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Qianwen Chen,1,&ast; Qingqing Gu,1,&ast; Anwen Yin,2,&ast; Dabei Cai,1 Tingting Xiao,1 Yu Wang,1 Yuan Ji,1 Qingjie Wang,1 Jun Wei,3 Ling Sun1 1Department of Cardiology, the Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213000, People’s Republic of China; 2Department of Cardiology, the Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, People’s Republic of China; 3Department of Cardiovascular Surgery, the First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, 241000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qingjie Wang; Ling Sun, Department of Cardiology, the Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, 29 Xinglong Alley, Changzhou, Jiangsu, 213003, People’s Republic of China, Email wang-qingjie@hotmail.com; sunling85125@hotmail.comObjective: This study aimed to explore the association of preoperative neutrophil percentage (NEUT%) with the risk of acute kidney injury (AKI) in patients with acute myocardial infarction (AMI) having undergone coronary interventional therapy.Methods: A single-center, retrospective and observational study was conducted. From December 2012 to June 2021, patients with AMI were enrolled and divided into AKI group and non-AKI group. The NEUT% in the two groups was compared. The association between NEUT% with the risk of post-AMI AKI was analyzed by univariate and multivariable logistic regression. Kaplan-Meier survival curve was drawn to evaluate the prognostic ability of NEUT% for short-term all-cause death following AMI.Results: A total of 3001 consecutive patients were enrolled with an average age of 64.38 years. AKI occurred in 327 (10.9%) patients. The NEUT% was higher in the AKI group than in the non-AKI group ([76.65± 11.43]% versus [73.22± 11.83]%, P< 0.001). NEUT% was also identified as an independent risk factor for A

Ailin Zou,1,&ast; Tingting Xiao,1,&ast; Boyu Chi,1,2 Yu Wang,1 Lipeng Mao,1,2 Dabei Cai,1,2 Qingqing Gu,1 Qianwen Chen,1 Qingjie Wang,1 Yuan Ji,1 Ling Sun1,2 1Department of Cardiology, the Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu, People’s Republic of China; 2Changzhou Clinical Medical College, Dalian Medical University, Dalian, Liaoning, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ling Sun; Qingjie Wang, Department of Cardiology, the Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213003, People’s Republic of China, Email sunling85125@hotmail.com; wang-qingjie@hotmail.comBackground: Cardiac repair remains a thorny issue for survivors of acute myocardial infarction (AMI), due to the regenerative inertia of myocardial cells. Cell-free therapies, such as exosome transplantation, have become a potential strategy for myocardial injury. The aim of this study was to investigate the role of engineered exosomes in overexpressing Growth Differentiation Factor-15 (GDF-15) (GDF15-EVs) after myocardial injury, and their molecular mechanisms in cardiac repair.Methods: H9C2 cells were transfected with GDF-15 lentivirus or negative control. The exosomes secreted from H9C2 cells were collected and identified. The cellular apoptosis and autophagy of H2O2-injured H9C2 cells were assessed by Western blotting, TUNEL assay, electron microscopy, CCK-8 and caspase 3/7 assay. A rat model of AMI was constructed by ligating the left anterior descending artery. The anti-apoptotic, pro-angiogenic effects of GDF15-EVs treatment, as well as ensuing functional and histological recovery were evaluated. Then, mRNA sequencing was performed to identify the differentially expressed mRNAs after GDF15-EVs treatment.Results: GDF15-EVs inhibited apoptosis and promoted autophagy in H2O2 injured H9C2 cells. GDF15-EVs effectively decrea

Locally administered drug delivery systems are promising as they allow to circumvent the side effects associated with systematic administration. In this study, we constructed multifunctional hydrogels by simply mixing commercial alginate (ALG) sols with glucose oxidase (GOx)-conjugated polyacrylic acid-stabilized iron oxide nanoparticles (GPI NPs) and Toll-like receptor 7/8 agonist resiquimod (R848). The injectable sols were able to transform into hydrogels (GPI/R848@ALG) by the ionic cross-linking between ALG and physiological Ca2+ to trap the therapeutic components within the hydrogel framework. Upon intratumoral injection, the hydrogels were employed for starvation therapy, promoted chemodynamic therapy and tumor-associated macrophages (TAMs) repolarization. The energy supply was blocked by consuming the intratumoral glucose via the GOx-catalyzed conversion of glucose into gluconic acid and hydrogen peroxide (H2O2). In vitro results showed that the generated H2O2 could be further converted into highly cytotoxic hydroxyl radicals (·HO) by the Fenton reaction to induce enhanced chemodynamic therapy. The TAMs repolarization studies in vitro exhibited that the GPI/R848@ALG hydrogels up-regulated the expression of CD86 by 63% and down-regulated the proportion of CD206 by 14% with a synergistic effect of the presence of Fe3O4 and R848, suggesting that the multifunctional hydrogels exert functions to direct the remodeling of TAMs from the tumor supportive M2-like phenotype to the tumor destructive M1-like phenotype to further contribute to the antitumor effect. Moreover, both in vitro and in vivo experiments demonstrate that the multifunctional hydrogels exhibit admirable antitumor performance towards 4T1 tumors. This work thereby provides a promising multifunctional nanoplatform for synergistic cancer starvation therapy, chemodynamic therapy and TAMs repolarization.

