OBJECTIVE: To determine the levels and patterns of resistance to first- and second-line anti-tuberculosis (TB) drugs among new and previously treated sputum smear positive pulmonary TB (PTB) patients. METHODS: We conducted a nationally representative cross-sectional facility-based survey in June 2017-July 2018 involving 45 clusters selected based on probability proportional to size. The survey aimed to determine the prevalence of anti-TB drug resistance and associated risk factors among smear positive PTB patients in Tanzania. Sputum samples were examined using smear microscopy, Xpert MTB/RIF, culture and drug susceptibility testing (DST). Logistic regression was used to account for missing data and sampling design effects on the estimates and their standard errors. RESULTS: We enrolled 1557 TB patients, including 1408 (90.4%) newly diagnosed and 149 (9.6%) previously treated patients. The prevalence of multidrug-resistant TB (MDR-TB) was 0.85% [95% confidence interval (CI): 0.4-1.3] among new cases and 4.6% (95% CI: 1.1-8.2) among previously treated cases. The prevalence of Mycobacterium tuberculosis strains resistant to any of the four first-line anti-TB drugs (isoniazid, rifampicin, streptomycin and ethambutol) was 1.7% among new TB patients and 6.5% among those previously treated. Drug resistance to all first-line drugs was similar (0.1%) in new and previously treated patients. None of the isolates displayed poly-resistance or extensively drug-resistant TB (XDR-TB). The only risk factor for MDR-TB was history of previous TB treatment (odds ratio = 5.7, 95% CI: 1.9-17.2). CONCLUSION: The burden of MDR-TB in the country was relatively low with no evidence of XDR-TB. Given the overall small number of MDR-TB cases in this survey, it will be beneficial focusing efforts on intensified case detection including universal DST.

In 2012, the Centers for Disease Control and Prevention (CDC) established the Achieving Public Health Impact through Research (APHIR) contract mechanism. APHIR provides CDC's Centers, Institute, and Offices (CIOs) a mechanism that supports multiyear, high impact public health research. Awarded projects supported research on a wide range of topics (e.g., cancer surveillance, HIV education programs, development of biological assays, and evaluation of traumatic brain injury prevention programs) and achieved diverse outcomes (e.g., contribution to the body of knowledge in their field, changes in practice and health service delivery, and capacity building). This article describes how existing impact frameworks and a variety of methods and tools (key informant interviews, online survey, bibliometric analysis, Altmetric and document reviews) were used to identify the outcomes achieved by awarded projects. The approach discussed in this paper can be used to evaluate projects that involve a diversity of activities and outcomes.

Pyrazinamide is a potent sterilising agent that shortens the treatment duration needed to cure tuberculosis. It is synergistic with novel and existing drugs for tuberculosis. The dose of pyrazinamide that optimises efficacy while remaining safe is uncertain, as is its potential role in shortening treatment duration further.Pharmacokinetic data, sputum culture, and safety laboratory results were compiled from TBTC Studies 27 and 28 and PanACEA MAMS-TB, multi-center Phase 2 trials in which participants received rifampicin (range 10-35 mg·kg(-1)), pyrazinamide (range 20-30 mg·kg(-1)), plus two companion drugs. Pyrazinamide pharmacokinetic-pharmacodynamic (PK/PD) and PK-toxicity analyses were performed.In TBTC studies (n=77), higher pyrazinamide maximum concentration (Cmax) was associated with shorter time to culture conversion (TTCC) and higher probability of two-month culture conversion (p-value<0.001). Parametric survival analyses showed that relationships varied geographically, with steeper PK-PD relationships seen among non-African than African participants. In PanACEA MAMS-TB (n=363), TTCC decreased as pyrazinamide Cmax increased and varied by rifampicin Cmax (p-value<0.01). Modeling and simulation suggested that very high doses of pyrazinamide (>4500 mg) or increasing both pyrazinamide and rifampicin would be required to reach targets associated with treatment shortening. Combining all trials, liver toxicity was rare (3.9% with Grade 3 or higher liver function tests, LFT), and no relationship was seen between pyrazinamide Cmax and LFT levels.Pyrazinamide's microbiologic efficacy increases with increasing drug concentrations. Optimising pyrazinamide alone, though, is unlikely to be sufficient to allow tuberculosis treatment shortening; rather, rifampicin dose would need to be increased in parallel.

