Combination therapy with long-acting bronchodilators and the risk of major adverse cardiovascular events in patients with COPD: a systematic review and meta-analysis.

INTRODUCTION: Accumulated high-quality data from randomised controlled trials (RCTs) indicate that long-acting muscarinic antagonist (LAMA)/long-acting ß2 agonist (LABA) combination therapy significantly improves clinical symptoms and health status in patients with chronic obstructive pulmonary disease (COPD) and reduces exacerbation risk. However, there is a growing concern that LAMA/LABA therapy may increase the risk of cardiovascular disease in patients with COPD. The aim of this paper is to determine whether the use of LAMA/LABA combination therapy modifies the risk of cardiovascular disease in patients with COPD. METHODS: Two reviewers independently searched Embase, PubMed and Cochrane Library to identify relevant RCTs of LAMA/LABA or LABA/LAMA/inhaled corticosteroids (ICS) for the management of patients with COPD that reported on cardiovascular end-points. The primary outcome was major adverse cardiovascular events (MACE), which was a composite of cardiovascular death, myocardial infarction or stroke. RESULTS: A total of 51 RCTs enrolling 91 021 subjects were analysed. Both dual LAMA/LABA (1.6% versus 1.3%; relative risk 1.42, 95% CI 1.11-1.81) and triple therapy (1.6% versus 1.4%; relative risk 1.29, 95% CI 1.03-1.61) significantly increased the risk of MACE compared with ICS/LABA. The excess risk was most evident in RCTs in which the average underlying baseline risk for MACE was >1% per year. Compared with LAMA only, LABA only or placebo, dual LAMA/LABA therapy did not significantly increase the risk of MACE, though these comparisons may have lacked sufficient statistical power. CONCLUSION: Compared with ICS/LABA, dual LAMA/LABA or triple therapy increases cardiovascular risk in patients with COPD. This should be considered in the context of the incremental benefits of these therapies for symptoms and exacerbation rates in patients with COPD, especially in those with a MACE risk of >1% per year.

Association between a single nucleotide polymorphism of the ALOX5 gene and susceptibility to multisystem tuberculosis in a Chinese Han population.

BACKGROUND: Host genetic single nucleotide polymorphisms can exert an influence susceptibility to tuberculosis infection. Previous investigations have demonstrated an association between the polymorphism in the ALOX5 gene and a range of diseases, encompassing not only noninfectious conditions like asthma, acute myocardial infarction, and cerebral infarction but also infections caused by various pathogens. However, the relationship between ALOX5 gene polymorphism and susceptibility to tuberculosis has received limited research attention. The ALOX5 gene encodes arachidonic acid 5-lipoxygenase(5-LO), which serves as the initiating catalyst in the generation of the inflammatory mediator leukotriene. Leukotrienes, products derived from the 5-LO pathway, are potent proinflammatory lipid mediators that assume a pivotal role in tuberculosis infections.Consequently, ALOX5 gene variants may be intricately associated with the pathogenesis of tuberculosis. In instances where the host exhibits immunocompromisation, infection with Mycobacterium tuberculosis can impact multiple systems. The involvement of multiple systems significantly augments the complexity of treatment and escalates patient mortality rates. Regrettably, the underlying mechanisms driving multisystem tuberculosis pathogenesis remain enigmatic, with clinicians paying scant attention to this aspect. Although the protein encoded by the ALOX5 gene represents a pivotal enzyme that catalyzes the metabolism of arachidonic acid into LXA4, and thereby plays a significant role in the inflammatory response during tuberculosis infection, studies investigating ALOX5 gene polymorphism and its association with susceptibility to multisystem tuberculosis in the Chinese Han population are exceptionally scarce. Therefore, the primary objective of this study is to comprehensively examine the correlation between ALOX5 gene polymorphisms and susceptibility to tuberculosis within the Chinese Han population, with particular emphasis on multisystemic tuberculosis. METHODS: A case‒control study design was employed, encompassing 382 individuals with pulmonary tuberculosis and 367 individuals with multisystemic tuberculosis as the case groups, along with 577 healthy controls.Whole blood DNA was extracted from all patients and healthy controls. Subsequently, three tag polymorphisms (rs2029253, rs7896431, rs2115819) within the ALOX5 gene were selectively identified and genotyped. RESULTS: After adjusting for age and sex, the presence of allele A at rs2029253 exhibited a pronounced association with an elevated risk of TB susceptibility when compared to the tuberculosis group and healthy control group. (ORa: 2.174, 95% CI: 1.827-2.587; Pa<0.001, respectively). Notably, the rs2029253 AG genotype and AA genotype displayed a significantly increased susceptibility to tuberculosis (ORa: 2.236, 95% CI: 1.769-2.825; Pa <0.001 and ORa: 4.577, 95% CI: 2.950-7.100; Pa <0.001, respectively) compared to the GG genotype. Moreover, in the analysis utilizing genetic models, rs2029253 also exhibited a markedly heightened susceptibility to tuberculosis in additive models, dominant models, and recessive models (Pa <0.001). Conversely, no significant association was observed between rs7896431, rs2115819, and tuberculosis. In the subgroup analysis, when comparing the pulmonary tuberculosis group with the healthy control group, we observed no significant disparities in the distribution frequencies of alleles, genotypes, and gene models (additive model, dominant model, and recessive model) for the three tag SNPs, with P-values were >0.05 after adjusting for age and sex. Additionally, we noted that the presence of allele A at rs2029253 was linked to an increased susceptibility to tuberculosis in the multisystemic tuberculosis group relative to the healthy control group (ORa: 2.292, 95% CI: 1.870-2.810; Pa<0.001). Similarly, the rs2029253 AG genotype, AA genotype, and gene models, including the additive model, dominant model, and recessive model, demonstrated a significantly elevated risk of tuberculosis susceptibility. CONCLUSIONS: The polymorphism in the ALOX5 gene is associated with susceptibility to multisystemic tuberculosis in the Chinese Han population.

