The diagnostic and prognostic role of myocardial injury biomarkers in hospitalized patients with COVID-19.

OBJECTIVE: The aim of this study was to systematically and comprehensively evaluate the diagnostic and prognostic value of myocardial injury biomarkers in COVID-19 patients. METHODS: This is a retrospective cohort study of confirmed COVID-19 patients that were admitted to the Renmin Hospital of Wuhan University from January 30, 2020 to February 15, 2020. RESULTS: Receiver operating characteristic (ROC) curve analysis demonstrated that cTnI-ultra had the highest area under the curve (AUC) at 0.855, with a sensitivity of 67.3% and a specificity of 88.7% for the prediction of in-hospital mortality. Patients with higher troponin I-ultra (cTnI-ultra), creatinine kinase-myocardial band (CK-MB), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were associated with higher mortality, compared to those who lower levels. The multivariable cox regression indicated that age (hazard ratio (HR) 3.450, 95% confidence interval (CI) 1.627-7.314, P = 0.001), coronary heart disease (HR 1.855, 95% CI 1.006-3.421; P = 0.048), elevated cTnI-ultra (HR 3.083, 95% CI 1.616-5.883, P = 0.001), elevated CK-MB (HR 2.907, 95% CI 1.233-6.854; P = 0.015), and elevated NT-proBNP (HR 5.776, 95% CI 2.272-14.682; P < 0.001) were associated with in-hospital mortality. CONCLUSIONS: cTnI-ultra might be the best predictor of in-hospital mortality among myocardial injury biomarkers. Elevated cTnI-ultra, CK-MB, and NT-proBNP were independent biomarkers of the mortality in COVID-19 patients.

Down-regulation of lincRNA-EPS regulates apoptosis and autophagy in BCG-infected RAW264.7 macrophages via JNK/MAPK signaling pathway.

Macrophages play a major role in the control and elimination of invading Mycobacterium tuberculosis (Mtb). Long intergenic noncoding RNA erythroid prosurvival (lincRNA-EPS) plays an important role in regulating various biologic processes in macrophages, including inflammatory responses, cell apoptosis, and autophagy. Whereas the effect of lincRNA-EPS in regulating the immune response of macrophages to Mtb is little studied. This study aimed to explore lincRNA-EPS expression in monocytes from patients with active pulmonary tuberculosis (PTB) and from healthy individuals. We also sought to investigate the effect of lincRNA-EPS on Bacillus Calmette-Guérin (BCG)-infected macrophages apoptosis and autophagy. Our study found that lincRNA-EPS expression was down-regulated in the monocytes from patients with active PTB compared with healthy individuals, accompanied by significant attenuated monocyte apoptosis and enhanced autophagy. In vitro, knockdown of lincRNA-EPS inhibited apoptosis and promoted autophagy in BCG-infected RAW264.7 macrophages. Moreover, we revealed that lincRNA-EPS regulated apoptosis and autophagy of BCG-infected RAW264.7 macrophages via JNK/MAPK signaling pathway. In conclusion, our findings demonstrated that knockdown of lincRNA-EPS inhibits apoptosis and enhances autophagy by activating the JNK/MAPK signaling pathway in BCG-infected RAW264.7 macrophages. Suggesting that lincRNA-EPS could serve as a new potential therapeutic target for PTB.

NRAMP1 D543N and INT4 polymorphisms in susceptibility to pulmonary tuberculosis: A meta-analysis.

