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Objectives: This study aimed to investigate the association between drug exposure and adverse events (AEs) during the standardized multidrug-resistant tuberculosis (MDR -TB) treatment, as well as to identify predictive drug exposure thresholds. Methods: We conducted a prospective, observational multicenter study among participants receiving standardized MDR -TB treatment between 2016 and 2019 in China. AEs were monitored throughout the treatment and their relationships to drug exposure (e.g., the area under the drug concentration -time curve from 0 to 24 h, AUC0-24 h ) were analyzed. The thresholds of pharmacokinetic predictors of observed AEs were identified by boosted classification and regression tree (CART) and further evaluated by external validation. Results: Of 197 study participants, 124 (62.9%) had at least one AE, and 15 (7.6%) experienced serious AEs. The association between drug exposure and AEs was observed including bedaquiline, its metabolite M2, moxifloxacin and QTcF prolongation (QTcF > 450 ms), linezolid and mitochondrial toxicity, cycloserine and psychiatric AEs. The CART -derived thresholds of AUC0-24 h predictive of the respective AEs were 3.2 mg h/l (bedaquiline M2); 49.3 mg h/l (moxifloxacin); 119.3 mg h/l (linezolid); 718.7 mg h/l (cycloserine). Conclusions: This study demonstrated the drug exposure thresholds predictive of AEs for key drugs against MDR -TB treatment. Using the derived thresholds will provide the knowledge base for further randomized clinical trials of dose adjustment to minimize the risk of AEs., Funding Agencies|National Natural Science Foundation of China, Fudan University, Shanghai Health Committee [20190229]; Heart and Lung Foundation [SLS 20181256]; Stockholm County Council [2019-05 901]; Swedish Research Council [2019-05 912, FORSS-964535]; Research Council of south-eastern Sweden; [GWVI-11.1-05]; [81874273]

Although cycloserine is a recommended drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) according to World Health Organization (WHO), few studies have reported on pharmacokinetics (PK) and/or pharmacodynamics (PD) data of cycloserine in patients with standardized MDR-TB treatment. This study aimed to estimate the population PK parameters for cycloserine and to identify clinically relevant PK/PD thresholds, as well as to evaluate the current recommended dosage. Although cycloserine is a recommended drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) according to World Health Organization (WHO), few studies have reported on pharmacokinetics (PK) and/or pharmacodynamics (PD) data of cycloserine in patients with standardized MDR-TB treatment. This study aimed to estimate the population PK parameters for cycloserine and to identify clinically relevant PK/PD thresholds, as well as to evaluate the current recommended dosage. Data from a large cohort with full PK curves was used to develop a population PK model. This model was used to estimate drug exposure in patients with MDR-TB from a multicentre prospective study in China. The classification and regression tree was used to identify the clinically relevant PK/PD thresholds. Probability of target attainment was analyzed to evaluate the currently recommended dosing strategy. Cycloserine was best described by a two-compartment disposition model. A percentage of time concentration above MICs (T->MIC) of 30% and a ratio of area under drug concentration-time curve (AUC(0-24h)) over MIC of 36 were the valid predictors for 6-month sputum culture conversion and final treatment outcome. Simulations showed that with WHO-recommended doses (500 mg and 750 mg for patients weighing <45 kg and >= 45 kg), the probability of target attainment exceeded 90% at MIC <= 16 mg/L in MGIT for both T->MIC of 30% and AUC(0-24h)/MIC of 36. New clinically relevant PK/PD thresholds f, Funding Agencies|National Natural Science Foundation of China [81874273]; Swedish Research Council; Swedish Heart and Lung Foundation; County of Stockholm; Research Council of south-eastern Sweden

BACKGROUND: BCG vaccines are given to more than 100 million children every year, but there is considerable debate regarding the effectiveness of BCG vaccination in preventing tuberculosis and death, particularly among older children and adults. We therefore aimed to investigate the age-specific impact of infant BCG vaccination on tuberculosis (pulmonary and extrapulmonary) development and mortality. METHODS: In this systematic review and individual participant data meta-analysis, we searched MEDLINE, Web of Science, BIOSIS, and Embase without language restrictions for case-contact cohort studies of tuberculosis contacts published between Jan 1, 1998, and April 7, 2018. Search terms included mycobacterium tuberculosis, TB, tuberculosis, and contact. We excluded cohort studies that did not provide information on BCG vaccination or were done in countries that did not recommend BCG vaccination at birth. Individual-level participant data for a prespecified list of variables, including the characteristics of the exposed participant (contact), the index case, and the environment, were requested from authors of all eligible studies. Our primary outcome was a composite of prevalent (diagnosed at or within 90 days of baseline) and incident (diagnosed more than 90 days after baseline) tuberculosis in contacts exposed to tuberculosis. Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality. We derived adjusted odds ratios (aORs) using mixed-effects, binary, multivariable logistic regression analyses with study-level random effects, adjusting for the variable of interest, baseline age, sex, previous tuberculosis, and whether data were collected prospectively or retrospectively. We stratified our results by contact age and Mycobacterium tuberculosis infection status. This study is registered with PROSPERO, CRD42020180512. FINDINGS: We identified 14 927 original records from our database searches. We included participant-level data from 26 cohort

Limei Zhu,* Ran Wang,* Li Zhang, Chunlei Zuo, Rui Zhang, Shaolin Zhao Department of Clinical Laboratory, The First People’s Hospital of Lianyungang, Lianyungang, Jiangsu, China *These authors contributed equally to this work Background: Previous research indicated that overexpression of miRNA-211 could promote colorectal cancer cell growth by targeting tumor suppressive gene Chromodomain-helicase-DNA-binding protein 5 (CHD5) in human colon cancer (CC). Moreover, the function of the single-nucleotide polymorphism (SNP) located in the mature region of miR-211 has not been investigated. In this study, we found that SNP of rs187960998 in miR-211 was involved in the occurrence of CC by acting as a tumor suppressor by mal-regulation of its target gene CHD5.Materials and methods: The genotype of total 685 CC patients was detected by real-time PCR, the proliferation of CC cell lines with different genotypes of miR-211 was determined by Cell Counting Kit-8, cell invasion evaluated by transwell and the activity of the CHD5 promoter in CC cell lines transfected with different miR-211 was determined by luciferase assay. The expression of CHD5 in CC patients was determined by the immunohistochemistry, and the relapse-free survival rate was analyzed by Kaplan–Meier analysis.Results: C/T SNP of miR-211 could inhibit CC cell proliferation and invasion by upregulation of CHD5. And SNP in rs187960998 of miR-211 was associated with tumor size, metastasis and tumor differentiation in CC patients. Patients with CC genotype have significantly low CHD5 expression than the T-carrier, while no significant expression difference in miR-211 expression among different genotype subsets. Patients with CC genotype have significantly shorter postsurgery survival rate compared to the T-carrier.Conclusion: rs187960998 in miR-211 was highly associated with a decreased risk of CC in the Chinese population by deregulating a tumor suppressive gene CHD5. Keywords: miR-211, colon cancer