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Objectives: Mycobacterium kansasii pulmonary disease is frequently misdiagnosed and treated as tuberculosis, especially in countries with high tuberculosis burden. This study aimed to investigate the drug resistance profile of M.kansasii in patients with M.kansasii pulmonary disease in Shanghai and to determine the variations in drug resistance after 2 months of antimycobacterial treatment., Methods: All patients with a diagnosis of M.kansasii pulmonary disease from 2017 to 2019 in Shanghai were retrospectively analysed. Whole-genome sequencing was performed, and the minimum inhibitory concentration (MIC) to antimycobacterial drugs was measured using the broth microdilution method., Results: In total, 191 patients had a diagnosis of M.kansasii pulmonary disease. Of them, 24.1% (46/191) had persistent positive culture after 2 months of antimycobacterial treatment. Whole-genome sequencing revealed that the 46 paired isolates had a difference of <17 single nucleotide polymorphisms, thus excluding the possibility of exogenous reinfection. More than 90% of the baseline isolates were sensitive to rifampin, clarithromycin, moxifloxacin, or amikacin, whereas a high resistance to ethambutol (118/191, 61.8%) and 4 μg/mL of isoniazid (32/191, 16.8%) were observed. Two isolates presented high resistance to rifamycin (i.e. a rifampin MIC of >8 μg/mL and a rifabutin MIC of 8 μg/mL) both containing the rpoB mutation (S454L). The increase of MIC to rifampin, ethambutol, and/or isoniazid was identified in 50.0% (23/46) of the patients., Discussion: A high prevalence of innate resistance to ethambutol and isoniazid was observed among circulating M.kansasii clinical strains in Shanghai. The increase in drug resistance under empirical antimycobacterial treatment highlighted the urgency of definitive species identification before initiating treatment., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to identify the differences in diversity, composition, and function of the gut microbiota between tuberculosis (TB) patients and healthy controls (HCs)., Methods: A cross-sectional study was conducted in three cities of China. Stool samples from 94 treatment-naive TB patients and 62 HCs were analyzed by 16S rRNA gene sequencing. TB patients were further divided into antibiotic-free and antibiotic-exposure according to their use of non-specific antibiotics before the TB diagnosis., Results: Compared with HCs, antibiotic-free TB patients presented a different gut microbial community (P < 0.005) and decreased Shannon diversity (P < 0.005). Among TB patients, the relative abundances of short-chain fatty acid (SCFA)-producing genera such as Lachnospiraceae ND3007 group (log2(FC) = -2.74) were lower, while several conditional pathogen-related genera such as Enterococcus (log2(FC) = 12.05) and Rothia (log2(FC) = 6.322) were at higher levels. In addition, 41% of patients received antibiotics before TB diagnosis. Antibiotic exposure was correlated with an additional reduction in α diversity and depletion of SCFA-producing bacteria. Microbial functional analysis revealed that the biosynthesis capacity of amino acids and fatty acids was lower among TB patients compared to HCs., Conclusions: Significant alterations in gut microbiota composition and metabolic pathways of TB patients were observed. Antibiotic exposure could alter the gut microbiota of TB patients, which should be considered in anti-TB treatment., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: There could be various stakeholders who influencing multidrug-resistant tuberculosis (MDR-TB) policy development and implementation, yet their attributes and roles remain unclear in practice. This study aimed to identify key stakeholders in the process of policy-making for MDR-TB control and prevention and to analyse the attributes and relationships of the stakeholders, providing evidence for further policy research on MDR-TB control., Methods: This study was conducted from October 2018 to March 2019 and applied the stakeholder analysis guidelines and domestic stakeholder analysis. An initial candidate stakeholder list was developed by policy scanning. Ten experts were invited to identify these candidate stakeholders. The major attribute of these stakeholders were analysed using the Michell scoring method. Based on these results, the intertwined relationships among groups of stakeholders were analysed and mapped through a systematic scan of the policy and literature on MDR-TB control, as well as information obtained from the interviews., Results: A list of 21 types of candidate stakeholders was developed after a literature review and policy scanning, of which 11 received 100% approval. After expert evaluation and identification (the total expert authority was 0.80), 19 categories of stakeholders were approved and included in the stakeholder analysis. We categorized all of the stakeholders into three groups: (i) definitive stakeholders who are mainly involved in administrative departments and the Provincial Center for Disease Control and Prevention (CDC); (ii) expectant stakeholders who are mainly involved with MDR-TB patients, clinical departments of TB hospitals at different levels, community health care facilities, prefectural CDC and charity organizations; and (iii) latent stakeholders who mainly involved family members and neighbours of MDR-TB patients and TB related products manufacturers. Government departments and higher-level CDCs have strong decision-making power in developing MDR-TB control policies whereas the recommendations from service providers and the concerns of patients should be considered., Conclusions: The MDR-TB prevention system was a multistakeholder cooperation system that was mainly led by government stakeholders. Enhancing communications with front-line service providers and patients on their unmet needs and evidence-based suggestions would highly benefit policy-making of MDR-TB prevention and control., (© 2021. The Author(s).)

Background: Anti-tuberculosis therapy requires at least six-month treatment with continuous administration of combined antibiotics, including isoniazid, rifampicin, pyrazinamide, and ethambutol. The long-term exposure to antibiotics could cause consequent changes in gut microbiota, which may alter the gastrointestinal function and drug absorption in patients, thereby affect the outcome of treatment. The study aims to characterize the longitudinal changes of gut microbiota among tuberculosis (TB) patients under standardized first-line treatment and provide an understanding of the association between alterations in gut microbiota composition and unfavorable clinical outcomes., Methods: The study is a multicenter, observational prospective cohort study. Three study sites are purposively selected in the western (Sichuan Province) and eastern (Jiangsu Province and Shanghai) parts of China. Three-hundred patients with bacteriologically confirmed pulmonary TB are enrolled. All eligible patients should be investigated using structured questionnaires before treatment initiation; and be followed up during the treatment at Day-14, Month-2, Month-5, the end of treatment and the sixth month after ending therapy. Stool samples are to be collected at each visit, consisting of six stool samples from each patient. Additionally, 60 healthy volunteers from Sichuan province and Shanghai city will be recruited as healthy controls to form the baseline of patient gut microbiota in the Chinese population. The dynamic changes of gut microbiota in terms of alpha diversity, beta diversity, taxonomic composition are to be illustrated individually from the time at diagnosis until the sixth month after therapy is completed. Furthermore, the diversity and component of gut microbiota will be compared between the groups with and without unfavorable treatment outcome in terms of adverse effect and treatment failure., Discussion: Studies on the clinical manifestations, adverse reactions, and gut microbiota alterations will provide scientifically-sound evidence on the impact of gut microbiota alterations on TB treatment outcomes. The study is not only useful for guiding personalized TB treatment but also sheds light on the effects of continuous antibiotics administration on gut microbiota., Trial Registration: Chinese Clinical Trial Registry, trial ID: ChiCTR1900023369, May 24, 2019. Retrospectively registered.