The association of natural resistance associated macrophage protein 1 (NRAMP1) polymorphisms (D543N, INT4) with pulmonary tuberculosis (PTB) risk have been widely reported. However, the findings of previous studies were inconsistent. To clarify the role of these polymorphisms in PTB, we performed a meta-analysis of all available and relevant published studies. Based on comprehensive searches of the PubMed, Medline, Embase, Web of Science, Elsevier Science Direct and Cochrane Library database, we identified outcome data from all articles estimating the association between NRAMP1 polymorphisms and PTB risk. For D543NA/G polymorphism, no associations were found in all genetic models. For INT4C/G polymorphism, significant increased PTB risk was observed in recessive model (CC vs. GC+GG: P=0.025, OR=1.35, 95% CI=1.04-1.75). In the subgroup analysis by ethnicity, significantly increased risk were observed for D543NA/G polymorphism in Americans (GA vs. GG: P=0.03, OR=1.31, 95% CI=1.03-1.67; AA+AG vs. GG: P=0.032, OR=1.29, 95% CI=1.02-1.63). Moreover, the INT4C/G polymorphism was also associated with increased risk of TB for Africans in allele model (A vs. G: P=0.012, OR=1.41, 95% CI=1.08-1.85), heterozygous model (GA vs. GG: P=0.004, OR=1.53, 95% CI=1.14-2.04) and dominant model (AA+AG vs. GG: P=0.007, OR=1.49, 95% CI=1.12-1.98). This meta-analysis provides evidences that INT4C/G was associated with increased susceptibility to pulmonary tuberculosis in overall population in recessive model. D543NA/G polymorphism was associated with PTB increased risk in Americans, while INT4C/G polymorphism in Africans. Further well-designed, large scale studies are required to confirm this conclusion.

IRGM gene polymorphisms and haplotypes associate with susceptibility of pulmonary tuberculosis in Chinese Hubei Han population.

Human immunity-related GTPase M (IRGM) is found to play an important role in defense against intracellular pathogen Mycobacterium tuberculosis (M. tuberculosis) in vitro by regulating autophagy. The objective of the study was to determine the association between IRGM polymorphisms and susceptibility to pulmonary tuberculosis (PTB) in Chinese Hubei Han population. In this study, 237 PTB patients and 269 healthy controls were screened for IRGM promoter single nucleotide polymorphisms (SNPs) by gene sequencing, and an association study was performed. A luciferase assay was used to determine the transcriptional activity of the promoter polymorphism. The relative expression level of IRGM gene was measured by Real time Quantitative PCR (qRT-PCR). We identified 3 polymorphisms [-1208 (rs4958842), -1161 (rs4958843), and -947 (rs4958846)] in the IRGM promoter region. Our finding showed that the IRGM -947 CT genotype as well as CC genotype decreased the risk of PTB in comparison with TT genotype (OR = 0.216, 95% CI = 0.141-0.331,P < 0.001 and OR = 0.167, 95% CI = 0.088-0.318, P < 0.001,respectively). The -947C allele decreased the risk of PTB in comparison with T allele (OR = 0.266, 95% CI = 0.196-0.362, P < 0.001). There was linkage disequilibrium between these three IRGM SNPs and we further analyzed the haplotypes of these SNPs. Six haplotypes were identified and we found that the haplotype ACC played a protective role in the susceptibility to PTB. In contrast, the ACT haplotype was associated with an increased susceptibility to PTB. In addition, the ACT haplotype reduced the relative luciferase activity of IRGM promoter and decreased the expression of IRGM in PTB patients. Our findings indicated that IRGM functional polymorphisms and haplotypes in promoter were associated with the susceptibility to PTB in Chinese Hubei Han population.

The Fluorescence In Situ Hybridization for Diagnosis of Mycobacterium tuberculosis Complex in Sputum Samples.

