Genetic risk factors for modulation of age at onset in Machado-Joseph disease/spinocerebellar ataxia type 3: a systematic review and meta-analysis.

OBJECTIVES: To perform a systematic review and meta-analysis of genetic risk factors for age at onset (AO) in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD). METHODS: Two authors independently reviewed reports on the mathematical relationship between CAG length at the expanded ATXN3 allele (CAGexp), and other genetic variants if available, and AO. Publications from January 1994 to September 2017 in English, Portuguese or Spanish and indexed in MEDLINE (PubMed), LILACS or EMBASE were considered. Inclusion criteria were reports with >20 SCA3/MJD carriers with molecular diagnosis performed by capillary electrophoresis. Non-overlapping cohorts were determined on contact with corresponding authors. A detailed analysis protocol was registered at the PROSPERO database prior to data extraction (CRD42017073071). RESULTS: Eleven studies were eligible for meta-analysis, comprising 10 individual-participant (n=2099 subjects) and two aggregated data cohorts. On average, CAGexp explained 55.2% (95% CI 50.8 to 59.0; p<0.001) of AO variability. Population-specific factors accounted for 8.3% of AO variance. Cohorts clustered into distinct geographic groups, evidencing significantly earlier AO in non-Portuguese Europeans than in Portuguese/South Brazilians with similar CAGexp lengths. Presence of intermediate ATXN2 alleles (27-33 CAG repeats) significantly correlated with earlier AO. Familial factors accounted for ~10% of AO variability. CAGexp, origin, family effects and CAG length at ATXN2 together explained 73.5% of AO variance. CONCLUSIONS: Current evidence supports genetic modulation of AO in SCA3/MJD by CAGexp, ATXN2 and family-specific and population-specific factors. Future studies should take these into account in the search for new genetic modifiers of AO, which could be of therapeutic relevance.

Hospitalizations for primary care sensitive conditions: association with socioeconomic status and quality of family health teams in Belo Horizonte, Brazil.

Hospitalizations for primary care sensitive conditions (HPCSC) have been used as a measure of the effectiveness of primary care. Few studies, however, have measured the quality of primary health care (PHC) and how it impacts HPCSC trends. We employed previously calculated quality scores of PHC attributes (access, continuous/ongoing care, coordinated care and comprehensive care) assigned to health centres and investigated the correlation between these quality scores and HPCSC time trends in public hospitals in the city of Belo Horizonte, Brazil, adjusted by demographic and socioeconomic factors between 2010 and 2013. Socioeconomic risk was determined using the Health Vulnerability Index, a composite indicator including sanitation, habitation, education, income and health variables. Between 2010 and 2013, 447 500 hospitalizations, excluding births, were recorded in Belo Horizonte. Of these, 85 211 were HPCSC (19% of total admissions). Of 145 health centres, 133 were analysed in this study, with 75 059 HPCSC in the 4-year period. In the initial univariate model, only the PCH attribute 'access' and 'social vulnerability' had an effect on hospitalization rates. In the multilevel analysis, socioeconomic vulnerability became the only predictor of HPCSC rates. A 10% increase in high socioeconomic risk population meant an increase of 5 HPCSC/10 000 in women and 4/10 000 in men for each individual primary care unit, while a 10% increase in low-risk population meant a reduction in HPCSC of 6/10 000 in women and 5/10 000 in men. The results support the importance of using HPCSC as a measure of PHC effectiveness, considering individual, health service-related and socioeconomic characteristics; however, additional measures of effectiveness of care provided by family health teams seem necessary to assess PHC performance.