Pub Date : 2024-08-19DOI: 10.1136/thorax-2023-221041
Angela Bronte, Sofia González-Ibán, Elia Lecumberri de Fuentes, Héctor Lajusticia
{"title":"Angiosarcoma of the pulmonary artery as an unexpected evolution of an apparent pulmonary thromboembolism.","authors":"Angela Bronte, Sofia González-Ibán, Elia Lecumberri de Fuentes, Héctor Lajusticia","doi":"10.1136/thorax-2023-221041","DOIUrl":"10.1136/thorax-2023-221041","url":null,"abstract":"","PeriodicalId":23284,"journal":{"name":"Thorax","volume":" ","pages":"891-892"},"PeriodicalIF":9.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141559860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-19DOI: 10.1136/thorax-2023-220964
Senne Cuyx, Anabela Santo Ramalho, Steffen Fieuws, Nikky Corthout, Marijke Proesmans, Mieke Boon, Kaline Arnauts, Marianne S Carlon, Sebastian Munck, Lieven Dupont, Kris De Boeck, François Vermeulen
Background: Diagnosing cystic fibrosis (CF) is not always straightforward, in particular when sweat chloride concentration (SCC) is intermediate and <2 CF-causing CFTR variants are identified. The physiological CFTR assays proposed in the guidelines, nasal potential difference and intestinal current measurement, are not readily available nor feasible at all ages. Rectal organoid morphology analysis (ROMA) was previously shown to discriminate between organoids from subjects with and without CF based on a distinct phenotypical difference: compared with non-CF organoids, CF organoids have an irregular shape and lack a visible lumen. The current study serves to further explore the role of ROMA when a CF diagnosis is inconclusive.
Methods: Organoid morphology was analysed using the previously established ROMA protocol. Two indices were calculated: the circularity index to quantify the roundness of organoids and the intensity ratio as a measure of the presence of a central lumen.
Results: Rectal organoids from 116 subjects were cultured and analysed together with the 189 subjects from the previous study. ROMA almost completely discriminated between CF and non-CF. ROMA indices correlated with SCC, pancreatic status and genetics, demonstrating convergent validity. For cases with an inconclusive diagnosis according to current guidelines, ROMA provided additional diagnostic information, with a diagnostic ROMA classification for 18 of 24 (75%).
Discussion: ROMA provides additional information to support a CF diagnosis when SCC and genetics are insufficient for diagnostic classification. ROMA is standardised and can be centralised, allowing future inclusion in the diagnostic work-up as first-choice physiological assay in case of an unclear diagnosis.
背景：囊性纤维化（CF）的诊断并不总是那么简单，尤其是当汗液氯化物浓度（SCC）处于中间值且发现 CFTR 变异时。指南中提出的 CFTR 生理检测方法--鼻电位差和肠电流测量--并非在所有年龄段都可获得或可行。直肠类器官形态分析（ROMA）先前已被证明可根据一个明显的表型差异来区分有无CF患者的类器官：与非CF类器官相比，CF类器官形状不规则且缺乏可见的管腔。目前的研究旨在进一步探讨ROMA在CF诊断不确定时的作用：方法：使用之前制定的 ROMA 方案分析类器官形态。方法：使用之前建立的 ROMA 方案分析器质性组织形态，计算两个指数：圆度指数用于量化器质性组织的圆度，强度比用于衡量是否存在中心管腔：结果：对 116 名受试者的直肠器官组织进行了培养，并与之前研究中的 189 名受试者一起进行了分析。ROMA几乎完全区分了CF和非CF。ROMA指数与SCC、胰腺状态和遗传学相关，显示了趋同有效性。对于根据现行指南无法确定诊断结果的病例，ROMA提供了额外的诊断信息，24例病例中有18例（75%）通过ROMA进行了诊断分类：讨论：当SCC和遗传学不足以进行诊断分类时，ROMA可为CF诊断提供额外信息支持。ROMA是标准化的，可以集中管理，在诊断不明确时可作为首选生理检测方法纳入诊断工作。
