Alain Michils, Maxime Hackx, Lucas Mlynarski, Amaryllis Haccuria, Silvia Perez-Bogerd, Andreï Malinovschi, Alain Van Muylem
{"title":"How FEV<sub>1</sub> Improvement Induced by Anti-IL-5 in Severe Type-2 Asthma Is Linked to Mucus Plugs Clearance.","authors":"Alain Michils, Maxime Hackx, Lucas Mlynarski, Amaryllis Haccuria, Silvia Perez-Bogerd, Andreï Malinovschi, Alain Van Muylem","doi":"10.1111/all.16441","DOIUrl":"https://doi.org/10.1111/all.16441","url":null,"abstract":"","PeriodicalId":122,"journal":{"name":"Allergy","volume":" ","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851586","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}
Anna Freeman, Magdalena Minnion, Paul H Lee, Hans Michael Haitchi, Ramesh Kurukulaaratchy, Tom Wilkinson, Martin Feelisch
{"title":"Circulating Nitrite in Severe Asthma: Just Another Biomarker or Novel Treatment Target?","authors":"Anna Freeman, Magdalena Minnion, Paul H Lee, Hans Michael Haitchi, Ramesh Kurukulaaratchy, Tom Wilkinson, Martin Feelisch","doi":"10.1111/all.16435","DOIUrl":"https://doi.org/10.1111/all.16435","url":null,"abstract":"","PeriodicalId":122,"journal":{"name":"Allergy","volume":" ","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851675","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}
Aleix Arnau-Soler, Bénédicte L. Tremblay, Yidan Sun, Anne-Marie Madore, Mathieu Simard, Elin T. G. Kersten, Ahla Ghauri, Ingo Marenholz, Thomas Eiwegger, Elinor Simons, Edmond S. Chan, Kari Nadeau, Vanitha Sampath, Bruce D. Mazer, Susan Elliott, Christine Hampson, Lianne Soller, Andrew Sandford, Philippe Begin, Jennie Hui, Bethany F. Wilken, Jennifer Gerdts, Adrienn Bourkas, Anne K. Ellis, Denitsa Vasileva, Ann Clarke, Aida Eslami, Moshe Ben-Shoshan, David Martino, Denise Daley, Gerard H. Koppelman, Catherine Laprise, Young-Ae Lee, Yuka Asai
In this review, we provide an overview of food allergy genetics and epigenetics aimed at clinicians and researchers. This includes a brief review of the current understanding of genetic and epigenetic mechanisms, inheritance of food allergy, as well as a discussion of advantages and limitations of the different types of studies in genetic research. We specifically focus on the results of genome-wide association studies in food allergy, which have identified 16 genetic variants that reach genome-wide significance, many of which overlap with other allergic diseases, including asthma, atopic dermatitis, and allergic rhinitis. Identified genes for food allergy are mainly involved in epithelial barrier function (e.g., FLG, SERPINB7) and immune function (e.g., HLA, IL4). Epigenome-wide significant findings at 32 loci are also summarized as well as 14 additional loci with significance at a false discovery of < 1 × 10−4. Integration of epigenetic and genetic data is discussed in the context of disease mechanisms, many of which are shared with other allergic diseases. The potential utility of genetic and epigenetic discoveries is deliberated. In the future, genetic and epigenetic markers may offer ways to predict the presence or absence of clinical IgE-mediated food allergy among sensitized individuals, likelihood of development of natural tolerance, and response to immunotherapy.