Association between a single nucleotide polymorphism of the IL23R gene and tuberculosis in a Chinese Han population: a case‒control study.

BACKGROUND: Severe tuberculosis constitutes a significant menace to human safety and well-being, with a considerable mortality rate. The severity of tuberculosis can be impacted by genetic variations in host genes, particularly single nucleotide polymorphisms (SNPs). METHODS: A case‒control study was undertaken, encompassing a cohort of 1137 tuberculosis patients (558 with severe tuberculosis and 579 with mild tuberculosis), alongside 581 healthy controls within the age range of fifteen to forty-five years. Whole blood DNA was extracted from all participants, and three tag polymorphisms (rs1884444, rs7518660, rs7539625) of the IL23R gene were selectively identified and genotyped. RESULTS: No significant correlation was observed between the IL23R gene polymorphisms (rs1884444, rs7518660, and rs7539625) and tuberculosis. Upon comparing the tuberculosis group with the healthy control group, the mild tuberculosis group with the healthy control group, and the severe tuberculosis group with the healthy control group, the obtained P-values were> 0.05. However, in the comparison between severe tuberculosis and mild tuberculosis, the presence of rs1884444 G alleles exhibited a significantly increased risk of severe tuberculosis after adjusting for age and sex (ORa: 1.199, 95% CI: 1.009-1.424; Pa=0.039, respectively). In subgroup analysis, after accounting for confounding factors, including age and sex, rs1884444 G alleles continued to demonstrate a significantly heightened risk of severe tuberculosis. Nonetheless, the comparison between the multisystemic tuberculosis group and the mild tuberculosis group was no significant difference. Notably, rs1884444 of the IL23R gene exhibited a noteworthy association with the risk of severe tuberculosis in the comparison between severe tuberculosis and mild tuberculosis before and after adjusting for age and sex (ORa: 1.301, 95% CI: 1.030-1.643; Pa=0.027, respectively). Furthermore, the presence of the rs1884444 G allele exhibited a significantly increased risk of severe tuberculosis after adjusting for age and sex in the comparison between tuberculous meningitis and mild tuberculosis (ORa: 1.646, 95% CI: 1.100-2.461; Pa=0.015, respectively). CONCLUSIONS: The present study suggests that there is no significant association between IL23R gene polymorphism and tuberculosis susceptibility in the Chinese Han population. However, it does indicate a potential link between IL23R polymorphism and an increased risk of developing severe tuberculosis.

A Predictive Model for Chronic Hydrocephalus After Clipping Aneurysmal Subarachnoid Hemorrhage.