BACKGROUND: Fluorescence In Situ Hybridization (FISH) assay has been a rapid, accurate and affordable method for detection of Mycobacterium tuberculosis complex (MTBC) in clinical isolates and lymph nodes of clinical samples. However, no performance data exist from sputum samples. The aim of this study was to develop the FISH assay for the simultaneous detection of MTBC in clinical isolates and sputum samples. DESIGN: We identified the optimum conditions for the detection of MTBC by FISH in culture isolates. Then this approach was applied to detect 542 sputum samples from PTB suspects. RESULTS: Among 542 cases, 45 (8.3%) had sputum samples that were positive for TB by BACTEC Mycobacteria Growth Indicator Tube 960 TB culture and the FISH technique. The sensitivity of the FISH assay was 97.1% for smear-positive samples and 36.4% for smear-negative samples compared with culture results, and according to clinical data, the sensitivity, specificity, and positive and negative predictive values of the FISH assay were 76.4%, 99.6%, 95.6%, and 97.6%, respectively, compared to 81.8%, 100%, 100%, and 98%, respectively, for culture and 63.6%, 98.6%, 83.3%, and 96%, respectively, for smears. Moreover, the estimated cost of FISH was only $3-$5 per test. CONCLUSION: The FISH assay is accurate and affordable method for the detection of MTBC and may be an alternative to fluorescent smear as an effective method for detecting MTBC.

Diagnosis of Drug Resistance to Fluoroquinolones, Amikacin, Capreomycin, Kanamycin and Ethambutol with Genotype MTBDRsl Assay: a Meta-Analysis.

BACKGROUND: The Genotype MTBDRsl is a new-generation PCR-based line-probe assay for rapid identification of the resistance to the second-line antituberculosis drugs with a single strip. The aim of this meta-analysis was to evaluate the performance of Genotype MTBDRsl in detecting drug resistance to fluoroquinolones, amikacin, capreomycin, kanamycin and ethambutol in comparison with the phenotypic drug susceptibility test. DESIGN: We searched Pubmed, Embase and the Cochrane Library and calculated the sensitivity, the specificity, the positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), corresponding 95% confidence interval (CI), and the area under the summary receiver operating characteristic (SROC) curves (AUC), and tested heterogeneity in accuracy estimates with the Spearman correlation coefficient and Chi-square. RESULTS: The summarized sensitivity (95% CI), specificity (95% CI), and AUC (standard error) were 0.869 (0.847-0.890), 0.973 (0.965-0.979) and 0.9690 (0.0188) for fluoroquinolones, 0.868 (0.829-0.900), 0.998 (0.994-0.999) and 0.9944 (0.0050) for amikacin, 0.879 (0.838-0.914), 0.970 (0.958-0.978) and 0.9791 (0.0120) for capreomycin, 0.501 (0.461-0.541), 0.991 (0.983-0.996) and 0.9814 (0.0114) for kanamycin and 0.686 (0.663-0.709), 0.871 (0.852-0.888) and 0.7349 (0.0639) for ethambutol, respectively. CONCLUSION: The genotype MTBDRsl demonstrate excellent accuracy for detecting drug resistance to fluoroquinolones, amikacin, and capreomycin, but it may not be an appropriate choice for detection of kanamycin and ethambutol.

IL-10 Polymorphisms and Tuberculosis Susceptibility: An Updated Meta-Analysis.

PURPOSE: The association of interleukin-10 (IL-10) polymorphisms (-1082G/A, -819C/T, -592A/C) and interleukin-6 (IL-6) poly-morphisms (-174G/C) with tuberculosis (TB) risk has been widely reported. However, the results are controversial. To clarify the role of these polymorphisms in TB, we performed a meta-analysis of all available and relevant published studies. MATERIALS AND METHODS: Based on comprehensive searches of the PubMed, Medline, Embase, Web of Science, Elsevier Science Direct and Cochrane Library database, we identified outcome data from all articles estimating the association between IL-10 and IL-6 polymorphisms and TB risk. RESULTS: The results indicated significant association of the allele model, heterozygous model and dominant model of IL-6 -174G/C polymorphism with decreased risk of TB. In the stratified analysis by ethnicity, significantly increased risk was observed for IL-10 -1082G/A polymorphism in Europeans under recessive model, for IL-10 -819C/T polymorphism in Asians under heterozygous model and dominant model and IL-10 -592A/C polymorphism in Asians under Allele model, homozygous model and recessive model. Moreover, significantly decreased risk of TB was associated with Asians for IL-6 -174C/G polymorphism in allele model, heterozygous model and dominant model. We also performed the analyses by sample types in IL-10 -1082G/A polymorphism, and observed significantly increased TB risk in mixed group under homozygous model. CONCLUSION: The results suggested that the IL-10 -1082G/A polymorphism is associated with increased TB risk in Europeans, while IL-10 -819C/T and IL-10 -592A/C polymorphisms in Asians. However, IL-6 -174G/C polymorphism might be a genetic risk factor that decreases TB susceptibility in Asians.