{"title":"Food Allergy Genetics and Epigenetics: A Review of Genome-Wide Association Studies","authors":"Aleix Arnau-Soler, Bénédicte L. Tremblay, Yidan Sun, Anne-Marie Madore, Mathieu Simard, Elin T. G. Kersten, Ahla Ghauri, Ingo Marenholz, Thomas Eiwegger, Elinor Simons, Edmond S. Chan, Kari Nadeau, Vanitha Sampath, Bruce D. Mazer, Susan Elliott, Christine Hampson, Lianne Soller, Andrew Sandford, Philippe Begin, Jennie Hui, Bethany F. Wilken, Jennifer Gerdts, Adrienn Bourkas, Anne K. Ellis, Denitsa Vasileva, Ann Clarke, Aida Eslami, Moshe Ben-Shoshan, David Martino, Denise Daley, Gerard H. Koppelman, Catherine Laprise, Young-Ae Lee, Yuka Asai","doi":"10.1111/all.16429","DOIUrl":"10.1111/all.16429","url":null,"abstract":"<p>In this review, we provide an overview of food allergy genetics and epigenetics aimed at clinicians and researchers. This includes a brief review of the current understanding of genetic and epigenetic mechanisms, inheritance of food allergy, as well as a discussion of advantages and limitations of the different types of studies in genetic research. We specifically focus on the results of genome-wide association studies in food allergy, which have identified 16 genetic variants that reach genome-wide significance, many of which overlap with other allergic diseases, including asthma, atopic dermatitis, and allergic rhinitis. Identified genes for food allergy are mainly involved in epithelial barrier function (e.g., <i>FLG</i>, <i>SERPINB7</i>) and immune function (e.g., <i>HLA</i>, <i>IL4</i>). Epigenome-wide significant findings at 32 loci are also summarized as well as 14 additional loci with significance at a false discovery of < 1 × 10<sup>−4</sup>. Integration of epigenetic and genetic data is discussed in the context of disease mechanisms, many of which are shared with other allergic diseases. The potential utility of genetic and epigenetic discoveries is deliberated. In the future, genetic and epigenetic markers may offer ways to predict the presence or absence of clinical IgE-mediated food allergy among sensitized individuals, likelihood of development of natural tolerance, and response to immunotherapy.</p>","PeriodicalId":122,"journal":{"name":"Allergy","volume":"80 1","pages":"106-131"},"PeriodicalIF":12.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11724255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851681","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}
Nuria Contreras, Andrea Escolar‐Peña, María I. Delgado‐Dolset, Paloma Fernández, David Obeso, Elena Izquierdo, Heleia González Cuervo, José Ángel Cumplido, Victoria Múgica, Carolina Cisneros, Santiago Angulo‐Díaz‐Parreño, Coral Barbas, Carlos Blanco, Teresa Carrillo, Domingo Barber, Alma Villaseñor, María M. Escribese
RationaleBiologics are becoming increasingly important in the management of severe asthma. However, little is known about the systemic immunometabolic consequences of Th2 response blockage.ObjectivesTo provide a better immunometabolic understanding of the effects of mepolizumab and omalizumab treatments by identifying potential biomarkers for monitoring.MethodsIn this exploratory longitudinal study severe asthmatic patients were followed for 18 months after initiating mepolizumab (n = 36) or Omalizumab (n = 20) treatment. Serum samples were collected before, 6, and 18 months after treatment. Targeted omic approaches were performed to analyze inflammatory metabolites (n = 35) and proteins (n = 45). Multiomic integration was performed individually for each treatment applying supervised analysis Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO) framework. Then, potential biomarkers were confirmed using multivariate ROC analyses and correlated with clinical variables along treatment.Measurements and Main ResultsMepolizumab and omalizumab were both effective (improved clinical variables) and showed different and specific metabolic and protein profiles in severe asthmatic patients during treatment. Multiomic integration and multivariate ROC analyses identified specific biomarkers, such as arachidonic acid, palmitoleic acid, oleic acid, propionylcarnitine, bilirubin, CCL11, and TNFSF10, which can explain the differences observed with Mepolizumab treatment over 18 months and significantly correlate with clinical improvement. However, no significant biomolecules and no discriminative multivariate ROC curves were found for Omalizumab treatment.ConclusionsOur results provide a comprehensive insight into the differential effects of mepolizumab and omalizumab on the immunometabolic kinetics of the inflammatory response in severe asthma. We identified a set of biomolecules with potential for monitoring mepolizumab treatment which could be useful for personalized medicine.