Chronic hydrocephalus after clipping aneurysmal subarachnoid hemorrhage (aSAH) often results in poor outcomes. This study was to establish and validate model to predict chronic hydrocephalus after aSAH by least absolute shrinkage and selection operator logistic regression. The model was constructed from a retrospectively analyzed. Two hundred forty-eight patients of aSAH were analyzed retrospectively in our hospital from January 2019 to December 2021, and the patients were divided into chronic hydrocephalus (CH) group (n=55) and non-CH group (n=193) according to whether occurred CH within 3 months. In summary, 16 candidate risk factors related to chronic hydrocephalus after aSAH were analyzed. Univariate analysis was performed to judging the risk factors for CH. The least absolute shrinkage and selection operator regression was used to filter risk factors. Subsequently, the nomogram was designed by the above variables. And area under the curve and calibration chart were used to detect the discrimination and goodness of fit of the nomogram, respectively. Finally, decision curve analysis was constructed to assess the practicability of the risk of chronic hydrocephalus by calculating the net benefits. Univariate analysis showed that age (60 y or older), aneurysm location, modified Fisher grade, Hunt-Hess grade, and the method for cerebrospinal fluid drainage, intracranial infections, and decompressive craniectomy were significantly related to CH ( P <0.05). Whereas 5 variables [age (60 y or older), posterior aneurysm, modified Fisher grade, Hunt-Hess grade, decompression craniectomy] from 16 candidate factors were filtered by LASSO logistic regression for further research. Area under the curve of this model was 0.892 (95% confidence interval: 0.799-0.981), indicating a good discrimination ability. Meanwhile, the result of calibration indicated a good fitting between the prediction probability and the actual probability. Finally, decision curve analysis showed a good clinical efficacy. In summary, this model could conveniently predict the occurrence of chronic hydrocephalus after aSAH. Meanwhile, it could help physicians to develop personalized treatment and close follow-up for these patients.

Variants of Toll-like receptor 6 associated with tuberculosis susceptibility in the Chinese Tibetan population.

BACKGROUND: Our investigation attempted to understand the role of innate immunity related genes played in tuberculosis. The relationship between single-nucleotide polymorphisms (SNPs) of three innate immunity-related genes (TLR6, MyD88, and TIRAP) and tuberculosis (TB) risk in two Chinese populations were explored. METHODS: Totally 1185 Chinese Han, consisting of 580 active TB cases and 605 healthy controls (HCs), and 1216 Chinese Tibetan individuals including 613 TB patients and 603 HCs were enrolled to conduct two case-control studies. TagSNPs of the three genes were selected based on the HapMap database and genotyped by the SNPscan™ Kit. Haploview software 4.2 was applied to perform linkage disequilibrium (LD) analysis and online software SHEsis was used to discover significant haplotype block. RegulomeDB and HaploReg were applied to predict potential functional SNPs of the three genes. RESULTS: The results showed that minor alleles of rs5743808 and rs5743827 of TLR6 were related with increased TB risk (p = 0.001, OR 95%CI = 1.51 (1.18-1.95) and p = 0.002, OR 95%CI = 1.42 (1.14-1.77)), and significant association was also observed between rs5743827 and TB risk in male subgroup (p = 0.003, OR 95%CI = 1.67 (1.91-2.35)) in the Tibetan population. For the Tibetan population, frequency of haplotype ACGT of rs1039559-rs3775073-rs5743808-rs5743827 of TLR6 was significantly higher in the TB group (p = 0.0008), while haplotype ATAC was significantly higher in the control group (p = 0.0002). The above associations remained after permutation and Bonferroni correction. No significant association was found in the Han population. Probable functions of tagSNPs of TLR6 and some other linked variants were discovered after bioinformatic analysis. CONCLUSIONS: This study suggested that variants of TLR6 might be associated with TB risk in the Tibetan population, while not in the Han population. The difference between Chinese Han and Tibetan people will provide better understanding of tuberculosis.

Metabolomics and microbiomes for discovering biomarkers of antituberculosis drugs-induced hepatotoxicity.

