Search

Understanding factors associated with increased risk for tuberculosis (TB) recurrence is essential in lowering the TB burden. We aimed to quantify the burden, risk factors, and timing of TB presumptive recurrence.We analyzed test results from 2013 to 2017 in the South African National Health Laboratory Service's database. We defined a person's TB episode to start with their first positive TB test. In the absence of treatment outcome data, we assumed the episode concluded 6 months later for rifampicin-susceptible TB (RS-TB) and 18 months later for rifampicin-resistant TB (RR-TB), provided that at least one negative smear or culture test was recorded within this period. We defined a presumptive recurrent TB episode to start with a positive TB test after the completion of a prior episode. We calculated recurrence measures stratified by various demographics and RR-TB status.Of 574,316 people with RS-TB, 4.7% experienced at least one presumptive recurrent TB episode. Higher local TB notification rates, HIV coinfection, and males experienced higher recurrence rates. Most (89.4%) of the first RS-TB recurrences occurred within a year of the initial episode.Our findings of when and among whom recurrent TB is more likely to occur can be used to assist early interventions and inform impact on patient care..

Places of worship serve as a venue for both mass and routine gathering around the world, and therefore are associated with risk of large-scale SARS-CoV-2 transmission. However, such routine gatherings also offer an opportunity to distribute self-tests to members of the community to potentially help mitigate transmission and reduce broader community spread of SARS-CoV-2. Over the past four years, self-testing strategies have been an impactful tool for countries' response to the COVID-19 pandemic, especially early on to mitigate the spread when vaccination and treatment options were limited. We used an agent-based mathematical model to estimate the impact of various strategies of symptomatic and asymptomatic self-testing for a fixed percentage of weekly routine gatherings at places of worship on community transmission of SARS-CoV-2 in Brazil, Georgia, and Zambia. Testing strategies assessed included weekly and bi-weekly self-testing across varying levels of vaccine effectiveness, vaccine coverage, and reproductive numbers to simulate developing stages of the COVID-19 pandemic. Self-testing symptomatic people attending routine gatherings can cost-effectively reduce the spread of SARS-CoV-2 within places of worship and the community, resulting in incremental cost-effectiveness ratios of $69-$303 USD. This trend is especially true in contexts where population level attendance at such gatherings is high, demonstrating that a distribution approach is more impactful when a greater proportion of the population is reached. Asymptomatic self-testing of attendees at 100% of places of worship in a country results in the greatest percent of infections averted and is consistently cost-effective but remains costly. Budgetary needs for asymptomatic testing are expensive and likely unaffordable for lower-middle income countries (520-1550x greater than that of symptomatic testing alone), promoting that strategies to strengthen symptomatic testing should remain a higher priority., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. The views expressed in this manuscript are those of the authors and do not necessarily represent the official position of the WHO., (Copyright: © 2024 Hansen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Implicit statistical learning, whereby predictable relationships between stimuli are detected without conscious awareness, is important for language acquisition. However, while this process is putatively implicit, it is often assessed using measures that require explicit reflection and conscious decision making. Here, we conducted three experiments combining an artificial grammar learning paradigm with a serial reaction time (SRT-AGL) task, to measure statistical learning of adjacent and nonadjacent dependencies implicitly, without conscious decision making. Participants viewed an array of six visual stimuli and were presented with a sequence of three auditory (nonsense words, Expt. 1; names of familiar objects, Expt. 2) or visual (abstract shapes, Expt. 3) cues and were asked to click on the corresponding visual stimulus as quickly as possible. In each experiment, the final stimulus in the sequence was predictable based on items earlier in the sequence. Faster responses to this predictable final stimulus compared to unpredictable stimuli would provide evidence of implicit statistical learning, without requiring explicit decision making or conscious reflection. Despite previous positive results (Christiansen et al. 2009 and Misyak et al. 2010) we saw little evidence of implicit statistical learning in any of the experiments, suggesting that in this case, these SRT-AGL tasks were not an effective measure implicit statistical learning., Competing Interests: This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Jenkins et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In the United States, tuberculosis (TB) screening is recommended for pregnant individuals with TB risk factors. We conducted a retrospective study of perinatal TB infection testing and treatment in a tertiary health system. Of 165 pregnant individuals with positive TB infection tests, only 9% completed treatment within 4.6 years of follow-up., Competing Interests: Potential conflicts of interest. All authors: No potential conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: We assessed the impact of the COVID-19 pandemic on TB notifications in Ukraine, stratified by multiple subgroups., Design/methods: We analyzed data from Ukraine's National TB Program from January 2015 to December 2020 using interrupted time series models. We compared observed cases to counterfactual estimated cases had the pandemic not occurred and estimated trends through December 2020 nationally and by various demographics. We compared the proportions of individuals who underwent drug susceptibility testing (DST) in February 2020 and April 2020 to assess the pandemic impact on drug resistance testing., Results: In April 2020, there were 39% (95% CI 36-42) fewer TB notifications than the estimated counterfactual (3,060 estimated; 95% CI 2,918-3,202; 1,872 observed). We observed a greater decrease in notifications among refugees/migrants compared with non-refugees/migrants (64%, 95% CI 60-67 vs. 39%, 95% CI 36-42), and individuals aged <15 years compared with those aged ≥15 years (60%, 95% CI 57-64 vs. 38%, 95% CI 36-41). We also observed a decrease in the proportion of individuals receiving DST for several drugs., Conclusions: These findings underscore the challenges to TB prevention and care during disruption and may be generalizable to the current wartime situation, especially considering the substantial increase in refugees within and leaving Ukraine., (© 2024 The Authors.)

There is substantial heterogeneity in disease presentation for individuals with TB disease, which may correlate with disease outcomes. We estimated disease outcomes by disease severity at presentation among individuals with TB during the pre-chemotherapy era.We extracted data on people with TB enrolled between 1917 and 1948 in the USA, stratified by three disease severity categories at presentation using the U.S. National Tuberculosis Association diagnostic criteria. These criteria were based largely on radiographic findings ("minimal", "moderately advanced", and "far advanced"). We used Bayesian parametric survival analysis to model the survival distribution overall, and by disease severity and Bayesian logistic regression to estimate the severity-level specific natural recovery odds within 3 years.People with minimal TB at presentation had a 2% (95% CrI 0-11%) probability of TB death within 5 years vs. 40% (95% CrI 15-68) for those with far advanced disease. Individuals with minimal disease had 13.62 times the odds (95% CrI 9.87-19.10) of natural recovery within 3 years vs. those with far advanced disease.Mortality and natural recovery vary by disease severity at presentation. This supports continued work to evaluate individualized (e.g., shortened or longer) regimens based on disease severity at presentation, identified using radiography..