{"title":"Rectal organoid morphology analysis (ROMA) as a novel physiological assay for diagnostic classification in cystic fibrosis.","authors":"Senne Cuyx, Anabela Santo Ramalho, Steffen Fieuws, Nikky Corthout, Marijke Proesmans, Mieke Boon, Kaline Arnauts, Marianne S Carlon, Sebastian Munck, Lieven Dupont, Kris De Boeck, François Vermeulen","doi":"10.1136/thorax-2023-220964","DOIUrl":"10.1136/thorax-2023-220964","url":null,"abstract":"<p><strong>Background: </strong>Diagnosing cystic fibrosis (CF) is not always straightforward, in particular when sweat chloride concentration (SCC) is intermediate and <2 CF-causing <i>CFTR</i> variants are identified. The physiological CFTR assays proposed in the guidelines, nasal potential difference and intestinal current measurement, are not readily available nor feasible at all ages. Rectal organoid morphology analysis (ROMA) was previously shown to discriminate between organoids from subjects with and without CF based on a distinct phenotypical difference: compared with non-CF organoids, CF organoids have an irregular shape and lack a visible lumen. The current study serves to further explore the role of ROMA when a CF diagnosis is inconclusive.</p><p><strong>Methods: </strong>Organoid morphology was analysed using the previously established ROMA protocol. Two indices were calculated: the circularity index to quantify the roundness of organoids and the intensity ratio as a measure of the presence of a central lumen.</p><p><strong>Results: </strong>Rectal organoids from 116 subjects were cultured and analysed together with the 189 subjects from the previous study. ROMA almost completely discriminated between CF and non-CF. ROMA indices correlated with SCC, pancreatic status and genetics, demonstrating convergent validity. For cases with an inconclusive diagnosis according to current guidelines, ROMA provided additional diagnostic information, with a diagnostic ROMA classification for 18 of 24 (75%).</p><p><strong>Discussion: </strong>ROMA provides additional information to support a CF diagnosis when SCC and genetics are insufficient for diagnostic classification. ROMA is standardised and can be centralised, allowing future inclusion in the diagnostic work-up as first-choice physiological assay in case of an unclear diagnosis.</p>","PeriodicalId":23284,"journal":{"name":"Thorax","volume":" ","pages":"834-841"},"PeriodicalIF":9.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141617170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-19DOI: 10.1136/thorax-2024-221458
Alice Parry, Amir Awwad, Geoffrey Lie, Matt Matson, William Martin Ricketts
{"title":"When is an AVM not an AVM?","authors":"Alice Parry, Amir Awwad, Geoffrey Lie, Matt Matson, William Martin Ricketts","doi":"10.1136/thorax-2024-221458","DOIUrl":"10.1136/thorax-2024-221458","url":null,"abstract":"","PeriodicalId":23284,"journal":{"name":"Thorax","volume":" ","pages":"889-890"},"PeriodicalIF":9.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141493544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-19DOI: 10.1136/thorax-2024-221398
Jiahao Zhu, Houpu Liu, Rui Gao, Ruicheng Gong, Jing Wang, Dan Zhou, Min Yu, Yingjun Li
Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease for which there are no reliable biomarkers or disease-modifying drugs. Here, we integrated human genomics and proteomics to investigate the causal associations between 2769 plasma proteins and IPF. Our Mendelian randomisation analysis identified nine proteins associated with IPF, of which three (FUT3, ADAM15 and USP28) were colocalised. ADAM15 emerged as the top candidate, supported by expression quantitative trait locus analysis in both blood and lung tissue. These findings provide novel insights into the aetiology of IPF and offer translational opportunities in response to the clinical challenges of this devastating disease.
