MYOD1 involvement in myopathy

[Excerpt] Introduction Myogenic Differentiation 1 (MYOD1) encodes a transcription factor that plays an important role in myogenic determination into mature skeletal muscle [1]. The first loss-of-function mutation of MYOD1 in humans was described in three siblings with perinatal lethal fetal akinesia [2].[...]We thank the individual and family. Funding was provided by The Fonds de recherche du Québec - Santé (FRQS) and Canadian Institutes of Health Research (CIHR) to P.M.C., Fundação para a Ciência e Tecnologia (FCT) with the fellowship SFRH/BD/84650/2010 to F.L. and Groupe Pasteur Mutualité Foundation (GPM Foundation) to M.M.info:eu-repo/semantics/publishedVersio

The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress

The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions.Cell Death and Differentiation advance online publication, 12 June 2015; doi:10.1038/cdd.2015.81

The impact of socially-accountable, community-engaged medical education on graduates in the Central Philippines: implications for the global rural medical workforce

Introduction: Developing and retaining a high quality medical workforce, especially within low-resource countries has been a world-wide challenge exacerbated by a lack of medical schools, the maldistribution of doctors towards urban practice, health system inequities, and training doctors in tertiary centers rather than in rural communities. Aim: To describe the impact of socially-accountable health professional education on graduates; specifically: their motivation towards community-based service, preparation for addressing local priority health issues, career choices, and practice location. Methods: Cross-sectional survey of graduates from two medical schools in the Philippines: the University of Manila-School of Health Sciences (SHS-Palo) and a medical school with a more conventional curriculum. Results: SHS-Palo graduates had significantly (p < 0.05) more positive attitudes to community service. SHS-Palo graduates were also more likely to work in rural and remote areas (p < 0.001) either at district or provincial hospitals (p = 0.032) or in rural government health services (p < 0.001) as Municipal or Public Health Officers (p < 0.001). Graduates also stayed longer in both their first medical position (p = 0.028) and their current position (p < 0.001). Conclusions: SHS-Palo medical graduates fulfilled a key aim of their socially-accountable institution to develop a health professional workforce willing and able, and have a commitment to work in underserved rural communties

Optimal strategy to identify incidence of diagnostic of diabetes using administrative data

<p>Abstract</p> <p>Background</p> <p>Accurate estimates of incidence and prevalence of the disease is a vital step toward appropriate interventions for chronic disease like diabetes. A growing body of scientific literature is now available on producing accurate information from administrative data. Advantages of use of administrative data to determine disease incidence include feasibility, accessibility and low cost, but straightforward use of administrative data can produce biased information on incident cases of chronic disease like diabetes. The present study aimed to compare criteria for the selection of diabetes incident cases in a medical administrative database.</p> <p>Methods</p> <p>An exhaustive retrospective cohort of diabetes cases was constructed for 2002 using the Canadian National Diabetes Surveillance System case definition (one hospitalization or two physician claims with a diagnosis of diabetes over a 2-year period) with the Quebec health service database. To identify previous occurrence of diabetes in the database, a five-year observation period was evaluated using retrograde survival function and kappa agreement. The use of NDSS case definition to identify incident cases was compared to a single occurrence of an ICD-9 code 250 in the records using the McNemar test.</p> <p>Results</p> <p>Retrograde survival function showed that the probability of being a true incident case after a 5-year diabetes-free observation period was almost constant and near 0.14. Agreement between 10 years (maximum period) and 5 years and more diabetes-free observation periods were excellent (kappa > 0.9). Respectively 41,261 and 37,473 incident cases were identified using a 5-year diabetes-free observation period with NDSS definition and using a single ICD-9 code 250.</p> <p>Conclusion</p> <p>A 5-year diabetes-free observation period was a conservative time to identify incident cases in an administrative database using one ICD-9 code 250 record.</p

Bone mineral density measurement and osteoporosis treatment after a fragility fracture in older adults: regional variation and determinants of use in Quebec

