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1.  Chemotherapy regimens for advanced pancreatic cancer: a systematic review and network meta-analysis 
BMC Cancer  2014;14:471.
Background
Advanced pancreatic cancer confers poor prognosis and treatment advancement has been slow. Recent randomized clinical trials (RCTs) have demonstrated survival benefits for combination therapy compared to gemcitabine alone. However, the comparative benefits and harms of available combination chemotherapy treatments are not clear. We therefore conducted a systematic review and Bayesian network meta-analysis to assess the comparative safety and efficacy of chemotherapy regimens for the treatment of advanced pancreatic cancer.
Methods
MEDLINE, PubMed, EMBASE, Cochrane Central Registry of Clinical trials and abstracts from major scientific meetings were searched for RCTs published from 2002 to 2013. Key outcomes were overall survival (OS), progression free survival (PFS), and safety including grade 3–4 febrile neutropenia, neutropenia, vomiting, diarrhea, fatigue and sensory neuropathy. Bayesian network meta-analyses were conducted to calculate survival and safety outcomes using gemcitabine (GEM) as the reference comparator. Effect estimates and 95% credible intervals were calculated for each comparison. Mean ranks and the probability of being best were obtained for each treatment analyzed in the network meta-analysis.
Results
The search identified 23 studies involving 19 different treatment regimens and 9,989 patients. FOLFIRINOX, GEM/cisplatin/epirubicin/5FU (PEFG), GEM/NAB-paclitaxel (NAB-P), GEM/erlotinib+/-bevacizumab, GEM/capecitabine, and GEM/oxaliplatin were associated with statistically significant improvements in OS and PFS relative to gemcitabine alone and several other treatments. They were amongst the top ranked for survival outcomes amongst other treatments included. No significant differences were found for other combination chemotherapy treatments. Effect estimates from indirect comparisons matched closely to estimates derived from pairwise comparisons. Overall, combination therapies had greater risk for evaluated grade 3–4 toxicities over gemcitabine alone.
Conclusions
In the absence of head-to-head comparisons, we performed a mixed-treatment analysis to achieve high-quality information on the effectiveness and safety of each treatment. This study suggests that some combination therapies may offer greater benefits in the treatment of advanced pancreatic cancer than others. To more fully elucidate the comparative benefits and harms of different combination chemotherapy regimens, rigorously conducted comparative studies, or network meta-analysis of patient-level data are required.
doi:10.1186/1471-2407-14-471
PMCID: PMC4097092  PMID: 24972449
Advanced pancreatic cancer; Chemotherapy; Gemcitabine; Combination therapy; Randomized clinical trials; Systematic review; Network meta-analysis
2.  Systematic review and network meta-analysis comparing antithrombotic agents for the prevention of stroke and major bleeding in patients with atrial fibrillation 
BMJ Open  2014;4(6):e004301.
Objective
To examine the comparative efficacy and safety of antithrombotic treatments (apixaban, dabigatran, edoxaban, rivaroxaban and vitamin K antagonists (VKA) at a standard adjusted dose (target international normalised ratio 2.0–3.0), acetylsalicylic acid (ASA), ASA and clopidogrel) for non-valvular atrial fibrillation and among subpopulations.
Design
Systematic review and network meta-analysis.
Data sources
A systematic literature search strategy was designed and carried out using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and the grey literature including the websites of regulatory agencies and health technology assessment organisations for trials published in English from 1988 to January 2014.
Eligibility criteria for selecting studies
Randomised controlled trials were selected for inclusion if they were published in English, included at least one antithrombotic treatment and involved patients with non-valvular atrial fibrillation eligible to receive anticoagulant therapy.
Results
For stroke or systemic embolism, dabigatran 150 mg and apixaban twice daily were associated with reductions relative to standard adjusted dose VKA, whereas low-dose ASA and the combination of clopidogrel plus low-dose ASA were associated with increases. Absolute risk reductions ranged from 6 fewer events per 1000 patients treated for dabigatran 150 mg twice daily to 15 more events for clopidogrel plus ASA. For major bleeding, edoxaban 30 mg daily, apixaban, edoxaban 60 mg daily and dabigatran 110 mg twice daily were associated with reductions compared to standard adjusted dose VKA. Absolute risk reductions with these agents ranged from 18 fewer per 1000 patients treated each year for edoxaban 30 mg daily to 24 more for medium dose ASA.
Conclusions
Compared with standard adjusted dose VKA, new oral anticoagulants were associated with modest reductions in the absolute risk of stroke and major bleeding. People on antiplatelet drugs experienced more strokes compared with anticoagulant drugs without any reduction in bleeding risk. To fully elucidate the comparative benefits and harms of antithrombotic agents across the various subpopulations, rigorously conducted comparative studies or network meta-regression analyses of patient-level data are required.
Systematic review registration number
PROSPERO registry—CRD42012002721.
doi:10.1136/bmjopen-2013-004301
PMCID: PMC4054633  PMID: 24889848
CARDIOLOGY; EPIDEMIOLOGY
3.  The Effect of Telephone Support Interventions on Coronary Artery Disease (CAD) Patient Outcomes during Cardiac Rehabilitation: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(5):e96581.
Background
Cardiac rehabilitation is offered to individuals after cardiac events to aid recovery and reduce the likelihood of further cardiac illness. However, patient participation remains suboptimal and the provision of high quality care to an expanding population of patients with chronic heart conditions is becoming increasingly difficult. A systematic review and meta-analysis was conducted to determine the effect of telephone support interventions compared with standard post-discharge care on coronary artery disease patient outcomes.
