{"title":"A Letter from the Editor-in-Chief.","authors":"","doi":"10.1089/mdr.2023.29006.igb","DOIUrl":"https://doi.org/10.1089/mdr.2023.29006.igb","url":null,"abstract":"","PeriodicalId":18701,"journal":{"name":"Microbial drug resistance","volume":"29 9","pages":"387"},"PeriodicalIF":2.6,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10513562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cellular Attributes of <i>Candida albicans</i> Biofilm-Associated in Resistance Against Multidrug and Host Immune System.","authors":"Dushyant Kumar, Awanish Kumar","doi":"10.1089/mdr.2022.0347","DOIUrl":"https://doi.org/10.1089/mdr.2022.0347","url":null,"abstract":"<p><p>One of the ubiquitous hospital-acquired infections is associated with <i>Candida albicans</i> fungus. Usually, this commensal fungus causes no harm to its human host, as it lives mutually with mucosal/epithelial tissue surface cells. Nevertheless, due to the activity of various immune weakening factors, this commensal starts reinforcing its virulence attributes with filamentation/hyphal growth and building an absolute microcolony composed of yeast, hyphal, and pseudohyphal cells, which is suspended in an extracellular gel-like polymeric substance (EPS) called biofilms. This polymeric substance is the mixture of the secreted compounds from <i>C. albicans</i> as well as several host cell proteins. Indeed, the presence of these host factors makes their identification and differentiation process difficult by host immune components. The gel-like texture of the EPS makes it sticky, which adsorbs most of the extracolonial compounds traversing through it that aid in penetration hindrance. All these factors further contribute to the multidrug resistance phenotype of <i>C. albicans</i> biofilm that is spotlighted in this article. The mechanisms it employs to escape the host immune system are also addressed effectively. The article focuses on cellular and molecular determinants involved in the resistance of <i>C. albicans</i> biofilm against multidrug and the host immune system.</p>","PeriodicalId":18701,"journal":{"name":"Microbial drug resistance","volume":"29 9","pages":"423-437"},"PeriodicalIF":2.6,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10156202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"An <i>Enterococcus faecium</i> Isolated from Bovine Feces in Italy Shares <i>optrA</i>- and <i>poxtA</i>-Carrying Plasmids with Enterococci from Switzerland.","authors":"Marzia Cinthi, Sonia Nina Coccitto, Serena Simoni, Carla Vignaroli, Andrea Brenciani, Eleonora Giovanetti","doi":"10.1089/mdr.2023.0055","DOIUrl":"https://doi.org/10.1089/mdr.2023.0055","url":null,"abstract":"<p><p>To investigate the occurrence of oxazolidinone resistance genes, 18 florfenicol-resistant enterococci were isolated from 66 fecal samples collected from several cattle farms in central Italy. The PCR screening indicated that only a bovine florfenicol-resistant isolate, <i>Enterococcus faecium</i> 249031-C, was positive for the presence of <i>optrA</i> and <i>poxtA</i> genes. The strain was tested for its susceptibility to florfenicol, chloramphenicol, linezolid, tedizolid, tetracycline, erythromycin, and vancomycin. Whole Genome Sequencing analysis showed that <i>E. faecium</i> 249031-C, belonging to the ST22 lineage, harbored two plasmids: the <i>optrA</i>-carrying p249031-S (179 kb) and the <i>poxtA</i>-carrying p1818-c (23 kb). p249031-S, containing a new <i>optrA</i>-carrying Tn<i>7695</i> transposon, was closely related to the plasmid pF88_1 of <i>E. faecium</i> F88, whereas p1818-c had already been detected in a human <i>E. faecium</i>, both enterococci were from Switzerland. The linezolid resistance genes were cotransferred to the <i>E. faecium</i> 64/3 recipient. Circular forms from both <i>optrA</i>- and <i>poxtA</i>-carrying genetic contexts were obtained. The occurrence of oxazolidinone resistance genes in a bovine <i>E. faecium</i> isolate and their localization on conjugative and mobilizable plasmids pose a risk for public health.</p>","PeriodicalId":18701,"journal":{"name":"Microbial drug resistance","volume":"29 9","pages":"438-442"},"PeriodicalIF":2.6,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10156705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mark G Wise, James A Karlowsky, Meredith A Hackel, Miki Takemura, Yoshinori Yamano, Roger Echols, Daniel F Sahm