IL-1ß+3953C/T, -511T/C and IL-6 -174C/G polymorphisms in association with tuberculosis susceptibility: A meta-analysis.

BACKGROUND: Studies of the association between the interleukin-1ß gene (IL-1ß) (+3953C/T, -511T/C) and interleukin-6 gene (IL-6) (-174G/C) polymorphisms and susceptibility to tuberculosis (TB) have yielded inconsistent results. The aim of this study was to investigate the relationship between these polymorphisms and TB risk by this meta-analysis. METHODS: We systematically searched published literatures on IL-1ß gene and IL-6 gene polymorphisms and tuberculosis risk by the PubMed, Medline, Embase, Web of Science, Elsevier Science Direct and Cochrane Library databases, and identified outcome data from all articles. Statistical analysis was performed using Stata 12.0. A total of 15 studies comprising 3983TB patients and 3996 controls were included in the present study. RESULTS: We found that the IL-6 -174C/G polymorphism might be associated with decreased risk of TB (C vs. G: OR=0.77, 95% CI=0.64-0.91; CG vs. GG: OR=0.72, 95% CI=0.57-0.90; CC+CG vs. GG: OR=0.71, 95% CI=0.57-0.88). In the stratified analysis by ethnicity, significantly decreased risk were observed for IL-1ß -511T/C polymorphism in Africans (C allele vs. T allele: OR=0.86, 95% CI=0.74-0.99; CC vs. TT: OR=0.74, 95% CI=0.55-0.99). Moreover, the IL-6 -174 C/G polymorphism was also associated with decreased risk of TB in Asians (C vs. G: OR=0.71, 95% CI=0.54-0.93; CG vs. GG: OR=0.61, 95% CI=0.44-0.85; CC+CG vs. GG: OR=0.63, 95% CI=0.46-0.86). We also performed the analyses by sample types in IL-6 -174 C/G polymorphism, and significant decreased TB risk was observed in pulmonary tuberculosis group (C allele vs. G allele: OR=0.69, 95% CI=0.52-0.93; CG vs. GG: OR=0.69, 95% CI=0.52-0.91; CC+CG vs. GG: OR=0.71, 95% CI=0.55-0.93), and pulmonary tuberculosis plus extra-pulmonary tuberculosis mixed group (CC vs. GG: OR=0.44, 95% CI=0.22-0.88; CC vs. CG+GG: OR=0.48, 95% CI=0.25-0.94). CONCLUSIONS: This meta-analysis indicates that the IL-1ß -511T/C polymorphism is associated with TB decreased risk in Africans, and IL-6 -174C/G polymorphism in Asians. Further well-designed, large scale studies are required to confirm this conclusion.

Isoliquiritigenin, a flavonoid from licorice, blocks M2 macrophage polarization in colitis-associated tumorigenesis through downregulating PGE2 and IL-6.

