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There have been few independent evaluations of computer-aided detection (CAD) software for tuberculosis (TB) screening, despite the rapidly expanding array of available CAD solutions. We developed a test library of chest X-ray (CXR) images which was blindly re-read by two TB clinicians with different levels of experience and then processed by 12 CAD software solutions. Using Xpert MTB/RIF results as the reference standard, we compared the performance characteristics of each CAD software against both an Expert and Intermediate Reader, using cut-off thresholds which were selected to match the sensitivity of each human reader. Six CAD systems performed on par with the Expert Reader (Qure.ai, DeepTek, Delft Imaging, JF Healthcare, OXIPIT, and Lunit) and one additional software (Infervision) performed on par with the Intermediate Reader only. Qure.ai, Delft Imaging and Lunit were the only software to perform significantly better than the Intermediate Reader. The majority of these CAD software showed significantly lower performance among participants with a past history of TB. The radiography equipment used to capture the CXR image was also shown to affect performance for some CAD software. TB program implementers now have a wide selection of quality CAD software solutions to utilize in their CXR screening initiatives.

To characterize the genetic determinants of resistance to antituberculosis drugs, we performed a genome-wide association study (GWAS) of 6,465 Mycobacterium tuberculosis clinical isolates from more than 30 countries. A GWAS approach within a mixed-regression framework was followed by a phylogenetics-based test for independent mutations. In addition to mutations in established and recently described resistance-associated genes, novel mutations were discovered for resistance to cycloserine, ethionamide and para -aminosalicylic acid. The capacity to detect mutations associated with resistance to ethionamide, pyrazinamide, capreomycin, cycloserine and para -aminosalicylic acid was enhanced by inclusion of insertions and deletions. Odds ratios for mutations within candidate genes were found to reflect levels of resistance. New epistatic relationships between candidate drug-resistance-associated genes were identified. Findings also suggest the involvement of efflux pumps ( drrA and Rv2688c ) in the emergence of resistance. This study will inform the design of new diagnostic tests and expedite the investigation of resistance and compensatory epistatic mechanisms. A GWAS of multi- and extensively drug-resistant tuberculosis using 6,465 Mycobacterium tuberculosis clinical isolates from more than 30 countries identifies novel mutations associated with resistance. The capacity to detect resistance in particular to ethionamide, pyrazinamide, capreomycin, cycloserine and paraaminosalicylic acid was enhanced by inclusion of insertions and deletions.

To examine the transmission dynamics of Mycobacterium tuberculosis (Mtb) isolated from tuberculosis patients in Ho Chi Minh City, Vietnam, we sequenced the whole genomes of 1,635 isolates and compared these with 3,144 isolates from elsewhere. The data identify an underlying burden of disease caused by the endemic Mtb lineage 1 associated with the activation of long-term latent infection, and a threefold higher burden associated with the more recently introduced Beijing lineage and lineage 4 Mtb strains. We find that Beijing lineage Mtb is frequently transferred between Vietnam and other countries, and detect higher levels of transmission of Beijing lineage strains within this host population than the endemic lineage 1 Mtb. Screening for parallel evolution of Beijing lineage-associated SNPs in other Mtb lineages as a signal of positive selection, we identify an alteration in the ESX-5 type VII-secreted protein EsxW, which could potentially contribute to the enhanced transmission of Beijing lineage Mtb in Vietnamese and other host populations. Genomic analysis of Mycobacterium tuberculosis (Mtb) isolated from tuberculosis patients identifies the transmission dynamics of Mtb in Vietnam including frequent transmission of Beijing lineage and positive selection for EsxW Beijing variant.

Tuberculous meningitis remains highly lethal. In this trial, an intensified regimen of levofloxacin and higher-dose rifampin added to standard therapy was compared with standard antituberculosis therapy alone. The intensified regimen did not result in a higher survival rate. Early treatment with antituberculosis chemotherapy and adjunctive treatment with glucocorticoids reduce the rate of death and disability from tuberculous meningitis, but the disease still kills or disables almost half the patients with the condition. 1 , 2 The current guidelines recommend treatment with four antituberculosis drugs for at least the first 2 months of therapy, followed by treatment with two drugs (rifampin and isoniazid) for an additional 7 to 10 months. 3 , 4 However, these recommendations are based on data from pulmonary tuberculosis and do not take into account the differential ability of antituberculosis drugs to penetrate the brain. Rifampin is considered to . . .