Sporadic, yet frequent human infections with avian H5N1 influenza A viruses continue to pose a potential pandemic threat. Poor immunogenicity of unadjuvanted H5N1 vaccines warrants developing novel adjuvants and formulations as well as alternate delivery systems to improve their immunogenicity and efficacy. Here, we show that Protollin, a nasal adjuvant composed of Neisseria meningitides outer membrane proteins non-covalently linked to Shigella flexneri 2a lipopolysaccharide, is a potent nasal adjuvant for an inactivated split virion H5N1 clade 1 A/Viet Nam1203/2004 (A/VN/1203/04) vaccine in a mouse model. Protollin-adjuvanted vaccines elicited enhanced serum protective hemagglutination inhibition titers, mucosal IgA responses, and H5N1-specific cell-mediated immunity that resulted in complete protection against a lethal challenge with a homologous virus as well as a heterologous clade 2 virus A/Indonesia/05/2005 (A/IN/05/05). Detailed analysis of adaptive immunity revealed that Protollin increased the frequency of lymphoid- as well as local tissue-resident antibody-secreting cells, local germinal center reaction of B cells, broad-spectrum of CD4 T cell response. Our findings suggest that nasal delivery of H5N1 vaccine with Protollin adjuvant can overcome the poor immunogenicity of H5N1 vaccines, induce both cellular and humoral immune responses, enhance protection against challenge with clade 1 and clade 2 H5N1 viruses and achieve significant antigen dose-sparing.

Rapid progress has been made in the development of new diagnostic assays for tuberculosis in recent years. New technologies have been developed and assessed, and are now being implemented. The Xpert MTB/RIF assay, which enables simultaneous detection of Mycobacterium tuberculosis (MTB) and rifampicin (RIF) resistance, was endorsed by WHO in December, 2010. This assay was specifically recommended for use as the initial diagnostic test for suspected drug-resistant or HIV-associated pulmonary tuberculosis. By June, 2012, two-thirds of countries with a high tuberculosis burden and half of countries with a high multidrug-resistant tuberculosis burden had incorporated the assay into their national tuberculosis programme guidelines. Although the development of the Xpert MTB/RIF assay is undoubtedly a landmark event, clinical and programmatic effects and cost-effectiveness remain to be defined. We review the rapidly growing body of scientific literature and discuss the advantages and challenges of using the Xpert MTB/RIF assay in areas where tuberculosis is endemic. We also review other prospects within the developmental pipeline. A rapid, accurate point-of-care diagnostic test that is affordable and can be readily implemented is urgently needed. Investment in the tuberculosis diagnostics pipeline should remain a major priority for funders and researchers.

Research exploring the relationship between weight perception and depressed mood among adolescents is limited in the United States. The purpose of this study is to examine the association of perceived versus actual body weight and depressed mood in a representative sample of 8th and 11th grade public school students in Texas. Using data from the 2004-2005 School Physical Activity and Nutrition (SPAN) study, logistic regression analyses were conducted to assess the association of weight perception with depressed mood. Healthy weight students who perceived themselves to be a healthy weight were the reference group for all analyses. A high prevalence of misperception of body weight was observed. Overweight and obese 8th grade girls and boys who perceived themselves to be overweight had increased odds of depressed mood [Girls: OR 1.70 (95% CI: 1.07-2.69), Boys: OR 2.05 (95% CI: 1.16-3.62)]. Healthy weight 8th grade girls who perceived themselves to be overweight had 2.5 times greater odds of depressed mood (OR 2.63, 95% CI: 1.54-4.50). Healthy weight boys who perceived themselves to be underweight had more than twice the odds (OR 2.18, 95% CI: 1.23-3.89) of depressed mood. No weight category was significantly associated with depressed mood in boys or girls in 11th grade. The present study suggests that weight misperceptions are associated with depressed mood in young adolescents. Education about healthy body size is necessary to correct the common weight misperceptions observed. The high prevalence rates of depressed mood suggest a greater need for research into understanding factors that may contribute to depressed mood in adolescents.