Methods
The Cochrane Library, MEDLINE, EMBASE, and CINAHL were searched and randomized controlled trials that directly compared telephone interventions with standard post-discharge care in adults following a myocardial infarction or a revascularization procedure were included. Study selection, data extraction and quality assessment were completed independently by two reviewers. Where appropriate, outcome data were combined and analyzed using a random effects model. For each dichotomous outcome, odds ratios (OR) and 95% confidence intervals (CI) were derived for each outcome. For continuous outcomes, weighted mean differences (WMD) and standardized mean differences (SMD) and 95% CI were calculated.
Results
26 studies met the inclusion criteria. No difference was observed in mortality between the telephone group and the group receiving standard care OR 1.12 (0.71, 1.77). The intervention was significantly associated with fewer hospitalizations than the comparison group OR 0.62 (0.40, 0.97). Significantly more participants in the telephone group stopped smoking OR 1.32 (1.07, 1.62); had lower systolic blood pressure WMD −0.22 (−0.40, −0.04); lower depression scores SMD −0.10 (−0.21, −0.00); and lower anxiety scores SMD −0.14 (−0.24, −0.04). However, no significant difference was observed for low-density lipoprotein levels WMD −0.10 (−0.23, 0.03).
Conclusions
Compared to standard post-discharge care, regular telephone support interventions may help reduce feelings of anxiety and depression as well as, improve systolic blood pressure control and the likelihood of smoking cessation.
doi:10.1371/journal.pone.0096581
PMCID: PMC4010507  PMID: 24798429
4.  Clinical characteristics associated with adverse events in patients with exacerbation of chronic obstructive pulmonary disease: a prospective cohort study 
Background:
To assist physicians with difficult decisions about hospital admission for patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) presenting in the emergency department, we sought to identify clinical characteristics associated with serious adverse events.
Methods:
We conducted this prospective cohort study in 6 large Canadian academic emergency departments. Patients were assessed for standardized clinical variables and then followed for serious adverse events, defined as death, intubation, admission to a monitored unit or new visit to the emergency department requiring admission.
Results:
We enrolled 945 patients, of whom 354 (37.5%) were admitted to hospital. Of 74 (7.8%) patients with a subsequent serious adverse event, 36 (49%) had not been admitted after the initial emergency visit. Multivariable modelling identified 5 variables that were independently associated with adverse events: prior intubation, initial heart rate ≥ 110/minute, being too ill to do a walk test, hemoglobin < 100 g/L and urea ≥ 12 mmol/L. A preliminary risk scale incorporating these and 5 other clinical variables produced risk categories ranging from 2.2% for a score of 0 to 91.4% for a score of 10. Using a risk score of 2 or higher as a threshold for admission would capture all patients with a predicted risk of adverse events of 7.2% or higher, while only slightly increasing admission rates, from 37.5% to 43.2%.
Interpretation:
In Canada, many patients with COPD suffer a serious adverse event or death after being discharged home from the emergency department. We identified high-risk characteristics and developed a preliminary risk scale that, once validated, could be used to stratify the likelihood of poor outcomes and to enable rational and safe admission decisions.
doi:10.1503/cmaj.130968
PMCID: PMC3971051  PMID: 24549125
5.  Risk stratification of adult emergency department syncope patients to predict short-term serious outcomes after discharge (RiSEDS) study 
Background
While Canadian ED physicians discharge most syncope patients with no specific further follow-up, approximately 5% will suffer serious outcomes after ED discharge. The goal of this study is to prospectively identify risk factors and to derive a clinical decision tool to accurately predict those at risk for serious outcomes after ED discharge within 30 days.
Methods/Design
We will conduct a prospective cohort study at 6 Canadian EDs to include adults with syncope and exclude patients with loss of consciousness > 5 minutes, mental status changes from baseline, obvious witnessed seizure, or head trauma prior to syncope. Emergency physicians will collect standardized clinical variables including historical features, physical findings, and results of immediately available tests (blood, ECG, and ED cardiac monitoring) prior to ED discharge/hospital admission. A second emergency physician will evaluate approximately 10% of study patients for interobserver agreement calculation of predictor variables. The primary outcome will be a composite serious outcome occurring within 30 days of ED discharge and includes three distinct categories: serious adverse events (death, arrhythmia); identification of serious underlying disease (structural heart disease, aortic dissection, pulmonary embolism, severe pulmonary hypertension, subarachnoid hemorrhage, significant hemorrhage, myocardial infarction); or procedures to treat the cause of syncope. The secondary outcome will be any of the above serious outcomes either suspected or those occurring in the ED. A blinded Adjudication Committee will confirm all serious outcomes. Univariate analysis will be performed to compare the predictor variables in patients with and without primary outcome. Variables with p-values <0.2 and kappa values ≥0.60 will be selected for stepwise logistic regression to identify the risk factors and to develop the clinical decision tool. We will enroll 5,000 patients (with 125 positive for primary outcome) for robust identification of risk factors and clinical decision tool development.
Discussion
Once successfully developed, this tool will accurately risk-stratify adult syncope patients; however, validation and implementation will still be required. This program of research should lead to standardized care of syncope patients, and improve patient safety.
doi:10.1186/1471-227X-14-8
PMCID: PMC4003802  PMID: 24629180
Syncope; Serious outcomes; Prognosis; Arrhythmia; Emergency department; Management
6.  Effect of an intervention to improve the cardiovascular health of family members of patients with coronary artery disease: a randomized trial 
Background:
Family members of patients with coronary artery disease (CAD) have higher risk of vascular events. We conducted a trial to determine if a family heart-health intervention could reduce their risk of CAD.
