TCF1-LEF1 co-expression identifies a multipotent progenitor cell (TH2-MPP) across human allergic diseases.

Repetitive exposure to antigen in chronic infection and cancer drives T cell exhaustion, limiting adaptive immunity. In contrast, aberrant, sustained T cell responses can persist over decades in human allergic disease. To understand these divergent outcomes, we employed bioinformatic, immunophenotyping and functional approaches with human diseased tissues, identifying an abundant population of type 2 helper T (TH2) cells with co-expression of TCF7 and LEF1, and features of chronic activation. These cells, which we termed TH2-multipotent progenitors (TH2-MPP) could self-renew and differentiate into cytokine-producing effector cells, regulatory T (Treg) cells and follicular helper T (TFH) cells. Single-cell T-cell-receptor lineage tracing confirmed lineage relationships between TH2-MPP, TH2 effectors, Treg cells and TFH cells. TH2-MPP persisted despite in vivo IL-4 receptor blockade, while thymic stromal lymphopoietin (TSLP) drove selective expansion of progenitor cells and rendered them insensitive to glucocorticoid-induced apoptosis in vitro. Together, our data identify TH2-MPP as an aberrant T cell population with the potential to sustain type 2 inflammation and support the paradigm that chronic T cell responses can be coordinated over time by progenitor cells.

Early-life fecal metabolomics of food allergy.

BACKGROUND: Intestinal microenvironmental perturbations may increase food allergy risk. We hypothesize that children with clinical food allergy, those with food sensitization, and healthy children can be differentiated by intestinal metabolites in the first years of life. METHODS: In this ancillary analysis of the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we performed untargeted metabolomic profiling in 824 stool samples collected at ages 3-6 months, 1 year and 3 years. Subjects included 23 with clinical food allergy at age 3 and/or 6 years, 151 with food sensitization but no clinical food allergy, and 220 controls. We identified modules of correlated, functionally related metabolites and sought associations of metabolite modules and individual metabolites with food allergy/sensitization using regression models. RESULTS: Several modules of functionally related intestinal metabolites were reduced among subjects with food allergy, including bile acids at ages 3-6 months and 1 year, amino acids at age 3-6 months, steroid hormones at 1 year, and sphingolipids at age 3 years. One module primarily containing diacylglycerols was increased in those with food allergy at age 3-6 months. Fecal caffeine metabolites at age 3-6 months, likely derived from breast milk, were increased in those with food allergy and/or sensitization (beta = 5.9, 95% CI 1.0-10.8, p = .02) and were inversely correlated with fecal bile acids and bilirubin metabolites, though maternal plasma caffeine levels were not associated with food allergy and/or sensitization. CONCLUSIONS: Several classes of bioactive fecal metabolites are associated with food allergy and/or sensitization including bile acids, steroid hormones, sphingolipids, and caffeine metabolites.

Clinlabomics: leveraging clinical laboratory data by data mining strategies.

The recent global focus on big data in medicine has been associated with the rise of artificial intelligence (AI) in diagnosis and decision-making following recent advances in computer technology. Up to now, AI has been applied to various aspects of medicine, including disease diagnosis, surveillance, treatment, predicting future risk, targeted interventions and understanding of the disease. There have been plenty of successful examples in medicine of using big data, such as radiology and pathology, ophthalmology cardiology and surgery. Combining medicine and AI has become a powerful tool to change health care, and even to change the nature of disease screening in clinical diagnosis. As all we know, clinical laboratories produce large amounts of testing data every day and the clinical laboratory data combined with AI may establish a new diagnosis and treatment has attracted wide attention. At present, a new concept of radiomics has been created for imaging data combined with AI, but a new definition of clinical laboratory data combined with AI has lacked so that many studies in this field cannot be accurately classified. Therefore, we propose a new concept of clinical laboratory omics (Clinlabomics) by combining clinical laboratory medicine and AI. Clinlabomics can use high-throughput methods to extract large amounts of feature data from blood, body fluids, secretions, excreta, and cast clinical laboratory test data. Then using the data statistics, machine learning, and other methods to read more undiscovered information. In this review, we have summarized the application of clinical laboratory data combined with AI in medical fields. Undeniable, the application of Clinlabomics is a method that can assist many fields of medicine but still requires further validation in a multi-center environment and laboratory.

