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BACKGROUND: Occupational exposure-related risk of Mycobacterium tuberculosis infection has been reported for village doctors in China. This prospective study aims to estimate the infection acquisition in this key population.METHODS: At baseline, all village doctors registered in Zhongmu County were tested by QuantiFERON®-TB Gold In-Tube (QFT) and QuantiFERON®-TB Gold Plus (QFT-Plus) in parallel. Those negatives for either of the tests were retested to identify conversions at the 2-year follow-up investigation.RESULTS: A total of 367 eligible participants completed the 2-year follow-up survey with frequency of conversion of 5.0% (18/361) for QFT and 6.1% (21/343) for QFT-Plus. The agreement of follow-up results between the tests was 93.2% with a κ coefficient of 0.43 (95%CI 0.20–0.65). Among QFT-Plus convertors, the difference between TB1 and TB2 tubes (TB2-TB1) was significantly increased as compared with baseline results (P = 0.039). Participants from the villages with occurrence of microbiologically confirmed pulmonary TB showed higher frequency of QFT conversions (11.0% vs. 3.2%, P = 0.011) and QFT-Plus conversions (12.3% vs. 4.4%, P = 0.027) than those from the villages without occurrence.CONCLUSION: Our results consistently suggest that capability on occupational protection and M. tuberculosis infection control should be improved in village doctors in China.

Background Dynamically changed levels of serum cytokines might predict the development of active TB from latent tuberculosis infection (LTBI) and monitor preventive treatment effectiveness. The aim of the study was to identify potential serum cytokines associated with LTBI treatment which might predict active disease development in a Chinese population. Methods Based on a randomized controlled trial aiming to explore short-course regimens for LTBI treatment, the dynamic changes of serum cytokines determined by bead-based multiplex assays were investigated for the participants who developed active TB during follow-up and age and gender matched controls stayed healthy. Results Totally, 21 patients diagnosed with active tuberculosis (TB) during the 2-year follow-up (12 from treated groups and 9 from untreated controls) and 42 age and gender matched healthy controls (24 from treated groups and 18 from untreated controls) were included in the study. Before treatment, serum IL-1ra was statistically higher among those who developed active disease during follow-up as compared with those stayed healthy. As for treated participants, the levels of IL-1ra were significantly lower after treatment in comparison with those before treatment both in active TB group (p = 0.002) and non-TB group (p = 0.009). For untreated participants, the levels of IL-1ra were not statistically different between different time points both in active TB group (p = 0.078) and non-TB group (p = 0.265). Conclusion Our results suggested that declined serum level of IL-1ra was associated with LTBI treatment. Further studies are needed to verify whether it could be used to evaluate LTBI treatment and to predict active disease development.

Highlights • Improving the knowledge on TB management for rural doctors in China are essential. • The studied rural doctors showed relatively poor knowledge on TB management. • WeChat-based training is an effective means to achieve an improvement. • How to better enhance rural doctors’ engagement should be considered., Background In China, rural doctors played a crucial role in TB cases referral and management. The current study aimed to evaluate the effect of WeChat-based training program on improving the rural doctors’ knowledge on TB management. Methods A One-year WeChat-based training was conducted among registered rural doctors from Zhongmu County, located in middle China, by means of releasing original contents (in forms of text, poster, video or cartoon) through WeChat subscription account (WeChat SA) once a week. Pre-and-post-training offline tests were hold using the same self-administered questionnaire to evaluate the training effect. Results A total of 467 rural doctor were included in the study. During the training, 60 original articles were posted through WeChat SA. With respect to the two tests, the median score increased from 50 (40.0–60.0) to 60 (53.0–70.0) (p