{"title":"<i>In Vitro</i> Activity of Cefiderocol Against Meropenem-Nonsusceptible Gram-Negative Bacilli with Defined β-Lactamase Carriage: SIDERO-WT Surveillance Studies, 2014-2019.","authors":"Mark G Wise, James A Karlowsky, Meredith A Hackel, Miki Takemura, Yoshinori Yamano, Roger Echols, Daniel F Sahm","doi":"10.1089/mdr.2022.0279","DOIUrl":"10.1089/mdr.2022.0279","url":null,"abstract":"<p><p>We examined the <i>in vitro</i> susceptibility of meropenem-nonsusceptible Enterobacterales, <i>Pseudomonas aeruginosa</i>, and <i>Acinetobacter baumannii</i> complex isolates from five consecutive annual SIDERO-WT surveillance studies (2014-2019) to cefiderocol and comparator agents in the context of their carbapenemase carriage. 1,003 Enterobacterales, 1,758 <i>P. aeruginosa</i>, and 2,809 <i>A. baumannii</i> complex isolates from North America and Europe that were meropenem nonsusceptible (CLSI M100, 2022) were molecularly characterized for β-lactamase content by PCR followed by Sanger sequencing or by whole genome sequencing. Among Enterobacterales, 91.5% of metallo-β-lactamase (MBL)-producing, 98.4% of KPC-producing, 97.3% of OXA-48 group-producing, and 98.7% of carbapenemase-negative, meropenem-nonsusceptible isolates were cefiderocol susceptible (MIC ≤4 mg/L). Among <i>P. aeruginosa</i>, 100% of MBL-producing, 100% of GES carbapenemase-producing, and 99.8% of carbapenemase-negative, meropenem-nonsusceptible isolates were cefiderocol susceptible (MIC ≤4 mg/L). Among <i>A. baumannii</i> complex, 60.0% of MBL-producing, 95.6% of OXA-23 group-producing, 89.5% of OXA-24 group-producing, 100% of OXA-58 group-producing, and 95.5% of carbapenemase-negative, meropenem-nonsusceptible isolates were cefiderocol susceptible (MIC ≤4 mg/L). Cefiderocol was inactive against <i>A. baumannii</i> complex isolates carrying a PER or VEB β-lactamase (<i>n</i> = 103; 15.5% susceptible). Ceftazidime-avibactam and ceftolozane-tazobactam were inactive against MBL-carrying and <i>A. baumannii</i> complex isolates; ceftolozane-tazobactam was also inactive against serine carbapenemase-carrying Enterobacterales and <i>P. aeruginosa</i>. In summary, cefiderocol was highly active <i>in vitro</i> against Gram-negative isolates carrying MBLs and serine carbapenemases, as well as carbapenemase-negative, meropenem-nonsusceptible isolates.</p>","PeriodicalId":18701,"journal":{"name":"Microbial drug resistance","volume":"29 8","pages":"360-370"},"PeriodicalIF":2.6,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10387160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9917318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Emerging Role of Sphingolipids in Amphotericin B Drug Resistance.","authors":"Kashish Madaan, Vinay Kumar Bari","doi":"10.1089/mdr.2022.0353","DOIUrl":"https://doi.org/10.1089/mdr.2022.0353","url":null,"abstract":"<p><p>Invasive fungal infections in humans are common in people with compromised immune systems and are difficult to treat, resulting in high mortality. Amphotericin B (AmB) is one of the main antifungal drugs available to treat these infections. AmB binds with plasma membrane ergosterol, causing leakage of cellular ions and promoting cell death. The increasing use of available antifungal drugs to combat pathogenic fungal infections has led to the development of drug resistance. AmB resistance is not