Blood Cells Molecules and Diseases最新文献

{"title":"Prevalence of SARS-CoV-2 in hemoglobinopathies is modified by age and race","authors":"Jennifer K. Frediani ,&nbsp;Ezra Pak-Harvey ,&nbsp;Richard Parsons ,&nbsp;Adrianna L. Westbrook ,&nbsp;William O'Sick ,&nbsp;Greg S. Martin ,&nbsp;Wilbur A. Lam ,&nbsp;Joshua M. Levy","doi":"10.1016/j.bcmd.2023.102756","DOIUrl":"10.1016/j.bcmd.2023.102756","url":null,"abstract":"<div><p>Prior literature has established a positive association between sickle cell disease and risk of contracting SARS-CoV-2. Data from a cross-sectional study evaluating COVID-19 testing devices (<em>n</em> = 10,567) was used to examine the association between underlying health conditions and SARS-CoV-2 infection in an urban metropolis in the southern United States. Firth's logistic regression was used to fit the model predicting SARS-CoV-2 positivity using vaccine status and different medical conditions commonly associated with COVID-19. Another model using the same method was built using SARS-CoV-2 positivity as the outcome and hemoglobinopathy presence, age (&lt;16 Years vs. ≥16 Years), race/ethnicity and comorbidities, including hemoglobinopathy, as the factors. Our first model showed a significant association between hemoglobinopathy and SARS-CoV-2 infection (OR: 2.28, 95 % CI: (1.17,4.35), <em>P</em> = 0.016). However, in the second model, this association was not maintained (OR: 1.35, 95 % CI: (0.72,2.50), <em>P</em> = 0.344). We conclude that the association between SARS-CoV-2 positivity and presence of hemoglobinopathies like sickle cell disease is confounded by race, age, and comorbidity status. Our results illuminate previous findings by identifying underlying clinical/demographic factors that confound the reported association between hemoglobinopathies and SARS-CoV-2. These findings demonstrate how social determinants of health may influence disease manifestations more than genetics alone.</p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"102 ","pages":"Article 102756"},"PeriodicalIF":2.3,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10198733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9659326","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":"Two new mutations in the GLRX5 gene cause sideroblastic anemia","authors":"Andrés Felipe Melo Arias,&nbsp;Silvia Escribano Serrat,&nbsp;Jorge Martínez Nieto,&nbsp;Fiorella Medina Salazar,&nbsp;Paloma Ropero Gradilla,&nbsp;Celina Benavente Cuesta,&nbsp;Fernando Ataúlfo González Fernández","doi":"10.1016/j.bcmd.2023.102763","DOIUrl":"10.1016/j.bcmd.2023.102763","url":null,"abstract":"","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"102 ","pages":"Article 102763"},"PeriodicalIF":2.3,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10041805","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":"The utility of multiple genomic technologies for interpretation of modern next generation sequencing: A novel case of three FANCA gene variants resulting in autosomal recessive Fanconi anaemia","authors":"J. Coleman ,&nbsp;A.J. Green ,&nbsp;L. Bradley","doi":"10.1016/j.bcmd.2023.102762","DOIUrl":"10.1016/j.bcmd.2023.102762","url":null,"abstract":"<div><p><span>Fanconi anaemia<span><span> (FA) is a rare autosomal recessive condition resulting in changes in the FANC </span>gene family<span>. This report describes a case of Fanconi anaemia in a family with complex biallelic variants. The patient is a 32-year-old female diagnosed with FA on cascade testing during childhood with chromosome breakage<span> studies. On examination she had a fixed deformity of the right thumb and the proximal interphalangeal joint<span> was immobile. Her brother shared this radial abnormality and had FA, requiring a bone marrow transplant. She presented in adulthood seeking further </span></span></span></span></span><em>BRCA</em><span> advice and had next generation sequencing that showed three variants in the </span><span><em>FANCA</em></span> gene. One allele a known pathogenic change, the other had two sequence variants in tandem that have been reported as variants of uncertain significance. There is one other unrelated case of these two variants occurring together in cis, resulting in Fanconi anaemia. This case is an interesting example of three variants in the <em>FANCA</em><span> gene, one allele with a pathogenic deletion and the other with a single complex allele made up of two missense variants of uncertain significance, likely manifesting with FA. It highlights the utility of different genetic technologies in the interpretation of next generation sequencing.