Immigration from areas of high incidence is thought to have fueled the resurgence of tuberculosis (TB) in areas of low incidence. To reduce the risk of disease in low-incidence areas, the main countermeasure has been the screening of immigrants on arrival. This measure is based on the assumption of a prompt decline in the incidence of TB in immigrants during their first few years of residence in a country with low overall incidence. We have documented that this assumption is not true for 619 Somali immigrants reported in Denmark as having TB. The annual incidence of TB declined only gradually during the first 7 years of residence, from an initial 2,000 per 100,000 to 700 per 100,000. The decline was described by an exponential function with a half-time of 5.7 (95% confidence interval 4.0 to 9.7) years. This finding seriously challenges the adequacy of the customary practice of screening solely on arrival.

As countries approach the elimination phase of tuberculosis, specific problems and challenges emerge, due to the steadily declining incidence in the native population, the gradually increasing importance of the importation of latent tuberculosis infection and tuberculosis from other countries and the emergence of groups at particularly high risk of tuberculosis. Therefore, a Working Group of the World Health Organization (WHO), the International Union Against Tuberculosis and Lung Disease (IUATLD) and the Royal Netherlands Tuberculosis Association (KNCV) have developed a new framework for low incidence countries based on concepts and definitions consistent with those of previous recommendations from WHO/IUATLD Working Groups. In low-incidence countries, a broader spectrum of interventions is available and feasible, including: 1) a general approach to tuberculosis which ensures rapid detection and treatment of all the cases and prevention of unnecessary deaths; 2) an overall control strategy aimed at reducing the incidence of tuberculosis infection (risk-group management and prevention of transmission of infection in institutional settings) and 3) a tuberculosis elimination strategy aimed at reducing the prevalence of tuberculosis infection (outbreak management and provision of preventive therapy for specified groups and individuals). Government and private sector commitment towards elimination, effective case detection among symptomatic individuals together with active case finding in special groups, standard treatment of disease and infection, access to tuberculosis diagnostic and treatment services, prevention (e.g. through screening and bacille Calmette-Guéria immunization in specified groups), surveillance and treatment outcome monitoring are prerequisites to implementing the policy package recommended in this new framework document.

Infliximab is a humanized antibody against tumor necrosis factor alpha (TNF-alpha) that is used in the treatment of Crohn's disease and rheumatoid arthritis. Approximately 147,000 patients throughout the world have received infliximab. Excess TNF-alpha in association with tuberculosis may cause weight loss and night sweats, yet in animal models it has a protective role in the host response to tuberculosis. There is no direct evidence of a protective role of TNF-alpha in patients with tuberculosis.

Does immigration from a high-prevalence area contribute to an increased risk of tuberculosis in a low-incidence country? The tuberculosis incidence in Somalia is among the highest ever registered. Due to civil war and starvation, nearly half of all Somalis have been forced from their homes, causing significant migration to low-incidence countries. In Denmark, two-thirds of all tuberculosis patients are immigrants, half from Somalia. To determine the magnitude of Mycobacterium tuberculosis transmission between Somalis and Danes, we analyzed DNA fingerprint patterns of isolates collected in Denmark from 1992 to 1999, comprising >97% of all culture-positive patients (n = 3,320). Of these, 763 were Somalian immigrants, 55.2% of whom shared identical DNA fingerprint patterns; 74.9% of these were most likely infected before their arrival in Denmark, 23.3% were most likely infected in Denmark by other Somalis, and 1.8% were most likely infected by Danes. In the same period, only 0.9% of all Danish tuberculosis patients were most likely infected by Somalis. The Somalian immigrants in Denmark could be distributed into 35 different clusters with possible active transmission, of which 18 were retrieved among Somalis in the Netherlands. This indicated the existence of some internationally predominant Somalian strains causing clustering less likely to represent recent transmission. In conclusion, M. tuberculosis transmission among Somalis in Denmark is limited, and transmission between Somalis and Danes is nearly nonexistent. The higher transmission rates between nationalities found in the Netherlands do not apply to the situation in Denmark and not necessarily elsewhere, since many different factors may influence the magnitude of active transmission.