Differences in the Distribution of Species, Carbapenemases, Sequence Types, Antimicrobial Heteroresistance and Mortality Rates Between Pediatric and Adult Carbapenemase-Producing Enterobacterales in Bloodstream Infections.

The dissemination of carbapenemase-producing Enterobacterales (CPE) is worrisome given their scarce treatment options. CPE bloodstream infections (BSIs) had a high mortality rate in adults, and there was little data on pediatric CPE-BSIs around the world. We comprehensively explored the differences in the clinical and microbiological characteristics between pediatric and adult CPE-BSIs. Forty-eight pediatric and 78 adult CPE-BSIs cases were collected. All-cause 30 day-mortality in children with CPE-BSIs (14.6%, 7/48) was significantly lower than that in adult patients (42.3%, 33/78, p = 0.001). The subgroup in adults empirically treated with tigecycline as an active drug displayed a significantly higher 30-days crude mortality (63.3%, 19/30) than the subgroup treated without tigecycline (29.2%, 14/48, p = 0.003). K. pneumoniae was the most prevalent species in both the pediatric (45.8%, 22/48) and adult populations (64.1%, 50/78), with discrepant carbapenemase genes in each population: 95.4% (21/22) of the pediatric K. pneumoniae isolates carried bla NDM, while 82.0% (41/50) of the adult strains harbored bla KPC. The ratio of E. coli in children (37.5%) was significantly higher than that in adults (12.8%, p = 0.002). In both populations, the majority of E. coli expressed bla NDM, particularly bla NDM-5. With statistical significance, bla NDM was much more common in children (95.8%, 46/48) than in adults (34.6%, 27/78). The rate of multiple-heteroresistance phenotypes in children was as high as 87.5%, which was much lower in adults (57.1%). Agar dilution checkboard experiment against one pediatric carbapenemase-producing E. coli isolates showed that the combination of amikacin and fosfomycin yielded an additive effect. Overall, K. pneumoniae was the most common CPE-BSIs pathogen in both populations, with NDM-producing K. pneumoniae and KPC-producing ST11 K. pneumoniae being the most prevalent species in children and adults, respectively. E. coli was more prevalent in children than in adults, yet bla NDM-5 was the most common carbapenem-resistant mechanism in E. coli in both populations. The wide range of multiple-heteroresistance combination traits found in different pathogen species from different host populations should provide a good foundation for future combination therapy design. Further investigations from more CPE isolates of various species are needed to evaluate the possible in vitro partial synergy of the amikacin and fosfomycin combination.

Clinical and Microbiological Characterization of Carbapenem-Resistant Enterobacteriales: A Prospective Cohort Study.

Aim: We aim to depict the clinicoepidemiological and molecular information of carbapenem-resistant Enterobacteriales (CRE) in Chongqing, China. Methods: We performed a prospective, observational cohort study, recruiting inpatients diagnosed with CRE infections from June 1, 2018, to December 31, 2019. We carried out strain identification and molecular characterization of CRE. eBURST analysis was conducted to assess the relationships among the different isolates on the basis of their sequence types (STs) and associated epidemiological data using PHYLOViZ. Clinical parameters were compared between the carbapenemase-producing Enterobacteriales (CPE) and non-CPE group. Findings: 128 unique CRE isolates from 128 patients were collected during the study period: 69 (53.9%) CPE and 59 (46.1%) non-CPE. The majority of CPE isolates were bla KPC-2 (56.5%), followed by bla NDM (39.1%) and bla IMP (5.8%). Klebsiella pneumoniae carbapenemase (KPC)-producing clonal group 11 Klebsiella pneumoniae (K. pneumoniae) was the most common CPE. Antibiotic resistance was more frequent in the CPE group than in the non-CPE group. Independent predictors for CPE infection were ICU admission and hepatobiliary system diseases. Although, there was no significant difference in desirability of outcome ranking (DOOR) outcomes between the two groups. At 30 days after index culture, 35 (27.3% ) of these patients had died. Conclusion: CRE infections were related to high mortality and poor outcomes, regardless of CRE subgroups. CPE were associated with prolonged ICU stays and had different clinical and microbiological characteristics than non-CPE. The identification of CPE/non-CPE and CRE resistance mechanisms is essential for better guidance of the clinical administration of patients with CRE infections.

Efficacy of Intrawound Treatments to Prevent Surgical Site Infection after Spine Surgery: A Systematic Review and Network Meta-analysis.