very common and is usually caused by changes in the amount or type of ergosterol or changes in the cell wall. Intrinsic AmB resistance occurs in the absence of AmB exposure, whereas acquired AmB resistance can develop during treatment. However, clinical resistance arises due to treatment failure with AmB and depends on multiple factors such as the pharmacokinetics of AmB, infectious fungal species, and host immune status. <i>Candida albicans</i> is a common opportunistic pathogen that can cause superficial infections of the skin and mucosal surfaces, thrush, to life-threatening systemic or invasive infections. In addition, immunocompromised individuals are more susceptible to systemic infections caused by <i>Candida</i>, <i>Aspergillus</i>, and <i>Cryptococcus</i>. Several antifungal drugs with different modes of action are used to treat systemic to invasive fungal infections and are approved for clinical use in the treatment of fungal diseases. However, <i>C. albicans</i> can develop a variety of defenses against antifungal medications. In fungi, plasma membrane sphingolipid molecules could interact with ergosterol, which can lead to the alteration of drug susceptibilities such as AmB. In this review, we mainly summarize the role of sphingolipid molecules and their regulators in AmB resistance.</p>","PeriodicalId":18701,"journal":{"name":"Microbial drug resistance","volume":"29 8","pages":"319-332"},"PeriodicalIF":2.6,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9917822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ingrid Menezes Brasil, Claudia Ferreira de Andrade, Dominique Mendes de Oliveira, Nathalia G S Caldeira, Jaciara Rodrigues de Oliveira, Ana Paula A do Nascimento, Antonio Eugênio C C de Almeida, Ivano de Filippis
{"title":"Molecular Epidemiology of <i>Haemophilus influenzae</i> Strains with Reduced Susceptibility and Genetic Profiles of Resistance in the Postvaccination Period.","authors":"Ingrid Menezes Brasil, Claudia Ferreira de Andrade, Dominique Mendes de Oliveira, Nathalia G S Caldeira, Jaciara Rodrigues de Oliveira, Ana Paula A do Nascimento, Antonio Eugênio C C de Almeida, Ivano de Filippis","doi":"10.1089/mdr.2022.0156","DOIUrl":"https://doi.org/10.1089/mdr.2022.0156","url":null,"abstract":"<p><p><i>Haemophilus influenzae</i> serotype b has been the main cause of invasive infections in children, during the prevaccination period. More than 20 years after the introduction of the conjugate vaccine against Hib, HiNT has emerged as the cause of localized infections in children and adults. The main objective of this work is to evaluate the susceptibility and resistance mechanisms of <i>H. influenzae</i> strains from carriers and describe the molecular epidemiology and their clonal relationships by multilocus sequence typing (MLST). Sixty-nine strains from clinical cases and asymptomatic carriers from 2009 to 2019 were analyzed, confirmed as <i>H.</i> influenzae, and serotyped by polymerase chain reaction. The susceptibility to antibiotics was evaluated by E-test strips. Genotyping was performed by MLST. HiNT was the most frequent in all age groups. Resistance to ampicillin, sulfamethoxazole+trimethoprim, and amoxicillin+clavulanic acid was detected, with the production of β-lactamase being the main resistance mechanism. Among 21 HiNT strains with complete allelic MLST profiles, 19 new sequence types were described, reinforcing the already reported heterogeneity of nontypeable strains, and only one clonal complex (cc-1355) was observed. Our results show a high percentage of colonization regardless of age, increased antimicrobial resistance, and high genetic diversity, along with an increased number of cases caused by HiNT strains. These findings reinforce the need for continuous surveillance for HiNT strains as it has been reported worldwide after the introduction of the Hib conjugate vaccine.</p>","PeriodicalId":18701,"journal":{"name":"Microbial drug resistance","volume":"29 8","pages":"371-380"},"PeriodicalIF":2.6,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9916487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fatemeh Sodeifian, Moein Zangiabadian, Erfan Arabpour, Naghmeh Kian, Fartous Yazarlou, Mehdi Goudarzi, Rosella Centis, Zahra Sadat Seghatoleslami, Mahdis Chahar Kameh, Bardia Danaei, Hossein Goudarzi, Mohammad Javad Nasiri, Giovanni Sotgiu, Giovanni Battista Migliori