Objectives: To determine the most epidemiologically effective and cost-effective school-based SARS-CoV-2 antigen-detection rapid diagnostic test (Ag-RDT) self-testing strategies among teachers and students., Design: Mathematical modelling and economic evaluation., Setting and Participants: Simulated school and community populations were parameterised to Brazil, Georgia and Zambia, with SARS-CoV-2 self-testing strategies targeted to teachers and students in primary and secondary schools under varying epidemic conditions., Interventions: SARS-CoV-2 Ag-RDT self-testing strategies for only teachers or teachers and students-only symptomatically or symptomatically and asymptomatically at 5%, 10%, 40% or 100% of schools at varying frequencies., Outcome Measures: Outcomes were assessed in terms of total infections and symptomatic days among teachers and students, as well as total infections and deaths within the community under the intervention compared with baseline. The incremental cost-effectiveness ratios (ICERs) were calculated for infections prevented among teachers and students., Results: With respect to both the reduction in infections and total cost, symptomatic testing of all teachers and students appears to be the most cost-effective strategy. Symptomatic testing can prevent up to 69·3%, 64·5% and 75·5% of school infections in Brazil, Georgia and Zambia, respectively, depending on the epidemic conditions, with additional reductions in community infections. ICERs for symptomatic testing range from US$2 to US$19 per additional school infection averted as compared with symptomatic testing of teachers alone., Conclusions: Symptomatic testing of teachers and students has the potential to cost-effectively reduce a substantial number of school and community infections., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patient and public involvement (PPI) in healthcare professional education is important, yet publications often provide insufficient detail about the types of involvement patients undertake and the level of autonomy that they have. This study details the factors that promote or hinder PPI within a university healthcare professional education setting and the types of activities members conducted., Methods: PPI activities were described and mapped against a framework for PPI in healthcare professional education. Semi-structured interviews with PPI group members explored the motivators, enablers and barriers that influence involvement., Findings: The framework highlighted that the PPI group were involved in a range of activities, yet they received limited training for their role and were infrequently involved in planning the activities. When interviewed, PPI members did not consider that these factors were the important promoters or barriers to involvement, instead emphasising five themes: (1) their individual characteristics, (2) factors relating to the university organisation, (3) relationships between themselves, faculty and students, (4) time in their role and (5) evidence of their impact., Discussion and Conclusion: Supporting PPI members whilst working, rather than provision of formal training was considered most empowering for group members. This was mediated through having enough time in their role to develop supportive relationships with faculty, which in turn promoted self-confidence and increased autonomy. This should be considered when making PPI appointments. Small changes in processes during education planning can make it easier for PPI members to bring their own agenda forward and promote equity during education decision making., (© 2023 The Authors. The Clinical Teacher published by Association for the Study of Medical Education and John Wiley & Sons Ltd.)

The National Health Laboratory Service (NHLS) collects all public health laboratory test results in South Africa, providing a cohort from which to identify groups, by age, sex, HIV, and viral suppression status, that would benefit from increased tuberculosis (TB) testing. Using NHLS data (2012-2016), we assessed levels and trends over time in TB diagnostic tests performed (count and per capita) and TB test positivity. Estimates were stratified by HIV status, viral suppression, age, sex, and province. We used logistic regression to estimate the odds of testing positive for TB by viral suppression status. Nineteen million TB diagnostic tests were conducted during period 2012-2016. Testing per capita was lower among PLHIV with viral suppression than those with unsuppressed HIV (0.08 vs 0.32) but lowest among people without HIV (0.03). Test positivity was highest among young adults (aged 15-35 years), males of all age groups, and people with unsuppressed HIV. Test positivity was higher for males without laboratory evidence of HIV than those with HIV viral suppression, despite similar individual odds of TB. Our results are an important national baseline characterizing who received TB testing in South Africa. People without evidence of HIV, young adults, and males would benefit from increased TB screening given their lower testing rates and higher test positivity. These high-test positivity groups can be used to guide future expansions of TB screening., (© 2023. The Author(s).)

An investigation was carried out to examine the use of national Xpert MTB/RIF data (2013-2017) and GIS technology for MTB/RIF surveillance in South Africa. The aim was to exhibit the potential of using molecular diagnostics for TB surveillance across the country. The variables analysed include Mycobacterium tuberculosis ( Mtb ) positivity, the mycobacterial proportion of rifampicin-resistant Mtb (RIF), and probe frequency. The summary statistics of these variables were generated and aggregated at the facility and municipal level. The spatial distribution patterns of the indicators across municipalities were determined using the Moran's I and Getis Ord (Gi) statistics. A case-control study was conducted to investigate factors associated with a high mycobacterial load. Logistic regression was used to analyse this study's results. There was striking spatial heterogeneity in the distribution of Mtb and RIF across South Africa. The median patient age, urban setting classification, and number of health care workers were found to be associated with the mycobacterial load. This study illustrates the potential of using data generated from molecular diagnostics in combination with GIS technology for Mtb surveillance in South Africa. Spatially targeted interventions can be implemented in areas where high-burden Mtb persists.

BACKGROUND: An estimated 40% of people who developed TB in 2021 were not diagnosed or treated. Pre-chemotherapy era data are a rich resource on survival of people with untreated TB. We aimed to identify heterogeneities in these data to inform their more precise use. METHODS: We extracted survival data from pre-chemotherapy era papers reporting TB-specific mortality and/or natural recovery data. We used Bayesian parametric survival analysis to model the survival distribution, stratifying by geography (North America vs. Europe), time (pre-1930 vs. post-1930), and setting (sanitoria vs. non-sanitoria). RESULTS: We found 12 studies with TB-specific mortality data. Ten-year survival was 69% in North America (95% CI 54-81) and 36% in Europe (95% CI 10-71). Only 38% (95% CI 18-63) of non-sanitorium individuals survived to 10 years compared to 69% (95% CI 41-87) of sanitoria/hospitalized patients. There were no significant differences between people diagnosed pre-1930 and post-1930 (5-year survival pre-1930: 65%, 95% CI 44-88 vs. post-1930: 72%, 95% CI 41-94). CONCLUSIONS: Mortality and natural recovery risks vary substantially by location and setting. These heterogeneities need to be considered when using pre-chemotherapy data to make inferences about expected survival of people with undiagnosed TB.