Locally administered drug delivery systems are promising as they allow to circumvent the side effects associated with systematic administration. In this study, we constructed multifunctional hydrogels by simply mixing commercial alginate (ALG) sols with glucose oxidase (GOx)-conjugated polyacrylic acid-stabilized iron oxide nanoparticles (GPI NPs) and Toll-like receptor 7/8 agonist resiquimod (R848). The injectable sols were able to transform into hydrogels (GPI/R848@ALG) by the ionic cross-linking between ALG and physiological Ca2+ to trap the therapeutic components within the hydrogel framework. Upon intratumoral injection, the hydrogels were employed for starvation therapy, promoted chemodynamic therapy and tumor-associated macrophages (TAMs) repolarization. The energy supply was blocked by consuming the intratumoral glucose via the GOx-catalyzed conversion of glucose into gluconic acid and hydrogen peroxide (H2O2). In vitro results showed that the generated H2O2 could be further converted into highly cytotoxic hydroxyl radicals (·HO) by the Fenton reaction to induce enhanced chemodynamic therapy. The TAMs repolarization studies in vitro exhibited that the GPI/R848@ALG hydrogels up-regulated the expression of CD86 by 63% and down-regulated the proportion of CD206 by 14% with a synergistic effect of the presence of Fe3O4 and R848, suggesting that the multifunctional hydrogels exert functions to direct the remodeling of TAMs from the tumor supportive M2-like phenotype to the tumor destructive M1-like phenotype to further contribute to the antitumor effect. Moreover, both in vitro and in vivo experiments demonstrate that the multifunctional hydrogels exhibit admirable antitumor performance towards 4T1 tumors. This work thereby provides a promising multifunctional nanoplatform for synergistic cancer starvation therapy, chemodynamic therapy and TAMs repolarization.

Sirui Song,1 Liqin Chen,1 Qianqian Ning,2 Danying Zhu,1 Feng Qiu,2 Guang Li,2 Hong Zhang,3 Tingting Xiao,1 Guohui Ding,4 Min Huang1 1Department of Cardiology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Shanghai Center for Bioinformation Technology, Shanghai, People’s Republic of China; 3Department of Laboratory, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 4International Human Phenome Institutes, Shanghai, 200235, People’s Republic of ChinaCorrespondence: Min Huang, Department of Cardiology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China, Email huangmin@sjtu.edu.cn; Guohui Ding, International Human Phenome Institutes, Shanghai, 200235, People’s Republic of China, Email dingguohui@ihup.org.cnPurpose: Kawasaki disease (KD) is an acute systemic vasculitis mainly found in the medium-sized arteries, especially the coronary arteries. Immune system is involved in the pathogenesis of acute KD in children, but the functional differences in the immune system between healthy children and KD patients remain unclear.Patients and Methods: A total of 190 KD patients and 119 healthy controls were recruited for the next-generation sequencing of 512 targeted genes from 4 immune-related pathways. Subsequently, the peripheral blood mononuclear cells (PBMCs) were isolated. RNA sequencing of the LPS treated PBMCs from additional 20 KD patients and 20 healthy controls was used to examine the differentially expressed genes (DEGs). Then, an expression quantitative trait locus (eQTL) analysis combined with previously analyzed RNA data were used to examine the DEGs. Finally, the serum levels of 13 cytokines were detected before and after LPS treatment in 40 samples to confirm the findings from eQTL analysis.Results: A total of 319 significant eQ

Yunying Zhu,&ast; Tingting Xiao,&ast; Yuan Wang, Kai Yang, Yanzi Zhou, Qixia Luo, Ping Shen, Yonghong Xiao State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yonghong XiaoState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, People’s Republic of ChinaTel/Fax +86 571 87236421Email xiaoyonghong@zju.edu.cnBackground: Although infection with carbapenem-resistant Enterobacteriaceae (CRE) has become an urgent public health threat worldwide, the socioeconomic burden of CRE bloodstream infection (BSI) remains to be clarified.Methods: This retrospective study included all patients infected with Escherichia coli or Klebsiella pneumoniae who were hospitalized for BSI from 2013 to 2015. Socioeconomic burden, including direct and indirect economic burden, was compared in patients infected with carbapenem-sensitive Enterobacteriaceae (CSE) and CRE following 1:1 propensity score matching (PSM) to control for confounding variables.Results: Data from 879 patients with Enterobacteriaceae BSI were evaluated, including 152 (17.3%) patients infected with CRE and 727 (82.7%) infected with CSE. PSM yielded 112 pairs of 224 patients. Median hospital length of stay did not differ significantly in the CRE and CSE groups (35 vs 29 days, P = 0.089), but in-hospital 28-day mortality rate was significantly higher in patients infected with CRE than with CSE (45.5% vs 32.1%, P = 0.040). Median direct economic burden was significantly greater in pati

