The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis.
We sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian ...families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disease in two independent case-control series - one French Canadian (66 patients and 209 controls) and the other German (228 patients and 199 controls). We also genotyped the repeat in 20 Australian and 31 Indian index patients. We assayed gene and protein expression in two postmortem cerebellum specimens and two induced pluripotent stem-cell (iPSC)-derived motor-neuron cell lines.
In the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron of
, which encodes fibroblast growth factor 14. Cosegregation of the repeat expansion with disease in the families supported a pathogenic threshold of at least 250 GAA repeats (GAA
). There was significant association between
(GAA)
expansions and LOCA in the French Canadian series (odds ratio, 105.60; 95% confidence interval CI, 31.09 to 334.20; P<0.001) and in the German series (odds ratio, 8.76; 95% CI, 3.45 to 20.84; P<0.001). The repeat expansion was present in 61%, 18%, 15%, and 10% of French Canadian, German, Australian, and Indian index patients, respectively. In total, we identified 128 patients with LOCA who carried an
(GAA)
expansion. Postmortem cerebellum specimens and iPSC-derived motor neurons from patients showed reduced expression of
RNA and protein.
A dominantly inherited deep intronic GAA repeat expansion in
was found to be associated with LOCA. (Funded by Fondation Groupe Monaco and others.).
Abstract 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.
Aging is characterized by clonal expansion of myeloid-biased hematopoietic stem cells and by increased risk of myeloid malignancies. Exome sequencing of three elderly females with clonal ...hematopoiesis, demonstrated by X-inactivation analysis, identified somatic TET2 mutations. Recurrence testing identified TET2 mutations in 10 out of 182 individuals with X-inactivation skewing. TET2 mutations were specific to individuals with clonal hematopoiesis without hematological malignancies and were associated with alterations in DNA methylation.
Family Medicine Groups, implemented in Quebec in 2002, are interprofessional primary care teams designed to improve timely access to high-quality primary care. This study investigates whether Family ...Medicine Groups increased rates of guideline-recommended screenings for 3 chronic diseases: colorectal cancer (colonoscopy/sigmoidoscopy), breast cancer (mammography), and osteoporosis (bone mineral density testing).
Using population-based administrative health data from the provincial insurer (2000–2010), the authors examined elderly and chronically ill patients who registered with a general practitioner in the first 15 months of the Family Medicine Group policy. Propensity score weighting and a difference-in-differences model estimated differential change in biennial screening rates among Family Medicine Group and non-Family Medicine Group patients over 5 years of follow-up (analysis, 2016–2018).
Rates of mammography, colonoscopy/sigmoidoscopy, and bone mineral density testing increased after patient registration with a general practitioner, similarly for both Family Medicine Group and non-Family Medicine Group patients. Colonoscopy/sigmoidoscopy rates increased by 9.7% and 10.4% for Family Medicine Group and non-Family Medicine Group patients, mammography rates by 5.3% and 3.4%, and bone mineral density testing by 4.2% and 7.1%. Difference-in-differences estimates showed no detectable effect of Family Medicine Groups on disease screening rates: −0.06 percentage points (95% CI= −0.32, 0.20) for colonoscopy/sigmoidoscopy, 1.01 percentage points (95% CI= −0.25, 2.27) for mammography, and −0.32 (95% CI= −0.71, −0.07) for bone mineral density testing.
This study found no evidence that Family Medicine Groups affected screening rates for these 3 chronic diseases. Limitations in the implementation of the Family Medicine Group policy in its early years may have contributed to this lack of impact. Interprofessional primary care teams may need to include elements other than organizational changes to increase disease prevention efforts.
Introduction. Healthcare reforms launched in the early 2000s in Québec, Canada, involved the implementation of new forms of primary healthcare (PHC) organizations: Family Medicine Groups (FMGs) and ...Network Clinics (NCs). The objective of this paper is to assess how the organizational changes associated with these reforms have impact on patients’ experience of care, use of services, and unmet needs. Methods. We conducted population and organization surveys in 2005 and 2010 in two regions of the province of Québec. The design was a before-and-after natural experiment. Changes over time between new models and other practices were assessed using difference-in-differences statistical procedures. Results. Accessibility decreased between 2003 and 2010, but less so in the treatment than in the comparison group. Continuity of care generally improved, but the increase was less for patients in the treatment group. Responsiveness also increased during the period and more so in the treatment group. There was no other significant difference between the two groups. Conclusion. PHC reform in Québec has brought about major organizational changes that have translated into slight improvements in accessibility of care and responsiveness. However, the reform does not seem to have had an impact on continuity, comprehensiveness, perceived care outcomes, use of services, and unmet needs.