Background: Public health interventions that target children's physical, mental, and emotional health will enhance their ability to learn and grow. Although more complex, school initiatives that address multiple ecological levels and take a holistic view may be more effective and likely to lead to lasting change., Aims: This article presents the framework of Commit to Be Fit (C2BF) as an example of how schools can integrate multi-level and holistic approaches for health. This innovative school-based intervention includes activities addressing individual, home, school, and community to create a culture of wellness. We describe the implementation of C2BF and its basis in ecological models and give examples of activities across three components: cafeteria, classroom, and community. We discuss challenges and note that leadership engagement and alignment were critical elements for C2BF's success thus far., Discussion: C2BF uses a school-based multi-level approach to creating a culture of wellness and holistic health for students, teachers, and community members. C2BF is unique compared to other school-based programming and includes activities that address all eight domains posited for program sustainability within public health. Built to be flexible and adaptive, C2BF was able to successfully pivot during the COVID pandemic and also follow new science., Conclusion: C2BF and other multi-level holistic approaches are more likely to achieve long-term change by utilizing strategies across the multiple levels of the ecological model to improve health and wellbeing., Competing Interests: HJ, JT, and AB are RCPS employees who received at least partial salary support from the PATH Foundation through the C2BF grant. SG is the RCPS superintendent and received no compensation from PATH. HJ, JT, AB, and SG were not involved in data analyses outside of the participatory analysis in the Enhanced Force Field Analysis. LW, AR, and DP were contracted by the PATH Foundation to provide evaluation support for C2BF. KD and ME are employees of the PATH Foundation but did not have a role in the evaluation design, data collection, analysis, or interpretation of the findings that were the basis for this publication, and their support as C2BF program officers was critical to its implementation and success; however, their roles in this publication were limited to providing feedback on the final draft. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Redelfs, Smith, Merrill, Grimsley, Jenkins, Tederick, Butler, Dueck, Eastham Thomas, Perez and Whigham.)

Human migration facilitates the spread of infectious disease. However, little is known about the contribution of migration to the spread of tuberculosis in South Africa. We analyzed longitudinal data on all tuberculosis test results recorded by South Africa's National Health Laboratory Service (NHLS), January 2011-July 2017, alongside municipality-level migration flows estimated from the 2016 South African Community Survey. We first assessed migration patterns in people with laboratory-diagnosed tuberculosis and analyzed demographic predictors. We then quantified the impact of cross-municipality migration on tuberculosis incidence in municipality-level regression models. The NHLS database included 921,888 patients with multiple clinic visits with TB tests. Of these, 147,513 (16%) had tests in different municipalities. The median (IQR) distance travelled was 304 (163 to 536) km. Migration was most common at ages 20-39 years and rates were similar for men and women. In municipality-level regression models, each 1% increase in migration-adjusted tuberculosis prevalence was associated with a 0.47% (95% CI: 0.03% to 0.90%) increase in the incidence of drug-susceptible tuberculosis two years later, even after controlling for baseline prevalence. Similar results were found for rifampicin-resistant tuberculosis. Accounting for migration improved our ability to predict future incidence of tuberculosis., (© 2023. The Author(s).)

Background: Modeling studies have concluded that 60-80% of tuberculosis (TB) infections result from reinfection of previously infected persons. The annual rate of infection (ARI), a standard measure of the risk of TB infection in a community, may not accurately reflect the true risk of infection among previously infected persons. We constructed a model of infection and reinfection with Mycobacterium tuberculosis to explore the predictive accuracy of ARI and its effect on disease incidence., Methods: We created a deterministic simulation of the progression from TB infection to disease and simulated the prevalence of TB infection at the beginning and end of a theoretical year of infection. We considered 10 disease prevalence scenarios ranging from 100/100 000 to 1000/100 000 in simulations where TB exposure probability was homogeneous across the whole simulated population or heterogeneously stratified into high-risk and low-risk groups. ARI values, rates of progression from infection to disease, and the effect of multiple reinfections were obtained from published studies., Results: With homogeneous exposure risk, observed ARI values produced expected numbers of infections. However, when heterogeneous risk was introduced, observed ARI was seen to underestimate true ARI by 25-58%. Of the cases of TB disease that occurred, 36% were among previously infected persons when prevalence was 100/100 000, increasing to 79% of cases when prevalence was 1000/100 000., Conclusions: Measured ARI underestimates true ARI as a result of heterogeneous population mixing. The true force of infection in a community may be greater than previously appreciated. Hyperendemic communities likely contribute disproportionally to the global TB disease burden., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Improved understanding of the epidemiology and mortality risk factors of extrapulmonary tuberculosis (EPTB) may facilitate successful diagnosis and management., Methods: We analyzed national surveillance data from Ukraine to characterize EPTB subtypes (ie, localized in different anatomic sites). We calculated annual reported incidence, stratified by age, sex, and human immunodeficiency virus (HIV) status. Using Cox regression, we estimated mortality risk factors., Results: Between January 2015 and November 2018, 14 062 adults/adolescents (≥15 years) and 417 children (<15 years) had EPTB with or without concomitant pulmonary TB. The most commonly reported EPTB subtypes were pleural, peripheral lymph node, and osteoarticular. Most EPTB subtype notifications peaked at age 30-39 years and were higher in males. In adults/adolescents, most peripheral TB lymphadenitis, central nervous system (CNS) TB, and abdominal TB occurred in those with untreated HIV. CNS TB notifications in people without HIV peaked before age 5 years. Adults/adolescents with CNS TB (adjusted hazard ratio [aHR]: 3.22; 95% CI: 2.89-3.60) and abdominal TB (aHR: 1.83; 95% CI: 1.59-2.11) were more likely to die than those with pulmonary TB. Children with CNS TB were more likely to die (aHR: 88.25; 95% CI: 43.49-179.10) than those with non-CNS TB. Among adults/adolescents, older age and HIV were associated with death. Rifampicin resistance was associated with mortality in pleural, peripheral lymph node, and CNS TB., Conclusions: We identified the most common EPTB subtypes by age and sex, patterns of EPTB disease by HIV status, and mortality risk factors. These findings can inform diagnosis and care for people with EPTB., Competing Interests: Potential conflicts of interest. E. J. C. serves on the Technical Review Committee of Unitaid and the Training Division of the International Union Against Tuberculosis and Lung Disease (IUATLD). C. R. H. serves on the data safety monitoring board, the safety advisory board, and the steering committee of BEAT-Tuberculosis, TB PRACTECAL, and STREAM, respectively. He also serves as Vice President of the North American Region of the IUATLD. M. D. reports providing expert support in development of the national tuberculosis (TB) care standard. V. P. reports being a member of the TB Expert Board of Ministry of Health of Ukraine. I. T. reports being a lead of NTP or Ukraine and is responsible for TB-related data analysis and presenting. I. V. reports being a member of Ukrainian NTP team and being responsible for TB-related data analysis and presenting. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Mobile screening units can help close tuberculosis case detection gaps. Placing screening units where people at high risk for undiagnosed tuberculosis preferentially spend time could make screening more resource-effective. We conducted a case-control study in Lima, Peru to identify locations where people with tuberculosis were more likely to spend time than community controls. We surveyed participants about activity locations over the past 6 months. We used density-based clustering to assess how patient and control activity locations differed, and logistic regression to compare location-based exposures. We included 109 tuberculosis patients and 79 controls. In density-based clustering analysis, the two groups had similar patterns of living locations, but their work locations clustered in distinct areas. Both groups were similarly likely to use public transit, but patients predominantly used buses and were less likely to use rapid transit (adjusted odds ratio [aOR] 0.31, 95% confidence interval [CI] 0.10-0.96) or taxis (aOR 0.42, 95% CI 0.21-0.85). Patients were more likely to have spent time in prison (aOR 11.55, 95% CI 1.48-90.13). Placing mobile screening units at bus terminals serving locations where tuberculosis patients have worked and within and around prisons could help reach people with undiagnosed tuberculosis., (© 2022. The Author(s).)