Background: ASAP1 (also known as AMAP1 or DDEF1) encodes an Arf GTPase-activating protein (Arf GAP), a multifunctional scaffold protein that induces hydrolysis of GTP bound to the ADP-ribosylation factor (Arf) family GTP-binding proteins. Reduction of ASAP1 expression in vitro was related to suppression of cell migration and invasiveness. The genetic variant rs4733781 of the ASAP1 gene was revealed as a significant locus for tuberculosis (TB) susceptibility, but the results still need to be validated., Methods: Blood samples from a total of 1914 active TB and healthy controls (HC) were collected to evaluate rs4733781 and the risk of TB. Meanwhile, a total of 48 noninfected HC, latent TB-infected (LTBI) controls, and active TB were collected to assay ASAP1 expression difference among the three groups. The QuantiFERON-TB Gold In-Tube was adopted to identify noninfected HC and LTBI., Results: The genetic variant of rs4733781 was found to be significantly associated with TB, and the A allele of rs4733781 (C>A) was 0.38 and 0.43 among TB cases and HC, respectively ( P = 0.0035). Meanwhile, the peripheral blood monocyte RNA fold changes for the ASAP1 gene among the 16 HC, 16 LTBI, and 16 active TB were 1.088 ± 0.4919, 2.237 ± 0.6505, and 10.12 ± 10.98 ( F = 9.559, P = 0.0003), respectively, and the expression of ASAP1 was increased by 2.06-fold ( P < 0.0001) and 9.30-fold ( P < 0.0052) for LTBI and active TB, when compared to the HC., Conclusions: Our data indicated that the A allele of rs4733781 for the ASAP1 gene was in association with a decreased risk of TB. But not only that, the overexpression of the ASAP1 gene among LTBI and TB was related to the progression of TB, which further implies that the expression of ASAP1 would be a potential biomarker for LTBI and TB diagnoses.

Genome-wide association studies (GWASs) have revealed the worldwide heterogeneity of genetic factors in tuberculosis (TB) susceptibility. Despite having the third highest global TB burden, no TB-related GWAS has been performed in China. Here, we performed the first three-stage GWAS on TB in the Han Chinese population. In the stage 1 (discovery stage), after quality control, 691 388 SNPs present in 972 TB patients and 1537 controls were retained. After replication on an additional 3460 TB patients and 4862 controls (stages 2 and 3), we identified three significant loci associated with TB, the most significant of which was rs4240897 (logistic regression P = 1.41 × 10-11, odds ratio = 0.79). The aforementioned three SNPs were harbored by MFN2, RGS12 and human leukocyte antigen class II beta chain paralogue encoding genes, all of which are candidate immune genes associated with TB. Our findings provide new insight into the genetic background of TB in the Han Chinese population., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Tuberculosis (TB) case detection in China has improved remarkably, partly benefiting from the reducing delay to TB care, whereas the timeliness of TB care in Malawi remains problematic., Methods: This study investigates barriers hindering timely TB diagnosis in Malawi and China, and attempts to share the experience in high burden countries. A cross-sectional study on TB diagnostic delay was conducted among 254 Malawian and 146 Chinese TB patients., Results: The medians of patient's delays were 22 and 20 days (p>0.05), and provider delays were 12 and 11.5 days (p>0.05) in Malawi and China, respectively. Malawian patients had a higher proportion (72.05% vs 67.12%) of patient's delay longer than 14 days (p=0.042), which was significantly associated with initial visits to lower-level health providers in the villages (aOR=1.989, 95% CI: 1.075-3.682), and patients conducting casual/piece work (aOR=3.318, 95% CI: 1.228-8.964). Initial healthcare visits at village level also led to longer provider delay in both Malawi (aOR=2.055, 1.211-3.487) and China (aOR=5.627, 2.218-14.276)., Conclusion: Establishing a good communication and referral mechanism between different levels of health facilities is crucial to timely TB diagnosis. China's experience on pro-poor interventions could be useful to its Malawian counterpart and other similar settings with high TB burden., (© The Author(s) 2018. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Malawi is a low-income country with high Tuberculosis (TB) burden. TB diagnosis delay and untimely initiation of treatment is still a major problem in Malawi which could increase the risk of tuberculosis transmission in the communities. This study investigated factors related to the diagnostic delay of tuberculosis from TB healthcare providers in the northern region of Malawi., Methods: Nine focus group discussions were conducted with 57 participants in total. The participants were healthcare cadres including district TB officers, clinical officers, TB nurses, laboratory technicians and Health Surveillance Assistants (HSAs). NVivo (11.0) software was used for data analysis., Results: The factors related to diagnostic delay were categorized into three themes: client factors, institutional factors and healthcare provider related factors. Client's stigma and fear for HIV test, resource shortage within healthcare institutions and the healthcare workers' poor attitude against potential patients were among the most influential factors behind the TB diagnostic delay., Conclusions: The TB control strategies should aim to reduce HIV stigma, improve resource supply and improve TB healthcare workers' morale in order to achieve timely TB diagnosis.