Objectives. To assess the extent to which new primary healthcare (PHC) models implemented in two regions of Quebec have improved patient experience of care, unmet needs, and use of services for ...individuals with and without chronic diseases, compared with other forms of PHC practices. Methods. In 2005 and 2010, we carried out population and organization surveys. We divided PHC organizations into new model practices and other practices and followed the evolution over time of patient experience of care. Results. Patients with chronic diseases had better accessibility but worse continuity of care in the new model practices than in the other practices at both time periods. Through the reform, accessibility decreased evenly in both groups, but continuity and perceived outcomes improved more in the other practices. Use of primary care services decreased more in the new model practices. Among patients without chronic disease, accessibility decreased much less in the new models and responsiveness increased more. There was no significant change in ER attendance and hospitalization. Conclusion. The evolution of patient experience of care has been more favorable for patients without chronic diseases. These findings raise concerns about equity since the aim of the PHC reform was targeting in priority individuals with the greatest needs.
Background. Commonly self-reported questions in population health surveys, such as “do you have a family physician?”, represent one of the best-known sources of information about patients’ attachment ...to family physicians. Is it possible to find a proxy for this information in administrative data? Objective. To identify the type of patient attachment to a family physician using administrative data. Methods. Using physician fee-for-service database and patients enrolment registries (Quebec, Canada, 2008–2010), we developed a step-by-step algorithm including three dimensions of the physician-patient relationship: patient enrolment with a physician, complete annual medical examinations (CME), and concentration of visits to a physician. Results. 68.1% of users were attached to a family physician; for 34.4% of them, attachment was defined by enrolment with a physician, for 31.5%, by CME without enrolment, and, for 34.1%, by concentration of visits to a physician without enrolment or CME. Eight types of patient attachment were described. Conclusion. When compared to findings with survey data, our measure comes out as a solid conceptual framework to identify patient attachment to a family physician in administrative databases. This measure could be of great value for physician/patient-based cohort development and impact assessment of different types of patient attachment on health services utilization.
Abstract Background Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also ...associated with other diseases or traits. Objectives This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. Methods In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. Results We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 ( KCNJ13-GIGYF2 ), 6p21 ( C2 ), 11p15 ( MRVI1-CTR9 ), 12q13 ( LRP1 ), 12q24 ( SCARB1 ), and 16q13 ( CETP ). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10−4 with a range of other diseases/traits. Conclusions We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.
Genetic sex and psychosocial factors relating to sex and gender influence a person's risk of developing neurocognitive impairment (NCI). Yet their role in mechanisms underlying APOE-ɛ4 ...pathophysiology of NCI remains unclear. We explore whether sex and gender independently modify the association between APOE-ɛ4 and NCI.
We conducted effect modification analyses in N=364,793 participants from the UK Biobank pan-ancestry dataset (return #2442) without prevalent cardiovascular disease or NCI. APOE-ɛ4 carrier status was inferred based on diplotypes derived from phased genotypes. NCI cases were identified in hospitalization, mortality, and self-report questionnaire datasets. Gender was measured using a previously constructed literature-based femininity score (FS) that leverages six psychosocial factors. We estimated adjusted generalized linear models (GLM) for NCI, as random effects for ancestry groups were not informative. To evaluate APOE-ɛ4 effect modification by gender, we stratified models by sex and introduced interaction terms for APOE-ɛ4 and FS. We estimated conditional effects corrected for multiplicity to illustrate modification across FS. To evaluate APOE-ɛ4 effect modification by sex, we introduced interaction terms for APOE-ɛ4 and sex and conditioned on FS. Sensitivity analyses were conducted with NCI cases identified from primary care data (N=169,125).
We identified N=6,123 participants with incident NCI in the sex-combined sample (1.7%), of which 2,990 were female. APOE-ɛ4 was associated with increased risk of NCI in females (p
Both sex and gender influence the effect of APOE-ɛ4 on NCI in diverse ancestries. More analyses are needed to clarify mechanisms by which gender influences risk conferred by APOE-ɛ4 in both sexes.
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