Background: Individuals with pulmonary fibrotic radiological lesions, indicating prior tuberculosis (TB), have been suggested to be at high likelihood of developing active disease from latent TB infection (LTBI). The burden of LTBI among this specific population has been rarely studied in China.Methods: We conducted a population-based screening study to investigate the prevalence of fibrotic radiological lesions and their TB infection rate among rural residents in China. Chest radiography examination was performed for all eligible participants, and Interferon Gamma Release Assay (IGRA) testing was conducted for those with a history of anti-TB treatment and those with radiographic abnormalities suggestive of prior TB. Risk factors associated with the present of fibrosis and IGRA positivity were analyzed.Results: A total of 45,901 rural residents participated in the study, 2,231 of them reported a history of anti-TB treatment. The prevalence of pulmonary fibrosis was 34.16% (762/2,231) and 2.81% (1,230/43,670) among the participants with and without anti-TB treatment. The present of fibrosis was found to be more frequent among individuals with a history of relapse of TB (50.35%, 72/143) or previous smear positive TB (44.23%,157/355). Among participants with fibrotic radiological lesions, IGRA positivity was 50.39% (384/762) and 25.44% (313/1,230) for those with and without anti-TB treatment records, respectively. Males, younger age and a previous smear positive TB were associated with higher IGRA positivity among individuals with anti-TB treatment record.Conclusions: Individuals with fibrotic radiological lesions and their remarkably high burden of TB infection should be attached more attention for TB control in China.

ObjectivesExploring biomarkers monitoring latent tuberculosis infection (LTBI) treatment effectiveness would benefit optimizing the therapeutic regimen. This study aims to identify potential mycobacteria-specific antigen-induced cytokines associated with host responses to preventive treatment.MethodsBased on a randomized controlled trial on LTBI treatment among individuals with chest radiography abnormalities suggestive of prior tuberculosis (TB), the dynamically changed cytokine levels in QuantiFERON-TB Gold In-Tube (QFT) supernatants were estimated during the treatment by bead-based multiplex assays and enzyme-linked immunosorbent assay.ResultsIn total, 63 treated participants and 32 untreated controls were included in the study. The levels of 13 background-corrected mycobacteria-specific antigen-stimulated cytokines [basic fibroblast growth factor (FGF), growth-regulated oncogene (GRO)-α, interleukin (IL)-1α, IL-1ra, IL-12 (p70), stem cell factor (SCF), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), IL-8, interferon (IFN)-α2, IL-5, IL-12 (p40), leukemia inhibitory factor (LIF), and IL-17A] were found to be statistically different between before and after treatment in treated participants, while no statistically differences were observed in untreated controls. Among these 13 cytokines, the level of IL-8 was significantly lower in the QFT reversed group than that in the non-reversed group (p= 0.028) among treated participants, while such a difference was not found for untreated controls (p= 0.292).ConclusionOur results suggested that the lower level of mycobacteria-specific antigen-induced IL-8 might be associated with the host’s positive response to LTBI treatment.

Aim: We developed a polycaprolactone-based nanoparticle (NP) to encapsulate tryptanthrin derivative CY-1-4 and evaluated its antitumor efficacy. Materials & methods: CY-1-4 NPs were prepared and evaluated for their cytotoxicity and associated mechanisms, indoleamine 2,3-dioxygenase (IDO)-inhibitory ability, immunogenic cell death (ICD)-inducing ability and antitumor efficacy. Results: CY-1-4 NPs were 123 nm in size. In vitro experiments indicated that they could both induce ICD and inhibit IDO. In vivo studies indicated that a medium dose reduced 58% of the tumor burden in a B16-F10-bearing mouse model, decreased IDO expression in tumor tissues and regulated lymphocytes subsets in spleen and tumors. Conclusion: CY-1-4 is a potential antitumor candidate that could act as a single agent with combined functions of IDO inhibition and ICD induction.

Summary Objectives To evaluate the performance of QuantiFERON-TB Gold Plus (QFT-Plus) on Mycobacterium tuberculosis (MTB) infection test among registered village doctors from China. Methods MTB infection of the registered village doctors in Zhongmu County were tested using QFT-Plus and two other interferon-gamma release assays (IGRAs) in parallel: QuantiFERON-TB Gold In-Tube (QFT) and T-SPOT.TB (T-SPOT). Retests were carried out for baseline positives at 3 and 6 months later, respectively. Results A total of 616 village doctors were included in the baseline examination. The positivity of QFT, QFT-Plus and T-SPOT was 27.91% (168/602), 31.22% (187/599) and 27.70% (169/610), respectively. The concordance between QFT and QFT-Plus was 94.81% (Kappa coefficient: 0.87) and between T-SPOT and QFT-Plus was 88.93% (Kappa coefficient: 0.73). Reversions were frequently observed for all three assays. With respect to QFT-Plus, the quantitative results of reversions in the serial testing were mostly distributed in an “uncertain range” zone (0.2-0.7 IU/mL). Similar patterns of distribution were observed for QFT and T-SPOT as well. Conclusion Village doctors should gain more attention as an at-risk group for TB infection control in rural China. Our results support, by means of serial testing, a good agreement between QFT-Plus and QFT in Chinese population.