Methods:
We assessed coronary risk factors and randomized 426 family members of patients with CAD to a family heart-health intervention (n = 211) or control (n = 215). The intervention included feedback about risk factors, assistance with goal setting and counselling from health educators for 12 months. Reports were sent to the primary care physicians of patients whose lipid levels and blood pressure exceeded threshold values. All participants received printed materials about smoking cessation, healthy eating, weight management and physical activity; the control group received only these materials. The main outcomes (ratio of total cholesterol to high-density lipoprotein [HDL] cholesterol; physical activity; fruit and vegetable consumption) were assessed at 3 and 12 months. We examined group and time effects using mixed models analyses with the baseline values as covariates. The secondary outcomes were plasma lipid levels (total cholesterol, low-density lipoprotein cholesterol, HDL cholesterol and triglycerides); glucose level; blood pressure; smoking status; waist circumference; body mass index; and the use of blood pressure, lipid-lowering and smoking cessation medications.
Results:
We found no effect of the intervention on the ratio of total cholesterol to HDL cholesterol. However, participants in the intervention group reported consuming more fruit and vegetables (1.2 servings per day more after 3 mo and 0.8 servings at 12 mo; p < 0.001). There was a significant group by time interaction for physical activity (p = 0.03). At 3 months, those in the intervention group reported 65.8 more minutes of physical activity per week (95% confidence interval [CI] 47.0–84.7 min). At 12 months, participants in the intervention group reported 23.9 more minutes each week (95% CI 3.9–44.0 min).
Interpretation:
A health educator–led heart-health intervention did not improve the ratio of total cholesterol to HDL cholesterol but did increase reported physical activity and fruit and vegetable consumption among family members of patients with CAD. Hospitalization of a spouse, sibling or parent is an opportunity to improve cardiovascular health among other family members. Trial registration: clinicaltrials.gov, no NCT00552591.
doi:10.1503/cmaj.130550
PMCID: PMC3883820  PMID: 24246588
7.  Computed tomographic coronary angiography for patients with heart failure (CTA-HF): a randomized controlled trial (IMAGE HF Project 1-C) 
Trials  2013;14:443.
Background
The prevalence of heart failure (HF) is rising in industrialized and developing countries. Though invasive coronary angiography (ICA) remains the gold standard for anatomical assessment of coronary artery disease in HF patients, alternatives are being sought. Computed tomographic coronary angiography (CTA) has emerged as an accurate non-invasive diagnostic tool for coronary artery disease (CAD) and has been demonstrated to have prognostic value. Whether or not CTA can be used in HF patients is unknown. Acknowledging the aging population, the growing prevalence of HF and the increasing financial burden of healthcare, we need to identify non-invasive diagnostic tests that are available, safe, accurate and cost-effective.
Methods/Design
The proposed study aims to provide insight into the efficacy of CTA in HF patients. A multicenter randomized controlled trial will enroll 250 HF patients requiring coronary anatomical definition. Enrolled patients will be randomized to either CTA or ICA (n = 125 per group) as the first test to define coronary anatomy. The primary outcomes will be collected to determine downstream resource utilization. Secondary outcomes will include the composite clinical events and major adverse cardiac events. In addition, the accuracy of CTA for detecting coronary anatomy and obstruction will be assessed in patients who subsequently undergo both CTA and ICA. It is expected that CTA will be a more cost-effective strategy for diagnosis: yielding similar outcomes with fewer procedural risks and improved resource utilization.
Trial registration
ClinicalTrials.gov, NCT01283659
Team grant #CIF 99470
doi:10.1186/1745-6215-14-443
PMCID: PMC3895694  PMID: 24369097
8.  Routine versus selective cardiac magnetic resonance in non-ischemic heart failure – OUTSMART-HF: study protocol for a randomized controlled trial (IMAGE-HF (heart failure) project 1-B) 
Trials  2013;14:332.
Background
Imaging has become a routine part of heart failure (HF) investigation. Echocardiography is a first-line test in HF given its availability and it provides valuable diagnostic and prognostic information. Cardiac magnetic resonance (CMR) is an emerging clinical tool in the management of patients with non-ischemic heart failure. Current ACC/AHA/CCS/ESC guidelines advocate its role in the detection of a variety of cardiomyopathies but there is a paucity of high quality evidence to support these recommendations.
The primary objective of this study is to compare the diagnostic yield of routine cardiac magnetic resonance versus standard care (that is, echocardiography with only selective use of CMR) in patients with non-ischemic heart failure. The primary hypothesisis that the routine use of CMR will lead to a more specific diagnostic characterization of the underlying etiology of non-ischemic heart failure. This will lead to a reduction in the non-specific diagnoses of idiopathic dilated cardiomyopathy and HF with preserved ejection fraction.
Design
Tertiary care sites in Canada and Finland, with dedicated HF and CMR programs, will randomize consecutive patients with new or deteriorating HF to routine CMR or selective CMR. All patients will undergo a standard clinical echocardiogram and the interpreter will assign the most likely HF etiology. Those undergoing CMR will also have a standard examination and will be assigned a HF etiology based upon the findings. The treating physician’s impression about non-ischemic HF etiology will be collected following all baseline testing (including echo ± CMR). Patients will be followed annually for 4 years to ascertain clinical outcomes, quality of life and cost. The expected outcome is that the routine CMR arm will have a significantly higher rate of infiltrative, inflammatory, hypertrophic, ischemic and ‘other’ cardiomyopathy than the selective CMR group.
Discussion
This study will be the first multicenter randomized, controlled trial evaluating the role of CMR in non-ischemic HF. Non-ischemic HF patients will be randomized to routine CMR in order to determine whether there are any gains over management strategies employing selective CMR utilization. The insight gained from this study should improve appropriate CMR use in HF.
Trial registration
NCT01281384.
doi:10.1186/1745-6215-14-332
PMCID: PMC4016591  PMID: 24119686
Heart failure; Echocardiography; Cardiac magnetic resonance; Randomized controlled trial
9.  An individual patient meta-analysis of five randomized trials assessing the effects of cardiac resynchronization therapy on morbidity and mortality in patients with symptomatic heart failure 
European Heart Journal  2013;34(46):3547-3556.