</span></p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"102 ","pages":"Article 102762"},"PeriodicalIF":2.3,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9721520","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":"The inhibitor of MyoD Family A (I-MFA) regulates megakaryocyte lineage commitment and terminal differentiation","authors":"Jeremy S. Houser ,&nbsp;Maulin Patel ,&nbsp;Kyle Wright ,&nbsp;Marta Onopiuk ,&nbsp;Leonidas Tsiokas ,&nbsp;Mary Beth Humphrey","doi":"10.1016/j.bcmd.2023.102760","DOIUrl":"10.1016/j.bcmd.2023.102760","url":null,"abstract":"<div><p><span><span><span>Hematopoiesis<span> and lineage commitment are regulated by several conserved cell-intrinsic </span></span>signaling pathways<span>, including MAPKs and β-catenin/TCF/LEF. The Inhibitor of </span></span>MyoD<span><span><span> Family A (I-MFA), a transcriptional repressor and </span>tumor suppressor gene, interacts with these pathways and is dysregulated in chronic and </span>acute myeloid leukemias<span>, suggesting it may play a role in development and differentiation during hematopoiesis. To study this, immune cell populations in the bone marrow (BM) and periphery were analyzed in mice lacking </span></span></span><em>Mdfi,</em><span> encoding I-MFA (I-MFA−/−), and wild type (WT) controls. I-MFA−/− mice had reduced spleen and BM cellularity, with significant hyposplenism, compared to WT mice. In blood, total red blood cells<span> and platelet counts were significantly reduced in I-MFA−/− mice, accompanied by a reduction in megakaryocyte<span><span><span> (MK)/erythrocyte progenitor cells and an increase in myeloid progenitors in BM compared to WT mice. The K562 cell line exhibits PMA-induced MK differentiation, and </span>shRNA knockdown of I-MFA resulted in reduced differentiation compared to control, with an increase and prolongation in phospho-JNK and phospho-ERK signaling. Overexpression of I-MFA promoted MK differentiation. These results suggest I-MFA plays a cell-intrinsic role in the response to differentiation signals, an effect that can be explored in the context of </span>hematological cancers or other blood proliferative disorders.</span></span></span></p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"102 ","pages":"Article 102760"},"PeriodicalIF":2.3,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9659338","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":"Drinking recommended daily water significantly alters haemato-biochemical parameters in prospective blood donors; a one-center quasi-experimental study in a tropical setting","authors":"Bright Kekeli Gbadago ,&nbsp;Juliet Antiaye ,&nbsp;Joseph Boachie ,&nbsp;Patrick Adu","doi":"10.1016/j.bcmd.2023.102757","DOIUrl":"10.1016/j.bcmd.2023.102757","url":null,"abstract":"<div><h3>Background</h3><p>In sub-Saharan Africa, the prevailing high ambient temperatures should warrant increased daily water intake (DWI) to prevent haemo-concentration and its potential to confound patients' laboratory data.</p></div><div><h3>Aim</h3><p>To assess the impact that the recommended DWI has on the haemato-biochemical variables in a tropical setting.</p></div><div><h3>Materials and methods</h3><p>This quasi-experimental study recruited 101 apparently healthy individuals (18–60 years) in the Bawku municipality. DWI, anthropometrics, and haemato-biochemical variables were assessed at baseline. Participants were encouraged to increase their DWI to ≥4 L over a 30-day period; haemato-biochemical variables were re-evaluated. Total body water (TBW) was anthropometrically estimated.</p></div><div><h3>Results</h3><p><span>The median post-treatment DWI significantly increased; consequently, anaemia cases increased by &gt;20-fold (2.0 % vs 47.5 % post-treatment). RBC<span> count, platelet count<span>, WBC count, and median haemoglobin significantly decreased compared to baseline (</span></span></span><em>p</em><span><span><span> &lt; 0.0001). Biochemically, median plasma osmolality (p &lt; 0.0001), </span>serum sodium (p &lt; 0.0001), </span>serum potassium (</span><em>p</em><span> = 0.0012) and random blood sugar (</span><em>p</em><span><span> = 0.0403) significantly decreased. Compared to baseline, significantly higher proportion of participants classified as thrombocytopenic (8.9 % vs 3.0 %), hyponatraemia (10.9 % vs 2.0 %), or normal </span>osmolarity (77.2 % vs 20.8 %). There were differential bivariate correlations between pre- and post-treatment haemato-biochemical variables.</span></p></div><div><h3>Conclusion</h3><p>Sub-optimal DWI is a likely confounder in haemato-biochemical data interpretation in the tropics.