QC 20200623

Multidrug-resistantKlebsiella pneumoniaeand hypervirulentK. pneumoniae(hvKP) have traditionally been considered two individual populations; however, strains displaying both phenotypes have emerged during the recent decade. Understanding the genotypic and phenotypic basis of the convergence could be of clinical importance. In this study, we aimed to evaluate the pathogenicity associated with different combinations of genotypes (i.e., sequence types, virulence factors, and capsular serotypes) and phenotypes (i.e., hypermucoviscosity and drug susceptibility) inK. pneumoniae.A total of 11K. pneumoniaeisolates causing bloodstream infections were included in the study, and they were assigned to seven STs (ST23, ST15, ST268, ST660, ST86, ST65, and ST1660) and carried various K-loci (KL1, KL2, KL16, KL20, and KL24). Hypermucoviscosity was observed for six isolates.bla(KPC-2)was detected in six carbapenem-resistant isolates, and the remaining ones were either multidrug-resistant or resistant to two types of antibiotics. Aerobactin- and yersiniabactin-encoding genes were detected in all isolates. AlthoughrmpA2was detected in all isolates, most contained frameshift mutations (82%). Genes encoding salmochelin, RmpA, and PEG344 were detected in seven isolates. Colibactin-encoding genes were carried by six isolates. Discrepancies among measured virulence inGalleria mellonellaand the serum-killing assay, and genotypes and phenotypes were detected. The results illustrate the complexity and difficulty with the current knowledge of hypervirulence to predict the phenotype by using genetic and phenotypic markers. Additionally, the emergence of carbapenem resistance in two isolates of KPC-2-producing hvKP of different sequence types emphasizes the urgency with which reliable clinical diagnostics for hvKP is needed., Funding Agencies|National Key Research and Development Program of China [2017YFC1200200]; Major Infectious Diseases such as AIDS and Viral Hepatitis Prevention and Control Technology Major Projects [2018ZX10712-001]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81702045, 81361138021]; Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (Formas)Swedish Research Council Formas [2016-00640]; Swedish Foundation for International Cooperation in Research and Higher Education (STINT) [CH2016-6707]; Shenzhen Basic Research Projects [JCYJ20190807144409307]

Multidrug-resistantKlebsiella pneumoniaeand hypervirulentK. pneumoniae(hvKP) have traditionally been considered two individual populations; however, strains displaying both phenotypes have emerged during the recent decade. Understanding the genotypic and phenotypic basis of the convergence could be of clinical importance. In this study, we aimed to evaluate the pathogenicity associated with different combinations of genotypes (i.e., sequence types, virulence factors, and capsular serotypes) and phenotypes (i.e., hypermucoviscosity and drug susceptibility) inK. pneumoniae.A total of 11K. pneumoniaeisolates causing bloodstream infections were included in the study, and they were assigned to seven STs (ST23, ST15, ST268, ST660, ST86, ST65, and ST1660) and carried various K-loci (KL1, KL2, KL16, KL20, and KL24). Hypermucoviscosity was observed for six isolates.bla(KPC-2)was detected in six carbapenem-resistant isolates, and the remaining ones were either multidrug-resistant or resistant to two types of antibiotics. Aerobactin- and yersiniabactin-encoding genes were detected in all isolates. AlthoughrmpA2was detected in all isolates, most contained frameshift mutations (82%). Genes encoding salmochelin, RmpA, and PEG344 were detected in seven isolates. Colibactin-encoding genes were carried by six isolates. Discrepancies among measured virulence inGalleria mellonellaand the serum-killing assay, and genotypes and phenotypes were detected. The results illustrate the complexity and difficulty with the current knowledge of hypervirulence to predict the phenotype by using genetic and phenotypic markers. Additionally, the emergence of carbapenem resistance in two isolates of KPC-2-producing hvKP of different sequence types emphasizes the urgency with which reliable clinical diagnostics for hvKP is needed., Funding Agencies|National Key Research and Development Program of China [2017YFC1200200]; Major Infectious Diseases such as AIDS and Viral Hepatitis Prevention and Control Technology Major Projects [2018ZX10712-001]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81702045, 81361138021]; Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (Formas)Swedish Research Council Formas [2016-00640]; Swedish Foundation for International Cooperation in Research and Higher Education (STINT) [CH2016-6707]; Shenzhen Basic Research Projects [JCYJ20190807144409307]