The whole-genome fingerprinting technique, fluorescent amplified-fragment length polymorphism (FAFLP) analysis, was applied to Mycobacterium tuberculosis. Sixty-five clinical isolates were analyzed to determine the value of FAFLP as a stand-alone genotyping technique and to compare it with the well-established IS6110 typing system. The genome sequence of M. tuberculosis strain H37Rv (S. T. Cole et al., Nature 393:537-544, 1998) was used to model computer-generated informative primer combination(s), and the precision and reproducibility of FAFLP were evaluated by comparing the results of in vitro and computer-generated experiments. Multiplex FAFLP was used to increase resolving power in a predictable and systematic fashion. FAFLP analysis was broadly congruent with IS6110 typing for those strains with multiple IS6110 copies. It was also able to resolve an epidemiologically unlinked group of strains with only one copy of IS6110; up to 10% of clinical isolates may fall into this category. For certain epidemiological investigations, it was concluded that a combination of FAFLP and IS6110 typing would give higher resolution than would either alone. FAFLP data were digital, precise, reproducible, and suitable for rapid electronic dissemination, manipulation, interlaboratory comparison, and storage in national or international epidemiological databases. Because FAFLP samples and analyzes base substitution across the genome as a whole, FAFLP could generate new information about the microevolution of the M. tuberculosis complex.

To estimate the risk and prevalence of Mycobacterium tuberculosis (MTB) infection and tuberculosis (TB) incidence, prevalence, and mortality, including disease attributable to human immunodeficiency virus (HIV), for 212 countries in 1997.

The present study is based on notified cases of tuberculosis (TB) in the National tbc. register 1972-1996. A decline in Tb incidence was seen from 1972 and until the mid-1980's. Subsequently the trend has reversed due to an increasing number of TB cases in foreigners. In 1996, 60% of all cases of TB in Denmark were found in foreigners reflecting the rising number of refugees and their families arriving in Denmark from highly endemic areas, mainly Somalia. Among native Danes the TB incidence fell from 14 per 100,000 in 1972 to 4 per 100,000 in the 1980's and stabilized at this very low level. The unchanged incidence in Danes covers a falling incidence in the older and a rising incidence in the younger and middle-aged adult population, mainly in the capital. Approximately half of the cases occur in high-risk groups. The TB-epidemic is close to elimination in the indigenous Danish population, but the disease is maintained at a low level probably due to increased patient and doctor delay and resulting microepidemics primarily in high-risk populations.

Abstract Background The country received malaria-free certification from WHO in September 2016, becoming only the second country in the WHO South East Asia region to be declared malaria-free. Imported malaria cases continue to be reported, with 278 cases reported between 2013 and 2017. The diagnosis of a severe Plasmodium vivax patient co-infected with HIV and tuberculosis is discussed with an overview of the rapid response mounted by the Anti Malaria Campaign (AMC), Sri Lanka. Case presentation A Sri Lankan gem miner who returned from Madagascar on the 6th of April 2018 presented to a private hospital for a malaria diagnostic test on the 21st April, 2 days after the onset of fever. He came on his own for this test due to the awareness he had regarding the risk of imported malaria. As the patient was positive for P. vivax malaria, he was admitted to a government hospital for further management. The patient had features of severe malaria upon admission with a systolic BP 

Michael Scolarici, Ken Dekitani, Ling Chen, Marcia Sokol-Anderson, Daniel F. Hoft, Soumya Chatterjee

by Michael Scolarici, Ken Dekitani, Ling Chen, Marcia Sokol-Anderson, Daniel F. Hoft, Soumya Chatterjee It is unknown whether patients with LTBI at high vs. low risk of developing active TB are currently adequately identified and treated in the US. In this study our objective was 1) To retrospectively apply the online calculator (tstin3d.com) to determine the probability of having LTBI and assign cumulative risk of progression. 2) Measure treatment outcomes in subjects with Low: 0-…

Micheli Luize Grenzel, Antonio José Grande, Anamaria Mello Miranda Paniago, Mauricio Antonio Pompilio, Sandra Maria do Valle Leone de Oliveira, Anete Trajman

by Micheli Luize Grenzel, Antonio José Grande, Anamaria Mello Miranda Paniago, Mauricio Antonio Pompilio, Sandra Maria do Valle Leone de Oliveira, Anete Trajman Introduction Prison inmates can transmit tuberculosis, including drug-resistant strains, to correctional facility workers and the community. In this systematic literature review, we investigated the magnitude of active and latent tuberculosis infection (LTBI) and associated risk factors among correctional facility workers. Methods We searched MEDLINE, EMBASE, LILACS, Cochrane CENTRAL, ISI Web of Science, CINAHL, and SCOPUS databases (January 1, 1989–December 31, 2017) for studies with the MeSH terms “prison” (and similar) AND “tuberculosis”, without language restriction. We searched for gray literature in Google Scholar and conference proceedings. Stratified analyses according to tuberculosis burden were performed. Results Of the 974 titles identified, 15 (nine good, six fair quality) fulfilled the inclusion criteria (110,393 correctional facility workers; six countries; 82,668 active tuberculosis; 110,192 LTBI). Pooled LTBI prevalence and incidence rates were 26% (12–42, I2 = 99.0%) and 2% (1–3, I2 = 98.6%), respectively. LTBI prevalence reached 44% (12–79, I2 = 99.0%) in high-burden countries. Active tuberculosis was reported only in low-burden countries (incidence range, 0.61–450/10,000 correctional facility workers/year). LTBI-associated risk factors included job duration, older age, country of birth, current tobacco smoking, reported contact with prisoners, and BCG vaccination. Conclusion Despite the risk of bias and high heterogeneity, LTBI was found to be prevalent in correctional facility workers, mainly in high-burden countries. LTBI risk factors suggest both occupational and community exposure. Active tuberculosis occurrence in low-burden countries suggests higher vulnerability from recent infection among correctional facility workers in these countries. Systematic surveillance and infection control measures are necessary to protect these highly vulnerable workers.…

