Serum levels of IL-6/IL-10/GLDH may be early recognition markers of anti-tuberculosis drugs (ATB) -induced liver injury.

To explore the potential value of serum glutamate dehydrogenase (GLDH) combined with inflammatory cytokines as diagnostic biomarkers for anti-tuberculosis drug -induced liver injury (ATB-DILI). We collected the residual serum from the patients who met the criteria after liver function tests. We have examined these parameters including GLDH which were determined by enzyme-linked immunosorbent assay and cytokines which were determined by cytokine combination detection kit. Multivariate logistics stepwise forward regression was applied to establish regression models. A total of 138 tuberculosis patients were included in the diagnostic markers study of ATB-DILI, including normal liver function group (n = 108) and ATB-DILI group(n = 30). Serum GLDH, IL-6 and IL-10 levels were significantly increased in the ATB-DILI group. Receiver operating characteristic curve (ROC) curve showed that the area under curve (AUC) of serum GLDH, IL-6 and IL-10 for the diagnosis of ATB-DILI were 0.870, 0.714 and 0.811, respectively. In logistic regression modeling, the AUC of GLDH combined with IL-10 as an ATB-DILI marker is 0.912. Serum IL-6、IL-10 and GLDH levels began to rise preceded the increase in ALT by 7 days, with significant differences in IL-6 compared with 7 days. Serum GLDH, IL-6 and IL-10 levels were correlated with the severity of liver injury. In conclusion, we found that GLDH, IL-6 and IL-10 alone as diagnostic markers of ATB-DILI had good diagnostic efficacy. Logistic regression model established by GLDH and IL-10 had better diagnostic efficacy and IL-6 may be an early predictor of liver injury in the setting of ATB poisoning.

Glutamate dehydrogenase combined with ferrochelatase as a biomarker of liver injury induced by antituberculosis drugs.

AIMS: To explore the potential value of serum glutamate dehydrogenase (GLDH), ferrochelatase (FECH), heme oxygenase-1 (HO-1) and glutathione-S-transferase-α (GST-α) as diagnostic biomarkers for liver injury caused by antituberculosis drugs. METHODS: We established a rat model of isoniazide-induced liver injury and recruited 122 hospitalized tuberculosis patients taking antituberculosis drugs. We detected the concentration of GLDH, FECH, HO-1 and GST-α by enzyme-linked immunosorbent assay. GraphPad Prism8 and SPSS 26.0 were used for statistical analysis. RESULTS: In the rat model, serum GLDH concentration gradually increased during isoniazid (INH) administration, while serum FECH, HO-1 and GST-α concentrations significantly increased after INH administration was stopped. The receiver operating characteristic curve showed that the areas under the curve (AUCs) of serum GLDH and FECH for the diagnosis of anti-tuberculosis (TB) drug-induced liver injury (anti-TB-DILI) were 0.7692 (95% confidence interval [CI] 0.5442-0.9943) and 0.7284 (95% CI 0.4863-0.9705) and the diagnostic accuracies were 81.25% and 78.79%, respectively. In clinical research, the AUCs of GLDH and FECH were 0.9124 (95% CI 0.8380-0.9867) and 0.6634 (95% CI 0.5391-0.7877), and the optimal thresholds were 10.40 mIU/mL and 1.304 ng/mL, respectively. The diagnostic accuracy, specificity and positive predictive value (PPV) of GLDH were 82.61%, 79.38% and 47.22%. We performed a joint diagnostic test for GLDH and FECH. The diagnostic accuracy (90.43%), specificity (91.75%) and PPV (65.21%) of serial tests were better than for GLDH and FECH alone. CONCLUSIONS: GLDH in the diagnosis of liver injury induced by anti-TB drugs has high sensitivity, but low specificity and low PPV. The combination of GLDH and FECH could significantly improve the specificity, PPV and diagnostic accuracy, and reduce the false-positive rate of anti-TB-DILI.

The Risk of Adverse Effects of TNF-α Inhibitors in Patients With Rheumatoid Arthritis: A Network Meta-Analysis.

