Household-Contact Investigation for Detection of Tuberculosis in Vietnam.

BACKGROUND: Active case finding is a top priority for the global control of tuberculosis, but robust evidence for its effectiveness in high-prevalence settings is lacking. We sought to evaluate the effectiveness of household-contact investigation, as compared with standard, passive measures alone, in Vietnam. METHODS: We performed a cluster-randomized, controlled trial at clinics in 70 districts (local government areas with an average population of approximately 500,000 in urban areas and 100,000 in rural areas) in eight provinces of Vietnam. Health workers at each district clinic or hospital were assigned to perform either household-contact intervention plus standard passive case finding (intervention group) or passive case finding alone (control group). In the intervention districts, household contacts of patients with positive results for tuberculosis on sputum smear microscopy (smear-positive tuberculosis) were invited for clinical assessment and chest radiography at baseline and at 6, 12, and 24 months. The primary outcome was the cumulative incidence of registered cases of tuberculosis among household contacts of patients with tuberculosis during a 2-year period. RESULTS: In 70 selected districts, we enrolled 25,707 household contacts of 10,964 patients who had smear-positive pulmonary tuberculosis. In the 36 districts that were included in the intervention group, 180 of 10,069 contacts were registered as having tuberculosis (1788 cases per 100,000 population), as compared with 110 of 15,638 contacts (703 per 100,000) in the control group (relative risk of the primary outcome in the intervention group, 2.5; 95% confidence interval [CI], 2.0 to 3.2; P<0.001); the relative risk of smear-positive disease among household contacts in the intervention group was 6.4 (95% CI, 4.5 to 9.0; P<0.001). CONCLUSIONS: Household-contact investigation plus standard passive case finding was more effective than standard passive case finding alone for the detection of tuberculosis in a high-prevalence setting at 2 years. (Funded by the Australian National Health and Medical Research Council; ACT2 Australian New Zealand Clinical Trials Registry number, ACTRN12610000600044 .).

Differences in DNA methylation profiles by histologic subtype of paediatric germ cell tumours: a report from the Children's Oncology Group.

BACKGROUND: Abnormal DNA methylation may be important in germ cell tumour (GCT) aetiology, as germ cells undergo complete epigenetic reprogramming during development. GCTs show differences in global and promoter methylation patterns by histologic subtype. We conducted an epigenome-wide study to identify methylation differences by GCT histology. METHODS: Using the Illumina HumanMethylation450K array we measured methylation in 154 paediatric GCTs (21 germinomas/seminomas/dysgerminoma, 70 yolk sac tumours [YST], 9 teratomas, and 54 mixed histology tumours). We identified differentially methylated regions (DMRs) between GCT histologies by comparing methylation beta values. RESULTS: We identified 8,481 DMRs (FWER < 0.05). Unsupervised hierarchical clustering of individual probes within DMRs resulted in four high level clusters closely corresponding to tumour histology. Clusters corresponding to age, location, sex and FFPE status were not observed within these DMRs. Germinomas displayed lower levels of methylation across the DMRs relative to the other histologic subtypes. Pathway analysis on the top 10% of genes with differential methylation in germinomas/seminomas/dysgerminoma compared to YST suggested angiogenesis and immune cell-related pathways displayed decreased methylation in germinomas/seminomas/dysgerminoma relative to YST. CONCLUSIONS: Paediatric GCT histologies have differential methylation patterns. The genes that are differentially methylated may provide insights into GCT aetiology including the timing of GCT initiation.

Trends in Awareness, Use of, and Beliefs About Electronic Cigarette and Snus Among a Longitudinal Cohort of US Midwest Young Adults.

