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Evidence for using bicyclol in drug-induced liver injury (DILI) is limited. This study aimed to explore the efficacy and safety of bicyclol in acute DILI.This was a multicenter, randomized, double-blinded, double-dummy, active-controlled, superiority and phase II trial. Patients with idiosyncratic acute DILI were randomized 1: 1:1 to low-dose bicyclol (25 mg times a day [TID]), high-dose bicyclol (50 mg TID) and polyene phosphatidylcholine (control) groups. The primary endpoint was the decrease from baseline in serum alanine aminotransferase (ALT) levels at post-treatment for 4 weeks.Overall, 241 patients were included in the full analysis set, with 81, 82 and 78 patients in the low-dose bicyclol, high-dose bicyclol, and control groups respectively. ALT levels decreased across groups (-249.2 ± 151.1, -273.6 ± 203.1, and -180.8 ± 218.2 U/L in the low-dose bicyclol, high-dose bicyclol and control groups, respectively; both p .001, the bicyclol-dependent groups vs. control group). The ALT normalization rates at weeks 1, 2, 4, 6 and 8 were higher in the bicyclol-dependent groups than in the control group (p = .002 at week 1 and all p .001 at weeks 2, 4, 6 and 8 respectively). The median times to ALT normalization in the low-dose bicyclol, high-dose bicyclol and control groups were 29, 16 and 43 days respectively. Adverse events, serious adverse events and adverse drug reactions were similar across groups.Bicyclol (25 and 50 mg TID) appeared efficacious and safe for treating idiosyncratic acute DILI, while bicyclol 50 mg TID showed higher efficacy.www.gov (registration no. NCT02944552).

Background: Extrapulmonary tuberculosis (EPTB) is a significant health problem which can lead to severe morbidity and mortality. In clinical practice, EPTB can have a variety of nonspecific clinical manifestations and can be concurrent with other types of EPTB. As information pertaining to concurrent EPTB is scarce, research efforts are needed to find concurrent EPTB types and to explore the association networks and rules of concurrent EPTB. Materials and Methods: An observational multicenter study was carried out at 21 hospitals from 15 provinces in China from Jan 1, 2011 to Dec 31, 2017. All the adult EPTB inpatients (≥15years) were included. Multivariable logistic regression analysis was used to examine the associations of gender and age group for concurrent EPTB. The association network and rules for concurrent EPTB were analyzed by the Apriori algorithm. Results: A total of 75,993 adult EPTB inpatients (not including EPTB concurrent with PTB) were included. The ratio of male: female was 1.32. The most common types of EPTB lesions were tuberculous pleurisy (46.47%). In the fully adjusted multivariable logistic regression models, it was found that female EPTB patients (aOR=1.129,95%CI: 1.081-1.178) were more likely to have concurrent EPTB. As age increased, the risk of concurrent EPTB decreased (aORConclusion: The present study revealed the occurrence of concurrent EPTB types and analyzed the association network and rules among adult EPTB for the first time in a large sample population. Clinicians should be alert to the incidence of concurrent EPTB and that these patients require administration of customized treatment regimens in order to achieve the best outcomes.

Background Diagnostics to identify tuberculosis infection are limited. We aimed to assess the diagnostic accuracy and safety of ESAT6-CFP10 (EC) skin test for tuberculosis infection in Chinese adults. Methods We conducted 2 randomized, parallel-group clinical trials in healthy participants and tuberculosis patients. All participants were tested with the T-SPOT.TB test, then received an EC skin test and tuberculin skin test (TST). The diameter of skin indurations and/or redness at injection sites were measured at different time periods. A bacillus Calmette Guerin (BCG) model was established to assess the diagnosis of tuberculosis infection using an EC skin test. Results In total, 777 healthy participants and 96 tuberculosis patients were allocated to receive EC skin test at 1.0 μg/0.1 mL or 0.5 μg/0.1 mL. The area under the curve was 0.95 (95% confidence interval [CI], .91–.97) for the EC skin test at 1.0 μg/0.1 mL at 24–72 hours. Compared with the T-SPOT.TB test, the EC skin test demonstrated similar sensitivity (87.5, 95% CI, 77.8–97.2 vs 86.5, 95% CI, 79.5–93.4) and specificity (98.9, 95% CI, 96.0–99.9 vs 96.1, 95% CI, 93.5–97.8). Among BCG vaccinated participants, the EC skin test had high consistency with the T-SPOT.TB test (96.3, 95% CI, 92.0–100.0). No serious adverse events related to the EC skin test were observed. Conclusions The EC skin test demonstrated both high specificity and sensitivity at a dose of 1.0 μg/0.1 mL, comparable to the T-SPOT.TB test. The diagnostic accuracy of the EC skin test was not impacted by BCG vaccination. Clinical Trials Registration NCT02389322 and NCT02336542.