OBJECTIVES: To evaluate the safety of each anti-TNF therapy for patients with rheumatoid arthritis (RA) and then make the best choice in clinical practice. METHODS: We searched PUBMED, EMBASE, and the Cochrane Library. The deadline for retrieval is August 2021. The ORs, Confidence Intervals (CIs), and p values were calculated by STATA.16.0 software for assessment. RESULT: 72 RCTs involving 28332 subjects were included. AEs were more common with adalimumab combined disease-modifying anti-rheumatic drugs (DMARDs) compared with placebo (OR = 1.60, 95% CI: 1.06, 2.42), DMARDs (1.28, 95% CI: 1.08, 1.52), etanercept combined DMARDs (1.32, 95% CI: 1.03, 1.67); certolizumab combined DMARDs compared with placebo (1.63, 95% CI: 1.07, 2.46), DMARDs (1.30, 95% CI: 1.10, 1.54), etanercept combined DMARDs (1.34, 95% CI: 1.05, 1.70). In SAEs, comparisons between treatments showed adalimumab (0.20, 95% CI: 0.07, 0.59), etanercept combined DMARDs (0.39, 95% CI: 0.15, 0.96), golimumab (0.19, 95% CI: 0.05, 0.77), infliximab (0.15, 95% CI: 0.03,0.71) decreased the risk of SAEs compared with golimumab combined DMARDs. In infections, comparisons between treatments showed adalimumab combined DMARDs (0.59, 95% CI: 0.37, 0.95), etanercept (0.49, 95% CI: 0.28, 0.88), etanercept combined DMARDs (0.56, 95% CI: 0.35, 0.91), golimumab combined DMARDs (0.51, 95% CI: 0.31, 0.83) decreased the risk of infections compared with infliximab combined DMARDs. No evidence indicated that the use of TNF-α inhibitors influenced the risk of serious infections, malignant tumors. CONCLUSION: In conclusion, we regard etanercept monotherapy as the optimal choice for RA patients in clinical practice when the efficacy is similar. Conversely, certolizumab + DMARDs therapy is not recommended. SYSTEMATIC REVIEW REGISTRATION: identifier PROSPERO CRD42021276176.

Curcumin attenuates isoniazid-induced hepatotoxicity by upregulating the SIRT1/PGC-1α/NRF1 pathway.

As a serious infectious disease, tuberculosis threatens global public health. Isoniazid is the first-line drug not only in active tuberculosis but also in its prevention. Severe hepatotoxicity greatly limits its use. Curcumin, extracted from turmeric, has been found to relieve isoniazid-induced hepatotoxicity. However, the mechanism of isoniazid-induced hepatotoxicity and the protective effects of curcumin are not yet understood completely. We established both cell and animal models about isoniazid-induced hepatotoxicity and investigated the new mechanism of curcumin against isoniazid-induced liver injury. The experimental data in our study demonstrated that curcumin ameliorated isoniazid-mediated liver oxidative stress. The protective effects of curcumin were demonstrated and confirmed to be correlated with upregulating SIRT1/PGC-1α/NRF1 pathway. Western blot revealed that while inhibiting SIRT1 by the siRNA1 (a SIRT1 inhibitor), the expressions of SIRT1, PGC-1α/Ac-PGC-1α, and NRF1 decreased, and the protective effect that curcumin exerted on isoniazid-treated L-02 cells was significantly attenuated. Furthermore, curcumin improved liver functions and reduced necrosis of the isoniazid-treated BALB/c mice, accompanied by downregulating oxidative stress and inflammation in liver. Western blot revealed that curcumin treatment activates the SIRT1/PGC-1α/NRF1 pathway in the isoniazid-treated BALB/c mice. In conclusion, we found one mechanism of isoniazid-induced hepatotoxicity downregulating the SIRT1/PGC-1α/NRF1 pathway, and curcumin attenuated this hepatotoxicity by activating it. Our study provided a novel approach and mechanism for the treatment of isoniazid-induced hepatotoxicity.

Effect of Statins on the Risk of Different Stages of Prostate Cancer: A Meta-Analysis.

INTRODUCTION: The aim of this article was to investigate the relationship between statins and the risk of different stages or grades of prostate cancer. METHODS: A comprehensive literature search was performed for articles published until December 18, 2020, on the PubMed, Embase, and the Cochrane Library databases. The pooled relative risk (RR) and 95% confidence interval (CI) were then analyzed using the STATA.16.0 software. RESULTS: A total of 588,055 patients from 14 studies were included in the analysis. We found that the use of statins expressed a significant correlation with a lower risk of advanced prostate cancer (RR = 0.81, 95% CI: 0.73-0.91; RR = 0.86, 95% CI: 0.75-0.99, respectively). However, no evidence suggested that the use of statins was beneficial for the prevention of localized prostate cancer incidence. Similarly, the pooled results also revealed no association between the use of statins and the risk of high-grade and low-grade prostate cancer. CONCLUSION: It has been found that the use of statins is associated with a lower risk of advanced prostate cancer but was not related to the risk of localized, low-grade, or high-grade prostate cancer.

Serum biomarkers of isoniazid-induced liver injury: Aminotransferases are insufficient, and OPN, L-FABP and HMGB1 can be promising novel biomarkers.

