The Impact of Optimal Glycemic Control on Tuberculosis Treatment Outcomes in Patients With Diabetes Mellitus: Systematic Review and Meta-Analysis.

BACKGROUND: Diabetes mellitus (DM) increases the risk of developing tuberculosis (TB), and optimal glycemic control has been shown to reduce the risk of complications and improve the TB treatment outcomes in patients with DM. OBJECTIVE: This study aims to investigate the role of glycemic control in improving TB treatment outcomes among patients with DM. METHODS: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials databases were searched for randomized controlled trials (RCTs) assessing the impact of oral glycemic control in patients with TB who have DM. Outcomes of interest were radiological findings, treatment success, sputum positivity, and mortality. Evaluations were reported as risk ratios (RRs) with 95% CIs using weighted random-effects models. RESULTS: The analysis included 6919 patients from 7 observational studies. Our meta-analysis showed significant differences between patients with optimal glycemic control and those with poor glycemic control with regard to improved treatment outcomes (RR 1.13, 95% CI 1.02-1.25; P=.02; I²=65%), reduced sputum positivity (RR 0.23, 95% CI 0.09-0.61; P=.003; I²=66%), and fewer cavitary lesions (RR 0.59, 95% CI 0.51-0.68; P<.001; I²=0%) in radiological findings. There was no significant difference between the 2 groups in terms of mortality (RR 0.57, 95% CI 0.22-1.49; P=.25; I²=0%), multilobar involvement (RR 0.57, 95% CI 0.22-1.49; P=.25; I²=0%) on radiologic examination, and upper lobe (RR 0.94, 95% CI 0.76-1.17; P=.58; I²=0%) and lower lobe (RR 1.05, 95% CI 0.48-2.30; P=.91; I²=75%) involvement on radiologic examination. CONCLUSIONS: We concluded that optimal glycemic control is crucial for reducing susceptibility, minimizing complications, and improving treatment outcomes in patients with TB with DM. Emphasizing effective health management and health care strategies are essential in achieving this control. Integrating comprehensive care among patients with TB with DM will enhance patient outcomes and alleviate the burden of disease in this population. TRIAL REGISTRATION: PROSPERO CRD42023427362; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=427362.

Construction of Metastasis-Specific Regulation Network in Ovarian Cancer Based on Prognostic Stemness-Related Signatures.

WE aimed to reveal the correlation between ovarian cancer (OV) metastasis and cancer stemness in OV. RNA-seq data and clinical information of 591 OV samples (551 without metastasis and 40 with metastasis) were obtained from TCGA. The edgeR method was used to determine differentially expressed genes (DEGs) and transcription factors (DETFs). Then, mRNA expression-based stemness index was calculated using one-class logistic regression (OCLR). Weighted gene co-expression network analysis (WGCNA) was used to define stemness-related genes (SRGs). Univariate and multivariate Cox proportional hazard regression were conducted to identify the prognostic SRGs (PSRGs). PSRGs, DETFs, and 50 hallmark pathways quantified by gene set variation analysis (GSVA) were integrated into Pearson co-expression analysis. Significant co-expression interactions were utilized to construct an OV metastasis-specific regulation network. Cell communication analysis was carried out based on single cell RNA sequencing data to explore the molecular regulation mechanism of OV. Eventually, assay for targeting accessible-chromatin with high throughout sequencing (ATAC), chromatin immunoprecipitation sequencing (ChIP-seq) validation, and multiple data sets were used to validate the expression levels and prognostic values of key stemness-related signatures. Moreover, connectivity map (CMap) was used to identify potential inhibitors of stemness-related signatures. Based on edgeR, WGCNA, and Cox proportional hazard regression, 22 PSRGs were defined to construct a prognostic prediction model for metastatic OV. In the metastasis-specific regulation network, key TF-PSRS interaction pair was NR4A1-EGR3 (correlation coefficient = 0.81, p < 0.05, positive), and key PSRG-hallmark pathway interaction pair was EGR3-TNFα signaling via NFκB (correlation coefficient = 0.44, p < 0.05, positive), which were validated in multi-omics databases. Thioridazine was postulated to be the most significant compound in treatment of OV metastasis. PSRGs played critical roles in OV metastasis. Specifically, EGR3 was the most significant PSRG, which was positively regulated by DETF NR4A1, inducing metastasis via TNFα signaling.