BACKGROUND: Intrawound treatments have been reported to have favorable efficacy for preventing surgical site infection (SSI); however, the best strategy remains unknown. OBJECTIVE: The aim of this systematic review and network meta-analysis was to evaluate the efficacy of intrawound treatments to prevent SSI after spine surgery. STUDY DESIGN: A systematic review and network meta-analysis. METHODS: We searched the Cochrane Library, EMbase, PubMed, Chinese Science and Technology Periodical Database (VIP), China National Knowledge Infrastructure (CNKI), and Wanfang Data from the date of inception to March 2, 2020. The randomized controlled trials (RCTs) and cohort studies were identified and extracted by 2 reviewers independently. We performed a traditional pairwise meta-analysis to evaluate overall efficacy of intrawound treatments. Meanwhile, a network meta-analysis was performed to compare and rank the treatment efficacy using frequentist approach. RESULTS: Thirty-three publications (6 RCTs and 27 retrospective cohort studies) were included, involving 22,763 patients. For pairwise meta-analysis, the combined results showed that the intrawound treatment had a significantly lower SSI rate than the control group (CG) (odds ratio [OR] = 0.41; 95% confidence interval [CI], 0.31-0.55). For network meta-analysis, the treatment of vancomycin (VA) (OR = 0.53; 95% CI, 0.39-0.71), povidone-iodine (PI) (OR = 0.10; 95% CI, 0.04 - 0.23), and vancomycin + povidone-iodine (VA+PI) (OR = 0.25; 95% CI, 0.11-0.58) were found to be significantly more efficacious than CG on reduction of SSI rate. PI ranked first on reducing SSI, followed by PI+HP, VA+PI, gentamicin (GM), VA, and hydrogen peroxide (HP); CG ranked last. LIMITATIONS: Firstly, only 6 RCTs are included in this systematic review. Retrospective cohort studies tend to exaggerate the real results, although most of them are high-quality according to the Newcastle-Ottawa Quality Assessment Scale (NOQAS). More high-quality RCTs need to be included to obtain convincing conclusions. Secondly, the population of this study involves both adult and pediatric cohorts, patients with tumor, congenital disease, or degenerative disease. There is no subgroup analysis for ages and type of diseases, which might have influence on the overall pooled analysis. Thirdly, we define the application of saline solution and no intrawound treatment as the control group, which might ignore their heterogeneity. Fourthly, follow-up periods are variable and the sample size of HP is small. Finally, additional research is needed to compare the complications of different treatments and the benefits of various dosages. CONCLUSION: We found that VA and PI show promising results on reducing SSI. PI is recommended as the most efficacious intrawound treatment to prevent SSI after spine surgery.

Emerging Threat of Multidrug Resistant Pathogens From Neonatal Sepsis.

Multidrug-resistant (MDR) pathogens are responsible for a substantial burden of morbidity and mortality from neonatal sepsis; however, data on these sepsis-related pathogens among hospitalized neonates in China are not well characterized. In this study, a total of 240 strains were isolated from four Women and Children's hospitals in Southwest China between 2014 and 2019. Of these included pathogens, 104 (43.33%) were gram-positive bacteria, 129 (53.75%) were gram-negative bacteria, and 7 (2.92%) were fungi. Escherichia coli (E. coli, 34.01%) and Klebsiella pneumoniae (K. pneumoniae, 15.35%) were the main pathogen of neonate bacteremia. ST167 were the most prevalent STs in E. coli and ST11 in K. pneumoniae. Our study found that E. coli (62.71%) was the predominate pathogen of early-onset sepsis, among which 64.86% were MDR. Late-onset sepsis was mainly caused by K. pneumoniae (28.31%) and E. coli (24.78%), with showing that 78.33% of these pathogens were MDR. Notably, the prevalence of EO/LO pathogens were quite different from Indian and south of China. Moreover, we found that blaCTX-M (42.06%) was most dominant resistant genes with about a third isolates (31.09%) were positive for blaCTX-M-15. All the carbapenem-resistant K. pneumoniae were positive for NDM-1. Moreover, late-onset sepsis and antibiotic exposure were significantly associated with MDR infection. Emerging multi-resistant pathogens of sepsis posts a serious threat to neonatal outcomes and emphasizes an urgent need to control their further spread.

Design of Rapid Detection System for Five Major Carbapenemase Families (bla KPC, bla NDM, bla VIM, bla IMP and bla OXA-48-Like) by Colorimetric Loop-Mediated Isothermal Amplification.