Aims
Cardiac resynchronization therapy (CRT) with or without a defibrillator reduces morbidity and mortality in selected patients with heart failure (HF) but response can be variable. We sought to identify pre-implantation variables that predict the response to CRT in a meta-analysis using individual patient-data.
Methods and results
An individual patient meta-analysis of five randomized trials, funded by Medtronic, comparing CRT either with no active device or with a defibrillator was conducted, including the following baseline variables: age, sex, New York Heart Association class, aetiology, QRS morphology, QRS duration, left ventricular ejection fraction (LVEF), and systolic blood pressure. Outcomes were all-cause mortality and first hospitalization for HF or death. Of 3782 patients in sinus rhythm, median (inter-quartile range) age was 66 (58–73) years, QRS duration was 160 (146–176) ms, LVEF was 24 (20–28)%, and 78% had left bundle branch block. A multivariable model suggested that only QRS duration predicted the magnitude of the effect of CRT on outcomes. Further analysis produced estimated hazard ratios for the effect of CRT on all-cause mortality and on the composite of first hospitalization for HF or death that suggested increasing benefit with increasing QRS duration, the 95% confidence bounds excluding 1.0 at ∼140 ms for each endpoint, suggesting a high probability of substantial benefit from CRT when QRS duration exceeds this value.
Conclusion
QRS duration is a powerful predictor of the effects of CRT on morbidity and mortality in patients with symptomatic HF and left ventricular systolic dysfunction who are in sinus rhythm. QRS morphology did not provide additional information about clinical response.
ClinicalTrials.gov numbers
NCT00170300, NCT00271154, NCT00251251.
doi:10.1093/eurheartj/eht290
PMCID: PMC3855551  PMID: 23900696
Cardiac resynchronization therapy; Morbidity; Mortality; Heart failure
10.  A tutorial on sensitivity analyses in clinical trials: the what, why, when and how 
Background
Sensitivity analyses play a crucial role in assessing the robustness of the findings or conclusions based on primary analyses of data in clinical trials. They are a critical way to assess the impact, effect or influence of key assumptions or variations—such as different methods of analysis, definitions of outcomes, protocol deviations, missing data, and outliers—on the overall conclusions of a study.
The current paper is the second in a series of tutorial-type manuscripts intended to discuss and clarify aspects related to key methodological issues in the design and analysis of clinical trials.
Discussion
In this paper we will provide a detailed exploration of the key aspects of sensitivity analyses including: 1) what sensitivity analyses are, why they are needed, and how often they are used in practice; 2) the different types of sensitivity analyses that one can do, with examples from the literature; 3) some frequently asked questions about sensitivity analyses; and 4) some suggestions on how to report the results of sensitivity analyses in clinical trials.
Summary
When reporting on a clinical trial, we recommend including planned or posthoc sensitivity analyses, the corresponding rationale and results along with the discussion of the consequences of these analyses on the overall findings of the study.
doi:10.1186/1471-2288-13-92
PMCID: PMC3720188  PMID: 23855337
Sensitivity analysis; Clinical trials; Robustness
11.  Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) IMAGE HF Project I-A: study protocol for a randomized controlled trial 
Trials  2013;14:218.
Background
Ischemic heart disease (IHD) is the most common cause of heart failure (HF); however, the role of revascularization in these patients is still unclear. Consensus on proper use of cardiac imaging to help determine which candidates should be considered for revascularization has been hindered by the absence of clinical studies that objectively and prospectively compare the prognostic information of each test obtained using both standard and advanced imaging.
Methods/Design
This paper describes the design and methods to be used in the Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) multi-center trial. The primary objective is to compare the effect of HF imaging strategies on the composite clinical endpoint of cardiac death, myocardial infarction (MI), cardiac arrest and re-hospitalization for cardiac causes.
In AIMI-HF, patients with HF of ischemic etiology (n = 1,261) will follow HF imaging strategy algorithms according to the question(s) asked by the physicians (for example, Is there ischemia and/or viability?), in agreement with local practices. Patients will be randomized to either standard (SPECT, Single photon emission computed tomography) imaging modalities for ischemia and/or viability or advanced imaging modalities: cardiac magnetic resonance imaging (CMR) or positron emission tomography (PET). In addition, eligible and consenting patients who could not be randomized, but were allocated to standard or advanced imaging based on clinical decisions, will be included in a registry.
Discussion
AIMI-HF will be the largest randomized trial evaluating the role of standard and advanced imaging modalities in the management of ischemic cardiomyopathy and heart failure. This trial will complement the results of the Surgical Treatment for Ischemic Heart Failure (STICH) viability substudy and the PET and Recovery Following Revascularization (PARR-2) trial. The results will provide policy makers with data to support (or not) further investment in and wider dissemination of alternative ‘advanced’ imaging technologies.
Trial registration
NCT01288560
doi:10.1186/1745-6215-14-218
PMCID: PMC3729711  PMID: 23866673
12.  Systematic reviews need to consider applicability to disadvantaged populations: inter-rater agreement for a health equity plausibility algorithm 
Background
Systematic reviews have been challenged to consider effects on disadvantaged groups. A priori specification of subgroup analyses is recommended to increase the credibility of these analyses. This study aimed to develop and assess inter-rater agreement for an algorithm for systematic review authors to predict whether differences in effect measures are likely for disadvantaged populations relative to advantaged populations (only relative effect measures were addressed).
Methods
A health equity plausibility algorithm was developed using clinimetric methods with three items based on literature review, key informant interviews and methodology studies. The three items dealt with the plausibility of differences in relative effects across sex or socioeconomic status (SES) due to: 1) patient characteristics; 2) intervention delivery (i.e., implementation); and 3) comparators. Thirty-five respondents (consisting of clinicians, methodologists and research users) assessed the likelihood of differences across sex and SES for ten systematic reviews with these questions. We assessed inter-rater reliability using Fleiss multi-rater kappa.