Abstract Background The enteric string test can be used to obtain a specimen for microbiological confirmation of tuberculosis in children, but it is not widely used for this. The aim of this analysis to evaluate this approach in children with tuberculosis symptoms. Methods We conducted a cross-sectional study to assess children’s ability to complete the test (feasibility), and self-reported pain (tolerability). We examined caregivers’ and children’s willingness to repeat the procedure (acceptability) and described the diagnostic yield of cultures for diagnostic tools. We stratified estimates by age and compared metrics to those derived for gastric aspirate (GA). Results Among 148 children who attempted the string test, 34% successfully swallowed the capsule. Feasibility was higher among children aged 11–14 than in children 4–10 years (83% vs 22% respectively, p 

Gokul Raj Kathamuthu, Kadar Moideen, Vaithilingam V. Banurekha, Dina Nair, R. Sridhar, Dhanaraj Baskaran, Subash Babu

by Gokul Raj Kathamuthu, Kadar Moideen, Vaithilingam V. Banurekha, Dina Nair, R. Sridhar, Dhanaraj Baskaran, Subash Babu B cell activating factor/a proliferation-inducing ligand (BAFF/APRIL) are members of the tumor necrosis factor alpha (TNF) α family of ligands, which are essential for B cell survival, development, and modulation of the immune system. To examine the association of circulating levels of BAFF and APRIL with pulmonary tuberculosis (PTB) and tuberculous lymphadenitis (TBL), we measured the systemic levels of APRIL and BAFF in individuals with PTB, TBL, latent tuberculosis (LTB) and healthy controls (HC). Further, we also examined the pre and post-treatment plasma levels of above-mentioned parameters in PTB and TBL individuals upon completion of anti-TB chemotherapy. Next, the association of these cytokines either with extent of disease, disease severity, bacterial burden in PTB and lymph node culture grade or the lymph node size in TBL was also assessed. Finally, ROC analysis was performed to examine the discrimination capacity of APRIL and BAFF between PTB or TBL with LTB. Our study revealed significantly diminished plasma levels of APRIL in PTB and higher plasma levels of BAFF in both PTB and TBL individuals compared to LTB and HC. Furthermore, we observed a significant increase in APRIL levels in TBL and significantly decreased plasma levels of BAFF in both PTB and TBL after the completion of successful anti-TB treatment. There was no statistically positive relationship between BAFF and APRIL levels and the extent of disease, disease severity and bacterial burden in PTB. In TBL, there was a significant correlation between APRIL (but not BAFF) levels with lymph node culture grades. In contrast, APRIL in PTB and BAFF in TBL were able to clearly discriminate from LTB in ROC analysis. In summary, our results showed altered levels of BAFF/APRIL and their modulation upon chemotherapy, suggesting that these cytokines might be involved in the immune-modulation of TB infection.

Isaac Mwangi Wangari, James Trauer, Lewi Stone

by Isaac Mwangi Wangari, James Trauer, Lewi Stone A tuberculosis (TB) model that accounts for heterogeneity in host susceptibility to tuberculosis is proposed, with the aim of investigating the implications this may have for the effectiveness of public health interventions. The model examines the possibility that recovered individuals treated from active TB and individuals treated with preventive therapy acquire different levels of immunity. This contrasts with recent studies that assume the two cohorts acquire the same level of immunity, and therefore both groups are reinfected at the same rate. The analysis presented here examines the impact of this assumption when designing intervention strategies. Comparison of reinfection rates between cohorts treated with preventive therapy and recovered individuals who were previously treated for active TB provides important epidemiological insights. It is found that the reinfection rate of the cohort treated with preventive therapy is the one that plays the key role in qualitative changes in TB dynamics. By contrast, the reinfection rate of recovered individuals (previously treated from active TB) plays a minor role. Moreover, the study shows that preventive treatment of individuals during early latency is always beneficial regardless of the level of susceptibility to reinfection. Further, if patients have greater immunity following treatment for late latent infection, then treatment is again beneficial. However, if susceptibility increases following treatment for late latent infection, the effect of treatment depends on the epidemiological setting. That is: (i) in (very) low burden settings, the effect on reactivation predominates and the burden declines with treatment; (ii) in moderate to high burden settings the effect of reinfection predominates and burden increases with treatment. The effect is most dominant between the two reinfection thresholds, RT2 and RT1, respectively associated with individuals being treated with preventive therapy and individuals with untreated late latent TB infection.