PURPOSE: Carbapenemase-producing Enterobacteriaceae (CPE) infection constitutes a public health threat. Timely and efficient diagnosis is of paramount importance for prompt and effective therapy. In order to quickly and comprehensively detect the five major families of carbapenemases (bla KPC, bla NDM, bla VIM, bla IMP, and bla OXA-48-like), colorimetric loop-mediated isothermal amplification (LAMP) was employed. MATERIALS AND METHODS: Five sets of LAMP primers were designed, each of which can, respectively, amplify all the carbapenemase subtypes described in this work. Twenty whole genome sequencing-verified-"standard strains", including 1 bla NDM-1, 1 bla NDM-5, 1 bla NDM-6, 1 bla NDM-7, 2 bla IMP-4, 1 bla IMP-8, 2 bla KPC-2, 1 bla KPC-3, 1 bla KPC-4, 1 bla KPC-5, 1 bla KPC-6, 1 bla KPC-7, 1 bla OXA-48 and 1 bla OXA-181 carrier, and 1 bla VIM and bla OXA-244, 1 bla KPC-2 and bla IMP-4, 1 bla KPC-2 and bla VIM-1 and 1 bla KPC-2 and bla NDM-1-co-carriers, were used to establish a 25-microliter visual LAMP reaction system (kept at 65°C for 30 minutes in water bath). Color change from bright pink to yellow indicated positive amplification. In addition, 126 pre-verified clinical carbapenem-resistant Enterobacteriaceae (CRE) isolates, including 65 CPE (23 bla NDM, 2 bla OXA-48-like, 1 bla KPC and bla VIM, 2 bla IMP, and 37 bla KPC carriers) and 61 non-CPE, were also detected. RESULTS: With the lowest detection limit of 10 colony forming units (CFU) per reaction for LAMP and 103 CFU per reaction for PCR, the LAMP system demonstrated dramatically higher sensitivity while retaining the same specificity. Furthermore, we demonstrated concordant results between the two methods for the 126 clinical isolates. CONCLUSION: Therefore, LAMP could be used for rapid identification of the five major carbapenemase gene families in routine clinical laboratories.

Myelin basic protein enhances axonal regeneration from neural progenitor cells.

INTRODUCTION: Stem cell therapy using neural progenitor cells (NPCs) shows promise in mitigating the debilitating effects of spinal cord injury (SCI). Notably, myelin stimulates axonal regeneration from mammalian NPCs. This led us to hypothesize that myelin-associated proteins may contribute to axonal regeneration from NPCs. METHODS: We conducted an R-based bioinformatics analysis to identify key gene(s) that may participate in myelin-associated axonal regeneration from murine NPCs, which identified the serine protease myelin basic protein (Mbp). We employed E12 murine NPCs, E14 rat NPCs, and human iPSC-derived Day 1 NPCs (D1 hNPCs) with or without CRISPR/Cas9-mediated Mbp knockout in combination with rescue L1-70 overexpression, constitutively-active VP16-PPARγ2, or the PPARγ agonist ciglitazone. A murine dorsal column crush model of SCI utilizing porous collagen-based scaffolding (PCS)-seeded murine NPCs with or without stable Mbp overexpression was used to assess locomotive recovery and axonal regeneration in vivo. RESULTS: Myelin promotes axonal outgrowth from NPCs in an Mbp-dependent manner and that Mbp's stimulatory effects on NPC neurite outgrowth are mediated by Mbp's production of L1-70. Furthermore, we determined that Mbp/L1-70's stimulatory effects on NPC neurite outgrowth are mediated by PPARγ-based repression of neuron differentiation-associated gene expression and PPARγ-based Erk1/2 activation. In vivo, PCS-seeded murine NPCs stably overexpressing Mbp significantly enhanced locomotive recovery and axonal regeneration in post-SCI mice. CONCLUSIONS: We discovered that Mbp supports axonal regeneration from mammalian NPCs through the novel Mbp/L1cam/Pparγ signaling pathway. This study suggests that bioengineered, NPC-based interventions can promote axonal regeneration and functional recovery post-SCI.

Characteristics of pediatric multi-system inflammatory syndrome (PMIS) associated with COVID-19: a meta-analysis and insights into pathogenesis.

