vitamin D levels are associated with unfavourable cardiac autonomic activity during an acute AngII stressor, offering a potential pathophysiological mechanism that may be acting to elevate CV risk in in populations with low vitamin D status.
PMCID: PMC3725496  PMID: 23752493
vitamin D and cardiovascular disease; vitamin D deficiency; cholecalciferol; cardiac autonomic nervous system; heart rate variability; angiotensin II
25.  Association of vitamin D status with socio-demographic factors in Calgary, Alberta: an ecological study using Census Canada data 
BMC Public Health  2013;13:316.
Low 25-hydroxyvitamin D levels are a global health problem with northern countries such as Canada at particular risk. A number of sociodemographic factors have been reported to be associated with low vitamin D levels but prior studies have been limited by the ability of the researchers to gather this data directly from clinical trial participants. The purpose of this study was to use a novel methodology of inferring sociodemographic variables to evaluate the correlates of vitamin D levels in individuals dwelling in the City of Calgary, Alberta, Canada.
We utilized data on vitamin D test results from Calgary Laboratory Services between January 1 2010 and August 31 2011. In addition to vitamin D level, we recorded age, sex, and vitamin D testing month as individual-level variables. We inferred sociodemographic variables by associating results with census dissemination areas and using Census Canada data to determine immigration status, education, median household income and first nations status as clustered variables. Associations between vitamin D status and the individual- and dissemination area-specific variables were examined using the population-averaged regression model by a generalized estimating equations approach to account for the clustering in the data.
158,327 individuals were included. Age, sex, month of vitamin D testing (at an individual level), and education, immigrant status, first nations status and income (at an aggregate level) were all statistically significant predictors of vitamin D status.
Vitamin D status was associated with a number of sociodemographic variables. Knowledge of these variables may improve targeted education and public health initiatives.
PMCID: PMC3637075  PMID: 23566290
Vitamin D; Ecological study; Sociodemographic factors

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