Abstract Background By 2014 although tuberculosis (TB) incidence had fallen by an average of 1.5% per year since 2000 and was 18% lower than the level of in 2000, 1.5 million people died for TB in that year. One of reason was that drug resistant Mycobacterium tuberculosis (DRTB) spread. This study aims to determine drug resistant characteristics and genotype of DRTB that isolated from patients in a tuberculosis referral hospital of southwest China. Methods Five hundred thirty-eight drug resistant tuberculosis samples were collected from July 2013 to March 2015. All the isolates were identified by genomic deletions in region of difference 105 (RD105) and genotyped by mycobacterial interspersed repetitive unit-variable number tandem repeat typing (MIRU-VNTR). Polymorphism and cluster analysis of each locus was carried out using Bionumerics Version 3.0 and phyloviz software. Results Five hundred thirty-eight TB strains included 503 Mycobacterium tuberculosis (MTB) isolates and 35 non Mycobacterium tuberculosis (NMTB) isolates. Of 503 isolates Beijing family type was 447 (88.9%, 447/503) and non-Beijing family type was 56 (11.1%, 56/503). Five hundred three DRTB isolates were divided into 345 genotypes, of which 265 isolates were single genotype and the remaining 238 strains were classified into 80 clusters with cluster rate of 47.3% and cluster ratio of 31.4%. Sixty-nine clusters belonged to Beijing family with cluster rate was 48.3% and clustering ratio was 32.9%. The non - Beijing family had 11 clusters with a cluster rate of 39.3% and the clustering ratio of 19.6%. Beijing genotype had a significant correlation with the age (P 

Abstract Background Toll-like receptor (TLR) single nucleotide polymorphisms (SNPs) have been associated with regulation of TLR expression and development of active tuberculosis (TB). The objectives of this study were to determine whether TLR8 and TLR9 SNPs were associated with the development of latent TB infection (LTBI) and the subsequent pulmonary TB (PTB) in a Chinese Han population. Methods Two independent samples were enrolled. The first sample contained 584 TB cases and 608 controls; the second sample included 204 healthy controls, 201 LTBI subjects and 209 bacteria-confirmed active PTB patients. Three SNPs (rs3764880, rs187084 and rs5743836) were genotyped. The associations between the SNPs and risk of LTBI or PTB were investigated using unconditional logistic regression analysis. Results The A-allele of TLR8 rs3764880 SNP was protective against the development of TB in males (A vs G, OR = 0.58, 95%CI = 0.37–0.91). The AA genotype of rs3764880 SNP was found to increase the risk of PTB among females with an OR of 4.81 (1.11–20.85). The G allele of TLR9 SNP rs187084 was found to increase the risk of PTB (G vs A, P = 0.01, OR = 1.48, 95% CI = 1.10–2.00), the significance was also observed under dominant genetic models. The GA-genotype of TLR9 rs187084 SNP was found to increase the risk of PTB with an OR of 1.68 (1.07–2.65), but was found to decrease the risk of MTB infection with an OR = 0.64 (0.41–0.98). TLR9_rs5743836 SNP was excluded from the data analyses, because the minimum allele frequency was

Meikle, V., Mossberg, A.-K., Mitra, A., Hakansson, A. P., Niederweis, M.

Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis (TB), has surpassed HIV/AIDS as the leading cause of death from a single infectious agent. The increasing occurrence of drug resistant strains has become a major challenge for health care systems and, in some cases, rendered TB untreatable. However, developing new TB drugs has been plagued with high failure rates and costs. Alternative strategies to increase the efficacy of current TB treatment regimens include host-directed therapies or agents that make Mtb more susceptible to existing TB drugs. In this study, we show that HAMLET, an alpha-lactalbumin - oleic acid complex derived from human milk, has bactericidal activity against Mtb. HAMLET consists of a micellar oleic acid core surrounded by a shell of partially denatured alpha-lactalbumin molecules and unloads oleic acid into cells upon contact with lipid membranes. At sub-lethal concentrations, HAMLET potentiated a remarkably broad array of TB drugs and antibiotics against Mtb. For example, the minimal inhibitory concentrations of rifampicin, bedaquiline, delamanid and clarithromycin were decreased by 8- to 16-fold. HAMLET also killed Mtb and enhanced the efficacy of TB drugs inside macrophages, a natural habitat of Mtb. Previous studies showed that HAMLET is stable after oral delivery in mice and non-toxic in humans and that it is possible to package hydrophobic compounds in the oleic acid core of HAMLET to increase their solubility and metabolic stability. The potential of HAMLET and other liprotides as drug delivery and sensitization agents in TB chemotherapy is discussed.…