ObjectiveTo explore antecedents, components and influencing factors on active case-finding (ACF) policy development and implementation.DesignScoping review, searching MEDLINE, Web of Science, the Cochrane Database of Systematic Reviews and the World Health Organization (WHO) Library from January 1968 to January 2018. We excluded studies focusing on latent tuberculosis (TB) infection, passive case-finding, childhood TB and studies about effectiveness, yield, accuracy and impact without descriptions of how this evidence has/could influence ACF policy or implementation. We included any type of study written in English, and conducted frequency and thematic analyses.ResultsSeventy-three articles fulfilled our eligibility criteria. Most (67%) were published after 2010. The studies were conducted in all WHO regions, but primarily in Africa (22%), Europe (23%) and the Western-Pacific region (12%). Forty-one percent of the studies were classified as quantitative, followed by reviews (22%) and qualitative studies (12%). Most articles focused on ACF for tuberculosis contacts (25%) or migrants (32%). Fourteen percent of the articles described community-based screening of high-risk populations. Fifty-nine percent of studies reported influencing factors for ACF implementation; mostly linked to the health system (eg, resources) and the community/individual (eg, social determinants of health). Only two articles highlighted factors influencing ACF policy development (eg, politics). Six articles described WHO’s ACF-related recommendations as important antecedent for ACF. Key components of successful ACF implementation include health system capacity, mechanisms for integration, education and collaboration for ACF.ConclusionWe identified some main themes regarding the antecedents, components and influencing factors for ACF policy development and implementation. While we know much about facilitators and barriers for ACF policy implementation, we know less about how to strengthen those facilitators and how to overcome those barriers. A major knowledge gap remains when it comes to understanding which contextual factors influence ACF policy development. Research is required to understand, inform and improve ACF policy development and implementation.

Menstrual Health (MH) knowledge, attitude and practice (KAP) are highly affected by access to information regarding menstruation. Despite being included in the school curriculum, Sexual and Reproductive Health (SRH) education is often not delivered in practice. School-based educational interventions have been shown to be effective in promoting MH. A school-based study was conducted in Indrawati rural municipality of Sindhupalchowk district in Nepal. 427 participants (175 boys and 252 girls), aged 11-13, completed a questionnaire evaluating MH KAP before receiving a structured training module on MH provided by experienced trainers from Putali Nepal using the Menstrupedia tool. The questionnaire was repeated one month after the training. Pre and post intervention scores were compared to determine the effect of the intervention. Focus group discussions were also conducted to understand the perceptions of participants toward SRH teaching. Association of independent socio-demographic with dependent variables knowledge and attitude towards menstrual health were analyzed using MANOVA test. The Wilcoxon signed-rank test was used to compare the median outcome of the pre and post-test attitude and knowledge. The maximum possible score was 6 for MH knowledge. The total attitude score ranged 14 to 70. The median knowledge score increased by 1 point (p = <0.001) and the median attitude score by 5 points (p = <0.001), one month after delivery of the intervention. Higher knowledge scores were significantly associated with Hindu religion, female gender, higher father's literacy, and mothers in an informal occupation on multivariate analysis. Higher attitude scores were significantly associated with Hindu religion while lower attitude scores were associated with a mother in an informal occupation. The Menstrupedia comic educational intervention improved knowledge and attitude towards menstruation among Nepali adolescents. A scale-up of the Menstrupedia based intervention would significantly change knowledge and attitude towards menstruation in Nepali adolescents.

Active case-finding (ACF), also referred to as community-based tuberculosis screening, is a component of the World Health Organization's End TB Strategy. ACF has potential benefits but also harms, which need to be carefully assessed when developing and implementing ACF policies. While empirical evidence on the benefits of ACF is still weak, evidence on the harms is even weaker. This study aimed to explore experts' views on the benefits and harms of ACF for people with presumptive TB and communities. This was an exploratory study. Semi-structured interviews were conducted with a purposive sample of 39 experts from international, non-governmental/non-profit organizations, funders, government institutions, international societies, think tanks, universities and research institutions worldwide. Framework analysis was applied. Findings elaborated perceived benefits of ACF, including reaching vulnerable populations, reducing patient costs, helping raise awareness for tuberculosis among individuals and engaging communities, and reducing tuberculosis transmission. Perceived harms included increasing stigma and discrimination, causing false-positive diagnoses, as well as triggering other unintended consequences related to screening for tuberculosis patients, such as deportation of migrants once confirmed to have tuberculosis. Most of the perceived benefits of ACF could be linked to its objective of finding and treating persons with tuberculosis early (theme 1), while ACF was also perceived as a \"double-edged sword\" and could cause harms, if inappropriately designed and implemented (theme 2). The analysis underlined the importance of considering the benefits and harms of ACF throughout the screening pathway. The study provides new insights into the perceived benefits and harms of ACF from the perspectives of experts in the field. This study highlights gaps in the evidence base surrounding ACF and can stimulate further research, debate and analysis regarding the benefits and harms of ACF to inform contextual optimization of design and implementation of ACF strategies.