Results
The proportion agreement was 66% for patient characteristics (95% confidence interval: 61%-71%), 67% for intervention delivery (95% confidence interval: 62% to 72%) and 55% for the comparator (95% confidence interval: 50% to 60%). Inter-rater kappa, assessed with Fleiss kappa, ranged from 0 to 0.199, representing very low agreement beyond chance.
Conclusions
Users of systematic reviews rated that important differences in relative effects across sex and socioeconomic status were plausible for a range of individual and population-level interventions. However, there was very low inter-rater agreement for these assessments. There is an unmet need for discussion of plausibility of differential effects in systematic reviews. Increased consideration of external validity and applicability to different populations and settings is warranted in systematic reviews to meet this need.
doi:10.1186/1471-2288-12-187
PMCID: PMC3552943  PMID: 23253632
Systematic reviews; Applicability; Health equity; Sex and gender; Socioeconomic status
13.  The implementation of a community-based aerobic walking program for mild to moderate knee osteoarthritis: A knowledge translation randomized controlled trial: Part II: Clinical outcomes 
BMC Public Health  2012;12:1073.
Background
Osteoarthritis (OA) is the most common joint disorder in the world, as it is appears to be prevalent among 80% of individuals over the age of 75. Although physical activities such as walking have been scientifically proven to improve physical function and arthritic symptoms, individuals with OA tend to adopt a sedentary lifestyle. There is therefore a need to improve knowledge translation in order to influence individuals to adopt effective self-management interventions, such as an adapted walking program.
Methods
A single-blind, randomized control trial was conducted. Subjects (n = 222) were randomized to one of three knowledge translation groups: 1) Walking and Behavioural intervention (WB) (18 males, 57 females) which included the supervised community-based aerobic walking program combined with a behavioural intervention and an educational pamphlet on the benefits of walking; 2) Walking intervention (W) (24 males, 57 females) wherein participants only received the supervised community-based aerobic walking program intervention and the educational pamphlet; 3) Self-directed control (C) (32 males, 52 females) wherein participants only received the educational pamphlet. One-way analyses of variance were used to test for differences in quality of life, adherence, confidence, and clinical outcomes among the study groups at each 3 month assessment during the 12-month intervention period and 6-month follow-up period.
Results
The clinical and quality of life outcomes improved among participants in each of the three comparative groups. However, there were few statistically significant differences observed for quality of life and clinical outcomes at long-term measurements at 12-months end of intervention and at 6- months post intervention (18-month follow-up). Outcome results varied among the three groups.
Conclusion
The three groups were equivalent when determining the effectiveness of knowledge uptake and improvements in quality of life and other clinical outcomes. OA can be managed through the implementation of a proven effective walking program in existing community-based walking clubs.
Trial registration
Current Controlled Trials IRSCTNO9193542
doi:10.1186/1471-2458-12-1073
PMCID: PMC3529193  PMID: 23234575
Osteoarthritis; Clinical trial; Walking; Compliance; Adherence; Education; Behavioural intervention; Guidelines implementation; Knowledge translation
14.  Nitric oxide and nitrous oxide turnover in natural and engineered microbial communities: biological pathways, chemical reactions, and novel technologies 
Nitrous oxide (N2O) is an environmentally important atmospheric trace gas because it is an effective greenhouse gas and it leads to ozone depletion through photo-chemical nitric oxide (NO) production in the stratosphere. Mitigating its steady increase in atmospheric concentration requires an understanding of the mechanisms that lead to its formation in natural and engineered microbial communities. N2O is formed biologically from the oxidation of hydroxylamine (NH2OH) or the reduction of nitrite (NO−2) to NO and further to N2O. Our review of the biological pathways for N2O production shows that apparently all organisms and pathways known to be involved in the catabolic branch of microbial N-cycle have the potential to catalyze the reduction of NO−2 to NO and the further reduction of NO to N2O, while N2O formation from NH2OH is only performed by ammonia oxidizing bacteria (AOB). In addition to biological pathways, we review important chemical reactions that can lead to NO and N2O formation due to the reactivity of NO−2, NH2OH, and nitroxyl (HNO). Moreover, biological N2O formation is highly dynamic in response to N-imbalance imposed on a system. Thus, understanding NO formation and capturing the dynamics of NO and N2O build-up are key to understand mechanisms of N2O release. Here, we discuss novel technologies that allow experiments on NO and N2O formation at high temporal resolution, namely NO and N2O microelectrodes and the dynamic analysis of the isotopic signature of N2O with quantum cascade laser absorption spectroscopy (QCLAS). In addition, we introduce other techniques that use the isotopic composition of N2O to distinguish production pathways and findings that were made with emerging molecular techniques in complex environments. Finally, we discuss how a combination of the presented tools might help to address important open questions on pathways and controls of nitrogen flow through complex microbial communities that eventually lead to N2O build-up.
doi:10.3389/fmicb.2012.00372
PMCID: PMC3478589  PMID: 23109930
isotopic signature; microsensors; molecular tools; dinitrogen oxide; nitrogen monoxide; pathway identification; quantum cascade laser absorption spectroscopy (QCLAS); site preference
15.  The implementation of a community-based aerobic walking program for mild to moderate knee osteoarthritis (OA): a knowledge translation (KT) randomized controlled trial (RCT): Part I: The Uptake of the Ottawa Panel clinical practice guidelines (CPGs) 
BMC Public Health  2012;12:871.