Objectives Bedaquiline treatment significantly improves multidrug-resistant tuberculosis (MDR-TB) patient treatment outcomes. However, safety and efficacy data are lacking for bedaquiline used with background regimens to treat Chinese TB patients. Here, we describe our initial clinical experience for bedaquiline treatment of a large multicentre cohort of MDR-TB and extensively drug-resistant tuberculosis (XDR-TB) patients in China. Methods Patients (177) received 24-week bedaquiline treatment combined with personalized anti-TB drug background regimens. As primary efficacy endpoints, times to initial sputum culture conversion were measured. Results Of 177 MDR-TB patients completing the 24-week treatment course, sputum culture conversion occurred for 151/177 (85.3%), while 26 had unfavourable outcomes, including 3/177 (1.7%) deaths and 23/177 (13.0%) non-responders at treatment completion. The median time to sputum culture conversion was 4 (interquartile range 2–8) weeks. Conversion rates were 33/39 (84.6%, 95% confidence interval (CI) 73.3–95.9) for MDR-TB patients, 47/56 (83.9%, 95% CI 74.3–93.6) for pre-XDR-TB patients and 71/82 (86.6%, 95% CI 79.2–94.0) for XDR-TB patients. Multivariate analysis demonstrated that patients with low body mass index (odds ratio 7.356; 95% CI 2.652–20.401) were at significantly high risk of unfavourable outcomes, with serious adverse events noted in 15 (8.5%) patients, including six with corrected QT interval (QTc) prolongation times (>500 ms). Conclusion Bedaquiline, when included in background regimens for treatment of MDR-TB and XDR-TB patients in China, was safe and associated with a high rate of culture conversion.

In clinical practice, PTB patients have concurrent many types of comorbidities such as pneumonia, liver disorder, diabetes mellitus, hematological disorder, and malnutrition. Detecting and treating specific comorbidities and preventing their development are important for PTB patients. However, the prevalence of most comorbid conditions in patients with PTB is not well described. We conducted a large-scale, multicenter, observational study to elucidate and illustrate the prevalence rates of major comorbidities in inpatients at 21 hospitals in China. The 19 specific comorbidities were selected for analysis in this patient cohort, and stratified the inpatient cohort according to age and gender. A total of 355,929 PTB inpatients were included, with a male:female ratio of 1.98 and the proportion of ≥ 65 years PTB inpatients was the most. Approximately 70% of PTB inpatients had at least one defined type of comorbidity. The prevalence of 19 specific comorbidities in inpatients with PTB was analyzed, with pneumonia being the most common comorbidity. The prevalence of most comorbidities was higher in males with PTB except thyroid disorders, mental health disorders, etc. The prevalence of defined most comorbidities in patients with PTB tended to increase with increasing age, although some specific comorbidities tended to increase initially then decrease with increasing age. Our study describes multiple clinically important comorbidities among PTB inpatients, and their prevalence between different gender and age groups. The results will enhance the clinical aptitude of physicians who treat patients with PTB to recognize, diagnose, and treat PTB comorbidities early.

Aims: A high proportion of all tuberculosis (TB) cases present with extrapulmonary tuberculosis (EPTB), including concurrent EPTB involving more than one extrapulmonary lesion site within the body. However, previous reports only characterised lesions of single-site EPTB cases. This study aimed to investigate epidemiological characteristics and association rules of concurrent EPTB cases in China. Methods: An observational multi-centre study was carried out in China from Jan 2011 to Dec 2017 that included a total of 208,214 patients with EPTB lesions. Multivariable logistic regression analysis was used to identify associations between gender and age with concurrent EPTB. Association rules were analysed for significance using the Apriori algorithm. Results: The most prevalent form of EPTB lesion was tuberculous pleurisy (49.8%), followed by bronchial tuberculosis (14.8%) and tuberculous meningitis (7.6%). The most predominant concurrent EPTB case type was tuberculous pleurisy concurrent with tuberculous peritonitis (1.80%). Altogether 22 association rules were identified that included 20 strong association rules, among which highest confidence rates were found for tuberculous myelitis concurrent with tuberculous meningitis and sacral TB concurrent with lumbar vertebral TB. Moreover, association rules of EPTB concurrent with other EPTB types were found to vary with gender and age. The confidence rate of tuberculous myelitis concurrent with tuberculous meningitis was higher in females (83.67%) than males and highest in patients of ages 25-34 years (87.50%). Conclusions: Many types of concurrent EPTB were found. Thus, greater awareness of concurrent EPTB disease characteristics is needed to ensure timely clinical diagnosis and treatment of this disease.