{"title":"Multiomic Integration Analysis for Monitoring Severe Asthma Treated With Mepolizumab or Omalizumab","authors":"Nuria Contreras, Andrea Escolar‐Peña, María I. Delgado‐Dolset, Paloma Fernández, David Obeso, Elena Izquierdo, Heleia González Cuervo, José Ángel Cumplido, Victoria Múgica, Carolina Cisneros, Santiago Angulo‐Díaz‐Parreño, Coral Barbas, Carlos Blanco, Teresa Carrillo, Domingo Barber, Alma Villaseñor, María M. Escribese","doi":"10.1111/all.16434","DOIUrl":"https://doi.org/10.1111/all.16434","url":null,"abstract":"RationaleBiologics are becoming increasingly important in the management of severe asthma. However, little is known about the systemic immunometabolic consequences of Th2 response blockage.ObjectivesTo provide a better immunometabolic understanding of the effects of mepolizumab and omalizumab treatments by identifying potential biomarkers for monitoring.MethodsIn this exploratory longitudinal study severe asthmatic patients were followed for 18 months after initiating mepolizumab (<jats:italic>n</jats:italic> = 36) or Omalizumab (<jats:italic>n</jats:italic> = 20) treatment. Serum samples were collected before, 6, and 18 months after treatment. Targeted omic approaches were performed to analyze inflammatory metabolites (<jats:italic>n</jats:italic> = 35) and proteins (<jats:italic>n</jats:italic> = 45). Multiomic integration was performed individually for each treatment applying supervised analysis Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO) framework. Then, potential biomarkers were confirmed using multivariate ROC analyses and correlated with clinical variables along treatment.Measurements and Main ResultsMepolizumab and omalizumab were both effective (improved clinical variables) and showed different and specific metabolic and protein profiles in severe asthmatic patients during treatment. Multiomic integration and multivariate ROC analyses identified specific biomarkers, such as arachidonic acid, palmitoleic acid, oleic acid, propionylcarnitine, bilirubin, CCL11, and TNFSF10, which can explain the differences observed with Mepolizumab treatment over 18 months and significantly correlate with clinical improvement. However, no significant biomolecules and no discriminative multivariate ROC curves were found for Omalizumab treatment.ConclusionsOur results provide a comprehensive insight into the differential effects of mepolizumab and omalizumab on the immunometabolic kinetics of the inflammatory response in severe asthma. We identified a set of biomolecules with potential for monitoring mepolizumab treatment which could be useful for personalized medicine.","PeriodicalId":122,"journal":{"name":"Allergy","volume":"54 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841020","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}
Marek Jutel, Magdalena Zemelka-Wiacek, Yoshitaka Okamoto, Oliver Pfaar
{"title":"Algorithms in Allergy: Assessment of Rhinitis Using Allergen Exposure Chambers.","authors":"Marek Jutel, Magdalena Zemelka-Wiacek, Yoshitaka Okamoto, Oliver Pfaar","doi":"10.1111/all.16444","DOIUrl":"https://doi.org/10.1111/all.16444","url":null,"abstract":"","PeriodicalId":122,"journal":{"name":"Allergy","volume":" ","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833195","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}
I. Agache, I. M. Adcock, C. A. Akdis, M. Akdis, G. Bentabol-Ramos, M. van den Berge, C. Boccabella, W. G. Canonica, C. Caruso, M. Couto, I. Davila, D. Drummond, J. Fonseca, A. Gherasim, S. del Giacco, D. J. Jackson, M. Jutel, A. Licari, S. Loukides, A. Moreira, M. Mukherjee, I. Ojanguren, O. Palomares, A. Papi, L. Perez de Llano, O. J. Price, M. Rukhazde, M. H. Shamji, D. Shaw, S. Sanchez-Garcia, A. Testera-Montes, M. J. Torres, I. Eguiluz-Gracia
As cholinergic innervation is a major contributor to increased vagal tone and mucus secretion, inhaled long-acting muscarinic antagonists (LAMA) are a pillar for the treatment of chronic obstructive pulmonary disease and asthma. By blocking the muscarinic receptors expressed in the lung, LAMA improve lung function and reduce exacerbations in asthma patients who remained poorly controlled despite treatment with inhaled corticosteroids and long-acting β2 agonists. Asthma guidelines recommend LAMA as a third controller to be added on before the initiation of biologicals. In addition to bronchodilation, LAMA also exert anti-inflammatory and anti-fibrotic effects by inhibiting muscarinic receptors present in neutrophils, macrophages, fibroblasts and airway smooth muscle cells. Thus, besides bronchodilation, LAMA might provide additional therapeutic effects, thereby supporting an endotype-driven approach to asthma management. The Position Paper, developed by the Asthma Section of the European Academy of Allergy and Clinical Immunology, discusses the main cholinergic pathways in the lung, reviews the findings of significant clinical trials and real-life studies on LAMA use in asthma, examines the placement of these drugs in asthma clinical guidelines, and considers the potential for personalised medicine with LAMA in both adult and paediatric asthma patients.