Anti-tuberculosis (TB) drug-induced hepatotoxicity (ATDH) was related to metabolic and microbial dysregulation, but only limited data was available about the metabolomes and microbiomes in ATDH. We aimed at detecting the metabolic and microbial signatures of ATDH. Urine samples were obtained from ATDH (n = 33) and non-ATDH control (n = 41) and analyzed by untargeted gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). Metabolites were analyzed by orthogonal projections to latent structures-discriminate analysis (OPLS-DA) and pathway analysis. Eight ATDH and eight non-ATDH control were evaluated by sequencing of 16S rRNA genes, and the Clusters of Orthologous Groups of proteins (COG) database were used for function prediction. Linear discriminant analysis (LDA) effect size (LEfSe) was applied to detect the differential microbiotas between the two groups. The differential microbiotas were further validated by correlation analysis with differential metabolites. OPLS-DA analysis suggested 11 metabolites that differed ATDH from non-ATDH control. Pathway analysis demonstrated that metabolism of arginine and proline, metabolism of d-arginine and d-ornithine, glutathione glycine metabolism, galactose metabolism, niacin and nicotinamide metabolism, and glycine, serine and threonine metabolism were related to ATDH. LEfSe suggested significant differences in microbiotas between the two groups. The o_ Bacteroidales, f_Prevotellaceae, and g_Prevotella were significantly increased in ATDH. In contrast, the f_Chitinophagaceae, c_Gammaproteobacteria, and p_Proteobacteria were significantly increased in non-ATDH group. The biological functions of the sequenced microbiota in this study were related to amino acid transport and metabolism and defense mechanisms. Finally, we detected strong association between urine metabolites and specific urine bacteria (|r| > 0.8). d-glucoheptose showed a strong relationship to Symbiobacterium. Creatine (r = -0.901; P < 0.001) and diglycerol were strongly associated with Alishewanella. Metabolomics and microbiomes indicate ATDH characterized by metabolic and microbial profiles may differ from non-ATDH control.

Genetic association of TOLLIP gene polymorphisms and HIV infection: a case-control study.

BACKGROUND: Previous studies have indicated that host genetic factors play an essential role in immunity to human immunodeficiency virus (HIV) infection. We aimed to investigate the association between the toll-interacting protein (TOLLIP) and mannose-binding lectin 2 (MBL2) genes and HIV infection susceptibility among Chinese Han patients. METHODS: This is a case-control study. A total of 435 HIV-infected patients and 1013 seronegative healthy individuals were recruited. DNA was extracted from whole blood. Two SNPs in the MBL2 gene (rs7096206 and rs1800450) and three SNPs in the TOLLIP gene (rs5743899, rs3750920, and rs5743867) were selected and genotyped using a SNPscan Kit (Cat#: G0104, Genesky Biotechnologies Inc., Shanghai, China). Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated using unconditional binary logistic regression. RESULTS: A significant association between the minor alleles rs5743899 (C allele) and rs5743867 (G allele) in the TOLLIP gene and susceptibility to HIV infection was found in this study after adjusting for age and sex (Pa = 0.011 and < 0.001, respectively). The rs5743867 in the TOLLIP gene was significantly associated with the risk of HIV infection in dominant, recessive, and additive models when adjusted for age and sex (Pa < 0.05). No significant association was found between MBL2 gene polymorphisms and HIV infection. CONCLUSION: Our study found a statistically significant association between the two SNPs (rs5743867 and rs5743899) in the TOLLIP gene and susceptibility to HIV infection in a Chinese Han population.

Efficacy of bedaquiline in the treatment of drug-resistant tuberculosis: a systematic review and meta-analysis.

BACKGROUND: Drug-resistant tuberculosis (DR-TB) remains a major public health concern worldwide. Bedaquiline, a novel diarylquinoline, was added to the WHO-recommended all-oral regimen for patients with multidrug-resistant tuberculosis. We performed a systematic review and meta-analysis to determine the effect of bedaquiline on tuberculosis treatment outcomes. METHODS: We searched the PubMed, Web of Science and EMBASE databases for relevant studies published up to March 12, 2021. We included studies in which some participants received bedaquiline and others did not. Stata version 16.0 (Stata Corp., College Station, Texas, USA) was used to analyze the results of the meta-analysis. Risk ratios (RRs) with 95% confidence intervals (95% CIs) were calculated to evaluate the effect of bedaquiline on drug-resistant tuberculosis. Between-study heterogeneity was examined by the I-squared test. Randomized controlled trials were assessed for quality using the Jadad scale, and cohort studies were assessed using the Newcastle-Ottawa scale. RESULTS: Eight studies, including 2 randomized controlled trials and 6 cohort studies involving a total of 21,836 subjects, were included. When compared with the control, bedaquiline treatment was associated with higher rates of culture conversion (risk ratio (RR):1.272 (1.165-1.389), P < 0.001). We found substantial evidence of a significant reduction in all-cause death (RR: 0.529 (0.454-0.616), P < 0.001)) in the bedaquiline treatment group. There was no significant reduction in treatment success (RR = 0.980 (0.948-1.013, P = 0.234)). CONCLUSIONS: This study demonstrated that compared with patients who do not receive bedaquiline, this drug has the potential to achieve a higher culture conversion rate and a lower mortality risk among drug-resistant tuberculosis cases.