Multidrug-resistantKlebsiella pneumoniaeand hypervirulentK. pneumoniae(hvKP) have traditionally been considered two individual populations; however, strains displaying both phenotypes have emerged during the recent decade. Understanding the genotypic and phenotypic basis of the convergence could be of clinical importance. In this study, we aimed to evaluate the pathogenicity associated with different combinations of genotypes (i.e., sequence types, virulence factors, and capsular serotypes) and phenotypes (i.e., hypermucoviscosity and drug susceptibility) inK. pneumoniae.A total of 11K. pneumoniaeisolates causing bloodstream infections were included in the study, and they were assigned to seven STs (ST23, ST15, ST268, ST660, ST86, ST65, and ST1660) and carried various K-loci (KL1, KL2, KL16, KL20, and KL24). Hypermucoviscosity was observed for six isolates.bla(KPC-2)was detected in six carbapenem-resistant isolates, and the remaining ones were either multidrug-resistant or resistant to two types of antibiotics. Aerobactin- and yersiniabactin-encoding genes were detected in all isolates. AlthoughrmpA2was detected in all isolates, most contained frameshift mutations (82%). Genes encoding salmochelin, RmpA, and PEG344 were detected in seven isolates. Colibactin-encoding genes were carried by six isolates. Discrepancies among measured virulence inGalleria mellonellaand the serum-killing assay, and genotypes and phenotypes were detected. The results illustrate the complexity and difficulty with the current knowledge of hypervirulence to predict the phenotype by using genetic and phenotypic markers. Additionally, the emergence of carbapenem resistance in two isolates of KPC-2-producing hvKP of different sequence types emphasizes the urgency with which reliable clinical diagnostics for hvKP is needed., Funding Agencies|National Key Research and Development Program of China [2017YFC1200200]; Major Infectious Diseases such as AIDS and Viral Hepatitis Prevention and Control Technology Major Projects [2018ZX10712-001]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81702045, 81361138021]; Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (Formas)Swedish Research Council Formas [2016-00640]; Swedish Foundation for International Cooperation in Research and Higher Education (STINT) [CH2016-6707]; Shenzhen Basic Research Projects [JCYJ20190807144409307]

Yuan Wang,* Tingting Xiao,* Yunying Zhu, Jing Ye, Kai Yang, Qixia Luo, Ping Shen, Yonghong Xiao State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yonghong XiaoState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, People’s Republic of ChinaTel/Fax +86 571 87236421Email xiaoyonghong@zju.edu.cnBackground: The prevalence of infections with extended-spectrum β-lactamase-producing Escherichia coli (ESBL-EC) is increasing worldwide, but the economic impact of ESBL-EC bloodstream infection (BSI) has not been comprehensively evaluated.Patients and Methods: A retrospective cohort including patients hospitalized at a tertiary hospital between January 2013 and December 2016 who were confirmed with a BSI of ESBL-EC or non-ESBL-EC was set. Clinical data and medical costs were collected by chart review of electronic and paper medical records. The economic burden was evaluated with disability-adjusted life years (DALYs).Results: A total of 580 patients with E. coli BSI, comprising 333 patients (57.4%) with ESBL-EC BSI and 247 patients (42.6%) with non-ESBL-EC BSI, were identified. There were no significant differences in comorbidity and severity of patients between ESBL-EC and non-ESBL-EC BSI. The median length of stay (LOS) after bacteremia was 12 days for ESBL-EC (interquartile range, 7 to 21) versus 11 days for non-ESBL-EC (interquartile range, 7 to 21) (P = 0.38), and appropriate empirical antimicrobial therapy occurred i

Xiaohui Chi, 1, 2,* Jing Guo, 1,* Yanzi Zhou, 1 Tingting Xiao, 1 Hao Xu, 1 Tao Lv, 1 Chunlei Chen, 1 Jian Chen, 3 Beiwen Zheng 1 1Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2Department of Environment and Health, School of Public Health, Shandong University, Jinan, People’s Republic of China;  3Intensive Care Unit, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China*These authors contributed equally to this work.Correspondence: Beiwen Zheng; Jian Chen Tel/Fax +86-571-87236421; Tel +86-571-87236666Email zhengbw@zju.edu.cn; cjicu@zju.edu.cnBackground: Citrobacter freundii is the most common class of pathogens in the genus Citrobacter and is an important pathogen associated with certain underlying diseases or immune dysfunction. The aim of this study was to elucidate the resistance mechanism of clinically derived carbapenem-resistant C. freundii isolate and to characterize the genetic environment and delivery pattern of the IncN1 plasmid carrying the blaIMP-4 gene from C. freundii isolate.Materials and Methods: We identified a clinical isolate of C. freundii L91 carrying blaIMP-4 and performed phylogenetic analysis by whole-genome sequencing. The complete genomic sequence of L91 was obtained using the Illumina HiSeq 4000-PE150 and PacBio RS II platforms. Antimicrobial susceptibility testing was determined by the VITEK 2 system. Plasmid characteristics were presented by S1-pulsed-field gel electrophoresis (PFGE), Southern blotting and conjugation experiments.Results: S1-PFGE, Southern blot and conjugation assay confirmed the presence of blaIMP-4 genes on a conjugative plasmid in this isolate. C. freundii L91 and transconjugant L91-E. coli 600 stra