BACKGROUND: Osteoporosis (OP) is a skeletal disorder characterized by reduced bone strength and predisposition to increased risk of fracture, with consequent increased risk of morbidity and mortality. It is therefore an important public health problem. International and Canadian associations have issued clinical guidelines for the diagnosis and treatment of OP. In this study, we identified potential predictors of bone mineral density (BMD) testing and OP treatment, which include place of residence. METHODS: Our study was a retrospective population-based cohort study using data from the Quebec Health Insurance Board. The studied population consisted of all individuals 65 years and older for whom a physician claimed a consultation for a low velocity vertebral, hip, wrist, or humerus fracture in 1999 and 2000. Individuals were considered to have undergone BMD testing if there was a claim for such a procedure within two years following a fracture. They were considered to have received an OP treatment if there was at least one claim to Quebec's health insurance plan (RAMQ) for OP treatment within one year following a fracture. We performed descriptive analyses and logistic regressions by gender. Predictors included age, site of fracture, social status, comorbidity index, prior BMD testing, prior OP treatment, long-term glucocorticoid use, and physical distance to BMD device. RESULTS: The cohort, 77% of which was female, consisted of 25,852 individuals with fragility fractures. BMD testing and OP treatment rates were low and gender dependent (BMD: men 4.6%; women 13.1%; OP treatment: men 9.9%; women 29.7%). There was an obvious regional variation, particularly in BMD testing, ranging from 0 to 16%. Logistic regressions demonstrate that individuals living in long term care facilities received less BMD testing. Patients who had suffered from vertebral fractures, or who had received prior OP treatment or BMD testing, regardless of gender, subsequently received more BMD testing and OP treatments. Furthermore, increasing the distance between a patient's residence and BMD facility precluded likelihood of BMD testing. CONCLUSION: BMD testing rate was extremely low but not completely explained by reduced physical access; gender, age, social status, prior BMD testing and OP treatment were all important predictors for future BMD testing and OP treatment

Access to myocardial revascularization procedures: Closing the gap with time?

BACKGROUND: Early access to revascularization procedures is known to be related to a more favorable outcome in myocardial infarction (MI) patients, but access to specialized care varies widely amongst the population. We aim to test if the early gap found in the revascularization rates, according to distance between patients' location and the closest specialized cardiology center (SCC), remains on a long term basis. METHODS: We conducted a population-based cohort study using data from the Quebec's hospital discharge register (MED-ECHO). The study population includes all patients 25 years and older living in the province of Quebec, who were hospitalized for a MI in 1999 with a follow up time of one year after the index hospitalization. The main variable is revascularization (percutaneous transluminal coronary angioplasty or a coronary artery bypass graft). The population is divided in four groups depending how close they are from a SCC (<32 km, 32–64 km, 64–105 km and ≥105 km). Revascularization rates are adjusted for age and sex. RESULTS: The study population includes 11,802 individuals, 66% are men. The one-year incidence rate of MI is 244 individuals per 100,000 inhabitants. At index hospitalization, a significant gap is found between patients living close (< 32 km) to a SCC and patients living farther (≥32 km). During the first year, a gap reduction can be observed but only for patients living at an intermediate distance from the specialized center (64–105 km). CONCLUSION: The gap observed in revascularization rates at the index hospitalization for MI is in favour of patients living closer (< 32 km) to a SCC. This gap remains unchanged over the first year after an MI except for patients living between 64 and 105 km, where a closing of the gap can be noticed

Mutations in the Mitochondrial Methionyl-tRNA Synthetase Cause a Neurodegenerative Phenotype in Flies and a Recessive Ataxia (ARSAL) in Humans

The study of Drosophila neurodegenerative mutants combined with genetic and biochemical analyses lead to the identification of multiple complex mutations in 60 patients with a novel form of ataxia/leukoencephalopathy

Neighbourhood immigration, health care utilization and outcomes in patients with diabetes living in the Montreal metropolitan area (Canada): a population health perspective

