A large-scale surveillance revealed that KPC variants mediated ceftazidime-avibactam resistance in clinically isolated Klebsiella pneumoniae.

To monitor the resistance rate and gain a deeper understanding of the resistance mechanisms, we conducted over a 2-year surveillance focusing on the Klebsiella pneumoniae associated with the clinical usage of ceftazidime-avibactam (CZA) in a teaching hospital. A total of 4,641 K. pneumoniae isolates were screened to identify the CZA resistance through antimicrobial susceptibility testing. Comprehensive analyses, including homology analysis, conjugation experiments, clone assays, and whole genome sequencing, were furtherly performed on the CZA-resistant strains. In total, four CZA-resistant K. pneumoniae (CZA-R-Kp) strains were separated from four patients, in which three of them received CZA treatment during the hospitalization, accounting for a 4% (3/75) resistance development rate of K. pneumoniae under CZA stress. All CZA-R-Kp isolates were found to possess variants of blaKPC-2. The identified mutations included blaKPC-33, blaKPC-86, and a novel variant designated as blaKPC-129, all of which were located in the Ω loop of the KPC enzyme. These mutations were found to impact the amino acid sequence and spatial structure of the enzyme's active center, consequently affecting KPC carbapenemase activity. This study underscores the importance of active surveillance to monitor the emergence of resistance to CZA, highlighting the need for ongoing research to develop effective strategies for combating antimicrobial resistance. Understanding the mechanisms behind resistance is crucial in maintaining the efficacy of CZA, a vital tool in the battle against multidrug-resistant infections.IMPORTANCEAs an effective drug for the treatment of carbapenem-resistant Klebsiella pneumoniae, ceftazidime-avibactam (CZA) began to develop resistance in recent years and showed an increasing trend. In order to effectively monitor the resistance rate of CZA and understand its resistance mechanism, we monitored K. pneumoniae for more than 2 years to find CZA-resistant strains. Through comprehensive analysis of the selected CZA-resistant strains, it was found that all the CZA-resistant strains had mutation, which could affect the activity of KPC carbapenemase. This study highlights the importance of proactive surveillance to monitor the emergence of CZA resistance, which highlights the need for ongoing research to develop effective strategies to combat antimicrobial resistance. Understanding the mechanisms behind resistance is critical to maintaining the effectiveness of CZA, an important tool in the fight against multidrug-resistant infections.

Association between Diabetes Mellitus and Contrast-Associated Acute Kidney Injury: A Systematic Review and Meta-Analysis of 1.1 Million Contrast Exposure Patients.

BACKGROUND: Although diabetes mellitus (DM) has been a common risk factor of contrast-associated acute kidney injury (CA-AKI) for a long time, several current studies showed that DM is not an independent risk factor. Due to this diverse finding, we aim to conduct a systematic review assessing the effect of DM on CA-AKI. METHODS: We searched Ovid Medline, Embase, and Cochrane Database of Systematic Reviews (to June 1, 2020) for studies assessing the association between DM and CA-AKI. Random meta-analysis was performed to derive the pooled estimates of the adjusted odds ratio (OR) and corresponding 95% confidence intervals (CIs). RESULTS: A total of 84 studies involving 1,136,827 participants were included in this meta-analysis. The presence of DM was associated with an higher risk of CA-AKI (pooled OR: 1.58, 95% CI: 1.48-1.70, I2 = 64%). Furthermore, the predictive effect of elevated CA-AKI for was stronger in the subgroup of DM patients with chronic kidney disease (CKD) (OR: 2.33, 95% CI: 1.21-4.51), while the relationship between DM and CA-AKI was not significant in subgroup patients without CKD (OR: 1.12, 95% CI: 0.73-1.72). CONCLUSION: This is the first meta-analysis to prove that DM is an independent risk factor of CA-AKI in patients. While the predictive value of DM for CA-AKI in patients with normal kidney function was weakened, more protective treatments are needed in diabetic patients with kidney dysfunction to avoid the occurrence of CA-AKI.

MicroRNA-146a-5p enhances T helper 17 cell differentiation via decreasing a disintegrin and metalloprotease 17 level in primary sjögren's syndrome.

In clinical practice, we found that microRNA (miR)-146a-5p is significantly up-regulated in peripheral blood mononuclear cells (PBMCs) of primary sjögren's syndrome (pSS) patients. In vitro experiments confirmed that miR-146a-5p promotes T helper 17 (Th17) cell differentiation, but the specific mechanism is still unknown. To solve this problem, 20 pSS patients and 20 healthy subjects were enrolled in this study and PBMCs were isolated from their blood. The expression of the membrane IL-23 R (mIL-23 R) in PBMCs was determined. CD3+ T cells were also isolated and used to further analyze the relationship between the ectodomain shedding of mIL-23 R and a disintegrin and metalloprotease 17 (ADAM17). Finally, miR-146a-5p inhibitor and mimics were transfected into PBMCs to evaluate the relationship between ADAM17 and mIL-23 R, and explore the role of mIL-23 R and ADAM17 in Th17 cell differentiation. Our results revealed a significantly increased expression of miR-146a-5p in PBMCs from pSS patients and significantly increased percentage of Th17 cells compared to PBMCs from healthy controls. Under polarization culture conditions, pSS patient-derived PBMCs can more easily differentiate into Th17 cells, which was, to a great extent, attributable to the increased expression of mIL-23 R. Moreover, ADAM17, an ectodomain sheddase of mIL-23 R, was targeted and negatively regulated by miR-146a-5p, which reduced the ectodomain shedding of mIL-23 R. Overall, our results suggested that miR-146a-5p could promote Th17 cell differentiation through targeting and negatively regulating ADAM17. Thus, these results might offer a new approach in the treatment of pSS.