Multidrug-resistantKlebsiella pneumoniaeand hypervirulentK. pneumoniae(hvKP) have traditionally been considered two individual populations; however, strains displaying both phenotypes have emerged during the recent decade. Understanding the genotypic and phenotypic basis of the convergence could be of clinical importance. In this study, we aimed to evaluate the pathogenicity associated with different combinations of genotypes (i.e., sequence types, virulence factors, and capsular serotypes) and phenotypes (i.e., hypermucoviscosity and drug susceptibility) inK. pneumoniae.A total of 11K. pneumoniaeisolates causing bloodstream infections were included in the study, and they were assigned to seven STs (ST23, ST15, ST268, ST660, ST86, ST65, and ST1660) and carried various K-loci (KL1, KL2, KL16, KL20, and KL24). Hypermucoviscosity was observed for six isolates.bla(KPC-2)was detected in six carbapenem-resistant isolates, and the remaining ones were either multidrug-resistant or resistant to two types of antibiotics. Aerobactin- and yersiniabactin-encoding genes were detected in all isolates. AlthoughrmpA2was detected in all isolates, most contained frameshift mutations (82%). Genes encoding salmochelin, RmpA, and PEG344 were detected in seven isolates. Colibactin-encoding genes were carried by six isolates. Discrepancies among measured virulence inGalleria mellonellaand the serum-killing assay, and genotypes and phenotypes were detected. The results illustrate the complexity and difficulty with the current knowledge of hypervirulence to predict the phenotype by using genetic and phenotypic markers. Additionally, the emergence of carbapenem resistance in two isolates of KPC-2-producing hvKP of different sequence types emphasizes the urgency with which reliable clinical diagnostics for hvKP is needed., Funding Agencies|National Key Research and Development Program of China [2017YFC1200200]; Major Infectious Diseases such as AIDS and Viral Hepatitis Prevention and Control Technology Major Projects [2018ZX10712-001]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81702045, 81361138021]; Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (Formas)Swedish Research Council Formas [2016-00640]; Swedish Foundation for International Cooperation in Research and Higher Education (STINT) [CH2016-6707]; Shenzhen Basic Research Projects [JCYJ20190807144409307]

Multidrug-resistantKlebsiella pneumoniaeand hypervirulentK. pneumoniae(hvKP) have traditionally been considered two individual populations; however, strains displaying both phenotypes have emerged during the recent decade. Understanding the genotypic and phenotypic basis of the convergence could be of clinical importance. In this study, we aimed to evaluate the pathogenicity associated with different combinations of genotypes (i.e., sequence types, virulence factors, and capsular serotypes) and phenotypes (i.e., hypermucoviscosity and drug susceptibility) inK. pneumoniae.A total of 11K. pneumoniaeisolates causing bloodstream infections were included in the study, and they were assigned to seven STs (ST23, ST15, ST268, ST660, ST86, ST65, and ST1660) and carried various K-loci (KL1, KL2, KL16, KL20, and KL24). Hypermucoviscosity was observed for six isolates.bla(KPC-2)was detected in six carbapenem-resistant isolates, and the remaining ones were either multidrug-resistant or resistant to two types of antibiotics. Aerobactin- and yersiniabactin-encoding genes were detected in all isolates. AlthoughrmpA2was detected in all isolates, most contained frameshift mutations (82%). Genes encoding salmochelin, RmpA, and PEG344 were detected in seven isolates. Colibactin-encoding genes were carried by six isolates. Discrepancies among measured virulence inGalleria mellonellaand the serum-killing assay, and genotypes and phenotypes were detected. The results illustrate the complexity and difficulty with the current knowledge of hypervirulence to predict the phenotype by using genetic and phenotypic markers. Additionally, the emergence of carbapenem resistance in two isolates of KPC-2-producing hvKP of different sequence types emphasizes the urgency with which reliable clinical diagnostics for hvKP is needed., Funding Agencies|National Key Research and Development Program of China [2017YFC1200200]; Major Infectious Diseases such as AIDS and Viral Hepatitis Prevention and Control Technology Major Projects [2018ZX10712-001]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81702045, 81361138021]; Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (Formas)Swedish Research Council Formas [2016-00640]; Swedish Foundation for International Cooperation in Research and Higher Education (STINT) [CH2016-6707]; Shenzhen Basic Research Projects [JCYJ20190807144409307]

Xiaohui Chi,1,2,* Guangchun Hu,3,* Hao Xu,2 Xiucun Li,4 Tingting Xiao,2 Yanzi Zhou,2 Huiyu Xia,1 Huiyun Zou,1 Hui Han,4 Beiwen Zheng,2 Haiyan Gao,4 Xuewen Li1 1Department of Environment and Health, School of Public Health, Shandong University, Jinan 250012, People’s Republic of China; 2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 3Division of Bacteria Diseases, Jinan Municipal Center for Disease Control and Prevention, Jinan, People’s Republic of China; 4Department of Infection Control, Qilu Hospital of Shandong University, Jinan 250012, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xuewen LiDepartment of Environment and Health, School of Public Health, Shandong University, Jinan 250012, People’s Republic of ChinaEmail lxw@sdu.edu.cnHaiyan GaoDepartment of Infection Control, Qilu Hospital of Shandong University, 107 Wenhua West Road, Jinan 250012, People’s Republic of ChinaEmail 565272040@qq.comPurpose: Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae bacteria causes nosocomial infections worldwide. However, KPC-producing K. pneumoniae outbreak has never been reported in Shandong Province, China. The purpose of our study was to elucidate the epidemiological and drug resistance mechanisms of KPC-producing K. pneumoniae strains collected from a large teaching hospital in Shandong during the outbreak. Moreover, we attempted to characterize the genetic environment and phylogenetic analysis of blaKPC-2 in outbreak isolates.Methods: We monitored a 64-day outbreak of infection in a general hospital in Shandong Province, and the bacteria causing the infection were all ST11-type K. pneumoniae. The genotype correlation of KPC-producing K. p