Identification and Validation of Ferroptosis-Related Subtypes and a Predictive Signature in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world with an immunosuppressive Tumor microenvironment (TME). Ferroptosis plays an essential role in tumor proliferation, invasion, and metastasis. However, the relationship between ferroptosis and TME of HCC has remained elusive. Methods: Differentially expressed ferroptosis-related genes (DE FRGs) between normal liver tissues and HCC tissues were obtained from The Cancer Genome Atlas (TCGA). On this basis, we identified the molecular subtypes mediated by DE FRGs and TME cell infiltration. Next, a predictive signature was established to quantity the ferroptosis-related characteristics by performing the least absolute shrinkage and selection operator Cox regression analyses. Univariate and multivariate COX analyses determined the independent prognostic factors. Finally, the expression stability of 3 ferroptosis-related signature genes was verified in cancer and paracancerous normal tissues of HCC. Results: We identified three different molecular subtypes and found that the subtype with the better prognosis was associated with high enrichment of immune- and metabolic-related hallmark signaling pathways and high infiltration of immune cells in TME. The signature was considered to be an independent prognostic factor. We also found that the signature can reflect the infiltration characteristics of different immune cells in TME. Immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), regulatory T cells, and type 17 T helper cells were significantly enriched in the high-risk group. The analysis data of immune checkpoints and tumor mutation load indicated that the signature had great potential in predicting Immunotherapy response and chemotherapeutic sensitivity. In addition, the overexpression of 3 ferroptosis-related signature genes was confirmed in HCC tissues and HCC cell lines. Ferroptosis inducer RSL3 inhibited the proliferation of HCC cells and was a potential cancer immunotherapy agent. Conclusion: These findings enhanced our understanding of the regulatory mechanism of ferroptosis in HCC and provided new insights into evaluating prognosis and developing more effective Immunotherapy and chemotherapy strategies.

Host-directed therapy against mycobacterium tuberculosis infections with diabetes mellitus.

Tuberculosis (TB) is caused by the bacterial pathogen Mycobacterium tuberculosis (MTB) and is one of the principal reasons for mortality and morbidity worldwide. Currently, recommended anti-tuberculosis drugs include isoniazid, rifampicin, ethambutol, and pyrazinamide. TB treatment is lengthy and inflicted with severe side-effects, including reduced patient compliance with treatment and promotion of drug-resistant strains. TB is also prone to other concomitant diseases such as diabetes and HIV. These drug-resistant and complex co-morbid characteristics increase the complexity of treating MTB. Host-directed therapy (HDT), which effectively eliminates MTB and minimizes inflammatory tissue damage, primarily by targeting the immune system, is currently an attractive complementary approach. The drugs used for HDT are repositioned drugs in actual clinical practice with relative safety and efficacy assurance. HDT is a potentially effective therapeutic intervention for the treatment of MTB and diabetic MTB, and can compensate for the shortcomings of current TB therapies, including the reduction of drug resistance and modulation of immune response. Here, we summarize the state-of-the-art roles and mechanisms of HDT in immune modulation and treatment of MTB, with a special focus on the role of HDT in diabetic MTB, to emphasize the potential of HDT in controlling MTB infection.

MAIT cells ameliorate liver fibrosis by enhancing the cytotoxicity of NK cells in cholestatic murine models.

BACKGROUND AND AIMS: Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that display a critical role in various liver diseases. However, the role of MAIT cells in cholestatic liver fibrogenesis remains obscure. Our study aims to assess the contribution of MAIT cells and underlying mechanisms during this process. METHODS: Cholestatic murine models using MAIT cell-deficient (MR1- /- ) and wild-type (WT) mice were established by feeding a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-enriched diet or bile duct ligation (BDL). Liver samples were collected to determine the severity of fibrosis. Lymphocytes of the liver were isolated for analysing the phenotype and function of MAIT cells. Cell co-culture experiments were performed to investigate the cross-talk between MAIT and NK cells. RESULTS: Liver MAIT cells were more activated with increased cytokines in cholestatic mice models than in control mice, although their frequency was decreased. MAIT cell deficiency led to severe liver inflammation and fibrosis with more activated HSCs in cholestatic mice. In addition, MR1- /- mice had an increased frequency of NK cells with higher expression of stimulatory receptors relative to WT mice. Paradoxically, activated MAIT cells significantly promoted the anti-fibrotic ability of NK cells by enhancing their cytotoxicity against HSCs in co-culture experiments. Importantly, this effect depended on direct cell-cell contact and TNF-α produced by MAIT cells. CONCLUSION: Our findings indicate that MAIT cells ameliorate cholestatic liver fibrosis by enhancing the cytotoxicity of NK cells against HSCs. An in-depth understanding of the MAIT cell-mediated regulatory effect will provide more valuable immunotherapy strategies to treat liver fibrosis.

Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-CoV-2: a prospective cohort study.