{"title":"Tigecycline-Containing Regimens and Multi Drug-Resistant <i>Acinetobacter baumannii</i>: A Systematic Review and Meta-Analysis.","authors":"Fatemeh Sodeifian, Moein Zangiabadian, Erfan Arabpour, Naghmeh Kian, Fartous Yazarlou, Mehdi Goudarzi, Rosella Centis, Zahra Sadat Seghatoleslami, Mahdis Chahar Kameh, Bardia Danaei, Hossein Goudarzi, Mohammad Javad Nasiri, Giovanni Sotgiu, Giovanni Battista Migliori","doi":"10.1089/mdr.2022.0248","DOIUrl":"https://doi.org/10.1089/mdr.2022.0248","url":null,"abstract":"<p><p><b><i>Introduction:</i></b> The use of tigecycline (TG) for the treatment of <i>Acinetobacter baumannii</i> is controversial. In this systematic review and meta-analysis, we aimed to better explore the safety and efficacy of TG for the treatment of multi drug-resistant (MDR) Acinetobacter. <b><i>Methods:</i></b> We searched PubMed/MEDLINE, Scopus, Cochrane Central, and Web of Science to identify studies reporting the clinical and microbiological efficacy and safety of regimens containing TG in patients with drug susceptibility testing (DST)-confirmed MDR <i>A. baumannii</i>, published until December 30, 2022. Observational studies were included if they reported clinical and microbiological efficacy of TG-based regimens. The Newcastle-Ottawa Scale (NOS) and Joana Briggs Institute (JBI) critical appraisal tool were used to assess the quality of included studies. <b><i>Results:</i></b> There were 30 observational studies, of which 19 studies were cohort and 11 studies were single group studies. Pooled clinical response and failure rates in the TG-containing regimens group were 58.1 (95% confidence interval [CI] 49.2-66.6) and 40.2 (95% CI 31.1-50.0), respectively. The pooled microbiological response rate was 32.1 (95% CI 19.8-47.5), and the pooled all-cause mortality rate was 41.1 (95% CI 34.1-48.4). Pooled clinical response and failure rates in the colistin-based regimens group were 52.7 (42.7-62.5) and 43.1 (33.1-53.8), respectively. The pooled microbiological response rate was 42.9 (16.2-74.5), and the pooled all-cause mortality rate was 34.3 (26.1-43.5). <b><i>Conclusions:</i></b> According to our results, the efficacy of the TG-based regimen is the same as other antibiotics. However, our study showed a high mortality rate and a lower rate of microbiological eradication for TG compared with colistin-based regimen. Therefore, our study does not recommend it for the treatment of MDR <i>A. baumannii</i>. However, this was a prevalence meta-analysis of observational studies, and for better conclusion experimental studies are required.</p>","PeriodicalId":18701,"journal":{"name":"Microbial drug resistance","volume":"29 8","pages":"344-359"},"PeriodicalIF":2.6,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10274582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiao Chen, Guanghui Li, Fen Wan, Peng Liu, Fangling Du, Yanting Shao, Qi Zhang, Zhibin Cheng, Yang Liu
