Journal of Medical Virology最新文献

{"title":"Epidemiology of Parvovirus B19 Infection In an Italian Metropolitan Area, 2012–2024: COVID-19 Pre-Pandemic, Pandemic and Post-Pandemic Trends","authors":"Simona Venturoli,&nbsp;Alessia Bertoldi,&nbsp;Elisabetta Manaresi,&nbsp;Tiziana Lazzarotto,&nbsp;Giorgio Gallinella","doi":"10.1002/jmv.70296","DOIUrl":"https://doi.org/10.1002/jmv.70296","url":null,"abstract":"<p>Parvovirus B19 (B19V) is the most relevant human pathogenic virus in the <i>Parvoviridae</i> family. In years 2023–2024, a high incidence of B19V infections has been reported from many countries; we reconstructed the circulation of B19V in an Italian metropolitan area during the past 12 years (2012–2024), to elucidate evolving epidemiological trends and the impact of the COVID-19 pandemic. To this aim, we included a consecutive time-series analysis of the B19V laboratory investigation carried out in the Microbiology Unit, S.Orsola University Hospital of Bologna, Italy. A total of 29020 serum samples, from July 2012 to June 2024, were tested for the presence of both B19V IgG/IgM antibodies and/or for the presence of B19V DNA. Results were treated in aggregate form, by elaboration of demographic and laboratory data. Data reveal how circulation patterns of B19V have been conditioned by the COVID-19 pandemic. From 2012 until 2019, alternating phases of lower (years 2012–2014, 2017–2018) or higher (years 2015–2016, 2019) circulation were present, respectively 1.8%–2.6% and 4.7%–4.9% of tested patients. From 2020 to 2023, the lowest incidence of B19V infection was reported, 1.0%–1.3%. An unprecedented increase was observed in the first 6 months of 2024, up to 20.1%, mainly in the 0–10 and 41–50 age groups. In 2024, 53 infections were diagnosed in 115 pregnant women (46.1%). Our data highlight the epidemiological trends in B19V and confirm both the block during the COVID-19 pandemic and ensuing upsurge in transmission in 2024. The inclusion of B19V in rationally planned screening and diagnostic protocols appears justified in terms of appropriate surveillance and clinical management.</p>","PeriodicalId":16354,"journal":{"name":"Journal of Medical Virology","volume":"97 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.70296","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Importance of Accurate Communication for Public Health Benefits and Commitment to Safety Monitoring","authors":"Seung Gu Kang,&nbsp;Hye Young Kim","doi":"10.1002/jmv.70297","DOIUrl":"https://doi.org/10.1002/jmv.70297","url":null,"abstract":"","PeriodicalId":16354,"journal":{"name":"Journal of Medical Virology","volume":"97 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of an Assay Evaluating the Inducible HIV-1 Latent Reservoir Based on Reverse Transcription Droplet Digital PCR for Unspliced/Intact Viral RNA","authors":"Xu Zhang,&nbsp;Shiyu Wu,&nbsp;Yingtong Lin,&nbsp;Wanying Zhang,&nbsp;Yiwen Zhang,&nbsp;Xiaomin Li,&nbsp;Linghua Li,&nbsp;Hui Zhang,&nbsp;Bingfeng Liu,&nbsp;Xin He","doi":"10.1002/jmv.70295","DOIUrl":"https://doi.org/10.1002/jmv.70295","url":null,"abstract":"<div>\u0000 \u0000 <p>HIV-1 establishes a stable latent reservoir in host cells such as CD4⁺ T lymphocytes, which cannot be recognized by the immune system. Accurately assessing the active latent reservoir by HIV-1 RNA is crucial for the clinical diagnoses and treatment. Reverse transcription (RT)-polymerase chain reaction (PCR)-based assays are commonly employed to detect HIV-1 reservoirs in clinical settings, but single-site probe designs limit their ability to distinguish between intact and defective HIV-1 proviral transcripts. In this study, we present and optimize a RT-droplet digital PCR-based assay (RT-ddPCR) that accurately quantifies unspliced/intact intracellular HIV-1 RNA, which sensitively detects the activity of HIV-1 latent reservoirs. By testing with various latency-reversing agents (LRAs) in multiple HIV-1 latent cell line models, we demonstrated that our method is more accurate than traditional RT-PCR-based assays for HIV-1 RNA. Moreover, the unspliced/intact HIV-1 RNA assay was used to monitor HIV-1 latent reservoir activity in individuals undergoing analytical treatment interruption (ATI) after antiviral therapeutic intervention. The level of unspliced/intact HIV-1 RNA in peripheral blood mononuclear cells (PBMCs), with an increase in unspliced/intact viral RNA levels detectable before viral rebound in plasma, positively correlated with the initial viral load at rebound. Compared to culture-based methods for detecting inducible reservoirs, this approach significantly reduces the required cell quantity, operational complexity, and detection time. The highly sensitive RT-ddPCR detection of unspliced/intact HIV-1 RNA shows good correlation with the viral rebound following ATI, which will also be valuable for predicting inducible viral reservoir size. This finding supports the assay's utility for faster and more accurate prediction of viral rebound and timely initiation of intervention therapy.