Background
The implementation of evidence based clinical practice guidelines on self-management interventions to patients with chronic diseases is a complex process. A multifaceted strategy may offer an effective knowledge translation (KT) intervention to promote knowledge uptake and improve adherence in an effective walking program based on the Ottawa Panel Evidence Based Clinical Practice Guidelines among individuals with moderate osteoarthritis (OA).
Methods
A single-blind, randomized control trial was conducted. Patients with mild to moderate (OA) of the knee (n=222) were randomized to one of three KT groups: 1) Walking and Behavioural intervention (WB) (18 males, 57 females) which included the supervised community-based aerobic walking program combined with a behavioural intervention and an educational pamphlet on the benefits of walking for OA; 2) Walking intervention (W) (24 males, 57 females) wherein participants only received the supervised community-based aerobic walking program intervention and the educational pamphlet; 3) Self-directed control (C) (32 males, 52 females) wherein participants only received the educational pamphlet. One-way analyses of variance were used to test for differences in quality of life, adherence, confidence, and clinical outcomes among the study groups at each 3 month assessment during the 12-month intervention period and 6-month follow-up period.
Results
Short-term program adherence was greater in WB compared to C (p<0.012) after 3 months. No statistical significance (p> 0.05) was observed for long-term adherence (6 to 12 months), and total adherence between the three groups. The three knowledge translation strategies demonstrated equivalent long-term results for the implementation of a walking program for older individuals with moderate OA. Lower dropout rates as well as higher retention rates were observed for WB at 12 and 18 months.
Conclusion
The additional knowledge translation behavioural component facilitated the implementation of clinical practice guidelines on walking over a short-term period. More studies are needed to improve the long-term walking adherence or longer guidelines uptake on walking among participants with OA. Particular attention should be taken into account related to patient’s characteristic and preference. OA can be managed through the implementation of a walking program based on clinical practice guidelines in existing community-based walking clubs as well as at home with the minimal support of an exercise therapist or a trained volunteer.
Trial Registration
Current Controlled Trials IRSCTNO9193542
doi:10.1186/1471-2458-12-871
PMCID: PMC3491047  PMID: 23061875
Osteoarthritis; Clinical trial; Walking; Adherence; Education; Behavioural intervention; Guidelines implementation; Knowledge translation
16.  Quality of cardiovascular disease care in Ontario, Canada: missed opportunities for prevention - a cross sectional study 
Background
Primary care plays a key role in the prevention and management of cardiovascular disease (CVD). We examined primary care practice adherence to recommended care guidelines associated with the prevention and management of CVD for high risk patients.
Methods
We conducted a secondary analysis of cross-sectional baseline data collected from 84 primary care practices participating in a large quality improvement initiative in Eastern Ontario from 2008 to 2010. We collected medical chart data from 4,931 patients who either had, or were at high risk of developing CVD to study adherence rates to recommended guidelines for CVD care and to examine the proportion of patients at target for clinical markers such as blood pressure, lipid levels and hemoglobin A1c.
Results
Adherence to preventive care recommendations was poor. Less than 10% of high risk patients received a waistline measurement, half of the smokers received cessation advice, and 7.7% were referred to a smoking cessation program. Gaps in care exist for diabetes and kidney disease as 54.9% of patients with diabetes received recommended hemoglobin-A1c screenings, and only 55.8% received an albumin excretion test. Adherence rates to recommended guidelines for coronary artery disease, hypertension, and dyslipidemia were high (>75%); however <50% of patients were at target for blood pressure or LDL-cholesterol levels (37.1% and 49.7% respectively), and only 59.3% of patients with diabetes were at target for hemoglobin-A1c.
Conclusions
There remain significant opportunities for primary care providers to engage high risk patients in prevention activities such as weight management and smoking cessation. Despite high adherence rates for hypertension, dyslipidemia, and coronary artery disease, a significant proportion of patients failed to meet treatment targets, highlighting the complexity of caring for people with multiple chronic conditions.
Trial Registration
NCT00574808
doi:10.1186/1471-2261-12-74
PMCID: PMC3477034  PMID: 22970753
Cardiovascular disease; Primary care; Diabetes; Evidence-based care; Preventive care; Quality of care
17.  Global Biodiversity of Aquatic Ammonia-Oxidizing Archaea is Partitioned by Habitat 
Archaea play an important role in nitrification and are, thus, inextricably linked to the global carbon and nitrogen cycles. Since the initial discovery of an ammonia monooxygenase α-subunit (amoA) gene associated with an archaeal metagenomic fragment, archaeal amoA sequences have been detected in a wide variety of nitrifying environments. Recent sequencing efforts have revealed extensive diversity of archaeal amoA sequences within different habitats. In this study, we have examined over 8000 amoA sequences from the literature and public databases in an effort to understand the ecological factors influencing the distribution and diversity of ammonia-oxidizing archaea (AOA), with a particular focus on sequences from aquatic habitats. This broad survey provides strong statistical support for the hypothesis that different environments contain distinct clusters of AOA amoA sequences, as surprisingly few sequences are found in more than one habitat type. Within aquatic environments, salinity, depth in the water column, and temperature were significantly correlated with the distribution of sequence types. These findings support the existence of multiple distinct aquatic AOA populations in the environment and suggest some possible selective pressures driving the partitioning of AOA amoA diversity.
doi:10.3389/fmicb.2012.00252
PMCID: PMC3399221  PMID: 22826704
biogeography; ammonia-oxidizing archaea; nitrification; Thaumarchaeota; amoA
18.  Changes in Body Weight and Psychotropic Drugs: A Systematic Synthesis of the Literature 
PLoS ONE  2012;7(6):e36889.
Introduction
Psychotropic medication use is associated with weight gain. While there are studies and reviews comparing weight gain for psychotropics within some classes, clinicians frequently use drugs from different classes to treat psychiatric disorders.