Long Viet Bui, Zohar Mor, Daniel Chemtob, Son Thai Ha, Hagai Levine

by Long Viet Bui, Zohar Mor, Daniel Chemtob, Son Thai Ha, Hagai Levine Objectives This study aimed to examine the potential of combining routine tuberculosis (TB) surveillance and demographic and socioeconomic variables into the Geographic Information System (GIS) to describe the geographical distribution of TB notified incidence in relation to distances to health services as well as local demographic and socioeconomic factors, including population density, urban/rural status, and household poverty rates in Nam Dinh, Vietnam. It also aimed to compare the conventional Generalized Linear Models (GLM) Poisson regression model and Geographically Weighted Poisson Regression (GWPR) models in order to determine the best fitting model that can be used to investigate the relationship between TB notified incidence and distances and the social risk factors. Methods The data of new and relapse patients with all forms of TB aged ≥15 years residing in Nam Dinh (Vietnam) from 2012 to 2015 were collected from the Administration of Medical Services’ (Ministry of Health of Vietnam) TB surveillance database. Data on the population and household poverty rates from 2012 to 2015 were gathered from the Nam Dinh Statistical Office. Distances between communes and the nearest TB diagnostic facilities in districts were computed. The TB notified incidence per 100,000 population was denoted by indirect age and sex standardized incidence ratio. GLM Poisson regression and GWPR were performed to assess the relationship between distance and TB incidence. Results The average notified TB incidence level measured from 2012 to 2015 is 82 per 100,000 population (range: 79-84/100,000). The distance to the nearest TB diagnosis presents a negative effect on TB notified incidence. By capturing spatial heterogeneity, the GWPR may be better at fitting data (corrected Aikake information criterion [AICc] = 245.71, residual deviance = 221.12) than the traditional GLM (AICc = 251.53, residual deviance = 241.21) Conclusions GIS technologies benefit TB surveillance system. Distances should be considered when planning methods of improving access for those who live far from TB diagnostic services, thereby improving TB detection. Additional studies must confirm the association between geographic distance and TB case detection and must explore other factors that may affect TB notified incidence.…

Abstract Background Infection after vertebroplasty (VP) is a rare but serious complication. Previous literatures showed most pathogens for infection after VP were bacteria; tuberculosis (TB) induced infection after VP was extremely rare. We reported our treatment experiences of cases with infectious spondylitis after VP, and compared the differences between developed pyogenic and TB spondylitis. Methods From January 2001 to December 2015, 5749 patients had undergone VP at our department were reviewed retrospectively. The causative organisms were obtained from tissue culture of revision surgery. Parameters including type of surgery, the interval between VP and revision surgery, neurologic status, and visual analog scale (VAS) of back pain were recorded. Laboratory data at the time of VP and revision surgery were collected. Charlson comorbidity index (CCI), preoperative bacteremia, urinary tract infection (UTI), pulmonary TB history were also analyzed. Results Eighteen patients were confirmed with developed infectious spondylitis after VP (0.32%, 18/5749). Two were male and 16 were female. The median age at VP was 73.4 years. Nine patients were TB and the other nine patients were pyogenic. The interval between VP and revision surgery ranged from 7 to 1140 days (mean 123.2 days). The most common type of revision surgery was anterior combined with posterior surgery. Seven patients developed neurologic deficit before revision surgery. Three patients died within 6 months after revision surgery, with a mortality of 16.7%. Finally, VAS of back pain was improved from 7.4 to 3.1. Seven patients could walk normally, the other 8 patients had some degree of disability. Both pyogenic and TB group had similar age, sex, and CCI distribution. The interval between VP and revision surgery was shorter in the patients with pyogenic organisms (75.9 vs 170.6 days). At revision surgery, WBC and CRP were prominently elevated in the pyogenic group. Five in the pyogenic group had UTI and bacteremia; five in TB group had a history of lung TB. Conclusions Infection spondylitis after VP required major surgery for salvage with a relevant part of residual disability. Before VP, any bacteremia/UTI or history of pulmonary TB should be reviewed rigorously; any elevation of infection parameters should be scrutinized strictly.…