Introduction: Few longitudinal studies have examined how awareness, use of, and beliefs about electronic cigarettes (e-cigarettes) and snus change over time. We assessed these trends in a cohort of young adults from the US Midwest. Methods: Data were from the Minnesota Adolescent Community Cohort (MACC) Study, collected annually during 2010-2013 when participants were 21-29 years old (n = 2622). Participants were asked if they had heard of and ever used e-cigarettes and snus, and the number of days they used these products in the past 30 days. Beliefs about whether these products are less harmful than cigarettes, less addictive than cigarettes, and could help people quit smoking were assessed. Repeated measures multiple linear and logistic regression models, adjusting for demographics, peer smoking and smoking status, were used to assess trends. Results: Compared to 2010-2011, participants in 2012-2013 were five times more likely to be aware of e-cigarettes, report ever used them, and report using them in the past 30-days. Increases in e-cigarette use were observed in all smoking status. Participants were also increasingly likely to believe that e-cigarettes are less harmful than combustible cigarettes and could help people quit smoking. There was only a modest increase in awareness of and ever using snus, as well as believing snus is less harmful than combustible cigarettes. These trends did not differ by smoking status. Conclusions: The increasingly favorable beliefs about e-cigarettes may explain the increasing prevalence of their use particularly among young adults, both among smokers and nonsmokers. Implications: Awareness and use of e-cigarettes have increased substantially over the past few years, and positive beliefs of e-cigarettes have also become more prevalent among young adults. Meanwhile, little changes in awareness, use of, and beliefs about snus among young adults. Given the potential of these products to have both positive and negative impact on public health depending on who use them and how they are used, strategically communicating the risks associated with e-cigarettes and snus use may help minimize the burden of tobacco use at the population level.

Problematic Drinking Among Postgraduate Students: Binge Drinking, Prepartying, and Mixing Alcohol With Energy Drinks.

BACKGROUND: Although problematic alcohol use has been studied extensively in undergraduate students, little is known about problematic drinking among postgraduate students. OBJECTIVES: This study examined binge drinking, prepartying, and mixing alcohol with energy drinks to determine: (1) the extent to which postgraduate students engage in these drinking behaviors, (2) how postgraduate students differ from undergraduate students in these behaviors, and (3) the demographic risk factors for these behaviors in postgraduate (and undergraduate) students. METHODS: This study utilized data from n = 695 students (n = 298 postgraduate; n = 397 undergraduate) who participated in the Healthy Minds Study at a large, public university in the Midwestern US. RESULTS: Past-two-week binge drinking, past-year and past-30-day prepartying, and past-30-day mixing alcohol with energy drinks were reported by 26.2%, 28.6%, 14.9%, and 8.1% of postgraduate students, respectively. Multivariate analyses indicated that postgraduate status was a significant negative predictor of binge drinking and prepartying, and that status interacted with age in predicting prepartying such that the effect of age on prepartying was negative for postgraduate students and nonsignificant for undergraduates. Age was a significant negative predictor of mixing alcohol with energy drinks for all students. CONCLUSIONS/IMPORTANCE: This study makes a unique contribution to the literature by providing information on problematic drinking in postgraduate students. Although there was evidence of "maturing out," a substantial number of postgraduate students were found to engage in binge drinking and prepartying, and a not insubstantial number of them were found to mix alcohol with energy drinks.

Cross platform analysis of methylation, miRNA and stem cell gene expression data in germ cell tumors highlights characteristic differences by tumor histology.