</p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"102 ","pages":"Article 102757"},"PeriodicalIF":2.3,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9667141","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":"Severe clinical picture in a cohort of six Brazilian children with hemoglobin Sβ-thalassemia IVS-I-5 G>A","authors":"Marcos Borato Viana ,&nbsp;Érica Louback Oliveira ,&nbsp;André Rolim Belisário","doi":"10.1016/j.bcmd.2023.102795","DOIUrl":"10.1016/j.bcmd.2023.102795","url":null,"abstract":"","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"104 ","pages":"Article 102795"},"PeriodicalIF":2.3,"publicationDate":"2023-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10201581","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":"Discovery of seven hox genes in zebrafish thrombopoiesis","authors":"Hemalatha Sundaramoorthi,&nbsp;Weam Fallatah,&nbsp;Jabila Mary,&nbsp;Pudur Jagadeeswaran","doi":"10.1016/j.bcmd.2023.102796","DOIUrl":"10.1016/j.bcmd.2023.102796","url":null,"abstract":"<div><p><span><span>Thrombopoiesis is the production of platelets from </span>megakaryocytes<span> in the bone marrow of mammals. In fish, thrombopoiesis involves the formation of thrombocytes without megakaryocyte-like precursors but derived from erythrocyte thrombocyte bi-functional precursor cells. One unique feature of thrombocyte differentiation involves the maturation of young thrombocytes in circulation. In this study, we investigated the role of </span></span><em>hox</em> genes in zebrafish thrombopoiesis to model platelet production. We selected <em>hoxa10b</em>, <em>hoxb2a</em>, <em>hoxc5a</em>, <em>hoxd3a,</em> and <em>hoxc11b</em><span> from thrombocyte RNA expression data, and checked whether they are expressed in young or mature thrombocytes. We found </span><em>hoxa10b</em>, <em>hoxb2a</em>, <em>hoxc5a</em>, and <em>hoxd3a</em> were expressed in both young and mature thrombocytes and <em>hoxc11b</em> was expressed in only young thrombocytes. We then performed knockdowns of these 5 <em>hox</em> genes and found <em>hoxc11b</em><span><span> knockdown resulted in thrombocytosis and the rest showed </span>thrombocytopenia. To identify </span><em>hox</em> genes that could have been missed by the above datasets, we performed knockdowns 47 <em>hox</em> genes in the zebrafish genome and found <em>hoxa9a</em>, and <em>hoxb1a</em> knockdowns resulted in thrombocytopenia and they were expressed in both young and mature thrombocytes. In conclusion, our comprehensive knockdown study identified Hoxa10b, Hoxb2a, Hoxc5a, Hoxd3a, Hoxa9a, and Hoxb1a, as positive regulators and Hoxc11b<em>,</em> as a negative regulator for thrombocyte development.</p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"104 ","pages":"Article 102796"},"PeriodicalIF":2.3,"publicationDate":"2023-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10634046","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":"Outcome of first or second transplantation using unrelated umbilical cord blood without ATG conditioning regimen for pediatric bone marrow failure disorders","authors":"Xia Chen ,&nbsp;Fang Liu ,&nbsp;Yuanyuan Ren ,&nbsp;Luyang Zhang,&nbsp;Yang Wan,&nbsp;Wenyu Yang,&nbsp;Xiaojuan Chen,&nbsp;Li Zhang,&nbsp;Yao Zou,&nbsp;Yumei Chen,&nbsp;Xiaofan Zhu,&nbsp;Ye Guo","doi":"10.1016/j.bcmd.2023.102793","DOIUrl":"10.1016/j.bcmd.2023.102793","url":null,"abstract":"<div><h3>Background</h3><p><span>Unrelated umbilical cord blood transplantation<span> (UCBT) for bone marrow failure (BMF) disorders using conditioning regimens without Anti-Thymocyte Globulin (ATG) has been used as an alternative transplantation for emerging patients without matched-sibling donors. Experience with this transplant modality in children is limited, especially as a secondary </span></span>treatment for transplant failure patients.</p></div><div><h3>Procedure</h3><p><span><span>We retrospectively reviewed 17 consecutive bone marrow failure patients who underwent unrelated umbilical cord blood transplantation in our center and received conditioning regimens of Total Body Irradiation (TBI) or </span>Busulfan<span> (BU) + Fludarabine (FLU) + </span></span>Cyclophosphamide (CY).</p></div><div><h3>Results</h3><p>Among the 17 BMF patients, 15 patients were treated with first cord blood transplantation and another 2 with secondary cord blood transplantation because of graft failure<span> after first haploidentical stem cell transplantation at days +38 and +82.</span></p><p><span>All patients engrafted with a median donor cell chimerism of 50 % at days +7 (range, 16 %–99.95 %) and finally rose to 100 % at days +30. Median time to neutrophil </span>engraftment<span><span> was 19 days (range, 12–30) and time to platelet engraftment was 32 days (range, 18–61). Pre-engraftment syndrome (PES) was found in 16 patients (94.11 %, 16/17). Cumulative incidence of grades II to IV acute GVHD was 58.8 % (95 % CI: 32.7–84.9 %), and 17.6 % (95 % CI: 2.6–37.9 %) of patients developed </span>chronic GVHD. The 3-year overall survival (OS) and failure-free survival (FFS) rates were 92.86 ± 6.88 %.