Posttraumatic Giant Intradiploic Epidermoid Cyst of Orbital Roof.

ABSTRACT: Epidermoid cysts are rare benign tumors that account for 0.3% to 1.8% of all intracranial space-occupying lesions. They are usually congenital in origin and are thought to derived from ectodermal cell inclusions occurring during closure of the neural tube around third to fifth week of gestation. They are most commonly located in the cerebellopontine angle and the parasellar area, and their location in the diploic space is very rare. In this article, a case of giant epidermoid cyst located in the orbital roof intradiploic space is presented with clinical, radiologic features and surgical treatment.

Impacts of metformin on tuberculosis incidence and clinical outcomes in patients with diabetes: a systematic review and meta-analysis.

BACKGROUND: Accumulating evidence suggested that the use of metformin had more benefits for both prevention and treatment of tuberculosis (TB) than non-metformin use in patients with diabetes mellitus (DM); however, it remains to be fully elucidated on this topic. Thus, we conducted a systematic review and meta-analysis of published studies to determine the association between metformin use and TB in patients with diabetes. METHODS: The MEDLINE, EMBASE, Information Sciences Institute (ISI) Web of Science, and Cochrane CENTRAL databases were searched from their inception to 15 April 2019. Studies that evaluated the use of metformin and TB disease were included. The quality of each study was evaluated through the Newcastle-Ottawa Scale (NOS). For pooled data, the relative risk (RR) and 95% confidence intervals (CIs) were calculated; otherwise, a systematic review. RESULTS: Seventeen observational studies were included, all of which indicated a low risk of bias according to the NOS. The pooled analysis showed that metformin use was associated with a significantly lower active TB incidence and mortality among individuals with DM (RR = 0.51; 95% CI, 0.38-0.69, P ⩽ 0.001) and with TB-DM (RR = 0.34; 95% CI, 0.20-0.57, P ⩽ 0.001), respectively. CONCLUSIONS: This meta-analysis indicated metformin use is related to benefits in both prevention and treatment outcomes of tuberculosis among patients with diabetes. Prospective clinical trials are needed to confirm these associations.

Polymorphisms in the airway epithelium related genes CDHR3 and EMSY are associated with asthma susceptibility.

BACKGROUND: As a main line of defense of the respiratory tract, the airway epithelium plays an important role in the pathogenesis of asthma. CDHR3 and EMSY were reported to be expressed in the human airway epithelium. Although previous genome-wide association studies found that the two genes were associated with asthma susceptibility, similar observations have not been made in the Chinese Han population. METHODS: A total of 300 asthma patients and 418 healthy controls unrelated Chinese Han individuals were enrolled. Tag-single nucleotide polymorphisms (Tag-SNPs) were genotyped and the associations between SNPs and asthma risk were analyzed by binary logistic regression analysis. RESULTS: After adjusting for confounding factors, the A allele of rs3847076 in CDHR3 was associated with increased susceptibility to asthma (OR = 1.407, 95% CI: 1.030-1.923). For the EMSY gene, the T alleles of both rs2508746 and rs12278256 were related with decreased susceptibility to asthma (additive model: OR = 0.718, 95% CI: 0.536-0.961; OR = 0.558, 95% CI: 0.332-0.937, respectively). In addition, the GG genotype of rs1892953 showed an association with increased asthma risk under the recessive model (OR = 1.667, 95% CI: 1.104-2.518) and the GATCTGAGT haplotype in EMSY was associated with reduced asthma risk (P = 0.037). CONCLUSIONS: This study identified novel associations of rs3847076 in CDHR3, as well as rs1892953, rs2508746 and rs12278256 in EMSY with adult asthma susceptibility in the Chinese Han population. Our observations suggest that CDHR3 and EMSY may play important roles in the pathogenesis of asthma in Chinese individuals. Further study with larger sample size is needed.

Association of heme oxygenase-1 single nucleotide polymorphisms with susceptibility to tuberculosis in Chinese Han population.