BACKGROUND: Alterations in methylation patterns, miRNA expression, and stem cell protein expression occur in germ cell tumors (GCTs). Our goal is to integrate molecular data across platforms to identify molecular signatures in the three main histologic subtypes of Type I and Type II GCTs (yolk sac tumor (YST), germinoma, and teratoma). METHODS: We included 39 GCTs and 7 paired adjacent tissue samples in the current analysis. Molecular data available for analysis include DNA methylation data (Illumina GoldenGate Cancer Methylation Panel I), miRNA expression (NanoString nCounter miRNA platform), and stem cell factor expression (SABiosciences Human Embryonic Stem Cell Array). We evaluated the cross platform correlations of the data features using the Maximum Information Coefficient (MIC). RESULTS: In analyses of individual datasets, differences were observed by tumor histology. Germinomas had higher expression of transcription factors maintaining stemness, while YSTs had higher expression of cytokines, endoderm and endothelial markers. We also observed differences in miRNA expression, with miR-371-5p, miR-122, miR-302a, miR-302d, and miR-373 showing elevated expression in one or more histologic subtypes. Using the MIC, we identified correlations across the data features, including six major hubs with higher expression in YST (LEFTY1, LEFTY2, miR302b, miR302a, miR 126, and miR 122) compared with other GCT. CONCLUSIONS: While prognosis for GCTs is overall favorable, many patients experience resistance to chemotherapy, relapse and/or long term adverse health effects following treatment. Targeted therapies, based on integrated analyses of molecular tumor data such as that presented here, may provide a way to secure high cure rates while reducing unintended health consequences.

Integrated genomic analysis reveals aberrations in WNT signaling in germ cell tumors of childhood and adolescence.

Germ cell tumors (GCTs) are neoplasms of the testis, ovary and extragonadal sites that occur in infants, children, adolescents and adults. Post-pubertal (type II) malignant GCTs may present as seminoma, non-seminoma or mixed histologies. In contrast, pre-pubertal (type I) GCTs are limited to (benign) teratoma and (malignant) yolk sac tumor (YST). Epidemiologic and molecular data have shown that pre- and post-pubertal GCTs arise by distinct mechanisms. Dedicated studies of the genomic landscape of type I and II GCT in children and adolescents are lacking. Here we present an integrated genomic analysis of extracranial GCTs across the age spectrum from 0-24 years. Activation of the WNT pathway by somatic mutation, copy-number alteration, and differential promoter methylation is a prominent feature of GCTs in children, adolescents and young adults, and is associated with poor clinical outcomes. Significantly, we find that small molecule WNT inhibitors can suppress GCT cells both in vitro and in vivo. These results highlight the importance of WNT pathway signaling in GCTs across all ages and provide a foundation for future efforts to develop targeted therapies for these cancers.

Household contact investigation for the detection of tuberculosis in Vietnam: economic evaluation of a cluster-randomised trial.

BACKGROUND: Active case finding is recommended as an important strategy to control tuberculosis, particularly in low-income and middle-income countries with a high prevalence of the disease. However, the costs and cost-effectiveness of active case finding are unclear due to the absence of evidence from randomised trials. We assessed the costs and cost-effectiveness of an active case finding strategy in Vietnam, where there is a high prevalence of tuberculosis. METHODS: We conducted an economic evaluation alongside the Active Case Finding in Tuberculosis (ACT2) trial-a pragmatic cluster-randomised controlled trial in 70 districts across eight provinces of Vietnam. Patients aged 15 years and older with smear-positive pulmonary tuberculosis were recruited to the trial if they lived with one or more other household members. Household contacts were verbally invited to the clinic by the index patient with tuberculosis. ACT2 compared a combination of active and passive case finding with usual care (passive case finding) of household contacts of patients with tuberculosis from a health system perspective. Clustering occurred at the district and household level. Districts were the unit of randomisation, and we used minimisation to ensure balance of intervention and control districts within each province. In the intervention group, participants were invited to attend screening at baseline, 6 months, 12 months, and 24 months. We determined health-care costs with a standardised national costing survey and reported results in 2017 $US. The primary outcome of our study was disability-adjusted life years (DALYs) averted over a 24-month period. ACT2 was registered prospectively with the Australian and New Zealand Clinical Trials Registry, number ACTRN126.100.00600044. FINDINGS: Between Aug 11, 2010, and Aug 11, 2015, 10 964 index patients and 25 707 household contacts completed the ACT2 study. There were 10 069 household contacts in the intervention group and 15 638 household contacts in the control group. The incremental cost-effectiveness ratio per DALY averted was $544 (330-1375). INTERPRETATION: Active case finding was shown to be highly cost-effective in a setting with a high prevalence of tuberculosis. Investment in the wide-scale implementation of this programme in Vietnam should be strongly supported. FUNDING: Australian National Health and Medical Research Council.

