Search

Cohort studies have identified several genetic determinants that could predict the clinical response to allopurinol. However, they have not been commonly used for genome-wide investigations to identify genetic determinants on allopurinol metabolism and concentrations. We conducted a genome-wide association study of a prior cross-sectional investigation of patients from the Montreal Heart Institute Biobank undergoing allopurinol therapy. Four endpoints were investigated, namely plasma concentrations of oxypurinol, the active metabolite of allopurinol, allopurinol, and allopurinol-riboside, as well as allopurinol daily dosing. A total of 439 participants (mean age 69.4 years; 86.4% male) taking allopurinol (mean daily dose 194.5 mg) and who had quantifiable oxypurinol concentrations were included in the genome-wide analyses. Participants presented with multiple comorbidities and received concomitant cardiovascular medications. No association achieved the predefined genome-wide threshold values for any of the endpoints (all p > 5 × 10−8). Our results are consistent with prior findings regarding the difficulty in identifying genetic determinants of drug concentrations or pharmacokinetics of allopurinol and its metabolites, as well as allopurinol daily dosing. Given the size of this genome-wide study, collaborative investigations involving larger and diverse cohorts may be required to further identify pharmacogenomic determinants of allopurinol and measure their clinical relevance to personalize allopurinol therapy. [ABSTRACT FROM AUTHOR]

Une meilleure integration des pratiques cliniques preventives (PCP) (a) dans la pratique medicale permettrait de reduire la morbidite et la mortalite liees a certaines maladies evitables (1). Pour soutenir cette [...], Objectives: Present a picture of physicians' preventive clinical practices (PCP) at a university medical centre, and identify the obstacles that hinder their implementation. Method: Self-administered questionnaire survey addressed to 367 general practitioners and specialists working at the Centre hospitalier de l'Universite de Montreal (CHUM) in 2006. Results: Respondents claim to be recommending PCP (often or very often) in approximately 60-82% of cases. Women physicians report a larger integration for screening and vaccination (p Conclusion: Despite observed encouraging results, actions must be taken to improve the integration of PCP to general and specialized health care and to bring physicians around to adopting healthy lifestyle habits themselves. Key words: Clinical prevention; preventive clinical practices; preventive clinical practice guidelines; preventive practice obstacles Objectifs : Decrire le portrait de la prestation des pratiques cliniques preventives (PCP) des medecins d'un centre hospitalier universitaire et identifier les barrieres a leur mise en oeuvre. Methode : Enquete par questionnaire auto-administre aupres de 367 medecins generalistes et specialistes oeuvrant au Centre hospitalier de l'Universite de Montreal (CHUM) en 2006. Resultats : Les repondants disent effectuer ou recommander les PCP (souvent ou tres souvent) dans environ 60 a 82 % des cas. Les femmes medecins rapportent une plus grande integration du depistage et de la vaccination (p Conclusion : Malgre les resultats encourageants observes, des actions doivent etre entreprises pour ameliorer l'integration des PCP aux soins generaux et specialises et pour amener les medecins eux-memes a adopter de saines habitudes de vie. Mots cles : prevention clinique; pratiques cliniques preventives; guide de pratiques cliniques preventives; barrieres aux pratiques preventives

Aims: The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme consisted of three parallel, randomized, double‐blind clinical trials comparing candesartan with placebo in patients with heart failure (HF) categorized according to left ventricular ejection fraction and tolerability to an angiotensin‐converting enzyme inhibitor. We conducted a pharmacogenomic study of the CHARM trials with the objective of identifying genetic predictors of HF progression and of the efficacy and safety of treatment with candesartan. Methods: We performed genome‐wide association studies in 2727 patients of European ancestry from CHARM‐Overall and stratified by CHARM study according to preserved and reduced ejection fraction and according to assignment to the interventional treatment with candesartan. We tested genetic association with the composite endpoint of cardiovascular death or hospitalization for heart failure for drug efficacy in candesartan‐treated patients and for HF progression using patients from both candesartan and placebo arms. The safety endpoints for response to candesartan were hyperkalaemia, renal dysfunction, hypotension, and change in systolic blood pressure between baseline and 6 weeks of treatment. To support our observations, we conducted a genome‐wide gene‐level collapsing analysis from whole‐exome sequencing data with the composite cardiovascular endpoint. Results: We found that the A allele (14% allele frequency) of the genetic variant rs66886237 at 8p21.3 near the gene GFRA2 was associated with the composite cardiovascular endpoint in 1029 HF patients with preserved ejection fraction from the CHARM‐Preserved study (hazard ratio: 1.91, 95% confidence interval: 1.55–2.35; P = 1.7 × 10−9). The association was independent of candesartan treatment, and the genetic variant was not associated with the cardiovascular endpoint in patients with reduced ejection fraction. None of the genome‐wide association studies for candesartan safety or efficacy conducted in patients treated with candesartan passed the significance threshold. We found no significant association from the gene‐level collapsing analysis. Conclusions: We have identified a candidate genetic variant potentially predictive of the progression of heart failure in patients with preserved ejection fraction. The findings require further replication, and we cannot exclude the possibility that the results may be chance findings. [ABSTRACT FROM AUTHOR]