Background: Evidence for the relationship between exposure to ambient air pollution and the mortality of tuberculosis (TB) patients is limited., Methods: We analyzed the association between long-term exposure to particulate matter <2.5μm in diameter (PM 2.5 ) and cause-specific mortality in a Chinese TB patients cohort from 2003 to 2013. Data from the Global Burden of Disease 2013 estimate were used to assess yearly average concentrations of PM 2.5 and ozone at the household addresses of participants. Cox regression was used to calculate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for cause-specific mortality, controlling for demographic and other TB-related factors., Results: There were 4444 eligible subjects, including 891 deaths, over a median follow-up of 2464days. Per an interquartile range increase (2.06μg/m 3 ), multivariable analysis indicated that exposure to PM 2.5 was significantly associated with overall mortality (aHR=1.30, 95% CI: 1.19, 1.42), mortality from TB (aHR=1.46, 95% CI: 1.15, 1.85), respiratory cancers (aHR=1.72, 95% CI: 1.36, 2.19), other respiratory diseases (aHR=1.19, 95% CI: 1.02, 1.38), and other cancers (aHR=1.76, 95% CI: 1.33, 2.32)., Conclusions: Long-term exposure to PM 2.5 increases the risk of death from TB and other diseases among TB patients. It suggests that the control of ambient air pollution may help decreasing the mortality caused by TB., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: To determine excess mortality in a cohort of people with tuberculosis in Shanghai., Methods: Participants were local residents in 4 (of 19) districts in Shanghai, registered in one of four tuberculosis clinics between January 1, 2004 and December 31, 2008. Baseline data were collected at the most recent diagnosis of tuberculosis and mortality was assessed between March and May of 2014. We calculated standardized mortality ratios (SMR) and case-fatality rates for all participants and for subgroups. Univariate and multivariate Cox regression models were used to quantify associations between co-morbidities and mortality from all causes and from tuberculosis., Findings: We registered 4569 subjects in the cohort. Overall, the cohort had an SMR for deaths from all causes of 5.2 (95% confidence interval, CI: 4.8-5.6). Males had a higher SMR than females (6.1 versus 3.0). After adjustment for age and sex, hazard ratios (HR) for deaths from all causes were significantly greater in previously treated people (HR: 1.26; 95% CI: 1.08-1.49) and sputum smear-test positive people (HR: 1.55; 95% CI: 1.35-1.78). The risk of death from tuberculosis was also significantly greater for previously treated people (HR: 1.88; 95% CI: 1.24-2.86) and smear positive people (HR: 3.16; 95% CI: 2.06-4.87)., Conclusion: People with tuberculosis in Shanghai have an increased risk of mortality. Earlier diagnosis and more vigilant follow-up may help to reduce mortality in this group.

Objectives: China is one of the 22 tuberculosis (TB) high-burden countries in the world. As TB is a major public health problem in China, spatial analysis could be applied to detect geographic distribution of TB clusters for targeted intervention on TB epidemics., Methods: Spatial analysis was applied for detecting TB clusters on county-based TB notification data in the national notifiable infectious disease case reporting surveillance system from 2005 to 2011. Two indicators of TB epidemic were used including new sputum smear-positive (SS+) notification rate and total TB notification rate. Global Moran's I by ArcGIS was used to assess whether TB clustering and its trend were significant. SaTScan software that used the retrospective space-time analysis and Possion probability model was utilized to identify geographic areas and time period of potential clusters with notification rates on county-level from 2005 to 2011., Results: Two indicators of TB notification had presented significant spatial autocorrelation globally each year (p<0.01). Global Moran's I of total TB notification rate had positive trend as time went by (t=6.87, p<0.01). The most likely clusters of two indicators had similar spatial distribution and size in the south-central regions of China from 2006 to 2008, and the secondary clusters in two regions: northeastern China and western China. Besides, the secondary clusters of total TB notification rate had two more large clustering centers in Inner Mongolia, Gansu and Qinghai provinces and several smaller clusters in Shanxi, Henan, Hebei and Jiangsu provinces., Conclusion: The total TB notification cases clustered significantly in some special areas each year and the clusters trended to aggregate with time. The most-likely and secondary clusters that overlapped among two TB indicators had higher TB burden and risks of TB transmission. These were the focused geographic areas where TB control efforts should be prioritized.

Objective: To describe the financial burden on TB patients for transportation during treatment, and to evaluate the impacts of the "transportation subsidy initiative on poor TB patients" in rural China for improving poor patients' access to TB treatment., Methods: A Case-cohort of 429 TB patients was investigated through questionnaire interviews in four counties of two provinces in China. Information on the financial burden for transportation during TB diagnosis and treatment was collected. Qualitative in-depth interviews with 26 TB patients were carried out to understand their perceptions of transportation subsidy initiative., Results: The mean transportation cost of TB medical care was 97 CNY (70 CNY in median), varying from 0 to 700 CNY. About 51% of the patients spent more than 10 CNY per round trip to the TB dispensary. Of the 429 TB patients investigated, 139 had received transportation subsidies after getting TB diagnosis; 15/139 (10.9%) showed dissatisfaction, mainly because the subsidy amount being insufficient. The income of patients receiving transportation subsidies was significantly lower than those not receiving the subsidies (p<0.05). The impression that an appropriate transportation subsidy enables patients to complete the required visits during their TB treatment was obtained after observation of over 80% of the patients., Conclusion: The transportation subsidy plays an important role in reducing financial burden on poor TB patients for the completion of treatment. However, the coverage was limited and the amount of subsidy was not enough under the present policy. Considering the poverty of rural TB patients, a universal coverage and a rational amount of transportation subsidy should be proposed.

As a key component of DOTS (directly observed treatment, short course) strategy, DOT is essential in the prevention of drug-resistant tuberculosis. However, DOT had very poor implementation in rural areas of China. One major reason to this problem was the lack of incentives for DOT providers. In 2005, the Chinese Minister of Health released an incentive strategy that aimed to improve the DOT performance of rural health workers by providing allowances. Our study used a qualitative method to explore the practical impact of this incentive strategy in motivating rural DOT providers, and searched for other potential incentive measures as well. A total of 16 focus group discussions were carried out among 102 rural health workers in eight counties of China. A semi-structured theme outline was used to collect the perception, attitude and experiences of health workers toward the DOT implementation as well as the cash incentive strategy. Findings showed that DOT allowance had some incentive effect to DOT providers, but its extent was circumscribed by the small amount and operational problems. Raising DOT allowance and removing existing barriers to DOT provision might result in a greater motivational impact, particularly in less developed areas of China, where health workers were more likely to encounter financial and other obstacles in delivering DOT services to TB patients in rural areas., (Copyright © 2013 John Wiley & Sons, Ltd.)

Objective: To study the prevalence and trend of tuberculosis for related policy development in Shandong., Methods: The population under the current study was randomly sampled, using both stratified clustering sampling and proportional population sampling methods, following the national survey protocol. A total of 35 clusters including about 1500 subjects per cluster were established, representing a population of 9.31 million. Questionnaire interview and chest X-ray exam were applied to all inhabitants above 15 years of age. Sputum microscopy and culture were given to all suspected cases with cough longer than 2 weeks or having abnormal X-ray results., Results: In total, 54 279 subjects were interviewed and examined, accounting for 95.78% of eligible population. Of them, 183 active pulmonary tuberculosis cases were identified, with 60.11% asymptomatic. Two of the 35 (5.71%) clusters had no active tuberculosis cases found, and 24 (68.57%) did not show smear positive results. The standardized prevalence rates of active, smear positive and bacteriologic positive pulmonary tuberculosis cases were 270.87/10(5), 17.45/10(5) and 29.57/10(5), with the estimated case numbers as 211 900 (170 100 - 253 600), 13 600 (5800 - 21 500) and 23 100 (13 200 - 33 000) respectively. Compared to the survey in 2000, the rates on smear positive and bacteriologic positive tuberculosis had decreased significantly, at a rate of 81.63%, and 75.56% respectively. The rates in urban areas and in women decreased quickly than those in rural areas and in men. People living in the rural areas, being elderly or males, had significantly higher prevalence rates of tuberculosis., Conclusion: Remarkable reduction of tuberculosis prevalence had been achieved despite the fact that tuberculosis remained a major public health problem in Shandong province. Symptomatic patients should be under more serious concern in order to improve the detection of early cases. More efforts should be given to rural population, especially elderly, male population.