Tianshui Niu,1 TingTing Xiao,1 Lihua Guo,1 Wei Yu,2 Yunbo Chen,1 Beiwen Zheng,1 Chen Huang,1 Xiao Yu,1 Yonghong Xiao1 1Collaborative Initiative Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China; 2Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, 310003, China Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) is a rapidly emerging, life-threatening nosocomial infection. This study aimed to explore the risk factors, clinical features, antimicrobial therapy, and outcomes of CRAB bloodstream infections (BSIs).Methods: This is a retrospective, comparative analysis of data from patients with A. baumannii BSI, treated from 2012 to 2015 at a tertiary teaching hospital. Risk factors associated with CRAB BSI and factors associated with the 28-day mortality were evaluated using logistic analyses.Results: Data from 293 patients with confirmed A. baumannii BSI were included; 242 (82.6%) patients had CRAB BSI and 51 (17.4%) patients had non-CRAB BSI. Risk factors significantly associated with CRAB BSI were a previous intensive care unit (ICU) stay (P=0.029), cefoperazone–sulbactam use (P=0.030), and carbapenem use (P=0.004). Among 236 patients with A. baumannii BSI who were evaluable at 28 days after receiving antibacterial therapy, there were 86 deaths. Factors associated with the 28-day mortality were ICU stay after BSI (P=0.040), readmission within 90 days (P=0.029), Acute Physiology and Chronic Health Evaluation II (APACHE II) score at diagnosis >19 (P=0.012), tigecycline therapy (P=0.021), presence of septic shock (P=0.029), and multiple organ failure (P=0.016). Death rates in patients treated with tigecycline were 53.5% vs 24.1% in patients treated with other agents. Among 186 patients

Tingting Xiao,1 Wei Yu,1,2 Tianshui Niu,1 Chen Huang,1 Yonghong Xiao1 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2Department of Infectious Diseases, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China Background: Carbapenem-nonsusceptible Klebsiella pneumoniae (CnSKP) is rapidly emerging as a life-threatening nosocomial infection. The efficacy of tigecycline in the treatment of bloodstream infections (BSIs) remains controversial.Methods: Data from a total of 428 patients with carbapenem-susceptible Klebsiella pneumoniae (CSKP) and CnSKP BSIs were collected at a single center between January 2013 and December 2015. A three-part analysis was conducted to identify the risk factors associated with CnSKP, explore prognosis, and evaluate treatments. Results: Data from 428 patients with Klebsiella pneumoniae (KP) BSIs were included, 31.5% (n=135) of them with CnSKP. Multivariate analysis showed that prior hospitalization, urinary catheterization, the use of immunosuppressive agents, prior use of antibiotics, pulmonary disease, and high Acute Physiology and Chronic Health Evaluation (APACHE) II scores were independent risk factors for CnSKP-BSIs. The 30-day mortality was higher in patients with CnSKP than in those with CSKP (58.5% vs 15.4%; P<0.001). In patients with KP-BSIs, neutropenia, multiple organ dysfunction, respiratory failure, CnSKP infection, high APACHE II score, and tigecycline therapy were independently associated with higher mortality risk. Among patients whose APACHE II score was <15, higher mortality rates were observed in patients treated with tigecycline than in those treated with other antibiotics (45.3% vs 7.7%; P<0.001). Central venous catheterization, mult

Chen Huang,1,* Beiwen Zheng,1,* Wei Yu,2 Tianshui Niu,1 Tingting Xiao,1 Jing Zhang,1 Yonghong Xiao1 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; 2Department of Infectious Diseases, Zhejiang Provincial People’s Hospital, Hangzhou, China *These authors contributed equally to this work Objectives: The aim of this study was to evaluate the bactericidal effects of moxalactam (MOX), cefotaxime (CTX), and cefoperazone/sulbactam (CFZ/SBT) against extended-spectrum β-lactamase (ESBL) producing Escherichia coli and Klebsiella pneumoniae, using an in vitro pharmacokinetics (PK)/pharmacodynamics model.Methods: Two clinical ESBL-producing strains (blaCTX-M-15 positive E. coli 3376 and blaCTX-M-14 positive K. pneumoniae 2689) and E. coli American Type Culture Collection (ATCC)25922 were used in the study. The PK Auto Simulation System 400 was used to simulate the human PK procedures after intravenous administration of different doses of MOX, CTX, and CFZ/SBT. Bacterial growth recovery time (RT) and the area between the control growth curve and bactericidal curves (IE) were employed to assess the antibacterial efficacies of all the agents.Results: The minimum inhibitory concentrations of MOX, CTX, and CFZ/SBT against E. coli ATCC25922, 3376, and 2689 strains were 0.5, 0.5, 0.25; 0.06, >256, 256; and 0.5/0.5, 16/16, 32/32 mg/L. All the agents demonstrated outstanding bactericidal effects against E. coli ATCC25922 (RT >24 h and IE >120 log10 CFU/mL·h−1) with simulating PK procedures, especially in the multiple dose administration models. Against ESBL producers, CTX and CFZ/SBT displayed only weak bactericidal effects, and subsequent regrowth was evident. MOX exhibited potent antibacterial activity against all the s