OBJECTIVES: There was an outbreak of pediatric multisystem inflammation syndrome (PMIS) was observed in multiple countries recently, and this syndrome was suspected to be associated with SARS-CoV-2 infection. At present, there is still no standardized diagnostic criteria and treatment regimen for PMIS, while the etiology and pathogenesis still remain unclear. METHODS: We performed a systematic review on PubMed and Embase from the time of inception to June 24th 2020 in order to find relevant cases. RESULTS: There are seven studies included, and 80% of patients suffered persistent fever and 90% appeared gastrointestinal symptoms. IgG antibody against SARS-CoV-2 was positive on 81% of patients, while 37% of the patients were nucleic acid positive. C-reactive protein, IL-6 and PCT were elevated and intravenous immunoglobulin was a routine treatment for PMIS. There were more than half of patients required inotropic supports and mechanical ventilation were applied to 33% of patients. The median length of hospital stay was 10.66 days and 74% had admitted to accept intensive care. CONCLUSIONS: Our study documented three common types of PMIS clinical presentation: persistent fever and gastrointestinal symptoms, shocked with heart dysfunction and Kawasaki disease-like syndrome. PMIS patients proved with a marked inflammatory state were possibly associated with SARS-CoV-2 infection.

Emergence of NDM-5-Producing Escherichia coli in a Teaching Hospital in Chongqing, China: IncF-Type Plasmids May Contribute to the Prevalence of bla NDM- 5.

The newly emerging NDM-5 confers increased antibiotic resistance and attracts extensive global attention, but the prevalence, dissemination mechanism, and clinical significance of NDM-5 among clinical Escherichia coli (E. coli) infections have not been thoroughly characterized to date. In the present study, 109 unique carbapenem-resistant E. coli (CR-EC) isolates were collected in Southwest China, from 2013 to 2017, among which 41 (37.61%) CR-EC isolates were identified as NDM-5-producers, with most isolates carrying the IncF-type plasmids. Molecular epidemiological studies revealed ST167 being the most common sequence type (ST). Moreover, we described the first report of a clinical CR-EC isolate co-harboring bla KPC- 2 and bla NDM- 5, which showed a higher level of resistance to carbapenems. In addition, bla NDM- 5 plasmid transformation and conjugation indicated that bla NDM- 5 itself did confer resistance to carbapenems. Complete sequencing of the bla NDM- 5-harboring IncF plasmid revealed highly conserved regions (ble MBL-trpF-tat) and some transposons around bla NDM- 5. Our findings revealed a new potential threat of NDM-5-postive CR-EC in mainland China and emphasized an urgent need to control their further spread.

Elevated Red Blood Cell Distribution Width as a Poor Prognostic Factor in Patients With Hematopoietic Stem Cell Transplantation.

Red cell distribution width (RDW), a measure of erythrocyte size variability, has been recently reported as an effective prognostic factor in critical illness. Hematopoietic stem cell transplantation (HSCT) has become the first choice of most patients with hematological malignancies. The aim of this study was to assess the changes of RDW in patients with HSCT and analyze the relationship between RDW and HSCT. In this study, we retrospectively enrolled 114 hematopoietic stem cell transplant patients during the period from 2015 to 2019. Logistic regression and Kaplan-Meier survival analysis were used for retrospective analysis. Multivariate analysis suggested that patients with elevated RDW (>14.5%) at three months post-transplantation have a poor clinical outcome compared with those with normal RDW ≤14.5% [odds ratio (OR) 5.12; P = 0.002]. Kaplan-Meier method analysis demonstrated that patients with elevated RDW levels (>14.5%) after hematopoietic stem cell transplantation experienced shorter progression-free survival compared to those with normal RDW levels (P = 0.008). Our study demonstrated that RDW could be an easily available and potential predictive biomarker for risk stratification in patients with HSCT. Further prospective studies are determined to confirm the prognostic value of RDW in HSCT patients.

Heteroresistance to cefepime in Pseudomonas aeruginosa bacteraemia.