Empirical use of fluoroquinolones (FQ) to treat a variety of bacterial infections may inadvertently select for FQ-resistant strains of Mycobacterium tuberculosis(MTB), especially in rural China where the use of FQ in treating infections has not been standardized. Here we determine the prevalence and describe the transmission of FQ-resistant MTB in two rural counties in eastern China through a combination of conventional epidemiology with IS6110-based restriction fragment length polymorphism(RFLP) analysis and DNA sequencing of drug-resistance determining regions. Phenotypic FQ resistance was detected in 31 of 351(8.8%) isolates. FQ resistance was equally distributed between patient-isolates deemed drug resistant and drug-susceptible, but mostly observed in those with treatment history of respiratory infection. Mutations in gyrA were found in 54.8% of FQ resistant isolates, and one isolate with a gyrB mutation. Despite predominating in entire bacilli population(69.2%), Beijing family strain had similar proportion of FQ resistance to the other(10.3% vs. 4.7%, p = 0.060). IS6110RFLP identified 2 clusters(4 isolates) among FQ resistant isolates and 3 clusters composed of both 4 FQ resistant isolates and 6 FQ susceptible isolates. Our results indicate that FQ-resistant MTB has emerged among the circulating bacillary population in rural eastern China. The relatively low level of clustering among FQ-resistant strains suggests most are acquired de novo, likely due to widespread FQ use., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Tuberculosis (TB) detection under the national TB control program in China follows passive case-finding guidelines, which could be influenced by the accessibility of health service and patient's health-care seeking behaviors. One intriguing topic is the correlation between men and women's knowledge on TB and their health-care seeking behaviors., Methods: Two cross-sectional studies were separately carried out in Yangzhong County, a rural area of China. One study, by using systematic sampling method, including 1,200 subjects, was conducted to investigate the TB knowledge among general population. Another study in the same source population screened 33,549 people aged 15 years or over among 20 stratified cluster-sampled villages for identifying prolonged cough patients at households and individual interviews were then carried out. Gender difference in the knowledge of TB and health-care seeking behaviors was analyzed particularly., Results: Among general population, only 16.0% (men 17.1% vs. women 15.0%) knew the prolonged cough with the duration of 3 weeks or longer was a symptom for suspicious TB. Fewer women than men knew the local appointed health facility for TB diagnosis and treatment as well as the current free TB service policy. Moreover, women were less likely to learn information about TB and share it with others on their own initiatives. On the contrary, after the onset of the prolonged cough, women (79.2%) were more likely to seek health-care than men (58.6%) did. However, a large part of women preferred to visit the lower level non-hospital health facilities at first such as village clinics and drugstores., Conclusion: TB and DOTS program were not well known by rural Chinese. Gender issues should be considered to reduce diagnostic delay of TB and improve both men and women's access to qualified health facility for TB care. Strengthening awareness of TB and improving the accessibility of health-care service is essential in TB control strategy, especially under the current vertical TB control system.

Objective: To study the feasibility and cost-effectiveness of a case-finding program on tuberculosis (TB) in richer rural areas., Methods: Screening was implemented every three months for a total period of 9 months, in rural areas with high case notification rates. Three villages, each with ten thousand population, were selected to carry out a household screening program. A suspect was defined as who coughed for more than 3 weeks. The suspect was then referred to further diagnosis in county TB dispensary to undergo chest X-ray and sputum test., Results: Of the 86,168 community population screened, 26 TB patients were identified with 7 of them were smear positive. The ratio of effectiveness vs. cost decreased on the second but slightly increased on the third screening program. The direct costs for the 3 screening programs were 6,312,397 and 1637 RMB respectively. Of total direct cost, 5.9% was paid by TB patients, whereas 35.9% was through financing of the county itself., Conclusion: The community household screening program could achieve higher case detection rate than passive case-finding approach which could be used in richer areas with low case detection rate in China.

Objective: To describe factors causing the delay of diagnosis among non-resident tuberculosis (TB) patients and to study its implications from demographic, socio-economic aspects in order to provide information to policy makers for TB control programs in Shanghai., Methods: A historical cohort study through questionnaire interview was conducted in 146 newly diagnosed TB patients. The questionnaire covered the general information of subjects and information on patients' health care seeking experiences from the first symptom to the TB diagnosis in health facilities. Index adopted to reflect the access to TB diagnosis would include the days due to delayed diagnosis consisting the days from both patient's and doctor's responsibilities., Results: The median days due to patients' delay was 19 (7-33.5) days, which was 3.8 times longer than 5 (2.5-10) days caused by doctor's. The median of total diagnostic delay was 31 (11-59) days. Female TB patients, patients with lower than annual 5000 Yuan income had an increased risk of a longer diagnostic delay with an OR of 3.226 and 11.958 relatively. Smear positive patients had a shorter delay (OR = 0.280, P < 0.05)., Conclusion: Delayed diagnosis was mostly caused by the patients, suggesting that TB control strategy for non-residents should aim at improving the access to TB diagnosis among patients with lower income and female non-residents.