{"title":"Virulence Characteristics and Drug Resistance of the Prevalent Capsule Types in <i>Acinetobacter baumannii</i>.","authors":"Jiao Chen, Guanghui Li, Fen Wan, Peng Liu, Fangling Du, Yanting Shao, Qi Zhang, Zhibin Cheng, Yang Liu","doi":"10.1089/mdr.2022.0310","DOIUrl":"https://doi.org/10.1089/mdr.2022.0310","url":null,"abstract":"<p><p><i>Acinetobacter baumannii</i> is a highly antibiotic-resistant pathogen causing nosocomial severe life-threatening infections, especially in critically ill patients. Capsular polysaccharide is a major virulence factor of <i>A. baumannii</i> both <i>in vitro</i> and <i>in vivo</i>. In this study, 220 isolates were collected in the hospital. The prevalent capsular types of <i>A. baumannii</i> were determined using polymerase chain reaction, and the clinical characteristics of infections were analyzed. The virulence of these strains was determined by serum-killing resistance, biofilm formation, and <i>Galleria mellonella</i> survival assays. Twenty-eight isolates (12.7%) carried KL2, and 22 isolates (10%) carried the types KL10, KL14, KL22, and KL52. Compared with non-KL2 (KL10, KL14, KL22, and KL52) isolates, KL2 isolates had significantly higher resistance to all antimicrobials except tigecycline, cefoperazone-sulbactam, or colistin. Seventy-five percent of KL2 <i>A. baumannii</i> and 72.7% of non-KL2 were highly virulent using a <i>G. mellonella</i> model. Biofilm formation was significantly different between the KL2 and non-KL2 groups. The biofilm production of non-KL2 <i>A. baumannii</i> was significantly stronger than that of KL2 <i>A. baumannii.</i> These findings highlight the role of KL2 as a powerful factor for drug resistance and virulence of <i>A. baumannii.</i></p>","PeriodicalId":18701,"journal":{"name":"Microbial drug resistance","volume":"29 7","pages":"274-279"},"PeriodicalIF":2.6,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9788131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marco S Perez-Ayala, José Antonio Alvarez, Alejandro E Macias, Brenda J Torres-Murillo
{"title":"How Does Time Affect the Antimicrobial Activity of Super-Oxidized Commercial Antiseptic Solutions? An <i>In Vitro</i> Test.","authors":"Marco S Perez-Ayala, José Antonio Alvarez, Alejandro E Macias, Brenda J Torres-Murillo","doi":"10.1089/mdr.2022.0212","DOIUrl":"10.1089/mdr.2022.0212","url":null,"abstract":"<p><p>This study aimed to identify variation in the minimum biocidal concentration (MBC) over time, comparing three commercial super-oxidized solutions with different chemical compositions. In the bactericidal assay, the following bacteria were tested: <i>Escherichia coli</i> (ATCC 25922), <i>Pseudomonas aeruginosa</i> (ATCC 27853), <i>Staphylococcus aureus</i> (ATCC 25923), and for each ATCC, one wild-type strain was used. <i>In vitro</i> experiments were performed in triplicate at 0, 60, and 120 days of follow up. A commercial formulation based on sodium and chloride ions (SCSS) was tested using a standard accelerated aging protocol. Data were analyzed with the Friedman and Wilcoxon signed-rank tests. The results showed that super-oxidized solution bases of 20 ppm of sodium (SSS) had a significant change in MBC at 120 days (<i>p</i> < 0.001), whereas SCSS remained stable during the same period (<i>p</i> = 0.18). However, after accelerated aging treatment, the MBC of SCSS increased (<i>p</i> < 0.001). With our proposed approach, the two SSS showed MBC variation at 120 days, whereas SCSS showed stability over time, similar to chlorhexidine, but lost its bactericidal properties after accelerated aging treatment.</p>","PeriodicalId":18701,"journal":{"name":"Microbial drug resistance","volume":"29 7","pages":"309-315"},"PeriodicalIF":1.9,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9788870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"RFS Proudly Announces the 2022 Award Recipient for <i>Microbial Drug Resistance</i>.","authors":"Sabine Schuster","doi":"10.1089/mdr.2023.29005.rfs2022","DOIUrl":"https://doi.org/10.1089/mdr.2023.29005.rfs2022","url":null,"abstract":"","PeriodicalId":18701,"journal":{"name":"Microbial drug resistance","volume":"29 7","pages":"273"},"PeriodicalIF":2.6,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9803996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}