INTRODUCTION: Heteroresistance to antibiotic agents can lead to diagnostic and therapeutic failures; however, to date, cefepime heteroresistance (FEP-HR) in Pseudomonas aeruginosa (P. aeruginosa) bacteraemia has not been characterised. The primary goal of this study was to investigate the molecular epidemiology, mechanisms and risk factors for cefepime-heteroresistant P. aeruginosa bacteraemia over approximately 6 years in Southwest China. RESULTS: A high prevalence (57.3%) of heteroresistance to cefepime was observed during the study period, and these FEP-HR isolates were not clonally related. Mechanistic studies revealed that AmpC hyperproduction contributed to the development of this phenomenon. In addition, patients with advanced age, haematological malignancies, central venous catheters, and previous cephalosporin therapy were identified as independent risk factors for acquiring FEP-HR P. aeruginosa bacteraemia. Furthermore, patients infected with FEP-HR were generally at a greater risk for an adverse prognosis compared with those with non-FEP-HR. More importantly, characterisation of three successive P. aeruginosa isolates recovered from the same patient revealed that heteroresistance can act as an intermediate stage during the evolution from susceptibility to full resistance in patients undergoing antibiotic therapy for prolonged periods. CONCLUSION: These findings emphasised the necessity of antimicrobial stewardship programs in clinical settings, as well as the need for some rapid screening methods for detecting this phenomenon.

Niacin analogue, 6-Aminonicotinamide, a novel inhibitor of hepatitis B virus replication and HBsAg production.

BACKGROUND: Hepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained seroconversion of HBsAg is an indicator for functional cure. However, the level of HBsAg could not be reduced by interferons and nucleoside analogs effectively. Therefore, identification of a new drug targeting HBsAg is urgently needed. METHODS: In this study, 6-AN was screened out from 1500 compounds due to its low cytotoxicity and high antiviral activity. The effect of 6-AN on HBV was examined in HepAD38, HepG2-NTCP and PHHs cells. In addition, the antivirus effect of 6-AN was also identified in mouse model. FINDINGS: 6-AN treatment resulted in a significant decrease of HBsAg and other viral markers both in vitro and in vivo. Furthermore, we found that 6-AN inhibited the activities of HBV SpI, SpII and core promoter by decreasing transcription factor PPARα, subsequently reduced HBV RNAs transcription and HBsAg production. INTERPRETATION: We have identified a novel small molecule to inhibit HBV core DNA, HBV RNAs, HBsAg production, as well as cccDNA to a minor degree both in vitro and in vivo. This study may shed light on the development of a novel class of anti-HBV agent.

Risk factors with the development of infection with tigecycline- and carbapenem-resistant Enterobacter cloacae.

BACKGROUND: Tigecycline is regarded as a last resort treatment for carbapenem-resistant Enterobacter cloacae (CREC) infections, and increasing numbers of tigecycline- and carbapenem-resistant E. cloacae (TCREC) isolates have been reported in recent years. However, risk factors and clinical impacts of these isolates are poorly characterized. PATIENTS AND METHODS: We conducted a retrospective case-case-control study of hospitalized patients with TCREC infection during the period 2012-2016 in Chongqing, China. Case patients with TCREC and those with CREC were compared to a control group with no E. cloacae infection. Multivariate logistic regression models were used to identify independent risk factors for acquiring TCREC and CREC. RESULTS: A total of 36 TCREC cases, 36 CREC cases, and 100 controls were enrolled in our study. Multivariable analysis indicated that nasal catheter (OR: 8.9; 95% CI: 1.1-75.2), exposure to penicillin (OR: 95.9; 95% CI: 8.9-1038.3), aminoglycosides (OR: 42.1; 95% CI: 2.1-830.6), and fluoroquinolones (OR: 18.6; 95% CI: 1.9-185.6) were independent predictors for acquiring TCREC. In addition, venous catheterization (OR: 12.2; 95% CI: 2.5-58.5), penicillin (OR: 30.8; 95% CI: 7.9-120.0), and broad-spectrum cephalosporin (OR: 5.0; 95% CI: 1.5-17.3) were independently associated with CREC acquisition. CONCLUSION: Reasonable antibiotic stewardship programs and surveillance are necessary to control the tigecycline resistance among high-risk patients.

Detection and characterization of tigecycline heteroresistance in E. cloacae: clinical and microbiological findings.