Tuberculosis (TB) is a serious infectious disease with high infection and mortality rates. 5%–10% of the latent tuberculosis infections (LTBI) are likely to develop into active TB, and there are currently no clinical biomarkers that can distinguish between LTBI, active TB and other non-tuberculosis populations. Therefore, it is necessary to develop rapid diagnostic methods for active TB and LTBI. In this study, urinary metabolome of 30 active TB samples and the same number of LTBI and non-TB control samples were identified and analyzed by UPLC-Q Exactive MS. In total, 3744 metabolite components were obtained in ESI- mode and 4086 in ESI + mode. Orthogonal partial least square discriminant analysis (OPLS-DA) and hierarchical cluster analysis (HCA) showed that there were significant differences among LTBI, active TB and non-TB. Six differential metabolites were screened in positive and negative mode, 3-hexenoic acid, glutathione (GSH), glycochenodeoxycholate-3-sulfate, N-[4′-hydroxy-(E)-cinnamoyl]- l -aspartic acid, deoxyribose 5-phosphate and histamine. The overlapping pathways differential metabolites involved were mainly related to immune regulation and urea cycle. The results showed that the urine metabolism of TB patients was disordered and many metabolic pathways changed. Multivariate statistical analysis revealed that GSH and histamine were selected as potential molecular markers, with area under curve of receiver operating characteristic curve over 0.75. Among the multiple differential metabolites, GSH and histamine changed to varying degrees in active TB, LTBI and the non-TB control group. The levels of GSH and histamine in 48 urinary samples were measured by ELISA in validation phase, and the result in our study provided the potential for non-invasive biomarkers of TB.

Background: In China, around 70% tuberculosis (TB) cases occurred in rural areas. Village doctors played a crucial role in TB cases referral and management. The current study aimed to evaluate the effect of WeChat-based training program on improving the village doctors’ knowledge on TB management.Methods: A One-year WeChat-based training was conducted by means of releasing original contents (in forms of text, poster, video or cartoon), through WeChat subscription account (WeChat SA) once a week, with the topics of TB detection, treatment, prevention and patient’s management. Based on a self-control design, pre-and post-training offline tests were hold using the same self-administered questionnaire to evaluate the training effect.Results: A total of 467 village doctor registered in Zhongmu County (Henan province, China), who worked in the local village clinic or community health center, were included in the study. During the training, sixty original articles were posted through WeChat SA during the one-year training. There are 19, 26 and 15 were displayed in the form of text, poster and other types (such as video or cartoon), and the corresponding average reading times were 245, 38, 199, respectively. With respect to the two tests, the median score increased from 50 (40.0-60.0) to 60 (53.0-70.0) (pConclusions: Our results indicated that WeChat-based training could improve the knowledge of village doctors on TB management. It is worthy to explore more effective new media-based training methods that might promote TB control work in rural China.

Background: Individuals with chest radiography indicating inactive tuberculosis (TB) has been suggested to be one of the high risk populations for developing active TB from latent infection. The burden of this specific population and their TB infection status has been rarely studied in China. Method: We conducted a population-based screening study to investigate the prevalence of inactive TB radiographic abnormalities and their current TB infection status among rural residents. Chest radiography examination and Interferon Gamma Release Assay (IGRA) testing were performed for all eligible rural residents with record of anti-TB treatment. While for participants without recorded previous TB, IGRA testing was conducted only for those with radiographic abnormalities indicating inactive TB (i.e. fibrosis, calcification, nodule, and pleural incrassation). Findings: A total of 46,041 rural residents voluntarily participated in the study. Around two thirds (70·39%, 1,583/2,249) of participants with anti-TB treatment records showed hint of inactive TB lesions, while it was 6·87% (3,008/43,792) for those without treatment history. Among participants with inactive TB lesions, IGRA positivity was 54.15% (855/1,579) and 28·77% (862/2,996) for those with and without anti-TB treatment records, respectively. IGRA positivity was found to be varied with respect to the type of inactive abnormalities. Interpretation: Individuals with inactive TB lesions and their remarkably high prevalence of TB infection should be attached more attention for preventing occurrence of active TB in high burden areas like China. Funding: This work was supported by the National Science and Technology Major Project of China [2017ZX10201302-002], the CAMS Innovation Fund for Medical Sciences [2016-I2M-1-013] and [2019-I2M-2-005]. Declaration of Interests: All co-authors declare that we have no conflicts of interest. Ethics Approval Statement: The ethics committees of the Institute of Pathogen Biology and the Chinese Academy of Medical Sciences approved the study protocol with approval number of IPB-2018-1.