</span></p></div><div><h3>Conclusion</h3><p>UCBT is an effective alternative treatment for bone marrow failure pediatric patients. TBI/BU + FLU + CY regimen ensure a high engraftment rate for unrelated umbilical cord blood transplantation, which overcomes the difficulty of graft failure. Secondary salvage use of cord blood transplantation may still be useful for patients who have failed after other transplantation.</p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"104 ","pages":"Article 102793"},"PeriodicalIF":2.3,"publicationDate":"2023-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10131323","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":"Molecular and clinical characterization of two unrelated families with factor V deficiency, including a novel nonsense variant (p.Gln1532*)","authors":"Ke Zhang,&nbsp;Longying Ye,&nbsp;Yanhui Jin,&nbsp;Yuan Chen,&nbsp;Shuting Jiang,&nbsp;Haixiao Xie,&nbsp;Lihong Yang,&nbsp;Mingshan Wang","doi":"10.1016/j.bcmd.2023.102794","DOIUrl":"10.1016/j.bcmd.2023.102794","url":null,"abstract":"<div><h3>Background</h3><p>Factor V (FV) is an essential cofactor in the coagulation cascade. The characterization of novel mutations is advantageous for the clinical management of FV-deficient patients.</p></div><div><h3>Methods</h3><p>Coagulation screening and thrombin generation assay were performed with the plate-poor plasma. All 25 exons of the <em>F5</em><span> gene were amplified and sequenced. The ClustalX-2.1 software was applied to the multiple sequence alignment<span><span>. The possible adverse effects of mutations were investigated with online bioinformatics software and </span>protein modeling.</span></span></p></div><div><h3>Results</h3><p><span><span>Two unrelated families with FV deficiency were under investigation. Proband<span> A was an 18-year-old youth with recurrent epistaxis. Proband B was a 29-year-old woman who did not present with any bleeding symptoms. Three heterozygous mutations (p.Gln1532*, p.Phe218Ser, and p.Asp2222Gly) were detected. Interestingly, they were compound </span></span>heterozygotes and both contained the p.Asp2222Gly, a polymorphism. The thrombin generation assay showed that both patients had impaired ability of thrombin generation, and in particular, proband A was more severe. Conservation, </span>pathogenicity and protein modeling studies all indicated that these three mutations could cause deleterious effects on the function and structure of FV.</p></div><div><h3>Conclusion</h3><p>These three mutations are responsible for the FV-deficient in two pedigrees. Moreover, the nonsense variant p.Gln1532* is first reported in the world.</p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"104 ","pages":"Article 102794"},"PeriodicalIF":2.3,"publicationDate":"2023-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10110346","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":"Bach1 inhibitor HPP-D mediates γ-globin gene activation in sickle erythroid progenitors","authors":"Chithra D. Palani ,&nbsp;Xingguo Zhu ,&nbsp;Manickam Alagar ,&nbsp;Otis C. Attucks ,&nbsp;Betty S. Pace","doi":"10.1016/j.bcmd.2023.102792","DOIUrl":"10.1016/j.bcmd.2023.102792","url":null,"abstract":"<div><p><span><span><span><span>Sickle cell disease (SCD) is the most common β-hemoglobinopathy caused by various mutations in the adult β-globin gene resulting in </span>sickle hemoglobin production, chronic </span>hemolytic anemia<span>, pain, and progressive organ damage. The best therapeutic strategies to manage the clinical symptoms of SCD is the induction of fetal hemoglobin (HbF) using chemical agents. At present, among the Food and Drug Administration-approved </span></span>drugs<span> to treat SCD, hydroxyurea<span><span> is the only one proven to induce HbF protein synthesis, however, it is not effective in all people. Therefore, we evaluated the ability of the novel Bach1 inhibitor, HPP-D to induce HbF in KU812 cells and primary sickle erythroid progenitors. HPP-D increased HbF and decreased Bach1 protein levels in both cell types. Furthermore, </span>chromatin immunoprecipitation assay<span> showed reduced Bach1 and increased NRF2 binding to the γ-globin promoter antioxidant response elements. We also observed increased levels of the active </span></span></span></span>histone<span> marks H3K4Me1 and H3K4Me3 supporting an open chromatin configuration. In primary sickle erythroid progenitors, HPP-D increased γ-globin transcription and HbF positive cells and reduced sickled erythroid progenitors under hypoxia conditions. Collectively, our data demonstrate that HPP-D induces γ-globin gene transcription through Bach1 inhibition and enhanced NRF2 binding in the γ-globin promoter antioxidant response elements.</span></p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"104 ","pages":"Article 102792"},"PeriodicalIF":2.3,"publicationDate":"2023-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10065919","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}