Aims and objectives: Multidrug-resistant tuberculosis (MDR-TB) has become a major public health problem worldwide, which lays a heavy burden on low- and middle-income countries. Compared with newly diagnosed tuberculosis (TB) patients, patients with a history of anti-TB treatment have increased mortality and a higher prevalence of drug resistance. However, these patients are neglected by both global and national TB control programs and have met barriers to access to medical care for potential drug resistance. This study aims to understand the drug-resistance status of patients with previous treatment history and to determine the factors associated with the accessibility of bacteriological-based TB diagnosis. Methods: A cross-sectional study was conducted in 8 county/district TB clinics in three provinces (Jiangsu, Shandong and Sichuan) of China, where a global fund-supported MDR-TB control project had been initiated. TB patients who had at least one previous treatment episode were interviewed using a structured questionnaire. Information on demographics, socioeconomic status of patients, and their experiences on seeking TB diagnosis and treatment were collected. Results: A total of 196 smear-positive TB patients were recruited, of which 78% (153/196) were male and the average age of these patients was 57 years old. About 70% (137/196) of the subjects were farmers, and 63% (121/195) had less than 6 years’ education. Among these patients, 120 cases (61.22%) received culture-based TB diagnosis in this treatment episode, while patients from Jiangsu province (versus Shandong/Sichuan aOR: 8.10/36.42, 95% CI: 2.70–24.25/12.20–108.66) and patients with a higher annual income per capita (aOR: 3.35, 95% CI: 1.26–8.92) were found to be more likely to reach culture tests after adjusting for gender and age. MTB complex and non-tuberculosis mycobacteria (NTM) strains were isolated from 92 and 10 patients, respectively, and the remaining 18 patients were negative to bacteria culture. Drug sensitivity testing (DST) for first-line anti-TB drugs, and kanamycin and ofloxacin, was completed for the 92 MTB isolates. The total proportion of drug-resistant tuberculosis was 52.48% (47/92), while the prevalence for resistance to a single drug, multidrug-resistant and other combinations of drug resistance were 16.30% (95% CI: 9.78–23.91%), 30.43% (95% CI: 21.74–40.22%), and 4.35% (95% CI: 1.09–8.70%), respectively. Resistance to isoniazid, rifampicin, streptomycin, ethambutol, kanamycin and ofloxacin was 36.96%, 35.87%, 23.91%, 10.87%, 4.35% and 6.52%, respectively. Conclusions: Patients with a previous treatment history are at extremely high risk of drug-resistant tuberculosis in China. The poor accessibility of bacteriological-based diagnosis may aggravate the difficulty of detection and control for drug-resistant TB patients. The next step of the anti-TB strategy should be focused on how to make bacteriological-based diagnosis cheaper, safer and more maneuverable and on how to assure the DST-guided treatment for these high-risk TB patients.

Purpose: To investigate the dysregulated pathways and identify reliable diagnostic biomarkers for tuberculosis using integrated analysis of metabolomics and transcriptomics. Methods: Three groups of samples, untargeted metabolomics analysis of healthy controls (HC), latent tuberculosis infection patients (LTBI), and active tuberculosis patients (TB), were analyzed using gas chromatography time-of-flight mass spectrometry (GC-TOF MS) and ultra-high performance liquid chromatography-quantitative mass spectrometry (UHPLC-QE-MS). Both univariate and multivariate and statistical analyses were used to select differential metabolites (DMs) among group comparison, and LASSO regression analysis was employed to discover potential diagnostic biomarkers. Metabolite set enrichment analysis was performed to identify the altered metabolic pathways specifically in patients with TB. Meanwhile, a transcriptomic dataset GSEG4992 was downloaded from the GEO database to explore the differentially expressed genes (DEGs) between TB and HC identified in significantly enriched pathways. Finally, an integrative analysis of DMs and DEGs was performed to investigate the possible molecular mechanisms of TB. Results: Thirty-three specific metabolites were significantly different between TB and HC, of which 7 (5-hydroxyindoleacetic acid, isoleucyl-isoleucine, heptadecanoic acid, indole acetaldehyde, 5-ethyl-2,4-dimethyloxazole, and 2-hydroxycaproic acid, unknown 71) were chosen as combinational potential biomarkers for TB. The area under the curve (AUC) value of these biomarkers was 0.97 (95% CI: 0.92– 1.00). Metabolites set enrichment analysis (MSEA) displayed that there were 3 significantly enriched pathways among all. The genes in 3 significantly enriched pathways were further analyzed, of which 9(ALDH3B1, BCAT1, BCAT2, GLYAT, GOT1, IL4I1, MIF, SDS, SDSL) were expressed differentially. The area under the curve (AUC) values of these DEGs enriched in pathways mostly were greater than 0.8. As a result, a connected network of metabolites and genes in the pathways were established, which provides insights into the credibility of selected metabolites. Conclusion: The newly identified metabolic biomarkers display a high potential to be developed into a promising tool for TB screening, diagnosis, and therapeutic effect monitoring. [ABSTRACT FROM AUTHOR]

Background: Multidrug-resistant tuberculosis (MDR-TB) is on the rise in China. This study used a dynamic Markov model to predict the longitudinal trends of MDR-TB in China by 2050 and to assess the effects of alternative control measures. Methods: Eight states of tuberculosis transmission were set up in the Markov model using a hypothetical cohort of 100 000 people. The prevalence of MDR-TB and bacteriologically confirmed drug-susceptible tuberculosis (DS-TB+) were simulated and MDR-TB was stratified into whether the disease was treated with the recommended regimen or not. Results: Without any intervention changes to current conditions, the prevalence of DS-TB+ was projected to decline 67.7% by 2050, decreasing to 20 per 100 000 people, whereas that of MDR-TB was expected to triple to 58/100 000. Furthermore, 86.2% of the MDR-TB cases would be left untreated by the year of 2050. In the case where MDR-TB detection rate reaches 50% or 70% at 5% per year, the decline in prevalence of MDR-TB would be 25.9 and 36.2% respectively. In the case where treatment coverage was improved to 70% or 100% at 5% per year, MDR-TB prevalence in 2050 would decrease by 13.8 and 24.1%, respectively. If both detection rate and treatment coverage reach 70%, the prevalence of MDR-TB by 2050 would be reduced to 28/100 000 by a 51.7% reduction. Conclusions: MDR-TB, especially untreated MDR-TB, would rise rapidly under China's current MDR-TB control strategies. Interventions designed to promote effective detection and treatment of MDR-TB are imperative in the fights against MDR-TB epidemics. [ABSTRACT FROM AUTHOR]

Objectives: The implementation of rapid and reliable drug susceptibilities diagnosis is fundamental for effective treatment of multidrug-resistant tuberculosis(MDR-TB). The present study aimed to assess the diagnostic performance of the 2nd-version GenoType MTBDRsl kit as well as the impact of its implementation on the turnaround time in a multi-center Chinese study.Methods: Totally 353 MDR-TB patient specimens were consecutively tested. The 2nd-version GenoType MTBDRsl assay, drug susceptibility testing with the MGIT 960 system, and sequencing were performed and compared.Results: MTBDRsl testing identified the major genotypes associated with fluoroquinolones resistance, predominated by gyrA MUT3B (Asp94Asn and Asp94Tyr, 26.5%) and MUT3C (Asp94Gly, 19.5%). The genotypes associated with resistance to 2nd-line injectable drugs(SLIDs) were rrsMUT1(A1401G, 64.9%) and absence of WT1(C1402T, 10.5%). The sensitivities for detection of resistance to fluoroquinolones, SLIDs, and their combination (extensively drug resistance, XDR) were 80.5%, 80.7% and 73.5% and specificities were 100.0%, 99.3% and 99.1%, respectively. Implementation of this test significantly reduced the turnaround time between sample collection and result reporting from 45 to 3 days, a reduction by 93.3% (p, 0.001).Conclusion: With a favorable diagnostic performance and short turnaround time, the 2nd-version GenoType MTBDRsl assay proves its value for early diagnosis of resistance to 2nd-line drugs as well as of XDR-TB in China. [ABSTRACT FROM AUTHOR]