BackgroundEnlarging tuberculosis (TB) preventive treatment among at-risk populations is a critical component of the End TB Strategy. There is an urgent need to develop suitable latent tuberculosis infection (LTBI) testing and treatment tools according to the local TB epidemic and available resources worldwide.MethodsBased on an open-label randomised controlled trial conducted since 2015 in China among rural residents aged 50–70 years with LTBI, the protective efficacy of a 6-week twice-weekly regimen of rifapentine plus isoniazid was further evaluated in a 5-year follow-up survey.Results1298 treated participants and 1151 untreated controls were included in the 5-year protective efficacy analysis. In the per-protocol analysis, the incidence rate was 0.49 (95% CI 0.30–0.67) per 100 person-years in the untreated control group and 0.19 (95% CI 0.07–0.32) per 100 person-years in the treated group; the protection rate was 61.22%. Subgroup analysis showed that the protection rate was 76.82% in the per-protocol analysis among participants with baseline interferon (IFN)-γ levels in the highest quartile (≥3.25 IU·mL−1). Multiple logistic regression analysis indicated that participants with baseline body mass index −2 and with pulmonary fibrotic lesions had increased hazard of developing active disease with an adjusted hazard ratio (aHR) of 3.64 (95% CI 1.20–11.00) and 5.99 (95% CI 2.20–16.27), respectively. In addition, individuals with higher baseline IFN-γ levels showed an increased risk of TB occurrence (aHR 2.27, 95% CI 1.13–4.58).ConclusionsOur findings suggest the 6-week twice-weekly regimen of rifapentine plus isoniazid for LTBI treatment might be an optional tool for TB control in the Chinese population.

Summary Background The management of latent Mycobacterium tuberculosis infection is a new priority action for the WHO End Tuberculosis (TB) Strategy. However, national guidelines on latent tuberculosis infection testing and treatment have not yet been developed in China. Here, we present the results from the 2-year follow-up of a study that aimed to track the development of active disease in individuals with latent tuberculosis infection, identify priority populations for latent infection management, and explore the most suitable latent infection diagnostic approach. Methods A population-based multicentre prospective study was done in four sites in rural China, between 2013 and 2015. The baseline survey in 2013 measured the prevalence of latent tuberculosis infection using QuantiFERON-TB Gold In-Tube (QFT) and tuberculin skin test (TST) in eligible participants. During the follow-up phase between 2014–15, we assessed individuals who had tuberculosis infection at baseline (QFT-positivity or TST tuberculin reaction size [induration] of ≥10 mm) for the development of active disease through active case finding. Eligible participants included in follow-up survey had a birth date before June 1, 2008 (5 years or older in 2013), and continuous residence at the study site for 6 months or longer in the past year. Participants with current active tuberculosis at baseline survey were excluded. Findings Between Sept 1, 2013, and Aug 31, 2015, 7505 eligible participants (aged 5 years or older) were included in tuberculosis infection test positive cohorts (4455 were QFT positive, 6404 had TST induration ≥10 mm, and 3354 were positive for both tests) after baseline examination. During the 2-year follow-up period, 84 incident cases of active tuberculosis were diagnosed. Of participants who developed active tuberculosis, 75 were diagnosed with latent infection by QFT, 62 were diagnosed by TST, and 53 were diagnosed by both tests. An incidence rate of 0·87 (95% CI 0·68–1·07) per 100 person-years was observed for individuals who tested positive with QFT, 0·50 (0·38–0·63) per 100 person-years for those who tested positive with TST (p Interpretation Our results suggest that high-risk populations in communities in rural China, such as individuals at a high risk of disease reactivation from previous tuberculosis, should be targeted for latent infection screening and treatment with an interferon-γ releasing assay rather than a TST. Funding National Science and Technology Major Project of China, Program for Changjiang Scholars and Innovative Research Team in University of China, CAMS Innovation Fund for Medical Sciences, and Sanming Project of Medicine in Shenzhen.