The aim of this study was to identify factors associated with the death of patients with COVID-19 pneumonia caused by the novel coronavirus SARS-CoV-2.All clinical and laboratory parameters were collected prospectively from a cohort of patients with COVID-19 pneumonia who were hospitalised to Wuhan Pulmonary Hospital (Wuhan City, Hubei Province, China) between 25 December 2019 and 7 February 2020. Univariate and multivariate logistic regression analysis revealed that age ≥65 years (OR 3.765, 95% CI 1.146­17.394; p=0.023), pre-existing concurrent cardiovascular or cerebrovascular diseases (OR 2.464, 95% CI 0.755­8.044; p=0.007), CD3+CD8+ T-cells ≤75 cells·µL−1 (OR 3.982, 95% CI 1.132­14.006; p<0.001) and cardiac troponin I ≥0.05 ng·mL−1 (OR 4.077, 95% CI 1.166­14.253; p<0.001) were associated with an increase in risk of mortality from COVID-19 pneumonia." has been corrected to: "Univariate and multivariate logistic regression analysis revealed that age ≥65 years (OR 3.765, 95% CI 1.201−11.803; p=0.023), pre-existing concurrent cardiovascular or cerebrovascular diseases (OR 2.464, 95% CI 1.279−4.747; p=0.007), CD3+CD8+ T-cells ≤75 cells·µL−1 (OR 3.982, 95% CI 1.761­9.004; p<0.001) and cardiac troponin I ≥0.05 ng·mL−1 (OR 4.077, 95% CI 1.778­9.349; p<0.001) were associated with an increase in risk of mortality from COVID-19 pneumonia. In a sex-, age- and comorbid illness-matched case-control study, CD3+CD8+ T-cells ≤75 cells·µL-1 and cardiac troponin I ≥0.05 ng·mL-1 remained as predictors for high mortality from COVID-19 pneumonia.We identified four risk factors: age ≥65 years, pre-existing concurrent cardiovascular or cerebrovascular diseases, CD3+CD8+ T-cells ≤75 cells·µL-1 and cardiac troponin I ≥0.05 ng·mL-1 The latter two factors, especially, were predictors for mortality of COVID-19 pneumonia patients.

Clinical and pharmacological hallmarks of rifapentine's use in diabetes patients with active and latent tuberculosis: do we know enough?

Rifapentine is a rifamycin derivate approved by the US Food and Drug Administration in 1998 for the treatment of active, drug-susceptible tuberculosis (TB). In 2014, rifapentine was approved for the treatment of latent TB infection in patients at high risk of progression to active disease and is currently under evaluation by the European Medicines Agency. Expanding indications of rifapentine largely affect diabetes patients, since about one-third of them harbor latent TB. Clinical consequences of rifapentine use in this population and potentially harmful interactions with hypoglycemic agents are widely underexplored and generally considered similar to the ones of rifampicin. Indeed, rifapentine too may decrease blood levels of many oral antidiabetics and compete with them for protein-binding sites and/or transporters. However, the two drugs differ in protein-binding degree, the magnitude of cytochrome P450 induction and auto-induction, the degree of renal elimination, and so on. Rifapentine seems to be more suitable for use in diabetes patients with renal impairment, owing to the fact that it does not cause renal toxicity, and it is eliminated via kidneys in smaller proportions than rifampicin. On the other hand, there are no data related to rifapentine use in patients >65 years, and hypoalbuminemia associated with diabetic kidney disease may affect a free fraction of rifapentine to a greater extent than that of rifampicin. Until more pharmacokinetic information and information on the safety of rifapentine use in diabetic patients and drug-drug interactions are available, diabetes in TB patients treated with rifapentine should be managed with insulin analogs, and glucose and rifapentine plasma levels should be closely monitored.

Diabetes and pulmonary tuberculosis: a global overview with special focus on the situation in Asian countries with high TB-DM burden.

BACKGROUND: The double burden of tuberculosis (TB) and diabetes mellitus (DM) is hitting certain Asian countries harder than other areas. In a global estimate, 15% of all TB cases could be attributable to DM, with 40% of those cases coming from India and China. Many other countries of South, East, and South-East Asia are of particular concern given their TB burdens, large projected increases in DM prevalence, and population size. OBJECTIVE: In this narrative review, we aimed to: (i) give an overall insight into the evidence on TB-DM epidemiology from high double burden Asian countries, (ii) present the evidence on bi-directional screening implementation in this region, (iii) discuss possible factors related to higher TB susceptibility of Asian diabetic patients, and (iv) identify TB-DM comorbidity treatment challenges. METHODS: The PubMed and Google Scholar databases were searched for all studies addressing DM/TB epidemiology, bi-directional screening and management in South, East and South-East Asia. RESULTS: We identified the DM prevalences among TB patients as ranging from approximately 5% to more than 50%, whereas TB prevalences among diabetic patients were 1.8-9.5 times higher than in the general population in developing Asian countries. Evidence from studies designed to address diagnosis and treatment of the dual disease in these critical regions is scarce as well as the evidence related to possible DM patients' genetic and acquired predisposition for TB. CONCLUSION: More prospective studies specifically designed to address adequate screening techniques, identify patients at risk, and define an adequate treatment of dual disease in this region are needed without delay.