{"title":"Genetic-informed proteome-wide scan reveals potential causal plasma proteins for idiopathic pulmonary fibrosis.","authors":"Jiahao Zhu, Houpu Liu, Rui Gao, Ruicheng Gong, Jing Wang, Dan Zhou, Min Yu, Yingjun Li","doi":"10.1136/thorax-2024-221398","DOIUrl":"10.1136/thorax-2024-221398","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease for which there are no reliable biomarkers or disease-modifying drugs. Here, we integrated human genomics and proteomics to investigate the causal associations between 2769 plasma proteins and IPF. Our Mendelian randomisation analysis identified nine proteins associated with IPF, of which three (FUT3, ADAM15 and USP28) were colocalised. ADAM15 emerged as the top candidate, supported by expression quantitative trait locus analysis in both blood and lung tissue. These findings provide novel insights into the aetiology of IPF and offer translational opportunities in response to the clinical challenges of this devastating disease.</p>","PeriodicalId":23284,"journal":{"name":"Thorax","volume":" ","pages":"878-882"},"PeriodicalIF":9.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141318409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-19DOI: 10.1136/thorax-2024-221864
Sheikh M Alif, Geza Benke
{"title":"Unveiling the occupational hazards: exploring the association between organic dust exposure and hypersensitivity pneumonitis and other interstitial lung diseases.","authors":"Sheikh M Alif, Geza Benke","doi":"10.1136/thorax-2024-221864","DOIUrl":"10.1136/thorax-2024-221864","url":null,"abstract":"","PeriodicalId":23284,"journal":{"name":"Thorax","volume":" ","pages":"805-806"},"PeriodicalIF":9.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141477533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-19DOI: 10.1136/thorax-2024-221571
Graham Bothamley
{"title":"Xpert Ultra for diagnosing tuberculosis at bronchoscopy: thoughts on practical applications.","authors":"Graham Bothamley","doi":"10.1136/thorax-2024-221571","DOIUrl":"10.1136/thorax-2024-221571","url":null,"abstract":"","PeriodicalId":23284,"journal":{"name":"Thorax","volume":" ","pages":"799-800"},"PeriodicalIF":9.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141559862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-19DOI: 10.1136/thorax-2024-221939
Cheryl Routley, Samantha Walker, Eric Wfw Alton, Ian P Hall
{"title":"Fixing lung health in the UK: accelerating respiratory research and innovation.","authors":"Cheryl Routley, Samantha Walker, Eric Wfw Alton, Ian P Hall","doi":"10.1136/thorax-2024-221939","DOIUrl":"10.1136/thorax-2024-221939","url":null,"abstract":"","PeriodicalId":23284,"journal":{"name":"Thorax","volume":" ","pages":"809-810"},"PeriodicalIF":9.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141890200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-07DOI: 10.1136/thorax-2023-221095
Jannie Marie Bülow Sand, Henrik Jessen, Diana Julie Leeming, Sheeline Yu, Chris J Lee, Buqu Hu, Ying Sun, Taylor Adams, Taylor Pivarnik, Angela Liu, Samuel Woo, John R McGovern, Vitória Fiorini, Tina Saber, Jean Paul Higuero-Sevilla, Mridu Gulati, Naftali Kaminski, William Damsky, Albert C Shaw, Subhasis Mohanty, Gillian Goobie, Yingze Zhang, Erica Lyndrup Herzog, Changwan Ryu
Introduction The pathogenesis of sarcoidosis involves tissue remodelling mediated by the accumulation of abnormal extracellular matrix, which is partly the result of an imbalance in collagen synthesis, cross-linking and degradation. During this process, collagen fragments or neoepitopes, are released into the circulation. The significance of these circulating collagen neoepitopes in sarcoidosis remains unknown. Methods We employed plasma samples from patients with sarcoidosis enrolled in A Case Control Etiologic Study of Sarcoidosis (ACCESS) and Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS), and healthy control patients recruited from the Yale community. Plasma concentrations of type III and VI collagen degradation (C3M and C6M) and formation (PRO-C3 and PRO-C6) were quantified via neoepitope-specific competitive ELISA, and statistical associations were sought with clinical phenotypes. Results Relative to healthy controls, the plasma of both sarcoidosis cohorts was enriched for C3M and C6M, irrespective of corticosteroid use and disease duration. While circulating collagen neoepitopes were independent of Scadding stage, there was a significant association between multiorgan disease and PRO-C3, PRO-C6 and C3M in the ACCESS cohort; PRO-C3 and C6M displayed this property in GRADS. These findings were unrelated to plasma levels of interleukin-4 (IL-4), IL-5, IL-6, IL-9, IL-10 and IL-13. Moreover, PRO-C3 was associated with dermatological disease in both cohorts. Discussion In two well-characterised sarcoidosis cohorts, we discovered that the plasma is enriched for neoepitopes of collagen degradation (C3M and C6M). In multiorgan disease, there was an association with circulating neoepitopes of type III formation (PRO-C3), perhaps mediated by dermatological sarcoidosis. Further investigation in this arena has the potential to foster new insights into the pathogenic mechanisms of this complex disease. Data are available upon reasonable request.