The generation interval (the time between infection of primary and secondary cases) and its often used proxy, the serial interval (the time between symptom onset of primary and secondary cases) are critical parameters in understanding infectious disease dynamics. Because it is difficult to determine who infected whom, these important outbreak characteristics are not well understood for many diseases. We present a novel method for estimating transmission intervals using surveillance or outbreak investigation data that, unlike existing methods, does not require a contact tracing data or pathogen whole genome sequence data on all cases. We start with an expectation maximization algorithm and incorporate relative transmission probabilities with noise reduction. We use simulations to show that our method can accurately estimate the generation interval distribution for diseases with different reproductive numbers, generation intervals, and mutation rates. We then apply our method to routinely collected surveillance data from Massachusetts (2010-2016) to estimate the serial interval of tuberculosis in this setting., (© The Author 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Annually, more than 30% of individuals with tuberculosis (TB) remain undiagnosed. We aimed to assess whether geographic accessibility measures can identify neighborhoods that would benefit from TB screening services targeted toward closing the diagnosis gap., Methods: We used data from a community-based mobile TB screening program in Carabayllo district, Lima, Peru. We constructed four accessibility measures from the geographic center of neighborhoods to health facilities. We used logistic regression to assess the association between these measures and screening uptake in one's residential neighborhood versus elsewhere, with quasi-information criterion values to assess the association., Results: We analyzed the screening locations for 25,000 Carabayllo residents from 49 neighborhoods. Pedestrian walk time was preferable to Euclidean distance or vehicular time in our models. For each additional 12 minutes walking time between the neighborhood and the health facility, the odds of residents using TB screening units located in their neighborhoods increased by 50% (95% CI: 26%-78%). Females had 9% (95% CI: 3%-16%) increased odds versus males of using a screening unit in their own neighborhood., Conclusion: Placing mobile TB screening units in neighborhoods with longer pedestrian time to access health facilities could benefit individuals who face more acute access barriers to health care., Competing Interests: Conflicts of interest The authors have no competing interests to declare., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Tuberculosis (TB) remains a leading infectious disease killer globally. Treatment outcomes are especially poor among people with extensively drug-resistant (XDR) TB, until recently defined as rifampicin-resistant (RR) TB with resistance to an aminoglycoside (amikacin) and a fluoroquinolone (ofloxacin). We used laboratory TB test results from Western Cape province, South Africa between 2012 and 2015 to identify XDR-TB and pre-XDR-TB (RR-TB with resistance to one second-line drug) spatial hotspots. We mapped the percentage and count of individuals with RR-TB that had XDR-TB and pre-XDR-TB across the province and in Cape Town, as well as amikacin-resistant and ofloxacin-resistant TB. We found the percentage of pre-XDR-TB and the count of XDR-TB/pre-XDR-TB highly heterogeneous with geographic hotspots within RR-TB high burden areas, and found hotspots in both percentage and count of amikacin-resistant and ofloxacin-resistant TB. The spatial distribution of percentage ofloxacin-resistant TB hotspots was similar to XDR-TB hotspots, suggesting that fluoroquinolone-resistace is often the first step to additional resistance. Our work shows that interventions used to reduce XDR-TB incidence may need to be targeted within spatial locations of RR-TB, and further research is required to understand underlying drivers of XDR-TB transmission in these locations., (© 2022. The Author(s).)

We reviewed autopsy data from general hospitals in Lviv, Ukraine to understand pediatric mortality due to tuberculosis (TB). We identified 14 (0.6%) of 2345 autopsied children with unrecognized or untreated TB. More sensitive TB diagnostics for children and improved strategies for identifying which children require TB evaluation are urgently needed., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To use routinely collected data, with the addition of geographic information and census data, to identify local hot spots of rates of reported tuberculosis cases., Design: Residential locations of tuberculosis cases identified from eight public health facilities in Lima, Peru (2013-2018) were linked to census data to calculate neighborhood-level annual case rates. Heat maps of tuberculosis case rates by neighborhood were created. Local indicators of spatial autocorrelation, Moran's I, were used to identify where in the study area spatial clusters and outliers of tuberculosis case rates were occurring. Age- and sex-stratified case rates were also assessed., Results: We identified reports of 1,295 TB cases across 74 neighborhoods during the five-year study period, for an average annual rate of 124.2 reported TB cases per 100,000 population. In evaluating case rates by individual neighborhood, we identified a median rate of reported cases of 123.6 and a range from 0 to 800 cases per 100,000 population. Individuals aged 15-44 years old and men had higher case rates than other age groups and women. Locations of both hot and cold spots overlapped across age- and gender-specific maps., Conclusions: There is significant geographic heterogeneity in rates of reported TB cases and evident hot and cold spots within the study area. Characterization of the spatial distribution of these rates and local hot spots may be one practical tool to inform the work of local coalitions to target TB interventions in their zones., Competing Interests: The authors have declared that no competing interests exist.

Tuberculous meningitis (TBM) remains a major cause of morbidity and mortality in children with tuberculosis (TB), yet there are currently no estimates of the global burden of pediatric TBM. Due to frequent non-specific clinical presentation and limited and inadequate diagnostic tests, children with TBM are often diagnosed late or die undiagnosed. Even when diagnosed and treated, 20% of children with TBM die. Of survivors, the majority have substantial neurological disability with significant negative impact on children and their families. Surveillance data on this devastating form of TB can help to quantify the contribution of TBM to the overall burden, morbidity and mortality of TB in children and the epidemiology of TB more broadly. Pediatric TBM usually occurs shortly after primary infection with Mycobacterium tuberculosis and reflects ongoing TB transmission to children. In this article we explain the public health importance of pediatric TBM, discuss the epidemiology within the context of overall TB control and health system functioning and the limitations of current surveillance strategies. We provide a clear rationale for the benefit of improved surveillance of pediatric TBM using a TB care cascade framework to support monitoring and evaluation of pediatric TB, and TB control more broadly. Considering the public health implications of a diagnosis of TBM in children, we provide recommendations to strengthen pediatric TBM surveillance and outline how improved surveillance can help us identify opportunities for prevention, earlier diagnosis and improved care to minimize the impact of TBM on children globally., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 du Preez, Jenkins, Donald, Solomons, Graham, Schaaf, Starke, Hesseling and Seddon.)

The burden of tuberculosis (TB) among children and young adolescents (<15 years old) is estimated at 1.1 million; however, only 400,000 are treated for TB, indicating a large gap between the number who are cared for and the number estimated to have TB. Accurate data on the burden of pediatric TB is essential to guide action. Despite several improvements in estimating the burden of pediatric TB in the last decade, as well as enhanced data collection efforts, several data gaps remain, both at the global level, but also at the national level where surveillance systems and collaborative research are critical. In this article, we describe recent advances in data collection and burden estimates for TB among children and adolescents, and the remaining gaps. While data collection continues to improve, burden estimates must evolve in parallel, both in terms of their frequency and the methods used. Currently, at the global level, there is a focus on age-disaggregation of TB notifications, the collection of data on TB-HIV, multi-drug resistant (MDR)-TB and treatment outcomes, as well as estimates of the disease burden. Additional data from national surveillance systems or research projects on TB meningitis, as well as other forms of extra-pulmonary TB, would be useful. We must capitalize on the current momentum in child and adolescent TB to close the remaining data gaps for these age groups to better understand the epidemic and further reduce morbidity and mortality due to TB.

