Blood advances最新文献

{"title":"Hydroxyurea reduces hyperadhesion measured by a VLA-4-targeting PET tracer in sickle transgenic Townes mice.","authors":"Nishi Yadav, Qin Zhu, Lynda Little-Ihrig, Joseph D Latoche, Kathryn E Day, Kanishka Sikligar, Sina Tavakoli, Enrico M Novelli, Carolyn J Anderson","doi":"10.1182/bloodadvances.2025019423","DOIUrl":"10.1182/bloodadvances.2025019423","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"6764-6767"},"PeriodicalIF":7.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147509138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Germ line landscape stratification defines distinct molecular and prognostic groups in therapy-related myeloid neoplasms.","authors":"Oriol Calvete, Julia Mestre, Lorea Chaparro-González, Lucía Ruiz Pérez-Hita, Alba Mesa, Blanca Xicoy, Lurdes Zamora, Isabel Granada, Mar Mallo, Emili Cid, Estefania Mancini, Claudia Lozano, Laura Palomo, Pamela Acha, María Julia Montoro, Koji Sasaki, Courtney DiNardo, Guillermo Garcia-Manero, Guillermo Montalban-Bravo, Neus Torres-Hernández, Marta Santiago-Balsera, José Cervera, Gonzalo Maortua, Raquel de Paz, Martí Mascaró, Alfonso García Da Vila, Sara García-Ávila, Juan José Rodriguez-Sevilla, Leonor Arenillas, Beatriz Bellosillo, Rashmi Kanagal-Shamanna, Francesc Solé","doi":"10.1182/bloodadvances.2026020704","DOIUrl":"10.1182/bloodadvances.2026020704","url":null,"abstract":"<p><strong>Abstract: </strong>Exposure to chemotherapy (CT) and/or radiotherapy increases the risk of therapy-related myeloid neoplasms (t-MN), a heterogeneous group of disorders currently classified by treatment history rather than molecular features. Although germ line predisposition has been suggested in ∼20% of patients, its prevalence and clinical impact remain insufficiently defined. To address this, we analyzed 100 patients with t-MN by integrating clinical characteristics, prior treatment regimens, and genomic profiling. Somatic and germ line variants were identified using targeted next-generation sequencing (n = 33) or whole-exome sequencing (n = 67). Somatic abnormalities, including cytogenetic and/or molecular alterations, were detected in 89.8% of patients. Germ line variants were identified in 32.3% of patients, including mutations in cancer predisposition genes (19.8%) and myeloid disease-related genes (14.6%). Patient stratification by germ line landscape and gene category defined 2 prognostic scenarios and 3 subgroups with distinct clinical outcomes. Patients harboring germ line cancer predisposition variants were enriched for TP53 mutations and complex karyotypes and had an adverse prognosis. In contrast, patients with germ line myeloid-related variants and those without detectable germ line variants exhibited recurrent mutations in TET2, DNMT3A, SF3B1, SRSF2, RUNX1, and ASXL1, were associated with normal karyotypes, and had favorable outcomes. These findings underscore the importance of the germ line landscape in t-MN pathogenesis and support its incorporation into disease classification and risk stratification. Notably, CT exposure was associated with complex karyotypes and poor prognosis in patients with germ line cancer predisposition variants, highlighting a subgroup that may benefit from targeted surveillance and preventive strategies.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"6703-6718"},"PeriodicalIF":7.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148418920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rapid and reproducible karyotyping with long-read sequencing in patients with AML.","authors":"Michael Heuser, Anna Dolnik, Isabell Arnhardt, Courteney K Lai, Ekaterina Jahn, Mustafa Salim, Gudrun Göhring, Yvonne Lisa Behrens, Jonathan L Lühmann, Doris Steinemann, Martin Wichmann, Jens Florian Schrezenmeier, Yasmine Alwie, Arnold Kloos, Gesa Baurmann, Jörg Westermann, Frederik Damm, Hartmut Döhner, Arnold Ganser, Felicitas R Thol, Olga Blau, Konstanze Döhner, Lars Bullinger, Razif Gabdoulline, Jan Eric Sträng","doi":"10.1182/bloodadvances.2026019960","DOIUrl":"10.1182/bloodadvances.2026019960","url":null,"abstract":"<p><strong>Abstract: </strong>Acute myeloid leukemia (AML) is characterized by recurrent chromosomal abnormalities that form the basis of the European LeukemiaNet risk classification and serve as essential determinants of prognosis and therapeutic decision-making. Conventional metaphase karyotyping remains the diagnostic gold