Abstract Background Globally recommended measures for comprehensive tuberculosis (TB) infection control (IC) are inadequately practiced in most health care facilities in Ethiopia. The aim of this study was to assess the extent of implementation of TB IC measures before and after introducing a comprehensive technical support package in two regions of Ethiopia. Methods We used a quasi-experimental design, whereby a baseline assessment of TB IC practices in 719 health care facilities was conducted between August and October 2013. Based on the assessment findings, we supported implementation of a comprehensive package of interventions. Monitoring was done on a quarterly basis, and one-year follow-up data were collected on September 30, 2014. We used the Student’s t-test and chi-squared tests, respectively, to examine differences before and after the interventions and to test for inter-regional and inter-facility associations. Results At baseline, most of the health facilities (69%) were reported to have separate TB clinics. In 55.2% of the facilities, it was also reported that window opening was practiced. Nevertheless, triaging was practiced in only 19.3% of the facilities. Availability of an IC committee and IC plan was observed in 29.11 and 4.65% of facilities, respectively. Health care workers were nearly three times as likely to develop active TB as the general population. After 12 months of implementation, availability of a separate TB room, TB IC committee, triage, and TB IC plan had increased, respectively, by 18, 32, 44, and 51% (p 

Stephen P. Carter, Andrew Robertson, Kate L. Palphramand, Mark A. Chambers, Robbie A. McDonald, Richard J. Delahay

by Stephen P. Carter, Andrew Robertson, Kate L. Palphramand, Mark A. Chambers, Robbie A. McDonald, Richard J. Delahay The deployment of baits containing vaccines or toxins has been used successfully in the management of wildlife populations, including for disease control. Optimisation of deployment strategies seeks to maximise uptake by the targeted population whilst ensuring cost-effectiveness. Tuberculosis (TB) caused by infection with Mycobacterium bovis affects a broad range of mammalian hosts across the globe, including cattle, wildlife and humans. The control of TB in cattle in the UK and Republic of Ireland is hampered by persistent infection in European badgers (Meles meles). The present study aimed to determine the best strategy for maximising uptake of an oral vaccine by wild badgers, using a surrogate novel bait deployed at 40 badger social groups. Baits contained a blood-borne biomarker (Iophenoxic Acid, IPA) in order to measure consumption in badgers subsequently cage trapped at targeted setts. Evidence for the consumption of bait was found in 83% (199/240) of captured badgers. The probability that badgers had consumed at least one bait (IPA >10 μg ml-1) was significantly higher following deployment in spring than in summer. Lower uptake amongst social groups where more badgers were captured, suggested competition for baits. The probability of bait consumption was significantly higher at groups where main and outlier setts were provided with baits than at those where outliers were present but not baited. Badgers captured 10–14 days post bait feeding had significantly higher levels of bait uptake compared to those caught 24–28 days later. Uptake rates did not vary significantly in relation to badger age and whether bait was placed above ground or down setts. This study suggests that high levels of bait uptake can be achieved in wild badger populations and identifies factors influencing the potential success of different deployment strategies. The implications for the development of an oral badger vaccine are discussed.

Tao Li, Xin Du, Hemant Deepak Shewade, Kyaw Thu Soe, Hui Zhang

by Tao Li, Xin Du, Hemant Deepak Shewade, Kyaw Thu Soe, Hui Zhang Background In China, internal migrants constitute one-fifth of tuberculosis (TB) patients registered for treatment in web-based TB information management system (TBIMS). Though China added a specific module in the web-based TBIMS in 2009, web-based transfer-out is not specifically recommended in the national guidelines. Objective In this country wide study among all registered migrant TB patients (2014–2015) that were transferred out using web-based TBIMS in China, to determine the i) timing of transfer-out in relation to period of treatment; ii) delay and attrition during transfer interval (between transfer-out and transfer-in); and iii) extent and risk factors for ‘not evaluated’ as the treatment outcome. Methods This was a cohort study involving review of web-based TBIMS data. Modified Poisson regression was used to build a predictive model for risk factors of ‘not evaluated’ as the treatment outcome. Results Among 7 284 patients, 5 900 (81.0%) were transferred out during the first two months after initiation of treatment or before treatment initiation and 7 088 (97.3%) patients had arrived at transfer-in unit. The median transfer interval was three (interquartile range: 0–14) days. Sixteen percent (1 176/7 284) patients had ‘not evaluated’ as their treatment outcome. ‘Not evaluated’ contributed to 66% of the unfavourable outcomes. Patients transferred from referral hospitals, migrated from out of prefecture, transferred out of prefecture, with sputum smear negative pulmonary TB, with TB pleurisy and with long delay between symptom onset and treatment initiation had significantly higher risk of ‘not evaluated’ as the outcome. Conclusion Web-based transfer helped as the delay and attrition during the transfer interval was quite short and treatment outcomes of more than four-fifths of transferred out migrant TB patients were available with transfer-out BMU. Once strategies to address the independent predictors of ‘not evaluated’ treatment outcome are devised, China may consider mandatory use of web-based TBIMS for transferring out migrant TB patients.…