Tuberculosis screening programs commonly target areas with high case notification rates. However, this may exacerbate disparities by excluding areas that already face barriers to accessing diagnostic services. We compared historic case notification rates, demographic, and socioeconomic indicators as predictors of neighborhood-level tuberculosis screening yield during a mobile screening program in 74 neighborhoods in Lima, Peru. We used logistic regression and Classification and Regression Tree (CART) analysis to identify predictors of screening yield. During February 7, 2019-February 6, 2020, the program screened 29,619 people and diagnosed 147 tuberculosis cases. Historic case notification rate was not associated with screening yield in any analysis. In regression analysis, screening yield decreased as the percent of vehicle ownership increased (odds ratio [OR]: 0.76 per 10% increase in vehicle ownership; 95% confidence interval [CI]: 0.58-0.99). CART analysis identified the percent of blender ownership (≤ 83.1% vs > 83.1%; OR: 1.7; 95% CI: 1.2-2.6) and the percent of TB patients with a prior tuberculosis episode (> 10.6% vs ≤ 10.6%; OR: 3.6; 95% CI: 1.0-12.7) as optimal predictors of screening yield. Overall, socioeconomic indicators were better predictors of tuberculosis screening yield than historic case notification rates. Considering community-level socioeconomic characteristics could help identify high-yield locations for screening interventions., (© 2022. The Author(s).)

Background: To stop tuberculosis (TB), the leading infectious cause of death globally, we need to better understand transmission risk factors. Although many studies have identified associations between individual-level covariates and pathogen genetic relatedness, few have identified characteristics of transmission pairs or explored how closely covariates associated with genetic relatedness mirror those associated with transmission., Methods: We simulated a TB-like outbreak with pathogen genetic data and estimated odds ratios (ORs) to correlate each covariate and genetic relatedness. We used a naive Bayes approach to modify the genetic links and nonlinks to resemble the true links and nonlinks more closely and estimated modified ORs with this approach. We compared these two sets of ORs with the true ORs for transmission. Finally, we applied this method to TB data in Hamburg, Germany, and Massachusetts, USA, to find pair-level covariates associated with transmission., Results: Using simulations, we found that associations between covariates and genetic relatedness had the same relative magnitudes and directions as the true associations with transmission, but biased absolute magnitudes. Modifying the genetic links and nonlinks reduced the bias and increased the confidence interval widths, more accurately capturing error. In Hamburg and Massachusetts, pairs were more likely to be probable transmission links if they lived in closer proximity, had a shorter time between observations, or had shared ethnicity, social risk factors, drug resistance, or genotypes., Conclusions: We developed a method to improve the use of genetic relatedness as a proxy for transmission, and aid in understanding TB transmission dynamics in low-burden settings., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To evaluate the diagnostic value of symptoms used by daycares and schools to screen children and adolescents for SARS-CoV-2 infection, we analyzed data from a primary care setting., Methods: This cohort study included all patients ≤17 years old who were evaluated at Providence Community Health Centers (PCHC; Providence, U.S.), for COVID-19 symptoms and/or exposure, and received SARS-CoV-2 polymerase chain reaction (PCR) testing between March-June 2020. Participants were identified from PCHC electronic medical records. For three age groups- 0-4, 5-11, and 12-17 years-we estimated the sensitivity, specificity, and area under the receiver operating curve (AUC) of individual symptoms and three symptom combinations: a case definition published by the Rhode Island Department of Health (RIDOH), and two novel combinations generated by different statistical approaches to maximize sensitivity, specificity, and AUC. We evaluated symptom combinations both with and without consideration of COVID-19 exposure. Myalgia, headache, sore throat, abdominal pain, nausea, anosmia, and ageusia were not assessed in 0-4 year-olds due to the lower reliability of these symptoms in this group., Results: Of 555 participants, 217 (39.1%) were SARS-CoV-2-infected. Fever was more common among 0-4 years-olds (p = 0.002); older children more frequently reported fatigue (p = 0.02). In children ≥5 years old, anosmia or ageusia had 94-98% specificity. In all ages, exposure history most accurately predicted infection. With respect to individual symptoms, cough most accurately predicted infection in <5 year-olds (AUC 0.69) and 12-17 year-olds (AUC 0.62), while headache was most accurate in 5-11 year-olds (AUC 0.62). In combination with exposure history, the novel symptom combinations generated statistically to maximize test characteristics had sensitivity >95% but specificity <30%. No symptom or symptom combination had AUC ≥0.70., Conclusions: Anosmia or ageusia in children ≥5 years old should raise providers' index of suspicion for COVID-19. However, our overall findings underscore the limited diagnostic value of symptoms., Competing Interests: The authors have declared that no competing interests exist.