Recurrence of tuberculosis among patients following treatment completion in eight provinces of Vietnam: A nested case-control study.

BACKGROUND: Patients completing treatment for tuberculosis (TB) in high-prevalence settings face a risk of developing recurrent disease. This has important consequences for public health, given its association with drug resistance and a poor prognosis. Previous research has implicated individual factors such as smoking, alcohol use, HIV, poor treatment adherence, and drug resistant disease as risk factors for recurrence. However, little is known about how these factors co-act to produce recurrent disease. Furthermore, perhaps factors related to the index disease means higher burden/low resource settings may be more prone to recurrent disease that could be preventable. METHODS: We conducted a case-control study nested within a cohort of consecutively enrolled adults who were being treated for smear positive pulmonary TB in 70 randomly selected district clinics in Vietnam. Cases were patients with recurrent TB, identified by follow-up from the parent cohort study. Controls were selected from the cohort by random sampling. Information on demographic, clinical and disease-related characteristics was obtained by interview. Treatment information was extracted from clinic registries. Logistic regression, with stepwise selection, was used to develop a fully adjusted model for the odds of recurrence of TB. RESULTS: We recruited 10,964 patients between October 2010 and July 2013. Median follow-up was 988 days. At the end of follow-up, 505 patients (4.7%) with recurrence were identified as cases and 630 other patients were randomly selected as controls. Predictors of recurrence included multidrug-resistant (MDR)-TB (adjusted odds ratio 79.6; 95% CI: 25.1-252.0), self-reported prior TB therapy (aOR=2.5; 95% CI: 1.7-3.5), and incomplete adherence (aOR=1.9; 95% CI 1.1-3.1). CONCLUSIONS: Index disease treatment history is a leading determinant of relapse among patients with TB in Vietnam. Further research is required to identify interventions that will reduce the risk of recurrent disease and enhance its early detection within high-risk populations.

Exploring the Validity of Developing an Interdisciplinarity Score of a Patient's Needs: Care Coordination, Patient Complexity, and Patient Safety Indicators.

Despite the Affordable Care Act's push to improve the coordination of care for patients with multiple chronic conditions, most measures of coordination quality focus on a specific moment in the care process (e.g., medication errors or transfer between facilities), rather than patient outcomes. One possible supplementary way of measuring the care coordination quality of a facility would be to identify the patients needing the most coordination, and to look at outcomes for that group. This paper lays the groundwork for a new measure of care coordination quality by outlining a conceptual framework that considers the interaction between a patient's interdisciplinarity, biological susceptibility, and procedural intensity. Interdisciplinarity captures the degree of specialized medical expertise needed for a patient's care and will be an important measure to estimate the number of specialists a patient might see. We then develop a preliminary measure of interdisciplinarity and run tests linking interdisciplinarity to medical mistakes, as defined by Agency for Healthcare Research and Quality's Patient Safety Indicators. Finally, we use our preliminary measure to verify that interdisciplinarity is likely to be statistically different from existing measures of comorbidity, like the Charlson score. Future research will need to build upon our findings by developing a more statistically validated measure of interdisciplinarity.

Variability in medical marijuana laws in the United States.

Marijuana use and its distribution raise several complex health, social, and legal issues in the United States. Marijuana is prohibited in only 23 states and promarijuana laws are likely to be introduced in these states in the future. Increased access to and legalization of medical marijuana may have an impact on recreational marijuana use and perception through increased availability and decreased restrictiveness around the drug. The authors undertook an analysis to characterize the policy features of medical marijuana legislation, including an emphasis on the types of medical conditions that are included in medical marijuana laws. A high degree of variability in terms of allowable medical conditions, limits on cultivation and possession, and restrictiveness of policies was discovered. Further research is needed to determine if this variability impacts recreational use in those states.