BACKGROUND: Tuberculosis (TB) is an infectious disease, caused by mycobacterium tuberculosis infection, which is associated with oxidative stress and the induction of host antioxidants to counteract this response. The heme oxygenase-1 (HO-1) single nucleotide polymorphisms have been reported to be associated with many critical diseases. Our purpose was to investigate the association of HO-1 single nucleotide polymorphisms with the susceptibility to tuberculosis in Chinese Han population. METHODS: A case-control study was performed on Chinese Han population, and a group of 638 TB patients was compared to 610 healthy controls. Three single nucleotide polymorphisms (SNPs) including rs2071746, rs5995098, and rs8140669 were genotyped using the MassARRAY platform. The genotype frequency was compared between TB patients and healthy controls. The association between the three genetic models of the three SNPs and TB risk was further investigated. RESULTS: The results showed that, in the case of additive model, there was significant difference of the genotype frequencies of SNP rs8140669 between the TB patients and control groups (P = .038). In the case of dominant model, the genotype frequencies of SNP rs8140669 may have difference between the two cohorts (P = .051), while the allele frequency and genotype distribution for other two SNPs showed no significant difference between the two groups (P > .05). CONCLUSION: HO-1 polymorphism was associated with TB susceptibility in Chinese Han population.

Genetic variants in IFNG and IFNGR1 and tuberculosis susceptibility.

BACKGROUND: Tuberculosis (TB) is the type of chronic infectious disease which majorly caused by Mycobacterium tuberculosis (M. TB). Emerging data suggest that interferon gamma (IFNG) and its receptor IFNGR1 may be involved in the risk of TB. METHODS: A total of 636 TB patients and 608 healthy controls were selected. The association between single nucleotide polymorphisms (SNPs) and TB was estimated by logistic analyses adjusting for age, gender and smoking status. SNPs genotyping was done by using the improved multiplex ligase detection reaction (iMLDR). RESULTS: The IFNG rs1861494 allele C was related to an increased risk for TB (OR = 1.25, 95%CI: 1.06-1.48; P = 0.009). Compared with TT genotype, CT (OR = 1.28, 95%CI: 1.01-1.63; P = 0.040) and CC (OR = 1.51, 95%CI: 1.04-2.19; P = 0.031) were also risk factors for TB. In the subgroup analysis, the association was stronger among participants < 25 years (OR = 2.40, 95%CI: 1.70-3.38; P < 0.001) and male groups (OR = 1.31, 95%CI: 1.03-1.66; P = 0.030). In addition, IFNG rs1861494 was associated with anti-TB treatment outcome (OR = 0.70, 95%CI: 0.52-0.94; P = 0.017). We also detected that IFNGR1 rs2234711 influenced the IFNG production. CONCLUSION: IFNG rs1861494 polymorphism was associated with TB, particularly in the younger and male subgroups.

Polymorphisms in the STAT4 gene and tuberculosis susceptibility in a Chinese Han population.

The signal transducer and activator of transcription 4 (STAT4) gene encodes a transcription factor that transmits signals induced by several cytokines which play critical roles in the development of autoimmune and chronic inflammatory diseases. We performed an association study between STAT4 single nucleotide polymorphisms (SNPs) and tuberculosis (TB). 624 TB cases and 598 healthy controls were studied to compare allele/genotype frequencies of 4 SNPs in STAT4. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression. Genotyping was performed with the Sequenom MassARRAY SNP genotyping platform. Out of 4 SNPs tested in the study, rs4853542 allele A showed a 25% decreased risk of TB compared with allele G (P = 0.013, OR = 0.75, 95%CI: 0.60-0.94). However, it did not show significant differences under any genetic model after Bonferroni correction. No association was found for the other 3 SNPs with TB. In subgroup analyses, the protective effects of rs485342 allele A were stronger among younger subjects <25 years (P = 0.002, OR = 0.49, 95%CI: 0.31-0.76). Allele A of the rs4853542 polymorphism in STAT4 is not associated with TB susceptibility, but we demonstrated that rs4853542A allele decreased risk of TB in younger adults after Bonferroni correction.

Treatment outcomes of tuberculous meningitis in adults: a systematic review and meta-analysis.