Objective
To undertake a systematic review of all classes of psychotropics to provide an all encompassing evidence-based tool that would allow clinicians to determine the risks of weight gain in making both intra-class and interclass choices of psychotropics.
Methodology and Results
We developed a novel hierarchical search strategy that made use of systematic reviews that were already available. When such evidence was not available we went on to evaluate randomly controlled trials, followed by cohort and other clinical trials, narrative reviews, and, where necessary, clinical opinion and anecdotal evidence. The data from the publication with the highest level of evidence based on our hierarchical classification was presented. Recommendations from an expert panel supplemented the evidence used to rank these drugs within their respective classes. Approximately 9500 articles were identified in our literature search of which 666 citations were retrieved. We were able to rank most of the psychotropics based on the available evidence and recommendations from subject matter experts. There were few discrepancies between published evidence and the expert panel in ranking these drugs.
Conclusion
Potential for weight gain is an important consideration in choice of any psychotropic. This tool will help clinicians select psychotropics on a case-by-case basis in order to minimize the impact of weight gain when making both intra-class and interclass choices.
doi:10.1371/journal.pone.0036889
PMCID: PMC3376099  PMID: 22719834
19.  Smoking status and sex as indicators of differences in 2582 obese patients presenting for weight management 
Background
Smoking remains the most common preventable cause of death. Very little tobacco exposure can increase cardiovascular disease risk. The relationship between smoking, sex, and weight remains unclear.
Methods
Between September 1992 and June 2007, 2582 consenting patients starting the Ottawa Hospital Weight Management program were grouped by sex and smoking status. “Former smokers” (771 females, 312 males) had quit for at least 1 year. “Smokers” (135 females, 54 males) smoked > 9 cigarettes daily. There were 979 females and 331 males who never smoked. Using SAS 9.2 statistical software, the prevalence of coronary artery disease (CAD), type 2 diabetes (T2DM), major depressive disorder (MDD), and medication use among the groups was compared (Chi-square [χ2]). Anthropometric measurements, lipid, glucose and thyroid levels were compared using analysis of variance (ANOVA). Interactions were assessed using 2-way ANOVA analysis for continuous data, and logistic regression for discrete data.
Results
Smokers were more likely to have MDD (χ2), lower high-density lipoprotein levels and higher triglyceride levels than other groups. Former smokers had a greater prevalence of CAD, T2DM on pharmacotherapy, and impaired fasting glucose than other groups. They were also more likely to be taking lipid-lowering agents and antihypertensives (χ2). Never smokers had less MDD, CAD, and were less likely to be on antidepressants than the other groups. Males were more likely to have CAD and T2DM than females. Females were more likely to have MDD than males. Interactions between smoking status and sex were found for age, weight, fasting glucose and thyroid-stimulating hormone levels.
Conclusion
Obese never smokers suffer from the fewest chronic diseases. Obese former smokers have a greater prevalence of CAD, T2DM on pharmacotherapy, and impaired fasting glucose than other groups. Thus, clinicians and researchers should avoid combining former smokers with never smokers as “nonsmokers” in research and treatment decisions. The results of this study call for a longitudinal study comparing these groups over the weight management program.
doi:10.2147/VHRM.S30089
PMCID: PMC3363146  PMID: 22661896
smoking status; weight management; obesity
20.  A Genome Wide Association Study for Coronary Artery Disease Identifies a Novel Susceptibility Locus in the Major Histocompatibility Complex 
Background
Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with CAD and/or MI risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered.
Methods and Results
We performed a discovery meta-analysis of 5 GWASs involving 13,949 subjects (7123 cases, 6826 controls) imputed at approximately 5 million SNPs using pilot 1000 Genomes based haplotypes. Promising loci were followed up in an additional 5 studies with 11,032 subjects (5211 cases, 5821 controls). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome wide significance in the combined analysis (rs3869109; pdiscovery=3.3×10−7, preplication=5.3×10−4 pcombined=1.12×10−9). A sub-analysis combining discovery GWASs showed an attenuation of significance when stringent corrections for European population structure were employed (p=4.1×10-10 versus 3.2×10-7) suggesting the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity and self cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association.
Conclusions
We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).
doi:10.1161/CIRCGENETICS.111.961243
PMCID: PMC3335297  PMID: 22319020
coronary artery disease; myocardial infarction; meta-analysis; genetics
21.  A Genome Wide Association Study for Coronary Artery Disease Identifies a Novel Susceptibility Locus in the Major Histocompatibility Complex 
Background
Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with CAD and/or MI risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered.
Methods and Results
We performed a discovery meta-analysis of 5 GWASs involving 13,949 subjects (7123 cases, 6826 controls) imputed at approximately 5 million SNPs using pilot 1000 Genomes based haplotypes. Promising loci were followed up in an additional 5 studies with 11,032 subjects (5211 cases, 5821 controls). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome wide significance in the combined analysis (rs3869109; pdiscovery=3.3×10−7, preplication=5.3×10−4 pcombined=1.12×10−9). A sub-analysis combining discovery GWASs showed an attenuation of significance when stringent corrections for European population structure were employed (p=4.1×10−10 versus 3.2×10−7) suggesting the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity and self cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association.
Conclusion
We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).
doi:10.1161/CIRCGENETICS.111.961243
PMCID: PMC3335297  PMID: 22319020
Coronary Artery Disease; Myocardial Infarction; Meta-Analysis; Genetics
22.  Does Consideration and Assessment of Effects on Health Equity Affect the Conclusions of Systematic Reviews? A Methodology Study 
PLoS ONE  2012;7(3):e31360.