Objectives Using QuantiFERON-TB Gold In-Tube (QFT-GIT) for monitoring tuberculosis (TB) and latent TB infection treatment effect is controversial. The present study aimed to evaluate the dynamic changes of interferon gamma (IFN-γ) levels along with latent TB infection treatment via a randomized controlled study. Methods A total of 910 participants treated with 8 weeks of once-weekly rifapentine plus isoniazid (group A), 890 treated with 6 weeks of twice-weekly rifapentine plus isoniazid (group B) and 818 untreated controls (group C) were followed for 2 years to track active TB development. QFT-GIT tests were repeated three times for all groups: before treatment (T0), at completion of treatment (T1) and 3 months after completion of treatment (T2). Results Similar rates of persistent QFT-GIT reversion were observed in groups A (19.0%, 173/910), B (18.5%, 165/890) and C (20.7%, 169/818) (p 0.512). The dynamic changes of IFN-γ levels were not statistically significant among the three groups. In treated participants, individuals with higher baseline IFN-γ levels showed increased TB occurrence (1.0%, 9/896) compared to those with lower baseline levels (0.2%, 2/904) (p 0.037). A similar but statistically insignificant trend was also observed in untreated controls (1.8% (7/400) vs. 0.5% (2/418), p 0.100). When TB cases were matched with non-TB cases on baseline IFN-γ levels, no significant differences were found with respect to the dynamic changes in IFN-γ levels with time, regardless of whether they received treatment. Conclusions QFT-GIT reversion or decreased IFN-γ levels should not be used for monitoring host response to latent TB infection treatment.

Elderly individuals in rural China have been known to be at increased risk of contracting tuberculosis (TB) and developing active disease. This study aims to estimate the burden of mycobacterium tuberculosis (MTB) infection and to identify potential targeted subgroups for infection control.As part of the investigation of an interventional study, 50- to 70-year-old rural residents in Zhongmu County were targeted for MTB infection testing using QuantiFERON-TB Gold In-Tube (QFT). Questionnaires and physical examinations were conducted to acquire their demographic information and health status.A total of 20 486 individuals were included in the analysis. The prevalence of QFT positivity was 20.79% (4259/20 486) and 50 participants (0.24%) had indeterminate results. A positive dose-response relation was found for QFT positivity with smoking intensity. Compared with non-drinkers, the risk of MTB infection was lower among participants with moderate alcohol consumption (10 g/day) with adjusted odds ratio (OR) of 0.82 (95% CI 0.71-0.94). In addition, gender of male, with a history of previous TB or silicosis, and hepatitis B/C virus infection were associated with increased risk of MTB infection. An indeterminate QFT result was related to being underweight (adjusted OR 3.18; 95% CI 1.09-9.26).Our results indicate a high burden of MTB infection among the elderly in this rural area. Smokers, individuals with a history of previous TB or silicosis, and those with hepatitis B/C virus infection should be prioritized for MTB infection control to reduce the risk of disease development from a new infection.

Latent tuberculosis infection (LTBI) management is now a critical component of the World Health Organization's End TB Strategy.In this randomised controlled trial (Chinese Clinical Trial Registry identifier ChiCTR-IOR-15007202), two short-course regimens with rifapentine plus isoniazid (a 3-month once-weekly regimen and a 2-month twice-weekly regimen) were initially designed to be evaluated for rural residents aged 50–69 years with LTBI in China.Due to the increasingly rapid growth and unexpected high frequency of adverse effects, the treatments were terminated early (after 8 weeks for the once-weekly regimen and after 6 weeks for the twice-weekly regimen). In the modified intention-to-treat analysis on the completed doses, the cumulative rate of active disease during 2 years of follow-up was 1.21% (14 out of 1155) in the untreated controls, 0.78% (10 out of 1284) in the group that received the 8-week once-weekly regimen and 0.46% (six out of 1299) in the group that received the 6-week twice-weekly regimen. The risk of active disease was decreased, with an adjusted hazard ratio of 0.63 (95% CI 0.27–1.43) and 0.41 (95% CI 0.15–1.09) for the treatments, respectively. No significant difference was found in the occurrence of hepatotoxicity (1.02% (13 out of 1279) versus 1.17% (15 out of 1279); p=0.704).The short regimens tested must be used with caution among the elderly because of the high rates of adverse effects. Further work is necessary to test the ultrashort regimens in younger people with LTBI.