</p></div>","PeriodicalId":16354,"journal":{"name":"Journal of Medical Virology","volume":"97 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Screening and Evaluation of Potential Inhibitors Against Vaccinia Virus From 767 Approved Drugs”","authors":"","doi":"10.1002/jmv.70300","DOIUrl":"https://doi.org/10.1002/jmv.70300","url":null,"abstract":"<p>Wu J, Liu Q, Xie H, et al. Screening and evaluation of potential inhibitors against vaccinia virus from 767 approved drugs. J Med Virol. 2019; 91: 2016-2024. https://doi.org/10.1002/jmv.25544. Epub 2019 Jul 25. PMID: 31294846.</p><p>Figure 4 initially showed duplicate D1 images (circled in red) for both TRA-135 and TRA-45 mg/kg groups.</p><p>Corrected Figure 4</p><p>We apologize for this error.</p>","PeriodicalId":16354,"journal":{"name":"Journal of Medical Virology","volume":"97 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.70300","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolomic Biomarkers of Pulmonary Fibrosis in COVID-19 Patients One Year After Hospital Discharge","authors":"Marina Botello-Marabotto,&nbsp;Julia Tarrasó,&nbsp;Alba Mulet,&nbsp;Lucía Presa-Fernández,&nbsp;Estrella Fernández-Fabrellas,&nbsp;José A Rodríguez Portal,&nbsp;Jose A. Ros,&nbsp;Desiré Lozano-Vicente,&nbsp;Andrea Bernardos,&nbsp;M. Carmen Martínez-Bisbal,&nbsp;Ramón Martínez-Máñez,&nbsp;Jaime Signes-Costa","doi":"10.1002/jmv.70289","DOIUrl":"https://doi.org/10.1002/jmv.70289","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 <p>Coronavirus disease 2019 (COVID-19) global pandemic has affected more than 600 million people up to date. The symptomatology and severity of COVID-19 are very broad, and there are still concerns about the long-term sequelae that it can have on discharged patients. The development of pulmonary fibrotic sequelae after this infection is especially worrying. Our aim was to determine if there was a metabolomic signature that could predict the development of pulmonary fibrotic sequelae. It is a multicenter prospective observation subcohort based on the COVID-FIBROTIC study. A metabolomic analysis was performed by nuclear magnetic resonance (NMR) on serum samples from patients admitted with bilateral COVID-19 pneumonia collected 2 months after hospital discharge. One year after admission, clinical, functional and radiological data were collected from these same patients. Finally, 109 patients (mean age 57.68 [DS14.03], 65.13% male) were available. Fibrotic sequelae 1 year after COVID-19 disease were found in 33% of them. Based on the NMR analysis of the serum samples, it was possible to distinguish with 80.82% of sensitivity, 72.22% of specificity and 0.83 of an area under the curve (AUC) value which patients would have radiological signs of pulmonary fibrotic pattern 1 year after sample collection. According to the metabolites participating in the discriminative model and the univariate statistics, glucose, valine, and fatty acids (═CH–CH2–CH═) were suggested as potential biomarkers of the development of pulmonary fibrotic sequelae after COVID-19.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial Registration Number</h3>\u0000 \u0000 <p>clinicaltrials.gov NCT04409275 (June 1, 2020).</p>\u0000 </section>\u0000 </div>","PeriodicalId":16354,"journal":{"name":"Journal of Medical Virology","volume":"97 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electrochemical Duplex Detection of E2 and E6 Genes of Human Papillomavirus Type 16 and Determination of Physical Status in High-Risk Cervical Carcinoma","authors":"Sinthu Karunaithas,&nbsp;Thanyarat Chaibun,&nbsp;Patutong Chatchawal,&nbsp;Chamras Promptmas,&nbsp;Waranun Buajeeb,&nbsp;Lee Su Yin,&nbsp;Patcharee Jearanaikoon,&nbsp;Benchaporn Lertanantawong","doi":"10.1002/jmv.70299","DOIUrl":"https://doi.org/10.1002/jmv.70299","url":null,"abstract":"<p>Human papillomavirus type 16 (HPV-16) is a key driver in the development of cervical carcinoma, with the integration of its genome into the host DNA marking a critical step in disease progression. Monitoring the physical state of HPV-16, particularly the transition from episomal to integrated forms, is essential for evaluating the risk of malignancy development in cervix. This study presents the development of a duplex electrochemical biosensor for the simultaneous detection of the E2 and E6 genes of HPV-16. Using a one-step sandwich hybridization assay, the biosensor was able to detect HPV-16 E2 and E6 genes with a sensitivity of 8 copies/mL and 12 copies/mL respectively and distinguish between the episomal and integrated forms based on the E2/E6 ratio (cut-off 0.77, 100% sensitivity/specificity). The sensor was validated with 30 clinical cervical tissue samples, providing results comparable to qPCR method. This novel biosensor offers a rapid and efficient platform for the detection and monitoring of HPV-16, with potential applications in cervical cancer screening and prognosis.