胆碱能神经支配是迷走神经张力和粘液分泌增加的主要原因，因此吸入长效毒蕈碱拮抗剂（LAMA）是治疗慢性阻塞性肺病和哮喘的支柱。通过阻断肺部表达的毒蕈碱受体，长效毒蕈碱拮抗剂可改善哮喘患者的肺功能并减少病情恶化，这些患者在使用吸入式皮质类固醇和长效β2受体激动剂治疗后病情仍未得到有效控制。哮喘指南建议在开始使用生物制剂之前，将 LAMA 作为第三种控制药物。除支气管扩张作用外，LAMA 还能抑制中性粒细胞、巨噬细胞、成纤维细胞和气道平滑肌细胞中的毒蕈碱受体，从而发挥抗炎和抗纤维化作用。因此，除了支气管扩张作用外，LAMA 还可能提供其他治疗效果，从而支持以内型为导向的哮喘治疗方法。这份由欧洲过敏与临床免疫学会哮喘分会编写的立场文件讨论了肺部的主要胆碱能通路，回顾了有关 LAMA 用于哮喘的重要临床试验和实际生活研究的结果，研究了这些药物在哮喘临床指南中的位置，并考虑了在成人和儿童哮喘患者中使用 LAMA 进行个性化治疗的潜力。
{"title":"The Bronchodilator and Anti-Inflammatory Effect of Long-Acting Muscarinic Antagonists in Asthma: An EAACI Position Paper","authors":"I. Agache, I. M. Adcock, C. A. Akdis, M. Akdis, G. Bentabol-Ramos, M. van den Berge, C. Boccabella, W. G. Canonica, C. Caruso, M. Couto, I. Davila, D. Drummond, J. Fonseca, A. Gherasim, S. del Giacco, D. J. Jackson, M. Jutel, A. Licari, S. Loukides, A. Moreira, M. Mukherjee, I. Ojanguren, O. Palomares, A. Papi, L. Perez de Llano, O. J. Price, M. Rukhazde, M. H. Shamji, D. Shaw, S. Sanchez-Garcia, A. Testera-Montes, M. J. Torres, I. Eguiluz-Gracia","doi":"10.1111/all.16436","DOIUrl":"10.1111/all.16436","url":null,"abstract":"<p>As cholinergic innervation is a major contributor to increased vagal tone and mucus secretion, inhaled long-acting muscarinic antagonists (LAMA) are a pillar for the treatment of chronic obstructive pulmonary disease and asthma. By blocking the muscarinic receptors expressed in the lung, LAMA improve lung function and reduce exacerbations in asthma patients who remained poorly controlled despite treatment with inhaled corticosteroids and long-acting β2 agonists. Asthma guidelines recommend LAMA as a third controller to be added on before the initiation of biologicals. In addition to bronchodilation, LAMA also exert anti-inflammatory and anti-fibrotic effects by inhibiting muscarinic receptors present in neutrophils, macrophages, fibroblasts and airway smooth muscle cells. Thus, besides bronchodilation, LAMA might provide additional therapeutic effects, thereby supporting an endotype-driven approach to asthma management. The Position Paper, developed by the Asthma Section of the European Academy of Allergy and Clinical Immunology, discusses the main cholinergic pathways in the lung, reviews the findings of significant clinical trials and real-life studies on LAMA use in asthma, examines the placement of these drugs in asthma clinical guidelines, and considers the potential for personalised medicine with LAMA in both adult and paediatric asthma patients.</p>","PeriodicalId":122,"journal":{"name":"Allergy","volume":"80 2","pages":"380-394"},"PeriodicalIF":12.6,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/all.16436","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826815","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}
Wouter W. de Weger, Aline. B. Sprikkelman, Catherina. E. M. Herpertz, Gerbrich N. van der Meulen, Judith. M. Vonk, Gerard. H. Koppelman, Arvid. W. A. Kamps
Background
Double-blind placebo-controlled food challenge (DBPCFC) is widely regarded as the “gold standard” to diagnose food allergy. Maximum efforts are made to reduce bias, yet DBPCFCs are costly, time-, and resource-intensive. Less demanding open food challenges are increasingly used in clinical practice. However, recommendations regarding the use of these challenges are based on low certainty of evidence, and no comparative studies have been performed using the most recent international food challenge guidelines. We hypothesised that the open food challenge is non-inferior to DBPCFC in children suspected of allergy to cashew nuts, hazelnuts or peanuts.