Risk factors for contrast-induced acute kidney injury (CI-AKI): protocol for systematic review and meta-analysis.

INTRODUCTION: Identifying the patients who are at risk for contrast-induced acute kidney injury (CI-AKI), which is defined as an increase in serum creatinine after exposure to contrast media, is a critical step in targeted prevention strategies. The absolute and relative importance of individual risk factors have not been systematically evaluated, let alone the new, controversial and modifiable risk factors of CI-AKI. METHODS AND ANALYSIS: On 1 July 2019, a search was performed on MEDLINE, Embase and the Cochrane Database of Systematic Reviews. We will perform a systematic review and meta-analysis to assess the important risk factors for developing CI-AKI, including those new, modifiable factors, which are considered controversial. The secondary endpoint will be all-cause mortality. Two authors will then independently screen studies that meet the criteria for inclusion, consulting with a third author to resolve any dispute. The quality of the included studies will be assessed according to the Newcastle-Ottawa scale. ETHICS AND DISSEMINATION: Ethics approval in this systematic review and meta-analysis protocol is not needed. We will disseminate the findings of this systematic review and meta-analysis via publications in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42019121534.

Glycogen Phosphorylase Isoenzyme Bb, Myoglobin and BNP in ANT-Induced Cardiotoxicity.

Anthracyline (ANT) has been demonstrated as a useful treatment for leukemia and solid tumors. However, ANT has previously reported cardiotoxic effects, which can reduce the therapeutic index for cancer treatment. This study aimed to investigate the associations of glycogen phosphorylase isoenzyme BB (GPBB), myoglobin (Mb), and brain natriuretic peptide (BNP) with anthracycline (ANT-induced cardiotoxicity (AIC)) amongst the Chinese population. Patients suffering from leukemia were recruited. Electrocardiogram and echocardiography were used along with chemotherapy to determine left ventricular ejection fraction (LVEF), mitral ratio of peak early to late diastolic filling velocity (E/A), E-wave deceleration time (EDT), and isovolumic relaxation time (IVRT). Double-antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA) was employed to examine and compare serum GPBB, Mb, and BNP levels. Following chemotherapy, the patients presented higher levels of serum GPBB, Mb, and BNP than before chemotherapy treatment. The levels of LVEF (%), E/A, and IVRT were significantly decreased after chemotherapy, while EDT was markedly increased. The cumulative ANT dose was positively corelated to serum GPBB, Mb, and BNP levels while it was negatively corelated to LVEF levels. In conclusion, serum GPBB, Mb, and BNP levels in combination might provide higher diagnostic accuracy in the early detection of AIC compared with other single indicators.

Promoter hypermethylation of MGMT gene may contribute to the pathogenesis of gastric cancer: A PRISMA-compliant meta-analysis.

BECKGROUND: The association of MGMT (O-methyguanine deoxyribonucleic acid methyltransferase) promoter hypermethylation with gastric cancer (GC) risk has been studied extensively, but the results remained unclear. Here, we performed a meta-analysis to evaluate whether promoter hypermethylation of the MGMT gene contributed to gastric pathogenesis. METHODS: Relevant studies were identified by retrieving the PubMed, Web of Science, Embase, and China National Knowledge Infrastructure (CNKI) databases. The Newcastle-Ottawa Scale was applied to assess methodological quality of the included studies. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to evaluate the association of MGMT promoter hypermethylation with gastric pathogenesis. Moreover, STATA 12.0 software was used to summarize the extracted data in this meta-analysis. RESULTS: Seventeen studies, comprising 1736 cases and 1291 controls, were included in this meta-analysis. The frequency of MGMT promoter hypermethylation in the GC group (32.97%) was significantly higher than those in the control group (18.00%) (OR = 2.83, CI = 1.93-4.15, P < .05). When stratified by cancer subtype, the results indicated that the frequency of MGMT promoter hypermethylation was significantly higher in gastric adenocarcinoma than in control group (OR = 3.47, CI = 1.06-11.35, P < .05). In addition, MGMT promoter hypermethylation significantly promoted distant metastasis and lymph node (LN) metastasis of gastric tumor (for distant metastasis, OR = 4.22, CI = 2.42-7.37, P < .05; for LN metastasis, OR = 1.56, CI = 1.14-2.13, P < .05). A significant association between MGMT promoter hypermethylation and TNM-stage was also found in the present meta-analysis (OR = 2.70, CI = 1.79-4.08, P < .05). CONCLUSION: The results of this meta-analysis suggested that MGMT gene-promoter hypermethylation was significantly associated with an increased risk of GC, especially in Asians. Furthermore, MGMT gene-promoter hypermethylation might be correlated with the distant metastasis and LN metastasis of GC.