Research Square最新文献

{"title":"Comparing methods for risk prediction of multicategory outcomes: dichotomized logistic regression vs. multinomial logit regression","authors":"lei li, Matthew A. Rysavy, G. Bobashev, Abhik Das","doi":"10.21203/rs.3.rs-3911212/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3911212/v1","url":null,"abstract":"Abstract Background Medical outcomes of interest to clinicians may have multiple categories. Researchers face several options for risk prediction of such outcomes, including dichotomized logistic regression and multinomial logit regression modeling. We aimed to compare these methods and provide practical guidance needed. Methods We described dichotomized logistic regression and competing risks regression, and an alternative to standard multinomial logit regression, continuation-ratio logit regression for ordinal outcomes. We then applied these methods to develop prediction models of survival and growth outcomes based on the NICHD Extremely Preterm Birth Outcome Tool model. The statistical and practical advantages and flaws of these methods were examined and both discrimination and calibration of the estimated models were assessed. Results The dichotomized logistic models and multinomial continuation-ratio logit model had similar discrimination and calibration in predicting death and survival without neurodevelopmental impairment. But the continuation-ratio logit model had better discrimination and calibration in predicting probabilities of neurodevelopmental impairment. The sum of predicted probabilities of outcome categories from the logistic models did not equal 100% for about half of the study infants, ranging from 87.7% to 124.0%, and the logistic model of neurodevelopmental impairment greatly overpredicted the risk among low-risk infants and underpredicted among high-risk infants. Conclusions Estimating multiple logistic regression models of dichotomized outcomes may result in poorly calibrated predictions. For an outcome with multiple ordinal categories, continuation-ratio logit regression is a useful alternative to standard multinomial logit regression. It produces better calibrated predictions and has the advantages of simplicity in model interpretation and flexibility to include outcome category-specific predictors and random-effect terms for patient heterogeneity by hospital.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139965434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repurposing mebendazole against triple-negative breast cancer leptomeningeal disease","authors":"Adrian Rodrigues, Sophia B. Chernikova, Yuelong Wang, Thy T. H. Trinh, D. Solow-Cordero, Ludmila Alexandrova, Kerriann M. Casey, Elizabeth Alli, Abhishek Aggarwal, Tyler Quill, Ashley Koegel, Brian J. Feldman, James M. Ford, M. Hayden-Gephart","doi":"10.21203/rs.3.rs-3915392/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3915392/v1","url":null,"abstract":"Abstract Purpose Triple-negative breast cancer (TNBC) is an aggressive subtype that often metastasizes to the brain. Leptomeningeal disease (LMD), a devastating brain metastasis common in TNBC, has limited treatment options. We sought to test whether the common anti-helminthic drug mebendazole (MBZ) may be effective against murine TNBC LMD. Methods A small-molecule screen involving TNBC cell lines identified benzimidazoles as potential therapeutic agents for further study. In vitro migration assays were used to evaluate cell migration capacity and the effect of MBZ. For in vivo testing, LMD was introduced into BALB/c athymic nude mice through internal carotid artery injections of brain-tropic MDA-MB-231-BR or MCF7-BR cells. Tumor growth and spread was monitored by bioluminescence imaging. MBZ was given orally at 50 and 100 mg/kg doses. MBZ bioavailability was assayed by mass spectrometry. Results Bioinformatic analysis and migration assays revealed higher migratory capacity of TNBC compared to other breast cancer subtypes. MBZ effectively slowed down migration of TNBC cell line MDA-MB-231 and its brain tropic derivative MDA-MB-231-BR. In animal studies, MBZ reduced tumor growth and extended survival in the LMD model produced by MDA-MB-231-BR cells. MBZ did not have an effect in the non-migratory MCF7-BR model. Conclusions We demonstrated that MBZ is a safe and effective oral agent in an animal model of TNBC LMD. Our findings are concordant with previous efforts involving MBZ and central nervous system pathology and further support the drug’s potential utility as an alternative therapeutic for TNBC LMD.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139965400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epidemiology of unintentional injuries among 15-24-year-old vocational school youth from Peshawar Pakistan: A cross-sectional survey.","authors":"Sarwat Masud, Adnan A Hyder, Uzma Rahim Khan, Nadeem Ullah Khan, Ahmed Raheem, Pammla Petrucka","doi":"10.21203/rs.3.rs-2603081/v1","DOIUrl":"10.21203/rs.3.rs-2603081/v1","url":null,"abstract":"<p><strong>Background: </strong>The burden of unintentional injuries among youth (15-24 years) is high. There is paucity of data on unintentional injuries in youth working in Vocational Training Institutes.