{"title":"Plasma collagen neoepitopes are associated with multiorgan disease in the ACCESS and GRADS sarcoidosis cohorts","authors":"Jannie Marie Bülow Sand, Henrik Jessen, Diana Julie Leeming, Sheeline Yu, Chris J Lee, Buqu Hu, Ying Sun, Taylor Adams, Taylor Pivarnik, Angela Liu, Samuel Woo, John R McGovern, Vitória Fiorini, Tina Saber, Jean Paul Higuero-Sevilla, Mridu Gulati, Naftali Kaminski, William Damsky, Albert C Shaw, Subhasis Mohanty, Gillian Goobie, Yingze Zhang, Erica Lyndrup Herzog, Changwan Ryu","doi":"10.1136/thorax-2023-221095","DOIUrl":"https://doi.org/10.1136/thorax-2023-221095","url":null,"abstract":"Introduction The pathogenesis of sarcoidosis involves tissue remodelling mediated by the accumulation of abnormal extracellular matrix, which is partly the result of an imbalance in collagen synthesis, cross-linking and degradation. During this process, collagen fragments or neoepitopes, are released into the circulation. The significance of these circulating collagen neoepitopes in sarcoidosis remains unknown. Methods We employed plasma samples from patients with sarcoidosis enrolled in A Case Control Etiologic Study of Sarcoidosis (ACCESS) and Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS), and healthy control patients recruited from the Yale community. Plasma concentrations of type III and VI collagen degradation (C3M and C6M) and formation (PRO-C3 and PRO-C6) were quantified via neoepitope-specific competitive ELISA, and statistical associations were sought with clinical phenotypes. Results Relative to healthy controls, the plasma of both sarcoidosis cohorts was enriched for C3M and C6M, irrespective of corticosteroid use and disease duration. While circulating collagen neoepitopes were independent of Scadding stage, there was a significant association between multiorgan disease and PRO-C3, PRO-C6 and C3M in the ACCESS cohort; PRO-C3 and C6M displayed this property in GRADS. These findings were unrelated to plasma levels of interleukin-4 (IL-4), IL-5, IL-6, IL-9, IL-10 and IL-13. Moreover, PRO-C3 was associated with dermatological disease in both cohorts. Discussion In two well-characterised sarcoidosis cohorts, we discovered that the plasma is enriched for neoepitopes of collagen degradation (C3M and C6M). In multiorgan disease, there was an association with circulating neoepitopes of type III formation (PRO-C3), perhaps mediated by dermatological sarcoidosis. Further investigation in this arena has the potential to foster new insights into the pathogenic mechanisms of this complex disease. Data are available upon reasonable request.","PeriodicalId":23284,"journal":{"name":"Thorax","volume":"45 1","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-07DOI: 10.1136/thorax-2024-221460
Nicklas Brustad, Jonathan Thorsen, Casper Emil Tingskov Pedersen, Mina Ali, Julie Kyvsgaard, Sarah Brandt, Jenni Lehtimäki, Nicole Prince, Nilofar V Følsgaard, Jessica Lasky-Su, Jakob Stokholm, Klaus Bønnelykke, Bo Chawes
Background Infections in childhood remain a leading global cause of child mortality and environmental exposures seem crucial. We investigated whether urbanicity at birth was associated with the risk of infections and explored underlying mechanisms. Methods Children (n=633) from the COPSAC2010 mother–child cohort were monitored daily with symptom diaries of infection episodes during the first 3 years and prospectively diagnosed with asthma until age 6 years. Rural and urban environments were based on the CORINE land cover database. Child airway immune profile was measured at age 4 weeks. Maternal and child metabolomics profiling were assessed at pregnancy week 24 and