Amrita Daftary, Ellen M. H. Mitchell, Michael J. A. Reid, Endalkachew Fekadu and Eric Goosby

Abstract. World leaders gather to consolidate their commitment to ending tuberculosis (TB). Vital to the success of renewed efforts is an overdue recognition of the pervasive and pernicious influence of TB stigma. TB stigma is sustained in structures, policies, traditions, and norms. Innovative modifications to infection control, drug dispensing, and surveillance practices are required to increase demand for TB screening and effective therapeutic alliances among those diagnosed. The authors argue that reducing TB stigma requires a scientific and inclusive process, with prominent roles for TB survivors and a willingness to integrate and learn from other stigmatized conditions.…

Choudhary, Rewa K; Wall, Kristin M.; Njuguna, Irene; Pavlinac, Patricia B.; Lacourse, Sylvia M.; Otieno, Vincent; Gatimu, John; Stern, Joshua; Maleche-Obimbo, Elizabeth; Wamalwa, Dalton; John-Stewart, Grace; Cranmer, Lisa M.

Background: The blood monocyte-to-lymphocyte ratio (MLR) is associated with active tuberculosis (TB) in adults, but has not been evaluated as a TB diagnostic biomarker in HIV-infected children in whom respiratory sampling is difficult. Setting: In a cohort of HIV-infected hospitalized Kenyan children initiating antiretroviral therapy, absolute monocyte and lymphocyte counts were determined at enrollment and 4, 12, and 24 weeks thereafter. Methods: Children were classified as confirmed, unconfirmed, or unlikely pulmonary TB. ROC curves of MLR cutoff values were generated to distinguish children with confirmed TB from those with unconfirmed and unlikely TB. General estimating equations were used to estimate change in MLR over time by TB status. Results: Of 160 children with median age 23 months, 13 (8.1%) had confirmed TB and 67 (41.9%) had unconfirmed TB. Median MLR among children with confirmed TB [0.407 (interquartile range (IQR) 0.378 - 0.675)] was higher than MLR in children with unconfirmed [0.207 (IQR 0.148 - 0.348), p < 0.01] or unlikely [0.212 (IQR 0.138 - 0.391), p = 0.01] TB. MLR above 0.378 identified children with confirmed TB with 77% sensitivity, 78% specificity, 24% positive predictive value, and 97% negative predictive value. After TB treatment, median MLR declined in children with confirmed TB and levels were similar to children with unlikely TB after 12 weeks. Conclusion: Blood MLR distinguished HIV-infected children with confirmed TB from those with unlikely TB and declined with TB treatment. MLR may be a useful diagnostic tool for TB in settings where respiratory-based microbiologic Corresponding Author: Lisa M. Cranmer, Department of Pediatrics, Emory University School of Medicine, 2015 Uppergate Drive NE, Suite 534, Atlanta, GA, USA 30322, lisa.cranmer@emory.edu, (Tel) +1 404-727-2905, (Fax) +1-404-727-9223. Conflicts of Interest and Source of Funding: The authors report no conflicts of interest. Contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The funding sources were not involved in the analyses or interpretation of data. None of the authors were paid to write this article by a pharmaceutical company or other agency. This work was supported by the National Institute of Child Health and Human Development (NICHD), National Institute of Allergy and Infectious Diseases (NIAID), Fogarty International Center, and National Center For Advancing Translational Sciences at the National Institutes of Health (NIH) (R01 HD023412 and K24 HD054314-06 to GJS, D43TW009783 to IN, T32 AI007140 to PBP, K12 HD000850 to LMC, K23 AI 120793-01 to SML, and UL1TR000423 for REDCap), University of Washington Center for AIDS Research (P30 AI027757), UW Global Center for Integrated Heath of Women, Adolescents and Children (Global WACh), the Pediatric Scientist Development Program (PSDP) through grants from the American Pediatric Society and American Academy of Pediatrics (LMC), and the Infectious Diseases Society of America Medical Scholars Program (RKC). Portions of these data were presented at the 48th Union World Conference on Lung Health in Guadalajara, Mexico on October 12, 2017. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

de Miranda Silva, C., Hajihosseini, A., Myrick, J., Nole, J., Louie, A., Schmidt, S., Drusano, G. L.