standard for detecting these abnormalities; however, its utility is limited by longer turnaround times, often delaying critical clinical management. Here, we present a long-read, low-coverage whole-genome sequencing (lcWGS) approach using Oxford Nanopore Technology as a rapid and scalable alternative for cytogenetic profiling. A total of 100 diagnostic AML samples were analyzed, comprising 50 retrospectively selected patients with known adverse-risk cytogenetics and 50 prospectively enrolled patients with clinically defined de novo AML. LcWGS demonstrated robust analytical performance, identifying chromosomal aberrations with 93% sensitivity, specificity, and overall accuracy, respectively. Complex karyotypes were reliably detected, with an area under the curve of 0.971. Reproducibility was validated through replicate sequencing at 2 independent laboratories (R = 0.99). LcWGS-derived estimates of clone size showed moderate correlation with conventional cytogenetic assessments (R = 0.54). Patients with complex karyotypes identified by lcWGS exhibited significantly shorter overall and relapse-free survival, closely mirroring outcomes defined by conventional karyotyping and underscoring the value of lcWGS for risk stratification. The median turnaround time from sample receipt to bioinformatics interpretation was ∼34 hours, enabling delivery of actionable karyotype results within 72 hours. These findings establish lcWGS as a rapid, reproducible, and accurate platform for detecting clinically relevant chromosomal abnormalities, addressing a critical need for timely risk stratification and treatment initiation in AML.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"6774-6784"},"PeriodicalIF":7.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148326817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vivo and ex vivo impact of THBD and PROCR polymorphisms on the anticoagulant response of the protein C pathway.","authors":"Sara Reda, Nadine Schwarz, Sebastian F Eckert, Jens Müller, Johannes Oldenburg, Bernd Pötzsch, Behnaz Pezeshkpoor, Heiko Rühl","doi":"10.1182/bloodadvances.2025018733","DOIUrl":"10.1182/bloodadvances.2025018733","url":null,"abstract":"<p><strong>Abstract: </strong>Venous thromboembolism (VTE) is multifactorial, and established hereditary risk factors explain only part of heritable risk. The protein C (PC) pathway is central to anticoagulant control, and common variants in thrombomodulin and endothelial PC receptor genes (THBD, PROCR) have been proposed as modulators. In 73 participants, we used standardized in vivo coagulation activation with recombinant activated factor VII (15 μg/kg) and measured thrombin markers and activated PC (APC) over 8 hours. Endothelial colony-forming cell-based ex vivo experiments were performed in 43 participants. In vivo, the ratio of APC area under the curve (AUC) to thrombin-antithrombin complex (TAT) AUC, which reflects the endogenous anticoagulant response relative to thrombin generation, provided the best model fit (adjusted R2 = 0.345). The APC response was lower in individuals with previous VTE (median, 0.13 vs 0.26) and PROCR 655A>G carriers (0.11 vs 0.26), but higher in factor V Leiden (FVL) carriers (0.32 vs 0.14) and THBD 1418C>T carriers (0.38 vs 0.13). The THBD 1418C>T effect was driven by reduced TAT AUC (30.6 vs 82.7 pmol × h/L), whereas the PROCR 655A>G effect reflected a lower APC AUC (8.6 vs 10.7 pmol × h/L). Ex vivo, the APC AUC/thrombin AUC ratio was lower with previous VTE and PROCR 655A>G, higher with FVL, and not associated with THBD 1418C>T. No in vivo or ex vivo association was observed for PROCR 4678C>G. This study provides in vivo evidence that common THBD and PROCR variants modulate PC pathway function, establishing the APC response as a sensitive end point for subtle genetic effects beyond FVL.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"6818-6827"},"PeriodicalIF":7.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Are statins interferon's best friends? Mechanistic insights.","authors":"Giacomo Maria Cerreto, Cecilia Carubbi, Marco Vitale, Elena Masselli","doi":"10.1182/bloodadvances.2026020672","DOIUrl":"10.1182/bloodadvances.2026020672","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"6845-6848"},"PeriodicalIF":7.