Background: The primary unit of tuberculosis (TB) medical care in China is the county TB dispensary or county designated hospital (CTD), where patients can receive free diagnosis and treatment. However, a substantial number of patients seek their anti-TB treatment from general health facilities (Non-CTDs). This study aimed to investigate the first anti-TB treatment experience and choice of health facilities of retreated TB patients and their determinants.Methods: A cross-sectional study was conducted in Jiangsu, Shandong and Sichuan provinces. All registered re-treated TB patients were investigated using a structured questionnaire covering information on demographics, socio-economic characteristics, and previous anti-TB treatment experiences.Results: Totally, 75.3% of 544 patients visited CTD directly for initial treatment. Patients who were female (OR:1.71, 95% CI: 1.01-2.87), over 40 years of age (OR:2.80, 95% CI: 1.24-6.33), from Jiangsu (OR:3.07, 95% CI: 1.57-6.01) and Sichuan (OR:4.47, 95% CI: 2.29-8.73) and those diagnosed before 2005 (OR:6.87, 95% CI: 4.24-11.13) had a significant higher risk receiving their initial treatment at a non-CTD. Patients were more likely to have standardized diagnosis and treatment regimens in CTD (89.8%) than in non-CTDs (65.9%). Patients treated in non-CTDs versus in CTD had a lower possibility to complete their treatment course during first TB episode (χ 2 = 3.926, P = 0.048), but there was no significant difference in the cure rate between different facilities (CTD 60.8%, Non-CTDs 59.1%). Patients in non-CTDs incurred higher costs (1,360 CNY) than those treated in CTD (920CNY).Conclusion: CTD play a key role in the National Tuberculosis Control Program. Patients should be guided to seek health care in county designated hospital, where they are more likely to receive appropriate examinations, treatment regimens and rigorous supervision, and to bear a lighter economic burden. [ABSTRACT FROM AUTHOR]

Summary Background Highly lethal outbreaks of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are increasing. Mycobacterium tuberculosis variant Beijing family and its members is regarded as a successful clone of M. tuberculosis that is associated with drug resistance in China. Understanding the genetic characteristics and molecular mechanism of drug resistant tuberculosis within Beijing family may help to clarify its origin and evolutionary history and the driving forces behind its emergence and current dissemination. Methods Totally of 1222 Mycobacterium tuberculosis isolates were recovered from patients in six counties of two provinces in eastern China within 2010/2012. Strain lineage and its major subgroups were studied respectively by using Spoligotyping and MIRU-VNTR. The 1 st -line drug susceptibility was analyzed by proportional method and 2 nd -line drug susceptibility was determined by the HAINs MTBDRsl test. The genetic characterization of drug resistance was analyzed by sequencing the previously reported genes and loci associated with drug resistance together with the multiple genotyping including MIRU-VNTR, Spoligotyping and LSP genotyping. Results Of the 1222 Mtb isolates, 298 (24.4%) were resistant to 1 st -line drug and 73 (5.9%) were simultaneously resistant to INH and RIF namely MDR-TB. Respectively 23.8% of 1 st -line drug resistant TB and 12.0% of the drug susceptible TB contained the mutation associated with 2 nd -line drugs by HAINs test. The Spoligotyping of 1222 Mtb isolates revealed the 967 (79.1%) of the isolates belonged to the W-Beijing family. Within W-Beijing family, 78.8% MDR-TB were observed in the isolates with simultaneous deletion of RD105 and RD207, with sub-lineage 181 accounting for 75% of MDR-TB. Analysis of 24 MIRU-VNTR loci revealed that 88.2% (15/17) of MDR and extensively drug resistant (XDR) clustered isolates were sub-lineage 181. Conclusions Sublineage 181 might have the capacity to spread throughout the general community in rural China. This is the first report on the extensive association of sub-lineage 181 with MDR TB and possibly pre-XDR TB and XDR TB. It is important to monitor sublineage 181 to verify its heightened transmission and understand its importance in the global MDR–TB and XDR–TB epidemics. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) patients with a history of multiple anti-TB treatments are the ‘neglected’ group to the free anti-TB treatment policy in China. To understand the experiences of TB patients with multiple previous treatments with regard to bacteriological diagnosis and treatment regimens, especially for second-line anti-TB drugs, and how this might influence the risks of multidrug and extensively drug-resistant TB (M/XDR-TB). A cross-sectional study was conducted in 10 county/district TB clinics in five provinces of China. The study participants were TB patients that had at least two previous treatment episodes that lasted longer than 1 month each. Face-to-face interviews and drug susceptibility testing (DST) were conducted with the consenting participants. A total of 328 TB patients were recruited. The proportion of multidrug-resistant tuberculosis (MDR-TB) was 58.2% in the 287 DST-confirmed patients. Forty-two percent of the patients did not complete their first treatment course. About 23.8% of the participants had a history of taking second-line drugs, and more than 77.8% of them were treated in county TB dispensaries where only sputum microscopy was applied. Multivariate analysis found that the use of second-line drugs was significantly associated with frequency of previous treatments (p<0.01), but not with drug resistance profiles of patients. Patients with multiple previous treatments are at extremely high risk of MDR-TB in China. The unregulated use of second-line drugs bring about the threat of XDR-TB epidemic. DST-guided treatment and strict regulations of anti-TB treatment should be assured for the high-risk TB patients for the prevention and control of M/XDR-TB. [ABSTRACT FROM AUTHOR]