Qingwen Wang,1 Xiankai Zhang,1 Tingting Xiao,2 Chenhua Pan,1 Xing Liu,3,4 Yulan Zhao1 1Department of Physiology, School of Life Sciences, East China Normal University, Shanghai, People’s Republic of China; 2Department of Botany, School of Life Sciences, Shanghai Normal University, Shanghai, People’s Republic of China; 3Department of Central Laboratory Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 4Shanghai Biochip Corporation Ltd./National Engineering Center for Biochip at Shanghai, Shanghai, People’s Republic of China Background: Recent studies have shown that Toll-like receptors (TLRs) may be associated with cancers. The aim of this meta-analysis is to summarize the predicting role of TLRs for survival in patients with a variety of carcinomas. Materials and methods: Eligible studies were identified and assessed for quality through multiple search strategies. We collected data from studies investigating the relationship between the expression level of TLRs and survival in cancer patients. Studies were pooled and combined hazard ratios (HRs) of TLRs for survival were analyzed. Results: A total of 24 studies, including 2,812 patients with various cancers, were identified for the meta-analysis. Importantly, this meta-analysis showed that higher expression levels of TLR4 or TLR7 in tumor tissues could predict poorer survival, with the pooled HR being 1.29 (95% CI: 1.17, 1.42) and 1.71 (95% CI: 1.38, 2.12), respectively. However, higher expression of TLR9 had no significant association with outcome as HR was 0.84 (95% CI: 0.62, 1.115). Heterogeneity existed in TLR4 and TLR9 studies (P-value <0.001) but not in TLR7 studies (P-value >0.05). Conclusion: The expression level of TLR4 or TLR7 in cancerous tissue may have a prognosis value in patients with various cancers. Keywords: Toll-like receptors, cancer

Wei Yu,1,2,* Jinru Ji,1,* Tingting Xiao,1 Chaoqun Ying,1 Jiaheng Fang,3 Ping Shen,1 Yonghong Xiao1 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, 2Department of Infectious Diseases, Zhejiang Provincial People’s Hospital, 3Department of Gastroenterology, Hang Zhou Normal University Affiliated Hospital, Hangzhou, People’s Republic of China *These authors contributed equally to this work Background: Dicloxacillin, a semisynthetic isoxazolyl penicillin, exhibits antimicrobial activity against a wide variety of Gram-positive bacteria, as well as stability against penicillinases and low level of toxicity. The objective of this study was to obtain optimal dosing regimen of oral administration of dicloxacillin by analyzing the pharmacokinetic (PK) index in healthy volunteers and in vitro antibacterial activity by using Monte Carlo simulation. Materials and methods: A total of 867 clinical isolates from community-onset infections were collected from 31 secondary hospitals in People’s Republic of China. The minimum inhibitory concentration (MIC) values of dicloxacillin were determined by the agar dilution method. Based on the MICs and the PK parameters of different dosage regimens, Monte Carlo simulation was performed to simulate the PK/pharmacodynamic indices of 250 mg once-daily (qd), 500 mg qd, 1,000 mg qd, 2,000 mg qd, 250 mg every 6 hours (q6h), and 500 mg q6h, respectively. The probability of target attainment was estimated at each MIC value, and the cumulative fraction of response (CFR) was calculated to evaluate the efficacy of these regimens. Results: Dicloxacillin showed poor antibacterial activity against Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Resistance to dicloxacillin was observed in 7.5% of coagulase-nega

We mainly study a taxpayer's optimal strategies of tax evasion and its relevant properties, in order to deduce some effective suggestions and theoretical bases for the tax authority to restrain tax evasion. Based on the Christiansen static model of tax evasion, we formulate a two-period model where the discovery of tax evasion in the second period induces a tax audit in the first period if it has not been done before. The taxpayer has to choose the amount of tax evasion in each period to maximize the total expected utility of the two periods. We show that the threat of having the first-period evasion discovered in the second period diminishes attractiveness of tax evasion in both periods. We also discuss the policy of audit power enhancement, where the audit probability in the second period will be increased if tax evasion is discovered in the first period. We find that this policy may play two roles. First, it can reduce the incentive of tax evasion in the second period if tax evasion is discovered in the first period. Second, a high potential increase of the audit probability may contain tax evasion in the first period but may cause more evasion in the second period.

We mainly study a taxpayer's optimal strategies of tax evasion and its relevant properties, in order to deduce some effective suggestions and theoretical bases for the tax authority to restrain tax evasion. Based on the Christiansen static model of tax evasion, we formulate a two-period model where the discovery of tax evasion in the second period induces a tax audit in the first period if it has not been done before. The taxpayer has to choose the amount of tax evasion in each period to maximize the total expected utility of the two periods. We show that the threat of having the first-period evasion discovered in the second period diminishes attractiveness of tax evasion in both periods. We also discuss the policy of audit power enhancement, where the audit probability in the second period will be increased if tax evasion is discovered in the first period. We find that this policy may play two roles. First, it can reduce the incentive of tax evasion in the second period if tax evasion is discovered in the first period. Second, a high potential increase of the audit probability may contain tax evasion in the first period but may cause more evasion in the second period.