Objective To investigate the effect of drug treatment combined with interventional cavity therapy for cavitary pulmonary tuberculosis. Methods One-hundred thirty patients who underwent transbronchial tuberculosis cavity plugging (TTCP) combined with drug therapy from 2012 to 2018 were selected as the observation group, and 130 patients with cavitary tuberculosis who underwent treatment with drugs only were selected as the control group. Changes in cavity size and sputum tests were compared between the two groups. In addition, adverse reactions were monitored. Results The number of cases with cavity closure was significantly higher in the observation group than in the control group at different time points. The number and proportion of negative sputum samples in the observation group were significantly higher than those in the control group. The treatment success rate was 98.46% in the observation group and 92.3% in the control group. No recurrence was observed in the observation group, and 8.3% of cases in the control group showed recurrence. Conclusions TTCP for the treatment of cavity tuberculosis showed good outcomes, with limited side effects and minimal complications.

Background Tuberculosis (TB), a multi-systemic disease with protean presentation, remains a major global health problem. Although concurrent pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) cases are commonly observed clinically, knowledge regarding concurrent PTB-EPTB is limited. Here a large-scale multi- center observational study conducted in China aimed to study epidemiology of concurrent PTB-EPTB cases by diagnostically defining TB types then implementing association rules analysis.Methods This study was conducted at 21 hospitals in 15 provinces in China and included all inpatients with confirmed TB diagnoses admitted from Jan 2011 to Dec 2017. Association rules analysis was conducted for cases with concurrent PTB and various types of EPTB using the Apriori algorithm. Results Evaluation of 438,979 TB inpatients indicated PTB was the most commonly diagnosed (82.05%) followed by tuberculous pleurisy (23.62%). Concurrent PTB- EPTB was found in 129,422 cases (29.48%) of which tuberculous pleurisy was the most common concurrent EPTB type observed. Fully adjusted multivariable logistic regression models demonstrated that odds ratios of concurrent PTB-EPTB cases varied by gender and age group. For PTB cases with concurrent EPTB, the strongest association was found between PTB and concurrent bronchial tuberculosis (lift=1.09). For EPTB cases with concurrent PTB, the strongest association was found between pharyngeal/laryngeal tuberculosis and concurrent PTB (lift=1.11).Confidence and lift values of concurrent PTB-EPTB cases varied with gender and age.Conclusions Numerous concurrent PTB-EPTB case types were observed, with confidence and lift values varying with gender and age. Clinicians should screen for concurrent PTB- EPTB in order to improve treatment outcomes.

Background Tuberculosis (TB) is a multi-systemic disease with a protean presentation and remains a major global health problem. Concurrent pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) are common in clinical practice. However, the information about concurrent PTB-EPTB is scarce. This study aimed to study the epidemiology of concurrent PTB-EPTB by summarizing the diagnostic types of TB and determine the association rules by a large-scale multi-center observational study in China.Methods The study was performed at 21 hospitals from 15 provinces in China. All the consecutive inpatient with confirmed TB diagnosis during the years from Jan 2011 to Dec 2017 was included in the study. The association rules of concurrent PTB-EPTB were analyzed by Apriori algorithm. Results Of 438,979 TB inpatients evaluated, the most common were PTB (82.05%), followed by tuberculous pleurisy (23.62%), etc. Concurrent PTB-EPTB occurred in 129,422 cases (29.48%). Concurrent PTB and tuberculous pleurisy was the most common concurrent PTB-EPTB types. In the fully adjusted multivariable logistic models, the odds ratio of concurrent PTB-EPTB was different by gender and age group. In PTB with concurrent EPTB, the strongest association rule was PTB with concurrent bronchial tuberculosis (lift=1.09). In EPTB with concurrent PTB, the strongest association rule was pharyngeal /laryngeal tuberculosis with concurrent PTB (lift=1.11). The confidence and lift of concurrent PTB-EPTB varied with gender and age. Conclusions There were many types of concurrent PTB-EPTB. The confidence and lift of concurrent PTB-EPTB varied with gender and age. The clinicians should be alert to the presence of concurrent PTB-EPTB and take effective treatment regimen.