BACKGROUND: To control the global HIV epidemic targeted interventions to reduce the incidence of HIV infections are urgently needed until an effective HIV vaccine is available. This study describes HIV-1 incidence and associated risk factors in a general population cohort of adults from Mbeya Region, Tanzania, who participated in a vaccine preparedness study. METHODS: We conducted a closed prospective cohort study with six-monthly follow-up from 2002-2006, enrolling adults from the general population. HIV-1 incidence and risk factors for HIV-1 acquisition were analysed using Cox regression. RESULTS: We observed 2,578 sero-negative participants for a mean period of 3.06 PY (7,471 PY in total). Overall HIV-1 incidence was 1.35 per 100 PY (95% confidence interval [CI]=1.10-1.64/100 PY). The highest overall HIV-1 incidence was found in females from Itende village (1.55 per 100 PY, 95%CI=0.99-2.30/100 PY), the highest age-specific incidence was observed in semi-urban males aged 30-34 years (2.75 per 100 PY, 95%CI=0.75-7.04). HIV-1 acquisition was independently associated with female gender (hazard ratio [HR]=1.64, 95%CI=1.05-2.57), younger age at enrolment (age 18-19 vs. 35-39: HR=0.29, 95%CI=0.11-0.75), alcohol consumption (almost daily vs. none: HR 2.01, 95%CI=1.00-4.07), education level (secondary school vs. none: HR 0.39, 95%CI=0.17-0.89) and number of lifetime sex partners (more than five vs. one: HR 2.22, 95%CI=1.13-4.36). CONCLUSIONS: A high incidence of HIV was observed in this cohort, and incident infection was strongly associated with young age, alcohol consumption, low school education level and number of sex partners. Targeted interventions are needed to address the elevated risk associated with these factors.

Diagnostic tests for detecting emerging influenza virus strains with pandemic potential are critical for directing global influenza prevention and control activities. In 2008, the Centers for Disease Control and Prevention received US Food and Drug Administration approval for a highly sensitive influenza polymerase chain reaction (PCR) assay. Devices were deployed to public health laboratories in the United States and globally. Within 2 weeks of the first recognition of 2009 pandemic influenza H1N1, the Centers for Disease Control and Prevention developed and began distributing a new approved pandemic influenza H1N1 PCR assay, which used the previously deployed device platform to meet a >8-fold increase in specimen submissions. Rapid antigen tests were widely used by clinicians at the point of care; however, test sensitivity was low (40%-69%). Many clinical laboratories developed their own pandemic influenza H1N1 PCR assays to meet clinician demand. Future planning efforts should identify ways to improve availability of reliable testing to manage patient care and approaches for optimal use of molecular testing for detecting and controlling emerging influenza virus strains.

BACKGROUND: Emergence of drug-resistant strains of influenza viruses, including avian H5N1 with pandemic potential, 1918 and 2009 A/H1N1 pandemic viruses to currently used antiviral agents, neuraminidase inhibitors and M2 Ion channel blockers, underscores the importance of developing novel antiviral strategies. Activation of innate immune pathogen sensor Retinoic Acid Inducible Gene-I (RIG-I) has recently been shown to induce antiviral state. RESULTS: In the present investigation, using real time RT-PCR, immunofluorescence, immunoblot, and plaque assay we show that 5'PPP-containing single stranded RNA (5PPP-RNA), a ligand for the intracytoplasmic RNA sensor, RIG-I can be used as a prophylactic agent against known drug-resistant avian H5N1 and pandemic influenza viruses. 5'PPP-RNA treatment of human lung epithelial cells inhibited replication of drug-resistant avian H5N1 as well as 1918 and 2009 pandemic influenza viruses in a RIG-I and type 1 interferon dependant manner. Additionally, 5'PPP-RNA treatment also inhibited 2009 H1N1 viral replication in vivo in mice. CONCLUSIONS: Our findings suggest that 5PPP-RNA mediated activation of RIG-I can suppress replication of influenza viruses irrespective of their genetic make-up, pathogenicity, and drug-sensitivity status.

BACKGROUND: Human immunodeficiency virus (HIV) vaccine development remains a global priority. We describe the safety and immunogenicity of a multiclade DNA vaccine prime with a replication-defective recombinant adenovirus serotype 5 (rAd5) boost. METHODS: The vaccine is a 6-plasmid mixture encoding HIV envelope (env) subtypes A, B, and C and subtype B gag, pol, and nef, and an rAd5 expressing identical genes, with the exception of nef. Three hundred and twenty-four participants were randomized to receive placebo (n=138), a single dose of rAd5 at 10(10) (n = 24) or 10(11) particle units (n = 24), or DNA at 0, 1, and 2 months, followed by rAd5 at either 10(10) (n= 114) or 10(11) particle units (n = 24) boosting at 6 months. Participants were followed up for 24 weeks after the final vaccination. RESULTS: The vaccine was safe and well tolerated. HIV-specific T cell responses were detected in 63% of vaccinees. Titers of preexisting Ad5 neutralizing antibody did not affect the frequency and magnitude of T cell responses in prime-boost recipients but did affect the response rates in participants that received rAd5 alone (P = .037). CONCLUSION: The DNA/rAd5 vaccination regimen was safe and induced HIV type 1 multi-clade T cell responses, which were not significantly affected by titers of preexisting rAd5 neutralizing antibody. Trial Registration. ClinicalTrials.gov identifier: NCT00123968 .