Introduction In mammals, dosage compensation of X-linked genes in females is achieved by the transcriptional silencing of 1 of the 2 X chromosomes during early development, a process known as [...], Skewing of X chromosome inactivation (XCI) can occur in normal females and increases in tissues with age. The mechanisms underlying skewing in normal females, however, remain controversial. To better understand the phenomenon of XCI in nondisease states, we evaluated XCI patterns in epithelial and hematopoietic cells of over 500 healthy female mother-neonate pairs. The incidence of skewing observed in mothers was twice that observed in neonates, and in both cohorts, the incidence of XCI was lower in epithelial cells than hematopoietic cells. These results suggest that XCI incidence varies by tissue type and that age-dependent mechanisms can influence skewing in both epithelial and hematopoietic cells. In both cohorts, a correlation was identified in the direction of skewing in epithelial and hematopoietic cells, suggesting common underlying skewing mechanisms across tissues. However, there was no correlation between the XCI patterns of mothers and their respective neonates, and skewed mothers gave birth to skewed neonates at the same frequency as nonskewed mothers. Taken together, our data suggest that in humans, the XCI pattern observed at birth does not reflect a single heritable genetic locus, but rather corresponds to a complex trait determined, at least in part, by selection biases occurring after XCI.

Abstract Background The goal of this project is to evaluate the implementation of an integrated and interdisciplinary program for prevention and management of cardiometabolic risk (PCMR). The intervention is based on the Chronic Care Model. The study will evaluate the implementation of the PCMR in 6 of the 12 health and social services centres (CSSS) in Montréal, and the effects of the PCMR on patients and the practice of their primary care physicians up to 40 months following implementation, as well as the sustainability of the program. Objectives are: 1-to evaluate the effects of the PCMR and their persistence on patients registered in the program and the practice of their primary care physicians, by implementation site and degree of exposure to the program; 2-to assess the degree of implementation of PCMR in each CSSS territory and identify related contextual factors; 3-to establish the relationships between the effects observed, the degree of PCMR implementation and the related contextual factors; 4-to assess the impact of the PCMR on strengthening local services networks. Methods/Design The evaluation will use a mixed design that includes two complementary research strategies. The first strategy is similar to a quasi-experimental "before-after" design, based on a quantitative approach; it will look at the program's effects and their variations among the six territories. The effects analysis will use data from a clinical database and from questionnaires completed by participating patients and physicians. Over 3000 patients will be recruited. The second strategy corresponds to a multiple case study approach, where each of the six CSSS constitutes a case. With this strategy, qualitative methods will set out the context of implementation using data from semi-structured interviews with program managers. The quantitative data will be analyzed using linear or multilevel models complemented with an interpretive approach to qualitative data analysis. Discussion Our study will identify contextual factors associated with the effectiveness, successful implementation and sustainability of such a program. The contextual information will enable us to extrapolate our results to other contexts with similar conditions. Trial registration ClinicalTrials.gov: NCT01326130