</p>","PeriodicalId":16354,"journal":{"name":"Journal of Medical Virology","volume":"97 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.70299","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cost-Effectiveness of Nirmatrelvir/Ritonavir in COVID-19 Patients at High-Risk for Progression in Spain","authors":"José Ramón Azanza,&nbsp;Juan María González Del Castillo,&nbsp;Raúl Ferrando,&nbsp;José María Molero,&nbsp;Alex Soriano,&nbsp;Carmen Peral,&nbsp;Alfonso de Lossada,&nbsp;Alba Bellmunt,&nbsp;Carla Garí,&nbsp;Tendai Mugwagwa,&nbsp;Vanessa López-Gómez","doi":"10.1002/jmv.70288","DOIUrl":"https://doi.org/10.1002/jmv.70288","url":null,"abstract":"<p>The objective was to estimate the cost-effectiveness of nirmatrelvir/ritonavir (NMV/r) in treating adults with COVID-19 at high-risk of developing severe COVID-19 who do not require supplemental oxygen, compared to no treatment, from the Spanish National Health System (NHS) perspective. A decision-tree for the first year followed by a two-state Markov model with annual cycles for a lifetime horizon was developed. A cohort of 1000 high-risk, symptomatic COVID-19 patients entered the decision-tree for each comparator, divided into hospitalized patients, considering their level of care, and outpatients, for whom only symptom duration was considered. Vaccination status of patients and COVID-19-specific mortality for hospitalized patients were considered. NMV/r efficacy in reducing hospitalizations, deaths and symptom days was applied. Patient quality of life and costs were included (€2024). All the parameters and assumptions were validated by experts. The model reported outputs including costs, quality-adjusted life-years (QALYs) and cost per QALY gained. NMV/r was dominant compared to no treatment, with a decrease in cost per patient of €169.69 and an increase in QALYs of 0.05. NMV/r is a dominant option compared to no treatment in high-risk adult patients with symptomatic COVID-19 not requiring supplemental oxygen, from the Spanish NHS perspective.</p>","PeriodicalId":16354,"journal":{"name":"Journal of Medical Virology","volume":"97 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.70288","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143581918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Compensatory Effect of S375F on S371F Is Vital for Maintaining the Infectivity of SARS-CoV-2 Omicron Variants","authors":"Shuo Liu,&nbsp;Pan Liu,&nbsp;Qiong Lu,&nbsp;Yanru Shen,&nbsp;Li Zhang,&nbsp;Ziteng Liang,&nbsp;Yuanling Yu,&nbsp;Weijin Huang,&nbsp;Youchun Wang","doi":"10.1002/jmv.70242","DOIUrl":"https://doi.org/10.1002/jmv.70242","url":null,"abstract":"<p>The emergence of Omicron variants dramatically changed the transmission rate and infection characteristics compared to previously prevalent strains, primarily due to spike protein mutations. However, the impact of individual mutations remained unclear. Here, we used virus-like particle (VLP) pseudotyped to investigate the functional contributions by 12 common mutations in the spike protein. We found that the S371F mutation in the receptor binding domain (RBD) of spike protein led to a 5- and 10-fold decrease of ACE2 utilization efficiency and viral infectivity, respectively, accompanied by a 5- to 11-fold reduction of neutralization sensitivity to monoclonal antibodies. However, the S375F mutation in the RBD had a compensatory effect, rescuing the infectivity of the S371F Omicron variant. Based on molecular dynamics simulations, we proposed a “tug of war” model to explain this compensation phenomenon. These results provide a comprehensive and dynamic perspective on the evolution of this important pandemic virus.