Background: Tuberculosis (TB) is a major global health problem in the whole world, especially in the developing countries. We aimed to assess diagnostic accuracy and safety of a novel ESAT6-CFP10 (EC) skin test for TB infection in Chinese adults. Methods: We conducted randomized, double-blinded, parallel-group clinical trials at two sites in healthy adults and TB/non-TB patients, respectively. TB infection-free healthy participants in a ratio of 1:1:1:1 to receive BCG vaccine or placebo, followed by EC skin test (0·5μg/0·1ml), or EC (1μg/0·1ml), along with the TST, T-SPOT.TB test, 12 weeks after the vaccination. TB patients or non-TB patients with pulmonary disease were randomly allocated in a ratio of 1:1 to receive EC skin test at 0·5μg/0·1ml, or 1μg/0·1ml, along with the TST and T-SPOT.TB test. The diameter of the skin indurations and/or redness at the injection sites were measured at 24 hours, 48 hours, and 72 hours after the skin tests. The studies was registered with ClinicalTrials.gov, number NCT02389322 and NCT02336542. Findings: We enrolled 223 TB infection-free healthy participants after screening, and randomly allocated them to receive BCG vaccination or placebo vaccination. Of them, 83 and 86 complete the EC skin test at 0·5μg/0·1ml or 1μg/0·1ml after vaccination. 96 TB patients and 95 non-TB patients with pulmonary diseases were allocated to receive the EC skin test at 0·5μg/0·1ml or 1μg/0·1ml, respectively. EC skin test at 1μg/0·1ml was found to be superior to 0·5μg/0·1ml based on the estimated AUCs, and the maximum AUCs of 0·927 was obtained at 1μg/0·1ml EC skin test at 48 hours using diameters of redness or induration as indicator. The highest diagnostic values achieved with cutoff values between 3·7~6·3 mm, and 5mm was determined as positive cutoff value for the responses of EC skin test. The incidence of adverse reaction following the EC skin tests were 27·8%, and no serious adverse event related to the EC skin tests was observed. Interpretation: The experimental EC skin test has an acceptable safety profile. EC skin test at 1μg/0·1ml can achieve both high specificity and sensitivity, and was selected as optimal dose for future studies. Funding: National Science and Technology Major Project (2012ZX10004710) Zhifei Longcom Biologic Pharmacy Co., China. Declaration of Interest: We declare no competing interests. Ethical Approval: We obtained approvals from the institutional review boards of the Jiangsu Provincial Center of Disease Control and Prevention, and Shanghai Public Health Clinical Center before initiation of the studies. Written informed consent were obtained from all participants. The trials were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.

Tuberculosis (TB) remains a serious global public health problem in the present. TB also affects other sites (extrapulmonary tuberculosis, EPTB), and accounts for a significant proportion of tuberculosis cases worldwide. In order to comprehensively understand epidemiology of EBTB in China, and improve early diagnosis and treatment, we conducted a large-scale multi-center observational study to assess the demographic data and the prevalence of common EPTB inpatients, and further evaluate the prevalence of EPTB concurrent with Pulmonary tuberculosis (PTB) and the associations between multiple EPTB types and gender-age group in China. All consecutive age≥15yr inpatients with a confirmed diagnosis of EPTB during the period from January 2011 to December 2017 were included in the study. The descriptive statistical analysis included median and quartile measurements for continuous variables, and frequencies and proportions with 95% confidence intervals (CIs) for categorical variables. Multinomial logistic regression analysis was used to compare the association of multiple EPTB types between age group and gender. The results showed that the proportion of 15-24 years and 25-34 years in EPTB inpatients were the most and the ratio of male: female was 1.51. Approximately 70% of EPTB inpatients were concurrent with PTB or other types of EPTB. The most common of EPTB was tuberculous pleurisy (50.15%), followed by bronchial tuberculosis (14.96%), tuberculous lymphadenitis of the neck (7.24%), tuberculous meningitis (7.23%), etc. It was found that many EPTB inpatients concurrent with PTB. The highest prevalence of EPTB concurrent with PTB was pharyngeal/laryngeal tuberculosis (91.31%), followed by bronchial tuberculosis (89.52%), tuberculosis of hilar lymph nodes (79.52%), tuberculosis of mediastinal lymph nodes (79.13%), intestinal tuberculosis (72.04%), tuberculous pleurisy (65.31%) and tuberculous meningitis (62.64%), etc. The results from EPTB concurrent with PTB suggested that females EPTB inpatients were less likely to be at higher risk of concurrent PTB (aOR = 0.819, 95%CI:0.803-0.835) after adjusted by age. As age increasing, the trend risk of concurrent PTB decreased (aOR = 0.994, 95%CI: 0.989-0.999) after adjusted by gender. Our study demonstrated that the common EPTB were tuberculous pleurisy, bronchial tuberculosis, tuberculous lymphadenitis of the neck, tuberculous meningitis, etc. A majority of patients with pharyngeal/laryngeal tuberculosis, bronchial tuberculosis, tuberculosis of hilar/mediastinal lymph nodes, intestinal tuberculosis, tuberculous pleurisy, tuberculous meningitis, etc. were concurrent with PTB. Female EPTB inpatients were less likely to be at higher risk of concurrent PTB, and as age increasing, the trend risk of concurrent PTB decreased. The clinicians should be alert to the presence of concurrent tuberculosis in EPTB, and all suspected cases of EPTB should be assessed for concomitant PTB to determine whether the case is infectious and to help for early diagnosis and treatment.