Background: Household contacts of patients with drug-resistant tuberculosis (TB) are at high risk for being infected with Mycobacterium tuberculosis and for developing TB disease. To guide regimen composition for the empirical treatment of TB infection and disease in these household contacts, we estimated drug-resistance profile concordance between index patients with drug-resistant TB and their household contacts., Methods: We performed a systematic review and meta-analysis of studies published through 24 July 2018 that reported resistance profiles of drug-resistant TB index cases and secondary cases within their households. Using a random-effects meta-analysis, we estimated resistance profile concordance, defined as the percentage of secondary cases whose M. tuberculosis strains were resistant to the same drugs as strains from their index cases. We also estimated isoniazid/rifampin concordance, defined as whether index and secondary cases had identical susceptibilities for isoniazid and rifampin only., Results: We identified 33 eligible studies that evaluated resistance profile concordance between 484 secondary cases and their household index cases. Pooled resistance profile concordance was 54.3% (95% confidence interval [CI], 40.7-67.6%; I2 = 85%). Pooled isoniazid/rifampin concordance was 82.6% (95% CI, 72.3-90.9%; I2 = 73%). Concordance estimates were similar in a subanalysis of 16 studies from high-TB-burden countries. There were insufficient data to perform a subanalysis among pediatric secondary cases., Conclusions: Household contacts of patients with drug-resistant TB should receive treatment for TB infection and disease that assumes that they, too, are infected with a drug-resistant M. tuberculosis strain. Whenever possible, drug susceptibility testing should be performed for secondary cases to optimize regimen composition., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Importance: The COVID-19 pandemic has severely disrupted US educational institutions. Given potential adverse financial and psychosocial effects of campus closures, many institutions developed strategies to reopen campuses in the fall 2020 semester despite the ongoing threat of COVID-19. However, many institutions opted to have limited campus reopening to minimize potential risk of spread of SARS-CoV-2., Objective: To analyze how Boston University (BU) fully reopened its campus in the fall of 2020 and controlled COVID-19 transmission despite worsening transmission in Boston, Massachusetts., Design, Setting, and Participants: This multifaceted intervention case series was conducted at a large urban university campus in Boston, Massachusetts, during the fall 2020 semester. The BU response included a high-throughput SARS-CoV-2 polymerase chain reaction testing facility with capacity to deliver results in less than 24 hours; routine asymptomatic screening for COVID-19; daily health attestations; adherence monitoring and feedback; robust contact tracing, quarantine, and isolation in on-campus facilities; face mask use; enhanced hand hygiene; social distancing recommendations; dedensification of classrooms and public places; and enhancement of all building air systems. Data were analyzed from December 20, 2020, to January 31, 2021., Main Outcomes and Measures: SARS-CoV-2 diagnosis confirmed by reverse transcription-polymerase chain reaction of anterior nares specimens and sources of transmission, as determined through contact tracing., Results: Between August and December 2020, BU conducted more than 500 000 COVID-19 tests and identified 719 individuals with COVID-19, including 496 students (69.0%), 11 faculty (1.5%), and 212 staff (29.5%). Overall, 718 individuals, or 1.8% of the BU community, had test results positive for SARS-CoV-2. Of 837 close contacts traced, 86 individuals (10.3%) had test results positive for COVID-19. BU contact tracers identified a source of transmission for 370 individuals (51.5%), with 206 individuals (55.7%) identifying a non-BU source. Among 5 faculty and 84 staff with SARS-CoV-2 with a known source of infection, most reported a transmission source outside of BU (all 5 faculty members [100%] and 67 staff members [79.8%]). A BU source was identified by 108 of 183 undergraduate students with SARS-CoV-2 (59.0%) and 39 of 98 graduate students with SARS-CoV-2 (39.8%); notably, no transmission was traced to a classroom setting., Conclusions and Relevance: In this case series of COVID-19 transmission, BU used a coordinated strategy of testing, contact tracing, isolation, and quarantine, with robust management and oversight, to control COVID-19 transmission in an urban university setting.

Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

In 2011, South Africa implemented a policy to decentralize treatment for rifampin-resistant tuberculosis (TB) to reduce durations of hospitalization and enable local treatment. We assessed policy implementation in Western Cape Province, where services expanded from 6 specialized TB hospitals to 406 facilities, by analyzing National Health Laboratory Service data on TB during 2012-2015. We calculated the percentage of patients who visited a TB hospital <1 year after rifampin-resistant TB diagnosis, the median duration of their hospitalizations, and the total distance between facilities visited. We assessed temporal changes with linear regression and stratified results by location. Of 2,878 patients, 65% were from Cape Town. In Cape Town, 29% visited a TB hospital; elsewhere, 68% visited a TB hospital. We found that hospitalizations and travel distances were shorter in Cape Town than in the surrounding areas.

Setting: Alcohol use increases the risk of tuberculosis (TB) disease and is associated with worse outcomes., Objective: To determine whether alcohol use affects TB severity at diagnosis in a high-burden setting., Design: Participants were smear-positive people living with TB (PLWTB) in India. Disease severity was assessed as 1) high versus low smear grade, 2) time to positivity (TTP) on liquid culture, 3) chest radiograph cavitation, and 4) percent lung affected. Alcohol use and being at-risk for alcohol use disorders (AUD) were assessed using the AUDIT-C. Univariable and multivariable analyses were conducted., Results: Of 1166 PLWTB, 691 (59.3%) were drinkers; of those, 518/691 (75.0%) were at-risk for AUD. Drinkers had more lung affected than non-drinkers (adjusted mean difference 10.8%, p<0.0001); this was not significant for those at-risk for AUD (adjusted mean difference 3.7%, p = 0.11). High smear grade (aOR 1.0, 95%CI: 0.7-1.4), cavitation (aOR 0.8, 95%CI 0.4-1.8), and TTP (mean difference 5.2 hours, p = 0.51) did not differ between drinkers and non-drinkers, nor between those at-risk and not at-risk for AUD., Conclusions: A large proportion of PLWTB were drinkers and were at-risk for AUD. Alcohol drinkers had more lung affected than non-drinkers. Studies are needed to explore mechanisms of this association., Competing Interests: The authors have declared that no competing interests exist.

Serial interval (SI), defined as the time between symptom onset in an infector and infectee pair, is commonly used to understand infectious diseases transmission. Slow progression to active disease, as well as the small percentage of individuals who will eventually develop active disease, complicate the estimation of the SI for tuberculosis (TB). In this paper, we showed via simulation studies that when there is credible information on the percentage of those who will develop TB disease following infection, a cure model, first introduced by Boag in 1949, should be used to estimate the SI for TB. This model includes a parameter in the likelihood function to account for the study population being composed of those who will have the event of interest and those who will never have the event. We estimated the SI for TB to be approximately 0.5 years for the United States and Canada (January 2002 to December 2006) and approximately 2.0 years for Brazil (March 2008 to June 2012), which might imply a higher occurrence of reinfection TB in a developing country like Brazil., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Predictive models can serve as early warning systems and can be used to forecast future risk of various infectious diseases. Conventionally, regression and time series models are used to forecast dengue incidence, using dengue surveillance (e.g., case counts) and weather data. However, these models may be limited in terms of model assumptions and the number of predictors that can be included. Machine learning (ML) methods are designed to work with a large number of predictors and thus offer an appealing alternative. Here, we compared the performance of ML algorithms with that of regression models in predicting dengue cases and outbreaks from 4 to up to 12 weeks in advance. Many countries lack sufficient health surveillance infrastructure, as such we evaluated the contribution of dengue surveillance and weather data on the predictive power of these models., Methods: We developed ML, regression, and time series models to forecast weekly dengue case counts and outbreaks in Iquitos, Peru; San Juan, Puerto Rico; and Singapore from 1990-2016. Forecasts were generated using available weekly dengue surveillance, and weather data. We evaluated the agreement between model forecasts and actual dengue observations using Mean Absolute Error and Matthew's Correlation Coefficient (MCC)., Results: For near term predictions of weekly case counts and when using surveillance data, ML models had 21% and 33% less error than regression and time series models respectively. However, using weather data only, ML models did not demonstrate a practical advantage. When forecasting weekly dengue outbreaks 12 weeks in advance, ML models achieved a maximum MCC of 0.61., Conclusions: Our results identified 2 scenarios when ML models are advantageous over regression model: 1) predicting dengue weekly case counts 4 weeks ahead when dengue surveillance data are available and 2) predicting weekly dengue outbreaks 12 weeks ahead when dengue surveillance data are unavailable. Given the advantages of ML models, dengue early warning systems may be improved by the inclusion of these models., Competing Interests: The authors have declared that no competing interests exist.