Use of bedaquiline and delamanid in diabetes patients: clinical and pharmacological considerations.

Antituberculosis (anti-TB) treatment may be affected by both diabetes and hypoglycemic agents in patients with these 2 comorbidities. However, data supporting this conclusion relate only to standard anti-TB therapies. Sirturo® (bedaquiline) and Deltyba® (delamanid), novel drugs for multidrug-resistant tuberculosis (MDR-TB), are recommended for diabetes patients when another effective treatment regimen cannot be provided. Currently, there are no clinical data related to the use of these agents in diabetes patients. Possible alterations in the pharmacokinetics of these novel drugs induced by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy in diabetes patients, and possible drug-drug interactions with hypoglycemic agents, are of special interest, since the efficacy of bedaquiline and delamanid is concentration dependent. Moreover, it is of fundamental importance to avoid possible additive or synergistic effects of adverse drug reactions in this already vulnerable patient group. We reviewed clinical particularities related to the use of bedaquiline and delamanid in patients with type 1 and 2 diabetes mellitus (DM), as well as pharmacological aspects of the concurrent use of these agents with oral and injectable hypoglycemic agents. Bedaquiline shares liver metabolic pathways with several oral hypoglycemic agents, whereas delamanid may compete with several oral hypoglycemic agents and insulin analogs at protein-binding sites. Special concern exists regarding the use of bedaquiline and delamanid in diabetes patients aged >65 years and patients with severe renal or hepatic impairment or electrolyte disturbances. Concurrent use of bedaquiline and delamanid with insulin analogs, and other hypoglycemic agents that prolong the heart rate-corrected QT interval, such as sulfonylureas and glinides, may enhance this adverse reaction. Hepatic-related adverse reactions may develop more frequently when these drugs are combined with thiazolidinediones and acarbose. Data from Phase III and postmarketing studies are needed to elucidate the effect of DM and hypoglycemic agents on bedaquiline and delamanid effects in MDR-TB patients.

A fluorescent sensor to detect sodium dodecyl sulfate based on the glutathione-stabilized gold nanoclusters/poly diallyldimethylammonium chloride system.

A simple method for the detection of sodium dodecyl sulfate (SDS) was developed based on glutathione-stabilized gold nanoclusters (GSH-AuNCs) and poly(diallyldimethylammonium)chloride (PDDA) enhanced fluorescent system. Fluorescent Au NCs were synthesized by a one-step approach employing GSH as reducing/protecting reagent. The electrostatic group repulsions between GSH-Au NCs and PDDA resulted in strong fluorescence enhancement from the GSH-Au NCs. Moreover, the addition of SDS was able to cause a significant fluorescence recovery due to the strong affinity of PDDA and SDS. Thus the SDS can be detected. Under optimized conditions, the linear response to detect SDS ranges from 0.2 to 12 µg mL(-1) with a detection limit of 0.02 µg mL(-1).

Electrochemiluminescence of a nanoAg-carbon nanodot composite and its application to detect sulfide ions.

This work presents the enhanced electrochemiluminescence (ECL) of a newly prepared nanosilver-carbon nanodot (Ag-C-dot) composite and its application for the sensitive detection of sulfide (S(2-)) ions. The Ag-C-dot composite was easily prepared by adding silver nitrate into C-dot colloids through an alkaline reduction. The obtained Ag-C-dots were characterized by UV-vis spectra, fluorescence spectra and transmission electron microscopy. The electrochemical and ECL behaviors of the Ag-C-dot composite were investigated by cyclic voltammetry. Moreover, a simple label-free method to detect S(2-) ions with a high selectivity and sensitivity has been developed based on the ECL of the Ag-C-dot composite in aqueous media. The sensing mechanism could be due to the strong and specific interaction between the S(2-) ions and the Ag atoms/ions on the surface of the Ag-C-dot composite, which dramatically affects the resulting ECL of the Ag-C-dot composite. The linear response to detect S(2-) ions ranges from 0.05 to 100 µM with a detection limit of 0.027 µM (~1 ppb). This work indicates that the Ag-C-dot nanocomposite possesses potential applications for environment sensing.