BACKGROUND: Tuberculous meningitis is the most devastating presentation of disease with Mycobacterium tuberculosis. We sought to evaluate treatment outcomes for adult patients with this disease. METHODS: The Ovid MEDLINE, EMBASE, Cochrane Library and Web of Science databases were searched to identify all relevant studies. We pooled appropriate data to estimate treatment outcomes at the end of treatment and follow-up. RESULTS: Among the articles identified, 22 met our inclusion criteria, with 2437 patients. In a pooled analysis, the risk of death was 24.7% (95%CI: 18.7-31.9). The risk of neurological sequelae among survivors was 50.9% (95%CI: 40.2-61.5). Patients diagnosed in stage III or human immunodeficiency virus (HIV) positive were significantly more likely to die (64.8, 53.4% respectively) during treatment. The frequency of cerebrospinal fluid (CSF) acid-fast-bacilli smear positivity was 10.0% (95% CI 5.5-17.6), 23.8% (15.2-35.3) for CSF culture positivity, and 22.3% (17.8-27.5) for CSF polymerase chain reaction positivity. We found that the headache, fever, vomiting, and abnormal chest radiograph were the most common symptoms and diagnostic findings among tuberculous meningitis patients. CONCLUSIONS: Despite anti-tuberculosis treatment, adult tuberculous meningitis has very poor outcomes. The mortality rate of patients diagnosed in stage III or HIV co-infection increased significantly during treatment.

Are genetic variations in glutathione S-transferases involved in anti-tuberculosis drug-induced liver injury? A meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: As a crucial protective role in the detoxifying mechanisms of drugs, glutathione S-transferases (GSTs) may affect an individual patient's susceptibility to anti-tuberculosis drug-induced liver injury (ATLI). However, the results of studies investigate the association between GSTM1, GSTT1 and GSTP1 polymorphisms and risk of ATLI are inconclusive. A meta-analysis on this topic was performed. METHODS: PubMed, EMBASE, ISI web of science and the Chinese National Knowledge Infrastructure (CNKI) were systematically searched to identify relevant studies. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated. Heterogeneity among articles and publication bias were also tested. RESULTS AND DISCUSSION: After excluding one study as an outlier, the null GSTM1 genotype was associated with an increased risk of ATLI (OR = 1.270, 95% CI (1.014-1.590, P = .038), especially in East Asians (OR = 1.501, 95% CI (1.303-1.730). With similar exclusion, the null GSTT1 genotype increased the risk of ATLI in the total population (OR = 1.169, 95% CI: 1.028-1.330) and in Indians (OR = 1.732, 95% CI: 1.229-2.416). No statistically significant association was observed between the mutant GSTP1 genotype with risk of ATLI, which may need more rigorous and uniform case-control or cohort studies for more robust inferences. WHAT IS NEW AND CONCLUSION: This up-to-date meta-analysis strongly suggests associations of GSTM1 and GSTT1 polymorphisms with ATLI. The results show the increased risk of ATL1 with the null GSTM1 and GSTT1 genotype on ATLI development. No such association is shown with the mutant GSTP1 genotype.

Association of TLR8 and TLR9 polymorphisms with tuberculosis in a Chinese Han population: a case-control study.

BACKGROUND: Toll-like receptor (TLR) single nucleotide polymorphisms (SNPs) have been associated with regulation of TLR expression and development of active tuberculosis (TB). The objectives of this study were to determine whether TLR8 and TLR9 SNPs were associated with the development of latent TB infection (LTBI) and the subsequent pulmonary TB (PTB) in a Chinese Han population. METHODS: Two independent samples were enrolled. The first sample contained 584 TB cases and 608 controls; the second sample included 204 healthy controls, 201 LTBI subjects and 209 bacteria-confirmed active PTB patients. Three SNPs (rs3764880, rs187084 and rs5743836) were genotyped. The associations between the SNPs and risk of LTBI or PTB were investigated using unconditional logistic regression analysis. RESULTS: The A-allele of TLR8 rs3764880 SNP was protective against the development of TB in males (A vs G, OR = 0.58, 95%CI = 0.37-0.91). The AA genotype of rs3764880 SNP was found to increase the risk of PTB among females with an OR of 4.81 (1.11-20.85). The G allele of TLR9 SNP rs187084 was found to increase the risk of PTB (G vs A, P = 0.01, OR = 1.48, 95% CI = 1.10-2.00), the significance was also observed under dominant genetic models. The GA-genotype of TLR9 rs187084 SNP was found to increase the risk of PTB with an OR of 1.68 (1.07-2.65), but was found to decrease the risk of MTB infection with an OR = 0.64 (0.41-0.98). TLR9_rs5743836 SNP was excluded from the data analyses, because the minimum allele frequency was< 1%. CONCLUSIONS: Our findings in two independent samples indicated that SNPs in TLR8 and TLR9 were associated with the development of TB, and highlight that SNPs may have different effects on disease pathogenesis and progression.