Background: During adolescence, childhood and adult forms of tuberculosis (TB) overlap, resulting in diverse disease manifestations. Knowing which patient characteristics are associated with which manifestations may facilitate diagnosis and enhance understanding of TB pathophysiology., Methods: In this cross-sectional study, we included 10-19-year-olds in Ukraine's national TB registry who started TB treatment between 2015 and 2018. Using multivariable regression, we estimated associations between patient characteristics and four presentations of TB: pleural, extrathoracic, cavitary and rifampicin-resistant (RR). We also described the epidemiology of adolescent TB in Ukraine., Results: Among 2491 adolescent TB cases, 88.4% were microbiologically confirmed. RR-TB was confirmed in 16.9% of new and 29.7% of recurrent cases. Of 88 HIV-infected adolescents, 59.1% were not on antiretroviral therapy at TB diagnosis. Among 10-14-year-olds, boys had more pleural disease (adjusted OR (aOR) 2.12, 95% CI: 1.08-4.37). Extrathoracic TB was associated with age 15-19 years (aOR 0.26, 95% CI: 0.18-0.37) and HIV (aOR 3.25, 95% CI: 1.55-6.61 in 10-14-year-olds; aOR 8.18, 95% CI: 3.58-17.31 in 15-19-year-olds). Cavitary TB was more common in migrants (aOR 3.53, 95% CI: 1.66-7.61) and 15-19-year-olds (aOR 4.10, 95% CI: 3.00-5.73); among 15-19-year-olds, it was inversely associated with HIV (aOR 0.32, 95% CI: 0.13-0.70). RR-TB was associated with recurrent disease (aOR 1.87, 95% CI: 1.08-3.13), urban residence (aOR 1.27, 95% CI: 1.01-1.62) and cavitation (aOR 2.98, 95% CI: 2.35-3.78)., Conclusions: Age, sex, HIV and social factors impact the presentation of adolescent TB. Preventive, diagnostic and treatment activities should take these factors into consideration., Competing Interests: Conflict of interest: S.S. Chiang reports grants from the National Institutes of Health during the conduct of the study. Conflict of interest: M. Dolynska has nothing to disclose. Conflict of interest: N.R. Rybak has nothing to disclose. Conflict of interest: A.T. Cruz has nothing to disclose. Conflict of interest: O. Aibana has nothing to disclose. Conflict of interest: Y. Sheremeta has nothing to disclose. Conflict of interest: V. Petrenko has nothing to disclose. Conflict of interest: A. Mamotenko has nothing to disclose. Conflict of interest: I. Terleeva has nothing to disclose. Conflict of interest: C.R. Horsburgh Jr has nothing to disclose. Conflict of interest: H.E. Jenkins reports grants from the US National Institutes of Health (R01GM122876) during the conduct of the study., (Copyright ©ERS 2020.)

Identifying predictors of loss to follow-up (LTFU; treatment lapse ≥ 2 months) among people with tuberculosis (TB) may assist programmatic efforts in controlling the spread of TB. Newly diagnosed smear-positive TB patients were enrolled in the Regional Prospective Observational Research for TB study in Puducherry and Tamil Nadu, India. Treatment records were used to identify LTFU of those who were enrolled from May 2014 through December 2017. This nested case-control study evaluated male TB patients. Predictors were assessed using multivariable logistic regression. Of 425 men with TB, 82 (19%) were LTFU. In the adjusted analyses of males, divorced/separated marital status (adjusted odds ratio [aOR] 3.80; 95% CI: 1.39-10.38) and at-risk alcohol use (aOR 1.92; 95% CI: 1.12-3.27) were significant predictors for increased risk of LTFU, and diabetes was a significant predictor for decreased risk of LTFU (aOR 0.52; 95% CI: 0.29-0.92). Of 53 men with recorded date of last treatment visit, 23 (43%) and 43 (81%) had LTFU within the first 2 and first 4 months of treatment, respectively. Addressing at-risk alcohol use and providing more intensive follow-up could lead to improved treatment completion.

Background: Estimating infectious disease parameters such as the serial interval (time between symptom onset in primary and secondary cases) and reproductive number (average number of secondary cases produced by a primary case) are important in understanding infectious disease dynamics. Many estimation methods require linking cases by direct transmission, a difficult task for most diseases., Methods: Using a subset of cases with detailed genetic and/or contact investigation data to develop a training set of probable transmission events, we build a model to estimate the relative transmission probability for all case-pairs from demographic, spatial and clinical data. Our method is based on naive Bayes, a machine learning classification algorithm which uses the observed frequencies in the training dataset to estimate the probability that a pair is linked given a set of covariates., Results: In simulations, we find that the probabilities estimated using genetic distance between cases to define training transmission events are able to distinguish between truly linked and unlinked pairs with high accuracy (area under the receiver operating curve value of 95%). Additionally, only a subset of the cases, 10-50% depending on sample size, need to have detailed genetic data for our method to perform well. We show how these probabilities can be used to estimate the average effective reproductive number and apply our method to a tuberculosis outbreak in Hamburg, Germany., Conclusions: Our method is a novel way to infer transmission dynamics in any dataset when only a subset of cases has rich contact investigation and/or genetic data., (© The Author(s) 2020; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Household contact studies of tuberculosis (TB) are a common way to study disease transmission dynamics. However these studies lack a mechanism for accounting for community transmission, which is known to be significant, particularly in high burden settings. We illustrate a statistical approach for estimating both the correlates with transmission of TB in a household setting and the probability of community transmission using a modified Bayesian mixed-effects model. This is applied to two household contact studies in Vitória, Brazil from 2008-2013 and Kampala, Uganda from 1995-2004 that enrolled households with an individual that was recently diagnosed with pulmonary TB. We estimate the probability of community transmission to be higher in Uganda (ranging from 0.21 to 0.69, depending on HHC age and HIV status of the index case) than in Brazil (ranging from 0.13 for young children to 0.50 in adults). These estimates are consistent with a higher overall burden of disease in Uganda compared to Brazil. Our method also estimates an increasing risk of community-acquired TB with age of the household contact, consistent with existing literature. This approach is a useful way to integrate the role of the community in understanding TB disease transmission dynamics in household contact studies., Competing Interests: The authors have declared that no competing interests exist.

Few reports have described pediatric Multidrug-resistant Tuberculosis (MDR-TB) in the former Soviet republics, despite the fact that these countries have the highest proportion of TB cases that are MDR. We aimed to examine pediatric MDR-TB in Ukraine. This retrospective cohort study included all children <18 years of age who started undergoing MDR-TB treatment between January 1, 2011 and July 31, 2016 at Kyiv City Pediatric TB Hospital. From each child's clinical chart, we abstracted demographic and clinical data. Using Fisher's exact test, we compared characteristics between children with microbiologically confirmed vs. probable (i.e., clinically diagnosed) MDR-TB. The study population included 20 children with a median age of 5 years. At diagnosis, 12 (60%) had intrathoracic lymphadenopathy as their only radiographic abnormality, and two (10%) were asymptomatic. Children with confirmed MDR-TB were more likely to be adolescents or have radiologic abnormalities in addition to intrathoracic lymphadenopathy. Median treatment duration was 20 months. Eighteen (90%) children were treated successfully. The remaining two were transferred to another facility, and their final outcomes were unknown. The excellent outcomes in this cohort are consistent with high treatment success rates for pediatric MDR-TB reported in other parts of the world., Competing Interests: We have no conflicts of interest to declare., (© Atlantis Press International B.V.)

