Validating linkage of multiple population-based administrative databases in Brazil.

BACKGROUND: Linking routinely-collected data provides an opportunity to measure the effects of exposures that occur before birth on maternal, fetal and infant outcomes. High quality linkage is a prerequisite for producing reliable results, and there are specific challenges in mother-baby linkage. Using population-based administrative databases from Brazil, this study aimed to estimate the accuracy of linkage between maternal deaths and birth outcomes and dengue notifications, and to identify potential sources of bias when assessing the risk of maternal death due to dengue in pregnancy. METHODS: We identified women with dengue during pregnancy in a previously linked dataset of dengue notifications in women who had experienced a live birth or stillbirth during 2007-2012. We then linked this dataset with maternal death records probabilistically using maternal name, age and municipality. We estimated the accuracy of the linkage, and examined the characteristics of false-matches and missed-matches to identify any sources of bias. RESULTS: Of the 10,259 maternal deaths recorded in 2007-2012, 6717 were linked: 5444 to a live birth record, 1306 to a stillbirth record, and 33 to both a live and stillbirth record. After identifying 2620 missed-matches and 124 false-matches, our estimated sensitivity was 72%, specificity was 88%, and positive predictive value was 98%. Linkage errors were associated with maternal education and self-identified race; women with more than 7 years of education or who self-declared as Caucasian were more likely to link. Dengue status was not associated with linkage error. CONCLUSION: Despite not having unique identifiers to link mothers and birth outcomes, we demonstrated a high standard of linkage, with sensitivity and specificity values comparable to previous literature. Although there were no differences in the characteristics of dengue cases missed or included in our linked dataset, linkage error occurred disproportionally by some social-demographic characteristics, which should be taken into account in future analyses

Contribution of Efflux to the Emergence of Isoniazid and Multidrug Resistance in Mycobacterium tuberculosis

Multidrug resistant (MDR) tuberculosis is caused by Mycobacterium tuberculosis resistant to isoniazid and rifampicin, the two most effective drugs used in tuberculosis therapy. Here, we investigated the mechanism by which resistance towards isoniazid develops and how overexpression of efflux pumps favors accumulation of mutations in isoniazid targets, thus establishing a MDR phenotype. The study was based on the in vitro induction of an isoniazid resistant phenotype by prolonged serial exposure of M. tuberculosis strains to the critical concentration of isoniazid employed for determination of drug susceptibility testing in clinical isolates. Results show that susceptible and rifampicin monoresistant strains exposed to this concentration become resistant to isoniazid after three weeks; and that resistance observed for the majority of these strains could be reduced by means of efflux pumps inhibitors. RT-qPCR assessment of efflux pump genes expression showed overexpression of all tested genes. Enhanced real-time efflux of ethidium bromide, a common efflux pump substrate, was also observed, showing a clear relation between overexpression of the genes and increased efflux pump function. Further exposure to isoniazid resulted in the selection and stabilization of spontaneous mutations and deletions in the katG gene along with sustained increased efflux activity. Together, results demonstrate the relevance of efflux pumps as one of the factors of isoniazid resistance in M. tuberculosis. These results support the hypothesis that activity of efflux pumps allows the maintenance of an isoniazid resistant population in a sub-optimally treated patient from which isoniazid genetically resistant mutants emerge. Therefore, the use of inhibitors of efflux should be considered in the development of new therapeutic strategies for preventing the emergence of MDR-TB during treatment