Summary: Background: There is limited information on the prevalence of latent tuberculosis infection (LTBI) and the risk factors among contacts of pulmonary TB, which might contribute significantly to TB burden and therefore become the major concern for TB control in Shanghai, China. Methods: A total of 45 diagnosed TB patients from each of 7 Shanghai districts were chosen and approximately 3 contacts per case were randomly selected. A structured questionnaire was used to acquire socio-demographic information and to assess the degree of exposure to index cases. LTBI screening was performed by T-SPOT.TB assay. Results: Of 969 enrolled contacts, 39% were men, average age was 45 ± 19.1 years, and 76.3% were household contacts. LTBI was identified in 29.6% of subjects. Those contacting smear-positive TB patients were 2.24 times (95%CI, 1.586–3.162) more likely to develop LTBI than those otherwise; household contact significantly increased the likelihood of LTBI by 1.52 times (95%CI, 1.061–2.180). Furthermore, among household contacts, the risk of LTBI was higher in spouses and first-degree relatives and increased with age and contact duration. Conclusions: A high prevalence of LTBI was observed among the TB contacts in Shanghai, highlighting the need of intervention among the household contacts and those contacting smear-positive TB patients. [ABSTRACT FROM AUTHOR]

Background: In China, less than one-fifth of multidrug-resistant tuberculosis (MDR-TB) cases are detected. MDR-TB screening is conducted amongst the following five high-risk groups of TB patients: chronic cases, close contacts of MDR-TB patients, patients with treatment failure, relapsed and returned patients, and smear-positive patients at the end of the third month of initial treatment. Objective: To estimate the possibility of detecting MDR-TB cases if only the high-risk screening strategy is applied in China. Methods: A secondary analysis was applied to the surveillance-based longitudinal data of all sputum smear-positive TB patients in Prefecture E and Prefecture W of China from 2013 to 2015. The population attributable risk (PAR) was estimated using odds ratios for five risk factors/predictors and exposure proportions amongst all MDR-TB cases. Results: A total of 3513 TB patients (2807 from Prefecture E and 706 from Prefecture W) were included. Males accounted for 77.91% (2737/3513) of the patients. The average age was 52.5 ± 20.0 years old. Overall, 40.34% (71/176) of MDR-TB patients were from the five high-risk groups during the three-year study period. The detected proportion of MDR-TB cases using the high-risk screening strategy was significantly higher in Prefecture E than in Prefecture W. The PAR% for all five risk factors/predictors was 43.4% (95% CI: 24.6-61.7%), 49.9% (95% CI: 31.3-67.0%), and 30.3% (95% CI: 12.9-50.1%) in Prefecture E and 36.6% (95% CI: 10.4-64.5%), 13.3% (95% CI: −1.7-39.7%), and −82.5% (95% CI: −117.5-−11.2%) in Prefecture W in 2013, 2014, and 2015, respectively. The PAR% for the five specific risk factors/predictors ranged from 0.4% (95% CI: −0.2-4.8%) to 21.0% (95% CI: 13.1-30.0%) in these two prefectures. Conclusion: In general, a high-risk screening strategy would miss more than half of the MDR-TB patients because they do not belong to the five high-risk groups. [ABSTRACT FROM AUTHOR]

Background Continuous understanding of the epidemiology of drug resistant TB, especially for multidrug/extensively drug resistant TB (MDR/XDR-TB) is essential to develop the appropriate strategies for preventing its epidemic. The present study aimed to investigate the longitudinal trend of the rates and dynamic change of MDR/XDR M.Tuberculosis and its transmission pattern to adjust the TB control activities in eastern rural China. Methods The data presented here spanned 8 years and was derived from three population-based studies of drug-resistant TB in two eastern rural counties: DQ and GY in terms of socio-demographic characteristics of drug-resistant cases, as well as the microbiological and molecular features of their infected M.Tuberculosis strains in eastern rural China. Results Of the 990 smear-positive patients within the studied period, 413 (41.7%) cases showed resistance to any of the detected first- (INH, RIF and EMB) and second-line (OFL, LEV, KAN, AMK, and CAP) anti-TB drugs: 89 with MDR (9.0%). Of these MDR-TB isolates, 34 cases (38.2%) showed resistance to any of the second-line anti-TB drugs: 25 (28.1%) with resistance either to FQs or second-line injective drugs (Pre-XDR) and 9 (10.1%) showed simultaneous resistance to the two categories (XDR). Molecular analysis of pncA gene revealed 185 M.Tuberculosis cases contained the mutation associated with PZA resistance, with a significantly higher proportion in MDR compared with the others (35% vs. 16.8%, p = 0.04). For the longitudinal perspective, MDR-TB (from 9.1% to 14.5%, p = 0.001), Pre-XDR-TB (from 2.5% to 4.5%, p = 0.01) and XDR-TB (from 0.9% to 3.6%, p = 0.04) exhibited an upward trend, while there was a significant decreasing change in the proportion of totally first-line drug sensitivity ( p = 0.047). Non-linear regression analysis showed that MDR-TB, Pre-XDR-TB and XDR-TB increased significantly over the study period with a double time of 4.8 year (95% CI: 3.69–5.92), 3.2 year (95% CI: 2.16–5.94) and 3.3 year (95% CI: 1.099–8.32). Being clustered, sputum smear result and previously treated history were factors increasing the trending of M/XDR-TB. The MIRU24 loci genotyping revealed the 21 clusters involving 48 (28.4%) drug-resistant cases in DQ and 28 clusters involving 59 (32.1%) drug-resistant cases in GY. Of these clusters, 11 were related to MDR/XDR-TB and 8 of these clustered genotypes were observed more than 5 years of the study period. Conclusion These results show that active transmission of MDR/XDR-TB is taking place and that the increasing trend in the observed rate of MDR/XDR-TB tends to be due to the variation in the distribution of patients with different socio-demographic features and the continued transmission of particular genetic clusters. Continuous surveillance of clinical isolates of M.Tuberculosis is needed to identify M/XDR-TB, especially in patients who have a history of TB and have received prior anti-TB treatment. [ABSTRACT FROM AUTHOR]