</p>","PeriodicalId":16354,"journal":{"name":"Journal of Medical Virology","volume":"97 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.70242","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143581917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of an NGS-Based Estimation of Integrated HBV DNA in Liver Biopsies and Detection in Liquid Biopsies","authors":"Hsin-Ni Liu,&nbsp;Selena Y. Lin,&nbsp;Ricardo Ramirez,&nbsp;Shin-En Chen,&nbsp;Zachary R. Heimer,&nbsp;Roman Kubas,&nbsp;Fwu-Shan Shieh,&nbsp;Elena S. Kim,&nbsp;Yuanjie Liu,&nbsp;Daryl T. Y. Lau,&nbsp;Ting-Tsung Chang,&nbsp;Haitao Guo,&nbsp;Zhili Wang,&nbsp;Ying-Hsiu Su","doi":"10.1002/jmv.70290","DOIUrl":"https://doi.org/10.1002/jmv.70290","url":null,"abstract":"<div>\u0000 \u0000 <p>This study characterized a hepatitis B virus (HBV) hybridization-capture next-generation sequencing (HBV-NGS) assay and applied it to develop a model for estimating the integrated HBV DNA (iDNA) quantity and for HBV genetics liquid biopsy. Using HBV monomers and reconstituted cell line DNA (SNU398, Hep3B, and PLC/PRF/5), the HBV-NGS assay demonstrated high coverage uniformity, reproducibility across HBV genotypes A-D, and 0.1% sensitivity for detecting iDNA. The iDNA sequence and structures from SNU398 and Hep3B are reported. An iDNA estimation model was developed using tissue biopsies from patients with serum viral load &lt; 4 log IU/mL and validated using SNU398 and Hep3B cell line DNA. The assay's utility for HBV genetic liquid biopsy was evaluated using matched plasma-urine samples with HBV DNA levels ranging from high to undetectable. In this pilot study, HBV-JS was detected in all body fluids, regardless of viral load. These findings indicate that the iDNA from patients with negligible or undetectable viral replication can be assessed for iDNA elimination efficacy in drug development. Moreover, a sensitive HBV genetics liquid biopsy can be feasible even for patients with undetectable serum viral load. This study underscores the potential of NGS-based methods to advance HBV management.</p>\u0000 </div>","PeriodicalId":16354,"journal":{"name":"Journal of Medical Virology","volume":"97 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143581919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HBx/DTL Positive Feedback Loop Promotes HBV-Related Hepatocellular Carcinoma Progression","authors":"Zhi-Qin Xie,&nbsp;Wen-Liang Tan,&nbsp;Zhi-Ming Wang,&nbsp;Yan Kang,&nbsp;Ming-Chang Zhang,&nbsp;Wen-Xin Li,&nbsp;Hong-Xia Li","doi":"10.1002/jmv.70284","DOIUrl":"https://doi.org/10.1002/jmv.70284","url":null,"abstract":"<div>\u0000 \u0000 <p>Although hepatitis B virus (HBV) infection is a well-documented etiologic factor for hepatocellular carcinoma (HCC), which ranks as the third leading cause of cancer-related mortality globally, the mechanism by which HBV facilitates cancer development remains largely elusive. In this study, we employed advanced methodologies including, single-cell RNA sequencing, flow cytometry, western blot analysis, chromatin immunoprecipitation-qPCR and Cut&amp;Tag to investigate the expression of DTL and its biological functions in HCC. We observed that DTL is overexpressed in HBV-positive HCC samples, with its elevated expression being associated with increased tumor cell proliferation and reduced overall and disease-free survival rates. The upregulation of DTL expression was specifically induced by the HBV regulatory protein HBx, thereby substantiating the oncogenic potential of HBV. Mechanistically, our findings indicated that the HBx protein augments DTL transcription by binding to its promoter region, subsequently facilitating HCC cell proliferation and modulating cell cycle progression, particularly by increasing the proportion of cells in the S phase. Furthermore, DTL was identified as a protein that interacts with HBx and associates with the Cullin4-RING ubiquitin ligases (CRL4s), thereby stabilizing HBx by reducing its ubiquitin-mediated degradation. In vivo experiments demonstrated that DTL not only facilitated cancer cell proliferation by modulating the cell cycle but also promoted tumorigenesis in nude mice. Moreover, DTL expression modifies the tumor immune microenvironment by increasing the proportion of regulatory T cells, thereby contributing to immune evasion. In summary, our findings underscore the pivotal role of DTL as a key regulator in HBV-related HCC by influencing cell cycle progression and establishing a positive feedback loop involving the HBx-DTL-CRL4s. These insights expand our understanding of HBV oncogenic mechanisms and suggest that DTL could serve as a novel biomarker and therapeutic target, potentially enhancing patient outcomes.</p>\u0000 </div>","PeriodicalId":16354,"journal":{"name":"Journal of Medical Virology","volume":"97 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143581849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}