Abstract Background The Canadian healthcare system is currently experiencing important organizational transformations through the reform of primary healthcare (PHC). These reforms vary in scope but share a common feature of proposing the transformation of PHC organizations by implementing new models of PHC organization. These models vary in their performance with respect to client affiliation, utilization of services, experience of care and perceived outcomes of care. Objectives In early 2005 we conducted a study in the two most populous regions of Quebec province (Montreal and Montérégie) which assessed the association between prevailing models of primary healthcare (PHC) and population-level experience of care. The goal of the present research project is to track the evolution of PHC organizational models and their relative performance through the reform process (from 2005 until 2010) and to assess factors at the organizational and contextual levels that are associated with the transformation of PHC organizations and their performance. Methods/Design This study will consist of three interrelated surveys, hierarchically nested. The first survey is a population-based survey of randomly-selected adults from two populous regions in the province of Quebec. This survey will assess the current affiliation of people with PHC organizations, their level of utilization of healthcare services, attributes of their experience of care, reception of preventive and curative services and perception of unmet needs for care. The second survey is an organizational survey of PHC organizations assessing aspects related to their vision, organizational structure, level of resources, and clinical practice characteristics. This information will serve to develop a taxonomy of organizations using a mixed methods approach of factorial analysis and principal component analysis. The third survey is an assessment of the organizational context in which PHC organizations are evolving. The five year prospective period will serve as a natural experiment to assess contextual and organizational factors (in 2005) associated with migration of PHC organizational models into new forms or models (in 2010) and assess the impact of this evolution on the performance of PHC. Discussion The results of this study will shed light on changes brought about in the organization of PHC and on factors associated with these changes.

Aims: Few investigations have been conducted to identify genetic determinants of common, polygenetic forms of heart failure (HF), and only a limited number of these genetic associations have been validated by multiple groups. Methods and results: We performed a case–control study to further investigate the potential impact of 14 previously reported candidate genes on the risk of HF and specific HF sub‐types. We also performed an exploratory genome‐wide study. We included 799 patients with HF and 1529 controls. After adjusting for age, sex, and genetic ancestry, we found that the C allele of rs2234962 in BAG3 was associated with a decreased risk of idiopathic dilated cardiomyopathy (odds ratio 0.42, 95% confidence interval 0.25–0.68, P = 0.0005), consistent with a previous report. No association for the other primary variants or exploratory genome‐wide study was found. Conclusions: Our findings provide independent replication for the association between a common coding variant (rs2234962) in BAG3 and the risk of idiopathic dilated cardiomyopathy. [ABSTRACT FROM AUTHOR]

Background: Naturally occurring human genetic variants provide a valuable tool to identify drug targets and guide drug prioritization and clinical trial design. Ivabradine is a heart rate lowering drug with protective effects on heart failure despite increasing the risk of atrial fibrillation. In patients with coronary artery disease without heart failure, the drug does not protect against major cardiovascular adverse events prompting questions about the ability of genetics to have predicted those effects. This study evaluates the effect of a variant in HCN4, ivabradine's drug target, on safety and efficacy endpoints. Methods: We used genetic association testing and Mendelian randomization to predict the effect of ivabradine and heart rate lowering on cardiovascular outcomes. Results: Using data from the UK Biobank and large GWAS consortia, we evaluated the effect of a heart rate-reducing genetic variant at the HCN4 locus encoding ivabradine's drug target. These genetic association analyses showed increases in risk for atrial fibrillation (OR 1.09, 95% CI: 1.06–1.13, P = 9.3 ×10−9) in the UK Biobank. In a cause-specific competing risk model to account for the increased risk of atrial fibrillation, the HCN4 variant reduced incident heart failure in participants that did not develop atrial fibrillation (HR 0.90, 95% CI: 0.83–0.98, P = 0.013). In contrast, the same heart rate reducing HCN4 variant did not prevent a composite endpoint of myocardial infarction or cardiovascular death (OR 0.99, 95% CI: 0.93–1.04, P = 0.61). Conclusion: Genetic modelling of ivabradine recapitulates its benefits in heart failure, promotion of atrial fibrillation, and neutral effect on myocardial infarction. [ABSTRACT FROM AUTHOR]

Approximately 1% of people worldwide carry a copy of the human herpesvirus 6A or 6B (HHV-6A/B) in every cell of their body. This condition is referred to as inherited chromosomally integrated HHV-6A/B (iciHHV-6A/B). The mechanisms leading to iciHHV-6A/B chromosomal integration are yet to be identified. A recent report suggested that the rs73185306 C/T single-nucleotide polymorphism (SNP) represents a favorable predisposing factor leading to HHV-6A/B integration. After genotype analysis of an independent cohort (N = 11 967), we report no association between the rs73185306 C/T SNP and HHV-6A/B chromosomal integration (odds ratio, 0.90 [95% confidence interval, .54-1.51]; P = .69). [ABSTRACT FROM AUTHOR]