Isoniazid (INH)-induced liver injury is a great challenge for tuberculosis treatment. Existing biomarkers cannot accurately determine the occurrence of this injury in the early stage. Therefore, developing early specific sensitive biomarkers of INH-induced liver injury is urgent. A rat model of liver injury was established with gastric infusion of INH or INH plus rifampicin (RFP). We examined seven potential novel serum biomarkers, namely, glutamate dehydrogenase (GLDH), liver-fatty acid-binding protein (L-FABP), high-mobility group box-1 (HMGB1), macrophage colony-stimulating factor receptor (MCSF1R), osteopontin (OPN), total cytokeratin 18 (K18), and caspase-cleaved cytokeratin-18 (ccK18), to evaluate their sensitivity and specificity on INH-induced liver injury. With the increase of drug dosage, combining with RFP and prolonging duration of administration, the liver injury was aggravated, showing as decreased weight of the rats, upgraded liver index and oxidative stress level, and histopathological changes of liver becoming marked. But the activity of serum aminotransferases decreased significantly. The area under the curve (AUC) of receiver-operating characteristic (ROC) curve of OPN, L-FABP, HMGB1, MCSF1R, and GLDH was 0.88, 0.87, 0.85, 0.71, and 0.70 (≥0.7), respectively, and 95% confidence interval of them did not include 0.5, with statistical significance, indicating their potential abilities to become biomarkers of INH-induced liver injury. In conclusion, we found traditional biomarkers ALT and AST were insufficient to discover the INH-induced liver injury accurately and OPN, L-FABP, and HMGB1 can be promising novel biomarkers.

Bamlanivimab plus etesevimab treatment have a better outcome against COVID-19: A meta-analysis.

Bamlanivimab is routinely used in the treatment of coronavirus disease 2019 (COVID-19) worldwide. We performed a meta-analysis to investigate the efficacy and safety of bamlanivimab treatment in patients with COVID-19. We searched articles from Web of Science, PubMed, Embase, the Cochrane Library, and medRxiv between January 30, 2020 and August 5, 2021. We selected randomized clinical trials (RCTs) and observational studies with a control group to assess the efficiency of bamlanivimab in treating patients with COVID-19. Our meta-analysis retrieved three RCTs and seven cohort studies including 14 461 patients. Bmlanivimab may help outpatients to prevent hospitalization or emergency department visits (RR 0.41, 95%CI 0.29-0.58), reduce ICU admission (RR 0.47, 95%CI 0.23-0.92), and mortality (RR 0.32, 95%CI 0.13-0.77) from the disease. The combination of bamlanivimab and etesevimab may have a greater potential for positive treatment outcomes. Bamlanivimab has demonstrated clinical efficacy on mild or moderate ill patients with COVID-19 to prevent hospitalization, reduce severity, and mortality from the disease. Combinations of bamlanivimab and etesevimab have a significant relative risk reduction for COVID-related hospitalization or death for patients than the monotherapy 700 mg group. Well-designed clinical trials to identify the clinical and biochemical characteristics in the COVID-19 patients' population that could benefit from bamlanivimab or plus etesevimab are warranted in the future.

Efficacy of IVIG (intravenous immunoglobulin) for corona virus disease 2019 (COVID-19): A meta-analysis.

BACKGROUND: The benefit of IVIG (Intravenous Immunoglobulin) therapy for COVID-19 remains controversial. We performed a meta-analysis to investigate the efficacy of IVIG treatment in patients with COVID-19. METHODS: We searched articles from Web of Science, PubMed, Embase, the Cochrane Library, MedRxiv between 1 January 2020 and February 17, 2021. We selected randomized clinical trials and observational studies with a control group to assess the efficiency of IVIG in treating patients with COVID-19. Subjects were divided into 'non-severe', 'severe' and 'critical' three subgroups based on the information of the study and the World Health Organization (WHO) definition of severity. We pooled the data of mortality and other outcomes using either a fixed-effect model or a random-effects model. RESULTS: Our meta-analysis retrieved 4 clinical trials and 3 cohort studies including 825 hospitalized patients. The severity of COVID-19 is associated with the efficiency of IVIG. In critical subgroup, IVIG could reduce the mortality compared with the control group [RR = 0.57 (0.42-0.79, I2 = 025%). But there was no significant difference in the severe or non-severe subgroups. CONCLUSION: IVIG has demonstrated clinical efficacy on critical ill patients with COVID-19. There may be a relationship between the efficacy of IVIG and the COVID-19 disease severity. Well-designed clinical trials to identify the clinical and biochemical characteristics in COVID-19 patients' population that could benefit from IVIG are warranted in the future.