Introduction
Tackling health inequities both within and between countries remains high on the agenda of international organizations including the World Health Organization and local, regional and national governments. Systematic reviews can be a useful tool to assess effects on equity in health status because they include studies conducted in a variety of settings and populations. This study aims to describe the extent to which the impacts of health interventions on equity in health status are considered in systematic reviews, describe methods used, and assess the implications of their equity related findings for policy, practice and research.
Methods
We conducted a methodology study of equity assessment in systematic reviews. Two independent reviewers extracted information on the reporting and analysis of impacts of health interventions on equity in health status in a group of 300 systematic reviews collected from all systematic reviews indexed in one month of MEDLINE, using a pre-tested data collection form. Any differences in data extraction were resolved by discussion.
Results
Of the 300 systematic reviews, 224 assessed the effectiveness of interventions on health outcomes. Of these 224 reviews, 29 systematic reviews assessed effects on equity in health status using subgroup analysis or targeted analyses of vulnerable populations. Of these, seven conducted subgroup analyses related to health equity which were reported in insufficient detail to judge their credibility. Of these 29 reviews, 18 described implications for policy and practice based on assessment of effects on health equity.
Conclusion
The quality and completeness of reporting should be enhanced as a priority, because without this policymakers and practitioners will continue lack the evidence base they need to inform decision-making about health inequity. Furthermore, there is a need to develop methods to systematically consider impacts on equity in health status that is currently lacking in systematic reviews.
doi:10.1371/journal.pone.0031360
PMCID: PMC3302723  PMID: 22427804
23.  American College of Rheumatology/European League against Rheumatism Preliminary Definition of Remission in Rheumatoid Arthritis for Clinical Trials 
Arthritis and rheumatism  2011;63(3):573-586.
Background
With remission in rheumatoid arthritis (RA) an increasingly attainable goal, there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome in clinical trials.
Methods
A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism and the Outcome Measures in Rheumatology Initiative (OMERACT) met to guide the process and review prespecified analyses from clinical trials of patients with RA. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures to define remission including at least joint counts and an acute phase reactant. Members were surveyed to select the level of each core set measure consistent with remission. Candidate definitions of remission were tested including those that constituted a number of individual measures in remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analyzed to examine the added contribution of patient reported outcomes and the ability of candidate measures to predict later good x-ray and functional outcomes.
Results
Survey results for the definition of remission pointed to indexes at published thresholds and to a count of core set measures with each measure scored as 1 or less (e.g. tender and swollen joint counts, CRP and global assessments on 0-10 scale). Analyses suggested the need to include a patient reported measure. Examination of 2 year follow-up data suggested that many candidate definitions performed comparably in terms of predicting later good x-ray and functional outcomes, although DAS28 based measures of remission did not predict good radiographic outcomes as well as did the other candidate definitions. Given these and other considerations, we propose that a patient be defined as in remission based on one of two definitions : 1: When their scores on the following measures are all <1: tender joint count, swollen joint count, CRP (in mg/dL) and patient global assessment (0-10 scale), OR 2: when their score on the SDAI is < 3.3.
Conclusion
We propose two new definitions of remission both of which can be uniformly applied and widely used in RA clinical trials. We recommend that one of these be selected in each trial as an outcome and that the results on both be reported in each trial.
doi:10.1002/art.30129
PMCID: PMC3115717  PMID: 21294106
24.  Improved Prediction of Cardiovascular Disease Based on a Panel of Single Nucleotide Polymorphisms Identified Through Genome-Wide Association Studies 
Background
Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) at multiple loci that are significantly associated with coronary artery disease (CAD) risk. In this study, we sought to determine and compare the predictive capabilities of 9p21.3 alone and a panel of SNPs identified and replicated through GWAS for CAD.
Methods and Results
We used the Ottawa Heart Genomics Study (OHGS) (3323 cases, 2319 control subjects) and the Wellcome Trust Case Control Consortium (WTCCC) (1926 cases, 2938 control subjects) data sets. We compared the ability of allele counting, logistic regression, and support vector machines. Two sets of SNPs, 9p21.3 alone and a set of 12 SNPs identified by GWAS and through a model-fitting procedure, were considered. Performance was assessed by measuring area under the curve (AUC) for OHGS using 10-fold cross-validation and WTCCC as a replication set. AUC for logistic regression using OHGS increased significantly from 0.555 to 0.608 (P=3.59×10–14) for 9p21.3 versus the 12 SNPs, respectively. This difference remained when traditional risk factors were considered in a subgroup of OHGS (1388 cases, 2038 control subjects), with AUC increasing from 0.804 to 0.809 (P=0.037). The added predictive value over and above the traditional risk factors was not significant for 9p21.3 (AUC 0.801 versus 0.804, P=0.097) but was for the 12 SNPs (AUC 0.801 versus 0.809, P=0.0073). Performance was similar between OHGS and WTCCC. Logistic regression outperformed both support vector machines and allele counting.
Conclusions
Using the collective of 12 SNPs confers significantly greater predictive capabilities for CAD than 9p21.3, whether traditional risks are or are not considered. More accurate models probably will evolve as additional CAD-associated SNPs are identified.
doi:10.1161/CIRCGENETICS.110.946269
PMCID: PMC3035486  PMID: 20729558
coronary disease; genetics; risk factors
25.  Large-scale association analyses identifies 13 new susceptibility loci for coronary artery disease 
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Nature genetics  2011;43(4):333-338.
We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 cases and 64,762 controls of European descent, followed by genotyping of top association signals in 60,738 additional individuals. This genomic analysis identified 13 novel loci harboring one or more SNPs that were associated with CAD at P<5×10−8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 novel loci displayed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6 to 17 percent increase in the risk of CAD per allele. Notably, only three of the novel loci displayed significant association with traditional CAD risk factors, while the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the novel CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
doi:10.1038/ng.784
PMCID: PMC3119261  PMID: 21378990

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