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13681321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148155179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Canadian emicizumab registry: a blueprint for the future.","authors":"Cedric Hermans","doi":"10.1182/bloodadvances.2026021680","DOIUrl":"10.1182/bloodadvances.2026021680","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":"10 19","pages":"6860-6861"},"PeriodicalIF":7.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13681389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic graft-versus-host disease after PTCy-based prophylaxis vs non-PTCy prophylaxis.","authors":"Joseph Pidala, Jongphil Kim, Jose Laborde, Samantha Knott, Krishnakar Mogili, Justin Zinn, Alicia Monroe, Rawan Faramand, Reshma Ramlal, Farhad Khimani, Doris K Hansen, Nancy Torres-Luna, Michael D Jain, Lia E Perez, Asmita Mishra, Nima Ghalehsari, Omar Castaneda-Puglianini, Melissa Alsina, Fabiana Perna, Michael Nieder, Abu-Sayeef Mirza, Hien Liu, Taiga Nishihori, Alaa Ali, Deepak Chellapandian, Frederick L Locke, Nelli Bejanyan, Claudio Anasetti, Aleksandr Lazaryan","doi":"10.1182/bloodadvances.2026020655","DOIUrl":"10.1182/bloodadvances.2026020655","url":null,"abstract":"<p><strong>Abstract: </strong>Chronic graft-versus-host disease (GVHD) is less frequent after posttransplant cyclophosphamide (PTCy)-based prophylaxis, but its clinical characteristics and outcomes compared with chronic GVHD after non-PTCy approaches remain understudied. We addressed this through a single-center retrospective study of 1534 consecutive adult transplant recipients (PTCy, n = 477; non-PTCy, n = 1057) who received grafts from matched related or matched/mismatched unrelated donors. The cumulative incidence of National Institutes of Health (NIH) moderate/severe chronic GVHD was significantly lower after PTCy (17% vs 46%; P< .001). Among patients with chronic GVHD (PTCy, n = 163; non-PTCy, n = 656), chronic GVHD after PTCy involved fewer organ sites, had lower severity scores, and had less NIH moderate/severe disease overall. However, this profile did not translate into improved survival. Univariate analysis demonstrated higher nonrelapse mortality (NRM; 24-month NRM, 22% vs 13%; P = .014) for the PTCy group, whereas multivariate analysis showed that NRM was associated with increased age, NIH overall moderate/severe chronic GVHD severity, prior grade III/IV acute GVHD, reduced platelet count, and increased bilirubin. Chronic GVHD after PTCy was associated with increased infectious complications despite reduced immunosuppressive (IS) therapy and higher rates of complete IS discontinuation. Overall, PTCy-based prophylaxis was associated with a lower incidence and severity of chronic GVHD, and after adjustment for established prognostic factors, mortality after chronic GVHD diagnosis was comparable to that observed with non-PTCy prophylaxis approaches. Multicenter validation of these findings and novel strategies to mitigate NRM in chronic GVHD are warranted.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"6598-6609"},"PeriodicalIF":7.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13652848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A phase 1b/2 study of ceralasertib, a selective inhibitor of ATR, in patients with relapsed or refractory MDS and CMML.","authors":"Andrew M Brunner, Yiwen Liu, Jacqueline S Garcia, Lourdes Mendez, Catherine Gutierrez Moore, Sridhar Nonavinkere Srivatsan, Jin Shao, Brandon J Aubrey, Philip Amrein, Rupa Narayan, Rahul Vedula, Eliana Friedman, Donna Neuberg, Marcio Andrade-Campos, Simon A Smith, Richard Stone, Amir T Fathi, Matthew J Walter, Timothy A Graubert, Meagan A Jacoby","doi":"10.1182/bloodadvances.2026019848","DOIUrl":"10.1182/bloodadvances.2026019848","url":null,"abstract":"<p><strong>Abstract: </strong>Pre-mRNA splicing gene mutations in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) induce R-loops, which trigger ataxia telangiectasis and Rad3-related kinase (ATR). We studied ceralasertib, an orally bioavailable ATR inhibitor, in adults with relapsed or refractory (R/R) MDS or CMML in a phase 1b/2 study 160mg twice daily during 28-day cycles on 2 dosing schedules: days 1 to 14 (14on/14off) or days 1-7 and 15-21 (7on/7off). Response rates and survival were estimated. Forty-four evaluable patients were treated. Grade ≥3 adverse events included thrombocytopenia (n = 13), anemia (n = 12), neutropenia (n = 9), febrile neutropenia (n = 9), pneumonia (n = 6), and hypoxia (n = 5). Thrombocytopenia requiring a platelet transfusion during