We mainly study a taxpayer's optimal strategies of tax evasion and its relevant properties, in order to deduce some effective suggestions and theoretical bases for the tax authority to restrain tax evasion. Based on the Christiansen static model of tax evasion, we formulate a two-period model where the discovery of tax evasion in the second period induces a tax audit in the first period if it has not been done before. The taxpayer has to choose the amount of tax evasion in each period to maximize the total expected utility of the two periods. We show that the threat of having the first-period evasion discovered in the second period diminishes attractiveness of tax evasion in both periods. We also discuss the policy of audit power enhancement, where the audit probability in the second period will be increased if tax evasion is discovered in the first period. We find that this policy may play two roles. First, it can reduce the incentive of tax evasion in the second period if tax evasion is discovered in the first period. Second, a high potential increase of the audit probability may contain tax evasion in the first period but may cause more evasion in the second period.

The thesis presents two essays on OM-marketing interface. In the first essay, we consider a supply chain with a retailer and a manufacturer introducing a new product into the market. Customers are initially uncertain about product fit. The retailer needs to determine whether to share market information with the manufacturer and whether to offer product demonstration to customers. We show that the retailer prefers to share information with the manufacturer when there is a high chance that the product will fit all the customers, or the marginal production cost is large. She prefers to offer product demonstration when the product may fit a small proportion of customers, or the marginal production cost is large. The retailer would be in general more likely to provide product demonstration when she does not share information with the manufacturer. We also demonstrate that the retailer may apply markups or markdowns under different situations. Finally, we find that the manufacturer always prefers the retailer to demonstrate the product and sometimes he can induce the retailer to do so with a side payment. In the second essay, we investigate firms’ design postponement strategies in a duopoly. The firms face two distinct customer segments and they need to balance the first-mover advantage with the benefits of design postponement. We study two cases where the drivers of postponement are respectively design enhancement (an increase in product value) and information on customers’ preference. In both cases, there are two possible equilibria. Both firms postpone design, or only one firm postpones design. In the first case, the asymmetric equilibrium where only one firm postpones design exists only when the asymmetry of segment size is intermediate. However, in the second case, the asymmetric equilibrium may also exist when the asymmetry of segment size is high. We also conduct sensitivity analysis and find some counterintuitive results.

The thesis presents two essays on OM-marketing interface. In the first essay, we consider a supply chain with a retailer and a manufacturer introducing a new product into the market. Customers are initially uncertain about product fit. The retailer needs to determine whether to share market information with the manufacturer and whether to offer product demonstration to customers. We show that the retailer prefers to share information with the manufacturer when there is a high chance that the product will fit all the customers, or the marginal production cost is large. She prefers to offer product demonstration when the product may fit a small proportion of customers, or the marginal production cost is large. The retailer would be in general more likely to provide product demonstration when she does not share information with the manufacturer. We also demonstrate that the retailer may apply markups or markdowns under different situations. Finally, we find that the manufacturer always prefers the retailer to demonstrate the product and sometimes he can induce the retailer to do so with a side payment. In the second essay, we investigate firms’ design postponement strategies in a duopoly. The firms face two distinct customer segments and they need to balance the first-mover advantage with the benefits of design postponement. We study two cases where the drivers of postponement are respectively design enhancement (an increase in product value) and information on customers’ preference. In both cases, there are two possible equilibria. Both firms postpone design, or only one firm postpones design. In the first case, the asymmetric equilibrium where only one firm postpones design exists only when the asymmetry of segment size is intermediate. However, in the second case, the asymmetric equilibrium may also exist when the asymmetry of segment size is high. We also conduct sensitivity analysis and find some counterintuitive results.

The thesis presents two essays on OM-marketing interface. In the first essay, we consider a supply chain with a retailer and a manufacturer introducing a new product into the market. Customers are initially uncertain about product fit. The retailer needs to determine whether to share market information with the manufacturer and whether to offer product demonstration to customers. We show that the retailer prefers to share information with the manufacturer when there is a high chance that the product will fit all the customers, or the marginal production cost is large. She prefers to offer product demonstration when the product may fit a small proportion of customers, or the marginal production cost is large. The retailer would be in general more likely to provide product demonstration when she does not share information with the manufacturer. We also demonstrate that the retailer may apply markups or markdowns under different situations. Finally, we find that the manufacturer always prefers the retailer to demonstrate the product and sometimes he can induce the retailer to do so with a side payment. In the second essay, we investigate firms’ design postponement strategies in a duopoly. The firms face two distinct customer segments and they need to balance the first-mover advantage with the benefits of design postponement. We study two cases where the drivers of postponement are respectively design enhancement (an increase in product value) and information on customers’ preference. In both cases, there are two possible equilibria. Both firms postpone design, or only one firm postpones design. In the first case, the asymmetric equilibrium where only one firm postpones design exists only when the asymmetry of segment size is intermediate. However, in the second case, the asymmetric equilibrium may also exist when the asymmetry of segment size is high. We also conduct sensitivity analysis and find some counterintuitive results.