The World Health Organization (WHO) stresses the importance of active case-finding (ACF) for early detection of tuberculosis (TB), especially in the 30 high-burden countries that account for almost 90% of cases globally. To describe the attitudes of National TB Programme (NTP) managers related to ACF policy development, implementation and scale-up in the 30 high-burden countries, and to review national TB strategic plans. This was a mixed-methods study with an embedded design: A cross-sectional survey with NTP managers yielded quantitative and qualitative data. A review of national TB strategic plans complemented the results. All data were analyzed in parallel and merged in the interpretation of the findings. 23 of the 30 NTP managers (77%) participated in the survey and 22 (73%) national TB strategic plans were reviewed. NTP managers considered managers in districts and regions key stakeholders for both ACF policy development and implementation. Different types of evidence were used to inform ACF policy, while there was a particular demand for local evidence. The NSPs reflected the NTP managers' unanimous agreement on the need for ACF scale-up, but not all included explicit aims and targets related to ACF. The NTP managers recognized that ACF may decrease health systems costs in the long-term, while acknowledging the risk for increased health system costs in the short-term. About 90% of the NTP managers declared that financial and human resources were currently lacking, while they also elaborated on strategies to overcome resource constraints. NTP managers stated that ACF should be scaled up but reported resource constraints. Strategies to increase resources exist but may not yet have been fully implemented, e.g. generating local evidence including from operational research for advocacy. Managers in districts and regions were identified as key stakeholders whose involvement could help improve ACF policy development, implementation and scale-up.

Background Tuberculosis (TB) remains the most common cause of infectious disease deaths worldwide. What is perhaps less appreciated is that the caseload of tuberculosis patients in South Asia is staggering. South Asia has almost 40% of the global TB burden with 4,028,165 cases in 2015. This region also has a disproportionate share of TB deaths (681,975 deaths, 38% of the global burden). Worldwide just 12.5% of TB cases are in HIV positive individuals, but much research and investment has focused on HIV-associated TB. Only 3.5% of patients with tuberculosis in South Asia have HIV co-infection. Not surprisingly with such a huge burden of disease, this region has an estimated 184,336 multi drug resistant (MDR) cases among notified TB cases which accounts for a third of global MDR burden. Crucially, at least 70% of the estimated MDR cases remain untreated in this region and MDR treatment success ranged from only 46% for India to 88% for Sri Lanka in the 2012 cohort that received treatment. This region represents many of the drivers of the modern TB epidemic: rapid urbanization and high density populations with dramatically rising incidence of diabetes, a burgeoning and largely unregulated private sector with escalating drug resistance and high air pollution both outdoor and household. Conclusion From bacterial biochemistry to policy implementation, we suggest ways in which South Asia can seize the opportunity lead global TB elimination by demonstrating feasibility in some of the world’s most densely populated cities and remotest reaches of the Himalayas. Clearly political will is essential, but we cannot defeat TB without understanding how to eliminate it in South Asia.

Antibiotic tolerance in Mycobacterium tuberculosis reduces bacterial killing, worsens treatment outcomes, and contributes to resistance. We studied rifampicin tolerance in isolates with or without isoniazid resistance (IR). Using a minimum duration of killing assay, we measured rifampicin survival in isoniazid-susceptible (IS, n=119) and resistant (IR, n=84) isolates, correlating tolerance with bacterial growth, rifampicin minimum inhibitory concentrations (MICs), and isoniazid-resistant mutations. Longitudinal IR isolates were analyzed for changes in rifampicin tolerance and genetic variant emergence. The median time for rifampicin to reduce the bacterial population by 90% (MDK90) increased from 1.23 days (IS) and 1.31 days (IR) to 2.55 days (IS) and 1.98 days (IR) over 15–60 days of incubation, indicating fast and slow-growing tolerant sub-populations. A 6 log10-fold survival fraction classified tolerance as low, medium, or high, showing that IR is linked to increased tolerance and faster growth (OR = 2.68 for low vs. medium, OR = 4.42 for low vs. high, p-trend = 0.0003). High tolerance in IR isolates was associated with rifampicin treatment in patients and genetic microvariants. These findings suggest that IR tuberculosis should be assessed for high rifampicin tolerance to optimize treatment and prevent the development of multi-drug-resistant tuberculosis.