Background: Tuberculosis is recognised as a major cause of morbidity and mortality in children, with most cases in children going undiagnosed and resulting in poor outcomes. Household contact management, which aims to identify children with active tuberculosis and to provide preventive therapy for those with HIV or those younger than 5 years, has long been recommended but has very poor coverage globally. New guidelines include widespread provision of preventive therapy to children with a positive tuberculin skin test (TST) who are older than 5 years., Methods: In this mathematical modelling study, we provide the first global and national estimates of the impact of moving from zero to full coverage of household contact management (with and without preventive therapy for TST-positive children older than 5 years). We assembled data on tuberculosis notifications, household structure, household contact co-prevalence of tuberculosis disease and infection, the efficacy of preventive therapy, and the natural history of childhood tuberculosis. We used a model to estimate households visited, children screened, and treatment courses given for active and latent tuberculosis. We calculated the numbers of tuberculosis cases, deaths, and life-years lost because of tuberculosis for each intervention scenario and country., Findings: We estimated that full implementation of household contact management would prevent 159 500 (75% uncertainty interval [UI] 147 000-170 900) cases of tuberculosis and 108 400 (75% UI 98 800-116 700) deaths in children younger than 15 years (representing the loss of 7 305 000 [75% UI 6 663 000-7 874 000] life-years). We estimated that preventing one child death from tuberculosis would require visiting 48 households, screening 77 children, giving 48 preventive therapy courses, and giving two tuberculosis treatments versus no household contact management., Interpretation: Household contact management could substantially reduce childhood disease and death caused by tuberculosis globally. Funding and research to optimise its implementation should be prioritised., Funding: UK Medical Research Council, US National Institutes of Health, Fulbright Commission, Janssen Global Public Health., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Tuberculosis (TB) is the leading global infectious cause of death. Understanding TB transmission is critical to creating policies and monitoring the disease with the end goal of TB elimination. To our knowledge, there has been no systematic review of key transmission parameters for TB. We carried out a systematic review of the published literature to identify studies estimating either of the two key TB transmission parameters: the serial interval (SI) and the reproductive number. We identified five publications that estimated the SI and 56 publications that estimated the reproductive number. The SI estimates from four studies were: 0.57, 1.42, 1.44 and 1.65 years; the fifth paper presented age-specific estimates ranging from 20 to 30 years (for infants <1 year old) to <5 years (for adults). The reproductive number estimates ranged from 0.24 in the Netherlands (during 1933-2007) to 4.3 in China in 2012. We found a limited number of publications and many high TB burden settings were not represented. Certain features of TB dynamics, such as slow transmission, complicated parameter estimation, require novel methods. Additional efforts to estimate these parameters for TB are needed so that we can monitor and evaluate interventions designed to achieve TB elimination.

Background: South Africa has the highest tuberculosis incidence globally (781/100,000), with an estimated 4.3% of cases being rifampicin resistant (RR). Control and elimination strategies will require detailed spatial information to understand where drug-resistant tuberculosis exists and why it persists in those communities. We demonstrate a method to enable drug-resistant tuberculosis monitoring by identifying high-burden communities in the Western Cape Province using routinely collected laboratory data., Methods and Findings: We retrospectively identified cases of microbiologically confirmed tuberculosis and RR-tuberculosis from all biological samples submitted for tuberculosis testing (n = 2,219,891) to the Western Cape National Health Laboratory Services (NHLS) between January 1, 2008, and June 30, 2013. Because the NHLS database lacks unique patient identifiers, we performed a series of record-linking processes to match specimen records to individual patients. We counted an individual as having a single disease episode if their positive samples came from within two years of each other. Cases were aggregated by clinic location (n = 302) to estimate the percentage of tuberculosis cases with rifampicin resistance per clinic. We used inverse distance weighting (IDW) to produce heatmaps of the RR-tuberculosis percentage across the province. Regression was used to estimate annual changes in the RR-tuberculosis percentage by clinic, and estimated average size and direction of change was mapped. We identified 799,779 individuals who had specimens submitted from mappable clinics for testing, of whom 222,735 (27.8%) had microbiologically confirmed tuberculosis. The study population was 43% female, the median age was 36 years (IQR 27-44), and 10,255 (4.6%, 95% CI: 4.6-4.7) cases had documented rifampicin resistance. Among individuals with microbiologically confirmed tuberculosis, 8,947 (4.0%) had more than one disease episode during the study period. The percentage of tuberculosis cases with rifampicin resistance documented among these individuals was 11.4% (95% CI: 10.7-12.0). Overall, the percentage of tuberculosis cases that were RR-tuberculosis was spatially heterogeneous, ranging from 0% to 25% across the province. Our maps reveal significant yearly fluctuations in RR-tuberculosis percentages at several locations. Additionally, the directions of change over time in RR-tuberculosis percentage were not uniform. The main limitation of this study is the lack of unique patient identifiers in the NHLS database, rendering findings to be estimates reliant on the accuracy of the person-matching algorithm., Conclusions: Our maps reveal striking spatial and temporal heterogeneity in RR-tuberculosis percentages across this province. We demonstrate the potential to monitor RR-tuberculosis spatially and temporally with routinely collected laboratory data, enabling improved resource targeting and more rapid locally appropriate interventions., Competing Interests: MBM is a member of the Editorial Board of PLOS Medicine. The authors declare no other competing interests exist.

Background: Childhood tuberculosis (TB) has historically been neglected, although in recent years there has been increased focus on this problem. In particular, there have been two efforts to estimate the burden of pediatric multidrug-resistant TB (MDR-TB)., Methods: We review current estimates of the global incidence of pediatric MDR-TB disease. We then combine pediatric MDR-TB treatment data from the World Health Organization and recently published case fatality ratio estimates for children with TB to produce mortality estimates for children with MDR-TB. Finally, we combine treatment data and estimates of household size and disease risk to estimate how many children could be treated for probable or confirmed MDR-TB by carrying out household contact investigations around adult MDR-TB patients., Results: Between 25 000 and 32 000 children develop MDR-TB disease annually, accounting for around 3% of all pediatric TB cases. Only 3-4% of these children are likely to receive MDR-TB treatment. We estimate that around 21% of children who develop MDR-TB disease will die. Carrying out household contact investigations around adult MDR-TB patients could find an estimated 12 times as many pediatric MDR-TB cases as are currently being identified., Discussion: The diagnosis and treatment of children with MDR-TB needs to be prioritized by TB programs.