</p><p><strong>Objective: </strong>To determine the incidence, characteristics, and risk factors of unintentional injuries among youth.</p><p><strong>Methods: </strong><b>Design::</b> <b>A</b> retrospective cross-sectional survey was conducted among select vocational school youth in Peshawar, Pakistan between February 2022 to October 2022.<b>Participants::</b> A total of 547 study participants participated in the survey, 356 were males while 191 were females. Data were collected on using the World Health Organization community survey guide for injuries and violence. Multilevel Negative Binomial Regression model was used to report incidence rate ratios of all unitentional injuries.</p><p><strong>Results: </strong><b>A</b> total of 503 injuries were reported by the youth, with road traffic injuries being the most common (n=197, 39%), followed by burns (n=89, 18%), falls (n=79, 16%) and poisonings (n=15, 3%), drownings (n=23, 7.1%). Occupational injuries reported during vocational training were (n=95, 18%). Males had a higher incidence rates of RTI 3.24[2.35-5.3], falls 1.30 [0.74-2.27], poisonings 2.14 [0.57-7.58] and drownings 2.46(0.84-7.21), while females had a higher incidence rate of burns 2.19 [1.785-3.46].Lack of education 4.6 [1.12 -18.91] (<i>p</i>=0.034), smoking 1.25 [1.05 -2.69] (<i>p</i>=0.049), lack of fathers education 4.71 [2.12 -10.49] (<i>p</i>=<0.001), carrying a gun 6.59 [2.54 -17.11] (<i>p</i>=<0.001), crowded families 3.59 [3.11 -5.07] (<i>p</i>=<0.001), lower family income 2.04 [1.04 -4.02](<i>p</i>=0.039*), lack of helmet use 4.54 [2.12 -9.76] (<i>p</i>=<0.001) and lack of seat belt use 1.3 [1.14 -1.69] <i>(p=</i> <0.001) were significant risk factors for unintentional injuries in youth.</p><p><strong>Conclusion added value of the study: </strong>This study is one of the first research studies conducted in vocational school youth in Pakistan. It provides the recent rate of unintentional injuries among the youth of Pakistan. High occupational injuries among vocational school youth were reported which needs further research.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10029088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9186958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Migrate3D: Software for simplified post-tracking analysis of 3D and 2D cell migration data.","authors":"Emily R Mynar, Matthew W Kinahan, Markus Thali, Menelaos Symeonides","doi":"10.21203/rs.3.rs-2451513/v1","DOIUrl":"10.21203/rs.3.rs-2451513/v1","url":null,"abstract":"<p><p>Migrate3D is a cell migration analysis tool whose purpose is to computationally process positional cell tracking data generated via other image acquisition/analysis software and generate biologically meaningful results. The functionalities of Migrate3D include step-based calculations of each cell track, single-cell-level summary statistics, mean squared displacement analysis, and machine learning-based evaluation of the entire dataset and subpopulations of cells found within it. The parameters calculated within Migrate3D have been previously developed and validated by other groups, and were selected to facilitate extraction of the maximum depth of information possible from input datasets. Variables are user-adjustable to enable customized analyses of diverse motility patterns and cell types, both in three-and two-dimensional timelapse data. Independent of any particular upstream image analysis or cell tracking software, Migrate3D only needs positional data over time to execute the suite of calculations. This presents a unique opportunity to standardize and streamline cell migration analysis.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9882690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10707529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"[WITHDRAWN] Serum biomarkers of liver fibrosis identify changes in striatal metabolite levels.","authors":"","doi":"10.21203/rs.3.rs-2729490/v1","DOIUrl":"10.21203/rs.3.rs-2729490/v1","url":null,"abstract":"<p><p>The full text of this preprint has been withdrawn by the authors due to author disagreement with the posting of the preprint. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10081358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9404004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A week in the life of the human brain: stable states punctuated by chaotic transitions.","authors":"Maxwell Wang, Max G'Sell, James F Castellano, R Mark Richardson, Avniel Ghuman","doi":"10.21203/rs.3.rs-2752903/v1","DOIUrl":"10.21203/rs.3.rs-2752903/v1","url":null,"abstract":"<p><p>Many important neurocognitive states, such as performing natural activities and fluctuations of arousal, shift over minutes-to-hours in the real-world. We harnessed 3-12 days of continuous multi-electrode intracranial recordings in twenty humans during natural behavior (socializing, using digital devices, sleeping, etc.) to study real-world neurodynamics. Applying deep learning with dynamical systems approaches revealed that brain networks formed consistent stable states that predicted behavior and physiology. Changes in behavior were associated with bursts of rapid neural fluctuations where brain networks chaotically explored many configurations before settling into new states. These trajectories traversed an hourglass-shaped structure anchored around a set of networks that slowly tracked levels of outward awareness related to wake-sleep stages, and a central attractor corresponding to default mode network activation. These findings indicate ways our brains use rapid, chaotic transitions that coalesce into neurocognitive states slowly fluctuating around a stabilizing central equilibrium to balance flexibility and stability during real-world behavior.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10081438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9387816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Planetary Child Health & Enterics Observatory (Plan-EO): a protocol for an interdisciplinary research initiative and web-based dashboard for mapping enteric infectious diseases and their risk factors and interventions in LMICs.","authors":"Josh M Colston, Pavel Chernyavskiy, Lauren Gardner, Malena Nong, Bin Fang, Eric Houpt, Samarth Swarup, Hamada Badr, Benjamin Zaitchik, Venkataraman Lakshmi, Margaret Kosek","doi":"10.21203/rs.3.rs-2640564/v3","DOIUrl":"10.21203/rs.3.rs-2640564/v3","url":null,"abstract":"<p><strong>Background: </strong>Diarrhea remains a leading cause of childhood illness throughout the world that is increasing due to climate change and is caused by various species of ecologically sensitive pathogens. The emerging Planetary Health movement emphasizes the interdependence of human health with natural systems, and much of its focus has been on infectious diseases and their interactions with environmental and human processes. Meanwhile, the era of big data has engendered a public appetite for interactive web-based dashboards for infectious diseases. However, enteric infectious diseases have been largely overlooked by these developments.</p><p><strong>Methods: </strong>The Planetary Child Health and Enterics Observatory (Plan-EO) is a new initiative that builds on existing partnerships between epidemiologists, climatologists, bioinformaticians, and hydrologists as well as investigators in numerous low- and middle-income countries. Its objective is to provide the research and stakeholder community with an evidence base for the geographical targeting of enteropathogen-specific child health interventions such as novel vaccines. The initiative will produce, curate, and disseminate spatial data products relating to the distribution of enteric pathogens and their environmental and sociodemographic determinants.</p><p><strong>Discussion: </strong>As climate change accelerates there is an urgent need for etiology-specific estimates of diarrheal disease burden at high spatiotemporal resolution. Plan-EO aims to address key challenges and knowledge gaps by making rigorously obtained, generalizable disease burden estimates freely available and accessible to the research and stakeholder communities. Pre-processed environmental and EO-derived spatial data products will be housed, continually updated, and made publicly available to the research and stakeholder communities both within the webpage itself and for download. These inputs can then be used to identify and target priority populations living in transmission hotspots and for decision-making, scenario-planning, and disease burden projection.</p><p><strong>Study registration: </strong>PROSPERO protocol #CRD42023384709.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10055683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9387786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FAK loss reduces BRAF^V600E-induced ERK phosphorylation to promote intestinal stemness and cecal tumor formation.","authors":"Chenxi Gao, Huaibin Ge, Shih-Fan Kuan, Chunhui Cai, Xinghua Lu, Farzad Esni, Robert Schoen, Jing Wang, Edward Chu, Jing Hu","doi":"10.21203/rs.3.rs-2531119/v2","DOIUrl":"10.21203/rs.3.rs-2531119/v2","url":null,"abstract":"<p><p><i>BRAF</i> ^V600E mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAF^V600E drives tumorigenesis through constitutive downstream extracellular signal-regulated kinase (ERK) activation, but high-intensity ERK activation can also trigger tumor suppression. Whether and how oncogenic ERK signaling can be intrinsically adjusted to a \"just-right\" level optimal for tumorigenesis remains undetermined. In this study, we found that FAK (Focal adhesion kinase) expression was reduced in <i>BRAF</i>^V600E-mutant adenomas/polyps in mice and patients. In <i>Vill-Cre</i>;<i>BRAF</i>^V600E/+;<i>Fak</i>^fl/fl mice, <i>Fak</i> deletion maximized BRAF^V600E's oncogenic activity and increased cecal tumor incidence to 100%. Mechanistically, our results showed that Fak loss, without jeopardizing BRAF^V600E-induced ERK pathway transcriptional output, reduced EGFR (epidermal growth factor receptor)-dependent ERK phosphorylation. Reduction in ERK phosphorylation increased the level of Lgr4, promoting intestinal stemness and cecal tumor formation. Our findings show that a \"just-right\" ERK signaling optimal for <i>BRAF</i>^V600E-induced cecal tumor formation can be achieved via Fak loss-mediated downregulation of ERK phosphorylation.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9915899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10685302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIV-1 interaction with an <i>O</i>-glycan-specific bacterial lectin enhances virus infectivity and resistance to neutralization by antibodies.","authors":"Daniel W Heindel, Dania M Figueroa Acosta, Marisa Goff, Clauvis Kunkeng Yengo, Muzafar Jan, Xiaomei Liu, Xiao-Hong Wang, Mariya I Petrova, Mo Zhang, Manish Sagar, Phillip Barnette, Shilpi Pandey, Ann J Hessell, Kun-Wei Chan, Xiang-Peng Kong, Benjamin K Chen, Lara K Mahal, Barbara A Bensing, Catarina E Hioe","doi":"10.21203/rs.3.rs-2596269/v2","DOIUrl":"10.21203/rs.3.rs-2596269/v2","url":null,"abstract":"<p><p>Bacteria dysbiosis has been associated with an increased risk of HIV-1 transmission and acquisition. The prevalent idea is that bacteria dysbiosis compromises mucosal integrity and promotes inflammatory conditions to cause recruitment and activation of immune cells that harbor or are targeted by HIV-1. However, it is also possible that HIV-1 directly binds bacteria or bacterial products to impact virus infectivity and transmissibility. This study evaluated HIV-1 interactions with bacteria through glycan-binding lectins. The <i>Streptococcal</i> Siglec-like lectin SLBR-N, which is part of the fimbriae shrouding the bacteria surface and recognizes α2,3 sialyated <i>O</i>-linked glycans, was noted for its ability to enhance HIV-1 infectivity in the context of cell-free infection and cell-to-cell transfer. Enhancing effects were recapitulated with <i>O</i>-glycan-binding plant lectins, signifying the importance of <i>O</i>-glycans. Conversely, <i>N</i>-glycan-binding bacterial lectins FimH and Msl had no effect. SLBR-N was demonstrated to capture and transfer infectious HIV-1 virions, bind to <i>O</i>-glycans on HIV-1 Env, and increase HIV-1 resistance to broadly neutralizing antibodies targeting different regions of Env. Hence, this study highlights the potential contribution of <i>O</i>-glycans in promoting HIV-1 infection through the exploitation of <i>O</i>-glycan-binding lectins from commensal bacteria at the mucosa.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9949255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9091395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Illuminating T cell-dendritic cell interactions in vivo by FlAsHing antigens.","authors":"Munir Akkaya, Jafar Al Souz, Daniel Williams, Rahul Kamdar, Olena Kamenyeva, Juraj Kabat, Ethan M Shevach, Billur Akkaya","doi":"10.21203/rs.3.rs-3193191/v3","DOIUrl":"10.21203/rs.3.rs-3193191/v3","url":null,"abstract":"<p><p>Delineating the complex network of interactions between antigen-specific T cells and antigen presenting cells (APCs) is crucial for effective precision therapies against cancer, chronic infections, and autoimmunity. However, the existing arsenal for examining antigen-specific T cell interactions is restricted to a select few antigen-T cell receptor pairs, with limited in situ utility. This lack of versatility is largely due to the disruptive effects of reagents on the immune synapse, which hinder real-time monitoring of antigen-specific interactions. To address this limitation, we have developed a novel and versatile immune monitoring strategy by adding a short cysteine-rich tag to antigenic peptides that emits fluorescence upon binding to thiol-reactive biarsenical hairpin compounds. Our findings demonstrate the specificity and durability of the novel antigen-targeting probes during dynamic immune monitoring in vitro and in vivo. This strategy opens new avenues for biological validation of T-cell receptors with newly identified epitopes by revealing the behavior of previously unrecognized antigen-receptor pairs, expanding our understanding of T cell responses.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10402196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10018842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}