2'-5'-Oligoadenylate synthetase 1 polymorphisms are associated with tuberculosis: a case-control study.

BACKGROUND: 2'-5'-Oligoadenylate synthetase 1 (OAS1) plays an important role in inflammatory immune reactions. OAS1 polymorphisms have been associated with increased susceptibility to various diseases. We investigated the association of polymorphisms in OAS1 with tuberculosis (TB). METHODS: A total of 1215 TB cases and 1114 healthy controls were enrolled from two independent studies. Genotyping was conducted using the improved multiplex ligase detection reaction (iMLDR) method. Associations between OAS1 polymorphisms (rs2240190, rs1131454, 10,774,671 and 11,066,453) and TB risk were established based on distributions of allelic frequencies using different genetic models. RESULTS: Significant association was observed between rs10774671, rs1131454 and TB. In the initial study, the G allele of rs10774671 was a significantly protective factor against TB (P = 0.006) and the genotype of GG differed significantly between TB patients and controls under the codominant model (P = 0.008) after Bonferroni correction. In the validation study, we also observed that the rs10774671 G allele (P = 0.001) and GG genotype (P = 0.001) were associated with TB. In addition, we found that the rs1131454 G allele (P = 0.004) and GG genotype (P = 0.001) were protective against TB in the Chinese Han population. CONCLUSIONS: We report novel associations of polymorphisms in OAS1 with TB in the Chinese Tibetan and Han populations. Similar studies in different populations and functional studies are warranted to confirm our results.

[Association of rs1495741 Single Nucleotide Polymorphism with Susceptibility of Anti-tuberculosis Drug-induced Hepatotoxicity].

OBJECTIVE: To investigate the potential association between the polymorphism of N- acetyltransferase 2 (NAT2) gene and anti-tuberculosis drug-induced hepatotoxicity (ATDH) in Han population. METHODS: The SNP rs1495741 was genotyped by using multiplex ligation detection reaction (MLDR) technique, and logistic regression analysis was used to analyze the association between this SNP and the susceptibility of ATDH. RESULTS: There were 247 PTB patients enrolled in this study, including 24 ATDH, and 223 controls (PTB without ATDH). No significant difference in genotype and allele distribution was observed for rs1495741 in NAT2 between the controls and ATDH group. After adjusting age, sex, body mass index (BMI) and smoking history, the SNP of rs1495741 showed a significant association with ATDH 〔odds ratio (OR)=2.728 (95% confidence interval: 1.022-7.281)〕 under recessive model (AA vs. GA+GG). CONCLUSIONS: The rs1495741 in NAT2 seems related to the development of ATDH among PTB patients, AA genotype of rs1495741 may be a causative factor for increased susceptibility to ATDH.

Rifampicin-induced antineutrophil cytoplasmic antibody-positive vasculitis: a case report and review of the literature.

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a pauci-immune necrotizing vasculitis that involves small vessels. Herein, we report an extremely rare case of rifampicin (RFP)-induced AAV. A 42-yearold female was transferred to the West China Hospital due to cough with phlegm for 3 months, fever for 1 month, and fatigue for 2 weeks. The patient was diagnosed with pulmonary tuberculosis (TB) and received anti-TB treatment with isoniazid, RFP, ethambutol, and pyrazinamide (PZA) at her local hospital. After 5 days of anti-TB treatment, her creatinine level rose to 420.2 µmol/L from a normal level prior to anti-TB treatment. Serum proteinase 3 (PR3)-ANCA was positive. After discontinuing the anti-TB drugs and administering protective renal treatment, her renal function improved, whereas PR3-ANCA remained positive. With RFP rechallenge after transfer to our hospital, the patient developed oliguria. Her urine volume increased gradually after RFP was discontinued 3 days later. Therefore, RFPinduced AAV was suspected. Eventually, the patient received prednisone and anti-TB therapy, including isoniazid, ethambutol, PZA, and moxifloxacin. After 2 months, PZA was discontinued. During 6 months of normal, and PR3-ANCA became negative at 4 months. This outcome is characteristic of RFP-induced AAV.