Abstract: Background: Understanding health care utilization by neighbourhood is essential for optimal allocation of resources, but links between neighbourhood immigration and health have rarely been explored. Our objective was to understand how immigrant composition of neighbourhoods relates to health outcomes and health care utilization of individuals living with diabetes. Methods: This is a secondary analysis of administrative data using a retrospective cohort of 111,556 patients living with diabetes without previous cardiovascular diseases (CVD) and living in the metropolitan region of Montreal (Canada). A score for immigration was calculated at the neighbourhood level using a principal component analysis with six neighbourhood-level variables (% of people with maternal language other than French or English, % of people who do not speak French or English, % of immigrants with different times since immigration (<5 years, 5–10 years, 10–15 years, 15–25 years)). Dependent variables were all-cause death, all-cause hospitalization, CVD event (death or hospitalization), frequent use of emergency departments, frequent use of general practitioner care, frequent use of specialist care, and purchase of at least one antidiabetic drug. For each of these variables, adjusted odds ratios were estimated using a multilevel logistic regression. Results: Compared to patients with diabetes living in neighbourhoods with low immigration scores, those living in neighbourhoods with high immigration scores were less likely to die, to suffer a CVD event, to frequently visit general practitioners, but more likely to visit emergency departments or a specialist and to use an antidiabetic drug. These differences remained after controlling for patient-level variables such as age, sex, and comorbidities, as well as for neighbourhood attributes like material and social deprivation or living in the urban core. Conclusions: In this study, patients with diabetes living in neighbourhoods with high immigration scores had different health outcomes and health care utilizations compared to those living in neighbourhoods with low immigration scores. Although we cannot disentangle the individual versus the area-based effect of immigration, these results may have an important impact for health care planning

Importance of proximity to resources, social support, transportation and neighborhood security for mobility and social participation in older adults: results from a scoping study

ABSTRACT: Background: Since mobility and social participation are key determinants of health and quality of life, it is important to identify factors associated with them. Although several investigations have been conducted on the neighborhood environment, mobility and social participation, there is no clear integration of the results. This study aimed to provide a comprehensive understanding regarding how the neighborhood environment is associated with mobility and social participation in older adults.Methods: A rigorous methodological scoping study framework was used to search nine databases from different fields with fifty-one keywords. Data were exhaustively analyzed, organized and synthesized according to the International Classification of Functioning, Disability and Health (ICF) by two research assistants following PRISMA guidelines, and results were validated with knowledge users.Results: The majority of the 50 selected articles report results of cross-sectional studies (29; 58 %), mainly conducted in the US (24; 48 %) or Canada (15; 30 %). Studies mostly focused on neighborhood environment associations with mobility (39; 78 %), social participation (19; 38 %), and occasionally both (11; 22 %). Neighborhood attributes considered were mainly 'Pro ducts and technology' (43; 86) and 'Services, systems and policies' (37; 74 %), but also 'Natural and human- made changes' (27; 54 %) and 'Support and relationships' (21; 42 %). Mobility and social participation were both positively associated with Proximity to resources and recreational facilities, Social support, Having a car or driver's license, Public transportation and Neighborhood security, and negatively associated with Poor user-friendliness of the walking environment and Neighborhood insecurity. Attributes of the neighborhood environment not covered by previous research on mobility and social participation mainly concerned 'Attitudes', and 'Services, systems and policies'.Conclusion: Results from this comprehensive synthesis of empirical studies on associations of the neighborhood environment with mobility and social participation will ultimately support best practices, decisions and the development of innovative inclusive public health interventions including clear guidelines for the creation of age-supportive environments. To foster mobility and social participation, these interventions must consider Proximity to resources and to recreational facilities, Social support, Transportation, Neighborhood security and User-friendliness of the walking environment. Future studies should include both mobility and social participation, and investigate how they are associated with 'Attitudes', and 'Services, systems and policies' in older adults, including disadvantaged older adults