Background: Tuberculosis remains a serious and substantial global public health problem today. Pulmonary tuberculosis (PTB) is the most common clinical presentation of TB. In clinical practice, PTB patients have concurrent many types of co-morbidities such as pneumonia, liver disorder, diabetes mellitus, hematological disorder, malnutrition, hemoptysis, etc. This causes the condition of PTB patients complicated. Detecting and treating specific co-morbidities and preventing their development are important for PTB patients. However, the prevalence of most co-morbid conditions in patients with PTB is not well described. Methods: We conducted a large-scale, multi-center, observational study using admission data at 21 hospitals in China from Jan 1, 2011 to Dec 31, 2017, to elucidate and illustrate the prevalence rates of major co-morbidities in inpatients admitted to hospital for pulmonary TB. The 20 specific co-morbidities were selected for analysis in this patient cohort, and stratified the patient cohort according to age and gender. Findings: A total of 355,929 PTB inpatients were included, with a male:female ratio of 1.97 and the median age 47 (IQR:28~62) years old. The prevalence of 20 specific co-morbidities in patients with PTB was analyzed, with pneumonia being the most common co-morbidity. The prevalence of most co-morbidities were higher in males with PTB except thyroid disorders, mental health disorders, etc. The prevalence of defined most co-morbidities in patients with PTB tended to increase with increasing age, although some specific co-morbidities tended to increase initially then decrease with increasing age. Interpretation: Early identification and management of co-morbidities in patients with PTB may positively influence treatment outcomes for PTB patients. Our study, together with future research into co-morbidity trends in non-hospitalized PTB patients, may be useful in determining community based prevalence rates for PTB co-morbidities, thus enhancing diagnostic and therapeutic decision-making, and clinical outcomes in all PTB patients. Funding Statement: Key Project of Chinese National Programs (Grant No. 2015ZX10003001), ‘Beijing Municipal Administration of Hospitals’ Ascent Plan (No. DFL20181601) and Tongzhou District Science and Technology Committee [No.KJ2017CX054]. Declaration of Interests: All the authors declare no conflicts of interest. Ethics Approval Statement: The Ethics Committee of Beijing Chest Hospital, Capital Medical University approved this study with a waiver of informed consent from the patients involved.

To find the potential reasons for the discrepancies in the drug susceptibility test (DST) ofM. tuberculosisisolates, twenty paired isolates with disputed drug susceptibilities to isoniazid (INH) were selected according to the MGIT960 testing and Löwenstein-Jensen (L-J) proportion methods. Their MICs were confirmed again by broth microdilution method and by L-J proportion method. The spoligotyping results showed that, of all the 20 paired strains, 11 paired isolates belonged to the Beijing genotype and 6 paired isolates belonged to SIT1634, and that each of the remaining 3 paired isolates had two genotypes, namely, SIT1 and SIT1634. Those 3 paired isolates with different intrapair spoligotypes were further confirmed as mixed infection by the results that those three pairs of isolates with different 12 locus MIRU intrapair types and one pair carried different base pair at codon 315 (AGC versus AAC). Totally mutations in thekatGgene were identified in 13 paired isolates. No mutations were found in the regulatory sequences and open reading frames (ORF) of theinhAandahpCgenes in any of the tested isolates. Those results showed that the different test systems and the mixed infection with particular genotypes ofM. tuberculosisstrains contributed to the drug susceptibility discrepancies.