at birth, respectively. Results We observed a mean (SD) total number of infections of 16.3 (8.4) consisting mainly of upper respiratory infections until age 3 years. Urban versus rural living increased infection risk (17.1 (8.7) vs 15.2 (7.9), adjusted incidence rate ratio; 1.15 (1.05–1.26), p=0.002) and altered the child airway immune profile, which increased infection risk (principal component 1 (PC1): 1.03 (1.00–1.06), p=0.038 and PC2: 1.04 (1.01–1.07), p=0.022). Urban living also altered the maternal and child metabolomic profiles, which also increased infection risk. The association between urbanicity and infection risk was partly mediated through the maternal metabolomic and child airway immune profiles. Finally, urbanicity increased the risk of asthma by age 6 years, which was mediated through early infection load (pACME<0.001). Conclusion This study suggests urbanicity as an independent risk factor for early infections partly explained by changes in the early metabolic and immunological development with implications for later risk of asthma. Data are available upon reasonable request. Data will be available on request by email to nicklas.brustad@dbac.dk.
{"title":"Urban metabolic and airway immune profiles increase the risk of infections in early childhood","authors":"Nicklas Brustad, Jonathan Thorsen, Casper Emil Tingskov Pedersen, Mina Ali, Julie Kyvsgaard, Sarah Brandt, Jenni Lehtimäki, Nicole Prince, Nilofar V Følsgaard, Jessica Lasky-Su, Jakob Stokholm, Klaus Bønnelykke, Bo Chawes","doi":"10.1136/thorax-2024-221460","DOIUrl":"https://doi.org/10.1136/thorax-2024-221460","url":null,"abstract":"Background Infections in childhood remain a leading global cause of child mortality and environmental exposures seem crucial. We investigated whether urbanicity at birth was associated with the risk of infections and explored underlying mechanisms. Methods Children (n=633) from the COPSAC2010 mother–child cohort were monitored daily with symptom diaries of infection episodes during the first 3 years and prospectively diagnosed with asthma until age 6 years. Rural and urban environments were based on the CORINE land cover database. Child airway immune profile was measured at age 4 weeks. Maternal and child metabolomics profiling were assessed at pregnancy week 24 and at birth, respectively. Results We observed a mean (SD) total number of infections of 16.3 (8.4) consisting mainly of upper respiratory infections until age 3 years. Urban versus rural living increased infection risk (17.1 (8.7) vs 15.2 (7.9), adjusted incidence rate ratio; 1.15 (1.05–1.26), p=0.002) and altered the child airway immune profile, which increased infection risk (principal component 1 (PC1): 1.03 (1.00–1.06), p=0.038 and PC2: 1.04 (1.01–1.07), p=0.022). Urban living also altered the maternal and child metabolomic profiles, which also increased infection risk. The association between urbanicity and infection risk was partly mediated through the maternal metabolomic and child airway immune profiles. Finally, urbanicity increased the risk of asthma by age 6 years, which was mediated through early infection load (pACME<0.001). Conclusion This study suggests urbanicity as an independent risk factor for early infections partly explained by changes in the early metabolic and immunological development with implications for later risk of asthma. Data are available upon reasonable request. Data will be available on request by email to nicklas.brustad@dbac.dk.","PeriodicalId":23284,"journal":{"name":"Thorax","volume":"64 1","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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