Tigecycline is regarded as a last-resort treatment for carbapenem-resistant Enterobacteriaceae (CRE), however, the emergence of tigecycline heteroresistance has posted the therapeutic challenge to combat this "nightmare bacteria". The primary purpose of this study was to demonstrate the existence of tigecycline heteroresistance in carbapenem-resistant E. cloacae (TH-CRECL) and further to explore the epidemiological characteristics and underlying molecular mechanisms. Our study identified a relative low prevalence of carbapenem-resistant E. cloacae (CRECL) isolates, about 20.0% (28/140), as heteroresistance to tigecycline. Molecular genetic relatedness of these heteroresistant isolates were characterized epidemiologically sporadic. In addition, mechanistic analysis revealed that Phe-Arg-ß-naphthylamide (PAßN) significantly reversed tigecycline MIC levels of resistant colonies in heteroresistant strains, as primarily related to the marked overproduction of efflux pump genes acrAB and oqxAB, as well as overexpression of transcriptional regulators (soxS and ramA). Moreover, logistic regression analysis showed that previous fluoroquinolone therapy was identified as the only potential independent risk factor for the acquisition of TH-CRECL. Most importantly, our data indicated that patients with TH-CRECL infection might lead to a remarkably prolonged hospital stay and deterioration in functional status. These findings emphasized the necessity of timely detection and intervention of patients infected with TH-CRECL.

PBK overexpression promotes metastasis of hepatocellular carcinoma via activating ETV4-uPAR signaling pathway.

Invasion and metastasis are the predominant causes of lethal outcomes in patients with hepatocellular carcinoma (HCC). However, the molecular mechanism underlying the invasive or metastatic process are still insufficiently understood. Here, we first integrated several public databases and identified a novel protein kinase, PDZ-binding kinase (PBK) that was frequently upregulated and correlated with poor prognosis in patients with HCC. Gain- or loss-of-function analysis revealed that PBK promoted migration and invasion of HCC cells both in vitro and in vivo. Mechanistically, PBK enhanced uPAR expression by activating its promoter activity. Chromatin immunoprecipitation (ChIP) assay showed that ETV4 directly bound to the core region of uPAR promoter while PBK could enhance the binding of ETV4 to uPAR promoter. In orthotopic mouse model, PBK knockdown markedly inhibited the lung metastasis of HCC cells, while this effect was significantly restored by uPAR overexpression. Finally, there was a positive correlation between PBK and uPAR, ETV4 and uPAR in HCC clinical samples. Collectively, these findings revealed that PBK acted as a crucial kinase by promoting invasion and migration via the ETV4-uPAR signaling pathway, and it therefore could be a promising diagnostic biomarker and therapeutic target for HCC metastasis.

Corrigendum: Carbapenem-Resistant E. cloacae in Southwest China: Molecular Analysis of Resistance and Risk Factors for Infections Caused by NDM-1-Producers.

[This corrects the article DOI: 10.3389/fmicb.2018.00658.].

Epidemiology of and risk factors for infection with extended-spectrum ß-lactamase-producing carbapenem-resistant Enterobacteriaceae: results of a double case-control study.

PURPOSE: Carbapenem-resistant Enterobacteriaceae (CRE) have been increasingly reported worldwide and pose a serious public threat, but the clinical significance of extended-spectrum ß-lactamase (ESBL) production in CRE is not well established. PATIENTS AND METHODS: A retrospective case-case-control study was conducted to identify the clinical characteristics of patients with ESBL-CRE. The susceptibility of isolates obtained from these patients was assessed. The detection of ESBL and carbapenemase-related genes was performed by PCR methods. Predictors of 30-day mortality in patients with ESBL-CRE infection were also identified in our study. RESULTS: A total of 149 patients with CRE infection caused by Enterobacter cloacae (n=74), Escherichia coli (n=38), and Klebsiella pneumoniae (n=37) were identified in Chongqing, Southwestern China, between January 2011 and December 2014. Of the 35 isolates detected with carbapenemase-related genes, 16 isolates had New Delhi metallo-ß-lactamase (NDM), nine isolates had K. pneumoniae carbapenemase (KPC), seven isolates had imipenemase (IMP), and four isolates had oxacillinase (OXA)-1. One strain of enterobacter cloacae carried both NDM-1 and IMP-8 genes. ESBL isolates included the genes CTX-M (72/149), SHV (64/149), and TEM (54/149). All ESBL-CRE isolates exhibited ertapenem resistance, and the rate of cephalosporin resistance was relatively high in general. Independent risk factors for infection with ESBL-CRE included previous exposure to ß-lactam antibiotics, transfer from another hospital, and some underlying diseases. In addition, solid tumors, hypoalbuminemia, and central venous catheters were independent predictors of mortality in patients with ESBL-CRE infection. CONCLUSION: Physicians should understand the peculiar predictors for the identification of these organisms among high-risk patients.