Introduction: In 2011, the Agence de la santé et des services sociaux de Montréal (ASSSM), in partnership with the region's Centres de santé et de services sociaux (CSSS), coordinated the implementation of a program on cardiometabolic risk based on the Chronic Care Model. The program, intended for patients suffering from diabetes or hypertension, involved a series of individual follow-up appointments, group classes and exercise sessions. Our study assesses the impact on patient health outcomes of variations in the implementation of some aspects of the program among the six CSSSs taking part in the study. Methods: The evaluation was carried out using a quasi-experimental "before and after" design. Implementation variables were constructed based on data collected during the implementation analysis regarding resources, compliance with the clinical process set out in the regional program, the program experience and internal coordination within the care team. Differences in differences using propensity scores were calculated for HbA1c results, achieving the blood pressure (BP) target, and two lifestyle targets (exercise level and carbohydrate distribution) at the 6- and 12-month follow-ups, based on greater or lesser patient exposure to the implementation of various aspects of the program under study. Results: The results focus on 1185 patients for whom we had data at the 6-month follow-up and the 992 patients from the 12-month follow-up. The difference in differences analysis shows no clear association between the extent of implementation of the various aspects of the program under study and patient health outcomes. Conclusion: The program produces effects on selected health indicators independent of variations in program implementation among the CSSSs taking part in the study. The results suggest that the effects of this type of program are more highly dependent on the delivery of interventions to patients than on the organizational aspects of its implementation. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the clinical characteristics and genetic basis of inherited retinal degeneration (IRD) in six unrelated pedigrees from Mexico. Methods: A complete ophthalmic evaluation including measurement of visual acuities, Goldman kinetic or Humphrey dynamic perimetry, Amsler test, fundus photography, and color vision testing was performed. Family history and blood samples were collected from available family members. DNA from members of two pedigrees was examined for known mutations using the APEX ARRP genotyping microarray and one pedigree using the APEX LCA genotyping microarray. The remaining three pedigrees were analyzed using a custom-designed targeted capture array covering the exons of 233 known retinal degeneration genes. Sequencing was performed on Illumina HiSeq. Reads were mapped against hg19, and variants were annotated using GATK and filtered by exomeSuite. Segregation and ethnicity-matched control sample analyses were performed by dideoxy sequencing. Results: Six pedigrees with IRD were analyzed. Nine rare or novel, potentially pathogenic variants segregating with the phenotype were detected inIMPDH1, USH2A, RPE65, ABCA4, andFAM161Agenes. Among these, six were known mutations while the remaining three changes inUSH2A, RPE65, andFAM161Agenes have not been previously reported to be associated with IRD. Analysis of 100 ethnicity-matched controls did not detect the presence of these three novel variants indicating, these are rare variants in the Mexican population. Conclusions: Screening patients diagnosed with IRD from Mexico identified six known mutations and three rare or novel potentially damaging variants inIMPDH1, USH2A, RPE65, ABCA4, andFAM161Agenes that segregated with disease. [ABSTRACT FROM PUBLISHER]

Background: Cancer is the leading cause of death in Canada. Early cancer diagnosis could improve patients' prognosis and quality of life. This study aimed to analyze the factors influencing elapsed time between the first help-seeking trigger and cancer diagnosis with respect to the three most common and deadliest cancer types: lung, breast, and colorectal.Methods: This paper presents the qualitative component of a larger project based on a sequential explanatory design. Twenty-two patients diagnosed were interviewed, between 2011 to 2013, in oncology clinics of four hospitals in the two most populous regions in Quebec (Canada). Transcripts were analyzed using the Model of Pathways to Treatment.Results: Pre-diagnosis elapsed time and phases are difficult to appraise precisely and vary according to cancer sites and symptoms specificity. This observation makes the Model of Pathways to Treatment challenging to use to analyze patients' experiences. Analyses identified factors contributing to elapsed time that are linked to type of cancer, to patients, and to health system organization.Conclusions: This research allowed us to identify avenues for reducing the intervals between first symptoms and cancer diagnosis. The existence of inequities in access to diagnostic services, even in a universal healthcare system, was highlighted. [ABSTRACT FROM AUTHOR]