M2 macrophage polarization is implicated in colorectal cancer development. Isoliquiritigenin (ISL), a flavonoid from licorice, has been reported to prevent azoxymethane (AOM) induced colon carcinogenesis in animal models. Here, in a mouse model of colitis-associated tumorigenesis induced by AOM/dextran sodium sulfate (DSS), we investigated the chemopreventive effects of ISL and its mechanisms of action. Mice were treated with AOM/DSS and randomized to receive either vehicle or ISL (3, 15 and 75 mg/kg). Tumor load, histology, immunohistochemistry, and gene and protein expressions were determined. Intragastric administration of ISL for 12 weeks significantly decreased colon cancer incidence, multiplicity and tumor size by 60%, 55.4% and 42.6%, respectively. Moreover, ISL inhibited M2 macrophage polarization. Such changes were accompanied by downregulation of PGE2 and IL-6 signaling. Importantly, depletion of macrophages by clodronate (Clod) or zoledronic acid (ZA) reversed the effects of ISL. In parallel, in vitro studies also demonstrated that ISL limited the M2 polarization of RAW264.7 cells and mouse peritoneal macrophages with concomitant inactivation of PGE2/PPARδ and IL-6/STAT3 signaling. Conversely, exogenous addition of PGE2 or IL-6, or overexpression of constitutively active STAT3 reversed ISL-mediated inhibition of M2 macrophage polarization. In summary, dietary flavonoid ISL effectively inhibits colitis-associated tumorigenesis through hampering M2 macrophage polarization mediated by the interplay between PGE2 and IL-6. Thus, inhibition of M2 macrophage polarization is likely to represent a promising strategy for chemoprevention of colorectal cancer.

Rapid and effective diagnosis of pulmonary tuberculosis with novel and sensitive loop-mediated isothermal amplification (LAMP) assay in clinical samples: a meta-analysis.

In recent years, Loop-mediated isothermal amplification (LAMP) assay has been introduced for the diagnosis of pulmonary tuberculosis (TB). We performed the meta-analysis to establish the overall accuracy of LAMP assay for diagnosing pulmonary TB. Based on comprehensive searches of the pubmed, embase and cochrane databases, we identified outcome datas from all articles estimating diagnostic accuracy with LAMP assay until 1 October 2012. A summary estimation for sensitivity, specificity, diagnostic odds ratios (DOR) and the area under the summary ROC curve (AUC) was calculated by using the bivariate random-effects approach. The meta-analysis included 10 studies (1920 suspected specimens). The summary estimate was 80.0% (95%CI, 78.0%-83.0%) for sensitivity, 96.0% (95%CI, 95.0%-97.0%) for specificity and 119.85/0.9633 for DOR/AUC in pulmonary TB. The findings in subgroup analysis were as follows: the accuracy of LAMP assay is higher in high quality level studies than moderate and low quality level studies. The pooled sensitivity for the diagnosis of pulmonary TB was 90.0% (95%CI, 86.0-93.0%) and 75.0% (95%CI, 71.0-78.0%) for high quality level studies and moderate combined low quality level studies, respectively, while the specificity was 99.0% (95%CI, 98.0-100.0%) and 91.0% (95%CI, 88.0-94.0%). Pulmonary TB can be rapidly and accurately diagnosed with LAMP assay.

Procalcitonin and C-reactive protein in the diagnosis and prediction of spontaneous bacterial peritonitis associated with chronic severe hepatitis B.

BACKGROUND: Procalcitonin (PCT), C-reactive protein (CRP), and white blood cells (WBCs) are inflammatory markers used to diagnose severe bacterial infections. We evaluated the diagnostic role of these markers and compared their accuracy for spontaneous bacterial peritonitis (SBP) associated with chronic severe hepatitis B (CSHB). METHODS: PCT and CRP concentrations, WBC count, and other hematological parameters were measured in serum from 84 well-characterized patients with CSHB, of whom 42 had SBP. Receiver operating characteristics (ROC) curve analysis was performed to assess the diagnostic accuracy. RESULTS: PCT and CRP concentrations were significantly higher in the CSHB patients with SBP (n=42) than CSHB patients without SBP (n=42). PCT and CRP concentrations were more accurate than WBC count for the diagnosis of CSHB-associated SBP. The optimal cutoff value of PCT was 0.48 ng/mL. The PCT concentration was significantly correlated with the CRP concentration and WBC count. CONCLUSIONS: Serum PCT and CRP seems to be better markers than WBC for the diagnosis of CSHB patients with SBP.