Methods
A total of 63 children, aged 4 years and older, were included if referred for suspected IgE-mediated allergy to cashew nut, hazelnut, or peanut. All study participants underwent DBPCFC first, followed by an open food challenge for the same food. Challenge outcomes were assessed by predefined criteria into positive, negative, or inconclusive.
Results
DBPCFC and open food challenge outcomes were the same for 36/41 (87.8%) patients. Sensitivity and specificity of the open food challenge were 0.91 (95% CI 0.79, 1.03) and 0.83 (95% CI 0.63, 1.01), respectively, with an AUC value of 0.87. Eliciting and stop doses were not significantly different between both food challenges.
Conclusion
The Diagnostic accuracy of open food challenge is non-inferior to that of DBPCFC. This finding implies less demanding open food challenges can be implemented for children from the age of 4 years suspected to be cashew nut, hazelnut, or peanut allergic. Further research is necessary to validate our findings and to investigate the diagnostic accuracy for other major food allergens.
{"title":"Comparison of Double-Blind and Open Food Challenges for the Diagnosis of Food Allergy in Childhood: The ALDORADO Study","authors":"Wouter W. de Weger, Aline. B. Sprikkelman, Catherina. E. M. Herpertz, Gerbrich N. van der Meulen, Judith. M. Vonk, Gerard. H. Koppelman, Arvid. W. A. Kamps","doi":"10.1111/all.16428","DOIUrl":"10.1111/all.16428","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Double-blind placebo-controlled food challenge (DBPCFC) is widely regarded as the “gold standard” to diagnose food allergy. Maximum efforts are made to reduce bias, yet DBPCFCs are costly, time-, and resource-intensive. Less demanding open food challenges are increasingly used in clinical practice. However, recommendations regarding the use of these challenges are based on low certainty of evidence, and no comparative studies have been performed using the most recent international food challenge guidelines. We hypothesised that the open food challenge is non-inferior to DBPCFC in children suspected of allergy to cashew nuts, hazelnuts or peanuts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A total of 63 children, aged 4 years and older, were included if referred for suspected IgE-mediated allergy to cashew nut, hazelnut, or peanut. All study participants underwent DBPCFC first, followed by an open food challenge for the same food. Challenge outcomes were assessed by predefined criteria into positive, negative, or inconclusive.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>DBPCFC and open food challenge outcomes were the same for 36/41 (87.8%) patients. Sensitivity and specificity of the open food challenge were 0.91 (95% CI 0.79, 1.03) and 0.83 (95% CI 0.63, 1.01), respectively, with an AUC value of 0.87. Eliciting and stop doses were not significantly different between both food challenges.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The Diagnostic accuracy of open food challenge is non-inferior to that of DBPCFC. This finding implies less demanding open food challenges can be implemented for children from the age of 4 years suspected to be cashew nut, hazelnut, or peanut allergic. Further research is necessary to validate our findings and to investigate the diagnostic accuracy for other major food allergens.</p>\u0000 </section>\u0000 </div>","PeriodicalId":122,"journal":{"name":"Allergy","volume":"80 1","pages":"248-257"},"PeriodicalIF":12.6,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/all.16428","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142820673","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}
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