Introduction: Chronic disease management requires substantial services integration. A cardiometabolic risk management program inspired by the Chronic Care Model was implemented in Montréal for patients with diabetes or hypertension. One of this study's objectives was to assess the impact of care coordination between the interdisciplinary teams and physicians on patient participation in the program, lifestyle improvements and disease control. Methods: We obtained data on health outcomes from a register of clinical data, questionnaires completed by patients upon entry into the program and at the 12-month mark, and we drew information on the program's characteristics from the implementation analysis. We conducted multiple regression analyses, controlling for patient sociodemographic and health characteristics, to measure the association between interdisciplinary team coordination with primary care physicians and various health outcomes. Results: A total of 1689 patients took part in the study (60.1% participation rate). Approximately 40% of patients withdrew from the program during the first year. At the 12-month follow-up (n = 992), we observed a significant increase in the proportion of patients achieving the various clinical targets. The perception by the interdisciplinary team of greater care coordination with primary care physicians was associated with increased participation in the program and the achievement of better clinical results. Conclusion: Greater coordination of patient services between interdisciplinary teams and primary care physicians translates into benefits for patients. [ABSTRACT FROM AUTHOR]

Background: Outpatient follow-up has been a key intervention point in addressing gaps in care after hospital discharge. We sought to estimate the association between enrolment in new team-based primary care practices and 30-day postdischarge physician follow-up among older patients and patients with chronic illnesses who were admitted to hospital in Quebec, Canada. Methods: Patients were selected into this cohort if a primary care physician enrolled them as a "vulnerable patient" between November 2002 and January 2005. Data for this analysis included province-wide health insurance claims for inpatient and outpatient services delivered between November 2002 and January 2009 in Quebec. The primary analysis examined time to the first outpatient postdischarge follow-up service provided by either a primary care physician or a medical specialist. We used marginal structural models to estimate adjusted rates of follow-up with a primary care physician or with a medical specialist by primary care delivery models. Results: We extracted billing data for 312 377 patients that represented 620 656 index admissions for any cause from 2002 to 2009. Rates of 30-day follow-up were 374 visits to primary care physicians and 422 visits to medical specialists per 1000 discharges. Rates of primary care physician follow-up were similar across primary care delivery models, except for patients with very high morbidity; these patients had significantly higher rates of follow-up with a primary care physician if they were enrolled in team-based primary care practices (30-d rate difference [RD] 13.3 more follow-up visits per 1000 discharges, 95% confidence interval [CI] 6.8 to 19.8). Rates of follow-up with a medical specialist were lower among patients enrolled in team-based practices, particularly within 15 days of hospital discharge (15-d RD 25.1 fewer follow-up visits per 1000 discharges, 95% CI 21.1 to 29.1). Interpretation: Our study found lower rates of postdischarge follow-up with a medical specialist among older patients and patients with chronic illness who were enrolled in team-based primary care practices compared with those enrolled in traditional primary care practices. Future research is needed to better understand the role of primary health care service organization in improving acute postdischarge care. [ABSTRACT FROM AUTHOR]

Background: Prenatal alcohol exposure is the leading preventable cause of behavioral and cognitive deficits, which may affect between 2 and 5 % of children in North America. While the underlying mechanisms of alcohol's effects on development remain relatively unknown, emerging evidence implicates epigenetic mechanisms in mediating the range of symptoms observed in children with fetal alcohol spectrum disorder (FASD). Thus, we investigated the effects of prenatal alcohol exposure on genome-wide DNA methylation in the NeuroDevNet FASD cohort, the largest cohort of human FASD samples to date. Methods: Genome-wide DNA methylation patterns of buccal epithelial cells (BECs) were analyzed using the Illumina HumanMethylation450 array in a Canadian cohort of 206 children (110 FASD and 96 controls). Genotyping was performed in parallel using the Infinium HumanOmni2.5-Quad v1.0 BeadChip. Results: After correcting for the effects of genetic background, we found 658 significantly differentially methylated sites between FASD cases and controls, with 41 displaying differences in percent methylation change >5 %. Furthermore, 101 differentially methylated regions containing two or more CpGs were also identified, overlapping with 95 different genes. The majority of differentially methylated genes were highly expressed at the level of mRNA in brain samples from the Allen Brain Atlas, and independent DNA methylation data from cortical brain samples showed high correlations with BEC DNA methylation patterns. Finally, overrepresentation analysis of genes with up-methylated CpGs revealed a significant enrichment for neurodevelopmental processes and diseases, such as anxiety, epilepsy, and autism spectrum disorders. Conclusions: These findings suggested that prenatal alcohol exposure is associated with distinct DNA methylation patterns in children and adolescents, raising the possibility of an epigenetic biomarker of FASD. [ABSTRACT FROM AUTHOR]