Aims and objectives The transmission pattern of drug resistant Mycobacterium tuberculosis (MTB) might vary due to the differences in geographic features, socio-economic development and TB epidemic in specific areas and populations. This might also reflect how effectively a TB control program would work. This study aimed to investigate the transmission pattern of drug resistant TB, especially multidrug-resistant (MDR)-TB, and to discuss its implications for an effective TB control program in rural China. Methods Applying a combination of conventional epidemiology with MIRU-VNTR-based genotyping and DNA sequencing, a descriptive cross-sectional study was performed in two Chinese rural counties: DQ, a long-term DOTS-covered county, and GY, where the DOTS program was launched 11 years later than DQ. Results In total, 238 bacteriologic confirmed pulmonary TB patients from DQ and 393 from GY diagnosed between 2008 and 2011 were recruited in the study. Of the 631 isolates, 220 (34.9%) were resistant to at least one anti-TB drug, including 95 (15.1%) simultaneously resistant to isoniazid and rifampicin or MDR, albeit with the similar distribution between DQ and GY (32/238 vs. 63/393; p , 0.378). The MIRU-VNTR genotyping revealed 35 isolates from DQ and 86 from GY exhibited 15 and 32 clustering patterns with four patterns shared between two counties. Compared with GY county, DQ had a significantly lower clustering proportion in MTB isolates susceptible to first-line drugs (25/167 vs. 46/198; p , 0.047) and total drug resistant TB isolates (12/71 vs. 44/149; p , 0.044), but a similar clustering proportion in MDR-TB isolates (8/32 vs. 18/63; p , 0.712). A significant higher clustering proportion was observed in the previously treated patients in both counties, but in the sputum smear-positive patients with cavitaries only in GY. Comparing the previously treated patients between the two counties, the proportion of MDR-TB and clustering proportion exhibited a similar distribution, while the average age of previously treated patients in DQ is significantly older than that in GY. Conclusions A lower proportion of recent transmissions was observed in the county with long-term DOTS implementation. However, DOTS itself might not have worked enough on blocking the recent transmission of MDR-TB. This observation suggests the urgent needs of implementing the Stop-TB strategies; in particular, accelerating the use of rapid molecular-based TB diagnosis and drug susceptibility testing, providing active case findings in a high risk population of MDR-TB and enhancing infection control in high MDR-TB burden countries. [ABSTRACT FROM AUTHOR]

• Revealed spatial heterogeneity of NTM-PD, focusing on MKC-PD, MAC-PD, and MABC-PD. • Utilized Bayesian spatial disease mapping to highlight high-risk NTM-PD areas. • Demonstrated distinct demographic and clinical characteristics of NTM-PD patients. • Linked environmental factors to varying NTM-PD distribution patterns. To investigate the spatial heterogeneity of nontuberculous mycobacterial pulmonary disease (NTM-PD) in Shanghai. A population-based retrospective study was conducted using presumptive pulmonary tuberculosis surveillance data of Shanghai between 2010 and 2019. The study described the spatial distribution of NTM-PD notification rates, employing hierarchical Bayesian mapping for high-risk areas and the Getis-Ord Gi* statistic to identify hot spots and explore associated factors. Of 1652 NTM-PD cases, the most common species was Mycobacterium kansasii complex (MKC) (41.9%), followed by Mycobacterium avium complex (MAC) (27.1%) and Mycobacterium abscessus complex (MABC) (16.2%). MKC-PD patients were generally younger males with a higher incidence of pulmonary cavities, while MAC-PD patients were more often farmers or had a history of tuberculosis treatment. MKC-PD hot spots were primarily located in the areas alongside the Huangpu River, while MAC-PD hot spots were mainly in the western agricultural areas. Patients with MKC-PD and MAC-PD exhibited a higher risk of spatial clustering compared to those with MABC-PD. Different types of NTM-PD exhibit distinct patterns of spatial clustering and are associated with various factors. These findings underscore the importance of environmental and host factors in the epidemic of NTM-PD. [Display omitted] [ABSTRACT FROM AUTHOR]

Little is known about how additional second-line drug resistance emerges during multidrug-resistant tuberculosis (MDR-TB) treatment. The present study aimed to investigate the influence of microevolution, exogenous reinfection and mixed infection on second-line drug resistance during the recommended 2-year MDR-TB treatment. Individuals with MDR-TB were enrolled between 2013 and 2016 in a multicentre prospective observational cohort study and were followed up for 2 years until treatment completion. Whole-genome sequencing (WGS) was applied for serial Mycobacterium tuberculosis isolates from study participants throughout the treatment, to study the role of microevolution, exogenous reinfection and mixed infection in the development of second-line drug resistance. Of the 286 enrolled patients with MDR-TB, 63 (22.0%) M. tuberculosis isolates developed additional drug resistance during the MDR-TB treatment, including 5 that fulfilled the criteria of extensively drug-resistant TB. By comparing WGS data of serial isolates retrieved from the patients throughout treatment, 41 (65.1%) of the cases of additional second-line drug resistance were the result of exogenous reinfection, 18 (28.6%) were caused by acquired drug resistance, i.e. microevolution, while the remaining 4 (6.3%) were caused by mixed infections with drug-resistant and drug-susceptible strains. In multivariate analysis, previous TB treatment (adjusted hazard ratio (aHR) 2.51, 95% CI 1.51–4.18), extensive disease on chest X-ray (aHR 3.39, 95% CI 2.03–5.66) and type 2 diabetes mellitus (aHR 4.00, 95% CI 2.22–7.21) were independent risk factors associated with the development of additional second-line drug resistance. A large proportion of additional second-line drug resistance emerging during MDR-TB treatment was attributed to exogenous reinfection, indicating the urgency of infection control in health facilities as well as the need for repeated drug susceptibility testing throughout MDR-TB treatment. [ABSTRACT FROM AUTHOR]

Summary Objectives To investigate natural-resistance-associated macrophage protein 1 (NRAMP1), mannose-binding lectin (MBL), vitamin D receptor (VDR) gene polymorphisms and their interaction with susceptibility to pulmonary tuberculosis (PTB) in a Chinese population. Methods A case-control study was conducted in PTB (n=151), age- and sex- matched healthy controls (HCs) (n=453). Genetic polymorphisms of NRAMP1 (INT4, D543NA and 3′UTR), MBL (HL, PQ, XY and AB) and VDR (FokI and Taq) were analyzed by using PCR-restriction fragment length polymorphism (RFLP) and PCR- single- strand conformation polymorphism (SSCP) techniques. Multifactor dimensionality reduction (MDR) analysis was carried out to assess the effects of the interaction between SNPs. Results The distribution of NRAMP1- 3′UTR (TGTG/del), MBL- HL (H/L) and FokI (F/f) were significantly different between PTB patients and HCs (p<0.05). HPYA (OR: 1.88; 95% CI: 1.22-2.91), LPXA (OR: 3.17; 95% CI: 1.69- 5.96), LQYA (OR: 3.52; 95%CI: 1.50-8.23) and LPYB (OR: 12.37; 95%CI: 3.75- 40.85) of MBL were risk haplotypes for PTB. The TGTG- H- f (OR: 1.70; 95%CI: 1.10-2.62) and del- H-f (OR: 3.48; 95% CI: 1.45-8.37) of 3′UTR- HL- FokI were also high-risk haplotypes associated with tuberculosis. Conclusions Our study suggests that genotypes of many polymorphic genes are associated with TB, it is necessary to further explore the mechanism of genotypes and gene-gene interaction in susceptibility to tuberculosis. [ABSTRACT FROM AUTHOR]