the first cycle was reduced to 1 of 10 patients on 7on/7off compared with 8/16 patients on 14on/14off among patients with a baseline platelet count >50 × 109/L (P = .087). Overall response rate (ORR) was 29.5% (13/44 patients) and included 1 complete response (CR), 5 marrow CR (2 with hematologic improvement [HI] in neutrophils [HI-N]), and 7 with HI (HI in erythroid/red cells, n = 4; HI-N, n = 2; HI in platelets, n = 1). Median progression-free survival (PFS) was 4.8 months, and overall survival (OS) was 12 months. ORR (P = .72), PFS (P = .9), and OS (P = .65) did not differ between schedules. Splicing factor mutation variant allele frequencies (VAFs) remained stable while RUNX1 mutation VAFs typically increased at progression. Serum inflammatory cytokine levels (TNFRSF8 [CD30], TNF family members) decreased during ceralasertib exposure; this effect was blunted in RUNX1-mutant samples. Ceralasertib 160 mg twice daily on days 1-7 and 15-21 was established as monotherapy dosing. This trial was registered at www.clinicaltrials.gov as NCT03770429.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"6645-6660"},"PeriodicalIF":7.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13654511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Donor-targeted anti-HLA-A2 antibody shows nanogram-level efficacy in a novel GVHD mouse model.","authors":"Kouta Niizuma, Alyssa H Chang, Yoshia Okamoto, Jeewon S Kim, Kazunari Sasaki, Stephan Busque, Ravindra Majeti, Hiromitsu Nakauchi, Yusuke Nakauchi","doi":"10.1182/bloodadvances.2025017791","DOIUrl":"10.1182/bloodadvances.2025017791","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"6812-6817"},"PeriodicalIF":7.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regional practice differences significantly affect the benefit of post-HCT gilteritinib in FLT3-ITD AML.","authors":"Mark J Levis, Mehdi Hamadani, Brent R Logan, Richard J Jones, Anurag K Singh, Mark R Litzow, John R Wingard, Esperanza B Papadopoulos, Alexander E Perl, Robert J Soiffer, Celalettin Ustun, Masumi Ueda Oshima, Geoffrey L Uy, Edmund K Waller, Sumithira Vasu, Melhem Solh, Asmita Mishra, Lori S Muffly, Hee-Je Kim, Matthias Stelljes, Yuho Najima, Masahiro Onozawa, Kirsty Thomson, Caroline Chen, Nahla Hasabou, Matt Rosales, Jason Hill, Stanley C Gill, Rishita Nuthethi, Denise King, Adam Mendizabal, Steven M Devine, Mary M Horowitz, Yi-Bin Chen","doi":"10.1182/bloodadvances.2026020327","DOIUrl":"10.1182/bloodadvances.2026020327","url":null,"abstract":"<p><strong>Abstract: </strong>BMT CTN 1506 (MORPHO) was a phase 3 study of post-hematopoietic cell transplantation (HCT) maintenance with gilteritinib vs placebo for patients with FLT3-ITD-mutated acute myeloid leukemia (AML) in first remission. Subgroup analysis indicated a significant benefit of post-HCT gilteritinib for participants in North America but no benefit for those in Europe or Asia. We conducted a post hoc analysis of the data focusing on the time from AML diagnosis to HCT, pre-HCT FLT3 inhibitor use, and FLT3-ITD measurable residual disease (MRD). Participants who underwent transplantation <120 days from AML diagnosis and/or those treated with FLT3 inhibition before HCT were more likely to have improved survival from post-HCT gilteritinib. Pre-HCT MRD levels were higher (P = .001) in participants who underwent transplantation within 120 days from diagnosis and in those treated with an FLT3 inhibitor before HCT and underwent transplantation within 120 days (P = .008). Pre-HCT MRD was dependent on both FLT3 inhibitor use and time to HCT, because participants treated with successive courses of chemotherapy + FLT3 inhibition had successively lower MRD by the time of HCT. Time from AML diagnosis to HCT and pre-HCT FLT3 inhibitor use both appeared to affect MRD levels immediately before HCT, and geographic differences in these 2 practice patterns likely accounted for the observed regional differences in benefit from post-HCT gilteritinib. Increasing the number of courses of treatment before HCT may lower MRD sufficiently to eliminate the need for post-HCT inhibition, but with a presumed risk of some patients experiencing early progression. This trial was registered at www.clinicaltrials.gov as #NCT02997202.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"6754-6763"},"PeriodicalIF":7.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148629388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}