Combination therapy is a successful approach to treat tuberculosis in patients with susceptible strains of Mycobacterium tuberculosis (M. tuberculosis). However, the emergence of resistant strains requires identification of new, effective therapies. Pretomanid (PA824) and moxifloxacin (MXF) are promising options currently under evaluation in clinical trials for the treatment of susceptible and resistant mycobacteria. We applied our recently described screening strategy to characterize the interaction between PA824 and MXF towards killing of M. tuberculosis in Logarithmic growth phase (Log-phase), Acid-phase and Non-Replicating Persister phase (NRP-phase). Respective in vitro data generated for H37Rv and 18b strains, was evaluated in a microdilution plate system containing both drugs in combination. The Universal Response Surface Approach model from Greco was used to characterize the nature of interaction between both drugs; synergistic or additive combinations would prompt additional evaluation in the hollow fiber infection model (HFIM) and in animal studies. The interaction between MXF and PA824 was additive against M. tuberculosis in Acid-phase (α = 5.56e–8 with 95% CI = -0.278 to 0.278 and α = 0.408; 95% CI = 0.105 to 0.711), NRP-phase (α = 0.625 with 95% CI =-0.556 to 1.81 and α = 2.92 with 95% CI = 0.215 to 5.63), and Log-phase organisms (α = 1.57e–6 with 95% CI = -0.930 to 0.930 and α = 1.83e–6 with 95% CI= -0.929 and 0.929), prompting further testing of this promising combination for the treatment of tuberculosis in the HFIM and in animal studies.…

Kwara, A., Yang, H., Antwi, S., Enimil, A., Gillani, F. S., Dompreh, A., Ortsin, A., Opoku, T., Bosomtwe, D., Sarfo, A., Wiesner, L., Norman, J., Alghamdi, W. A., Langaee, T., Peloquin, C. A., Court, M. H., Greenblatt, D. J.

We compared efavirenz pharmacokinetic (PK) parameters in children with TB/HIV coinfection on and off first-line antituberculosis therapy to that in HIV-infected children. Children aged 3 to 14 years old with HIV infection with and without TB were treated with standard efavirenz-based antiretroviral therapy without any efavirenz dose adjustments. The new World Health Organization recommended antituberculosis drugs dosages were used in the co-infected participants. Steady-state efavirenz concentrations after 4 weeks of antiretroviral therapy were measured using validated LC/MS/MS assays. Pharmacokinetic parameters were calculated using noncompartmental analysis. Between groups, PK parameters were compared by Wilcoxon Rank-sum test and within group by Signed-rank test. Of the 105 participants, 43 (41.0%) had TB coinfection. Children with TB/HIV coinfection compared to those with HIV infection were younger, had lower median weight-for-age-Z-score and received a higher median efavirenz weight-adjusted dose. Geometric mean (GM) efavirenz Cmax, C12h, Cmin and AUC0-24h were similar in children with HIV infection and those with TB/HIV coinfection during anti-TB therapy. Geometric mean efavirenz C12h, Cmin and AUC0-24h were lower in TB/HIV co-infected patients off anti-TB therapy than in the children with HIV infection or TB/HIV coinfection on anti-TB therapy. Efavirenz clearance was lower and AUC0-24h was higher on than off anti-TB therapy. Reduced efavirenz clearance by first-line anti-TB therapy at the population level led to similar PK parameters in HIV-infected children with and without TB coinfection. Our findings do not support modification of efavirenz weight-band dosing guidelines based on TB coinfection status in children.…

The PLOS ONE Staff

by The PLOS ONE Staff …

Brittney J. van de Water, Susan G. Silva, Janet Prvu Bettger, Janice Humphreys, Coleen K. Cunningham, Jason E. Farley

by Brittney J. van de Water, Susan G. Silva, Janet Prvu Bettger, Janice Humphreys, Coleen K. Cunningham, Jason E. Farley Title Provision of guideline-based care for drug-resistant tuberculosis in South Africa: Level of concordance between prescribing practices and guidelines. Objective We examined the influence of individual and site characteristics on the concordance between prescribed treatment regimens and recommended standardized regimen according to national guidelines for patients with drug-resistant tuberculosis (DR-TB) in South Africa. Methods Participants were 337 youth and adults treated for DR-TB between November 2014 and August 2016 at ten DR-TB treatment sites in Eastern Cape and KwaZulu Natal provinces, South Africa. Logistic regression was used to determine individual and system characteristics related to concordance at treatment initiation between the prescribed treatment regimens in terms of medication composition, dosage, and frequency and guideline-based standardized regimen that included four oral and one injectable medications. Results The sample was 19% (n = 64) youth (15–24 years), 53% (n = 179) male, 73% (n = 243) HIV coinfected, and 51% (n = 169) with prior history of TB treatment. Guideline medications were correctly prescribed for 88% (n = 295) of patients, but only 33% (n = 103) received the correct medications and doses. Complete guideline adherence to medications, doses, and frequency was achieved for 30% (n = 95) of patients. Younger age, HIV coinfection, and rural treatment setting were associated with the prescription of correct medications. Conclusion Most individuals are prescribed the correct DR-TB medications, yet few individuals receive correct medications, dosages, and frequencies. Further study is needed to examine the root causes for treatment guideline deviations and opportunities for improvement.…