中国医学科学院学报最新文献

{"title":"Research Progress in Blastic Plasmacytoid Dendritic Cell Neoplasm.","authors":"Fu-Yi Luo, Yan Li","doi":"10.3881/j.issn.1000-503X.15946","DOIUrl":"https://doi.org/10.3881/j.issn.1000-503X.15946","url":null,"abstract":"<p><p>Blastic plasmacytoid dendritic cell neoplasm(BPDCN)is an extremely rare invasive tumor with poor prognosis.The common clinical manifestations of BPDCN include skin injury,bone marrow involvement,and tumor cell spread.BPDCN is often misdiagnosed as other diseases and its diagnosis often requires a combination of clinical manifestations,imaging,histology,and immunophenotyping.Among them,immunophenotyping is crucial for the diagnosis of BPDCN.Although BPDCN is rare and no consensus has been reached on first-line treatment option,new drugs and options for treating this disease have emerged with the development of new drugs and increased awareness of BPDCN.This article reviews the research background,the origin of blastic plasmacytoid dendritic cells,and the recent research progress in the pathogenesis,diagnosis and differential diagnosis,treatment,and prognosis of BPDCN.</p>","PeriodicalId":6919,"journal":{"name":"中国医学科学院学报","volume":"46 6","pages":"949-957"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Knee Flexor and Extensor Strength on Subjective Function and Motor Performance of Knees After Anterior Cruciate Ligament Reconstruction.","authors":"Ming-Ze Liu, Xiao-Han Zhang, Lei Li, Jing-Yi Sun, Yi Qian, Chen He, Sen Guo, Hao Xu, Ya-Wei Gong, Zhuang Liu, Xiang-Yi Wang, Feng Gao, Jing-Bin Zhou","doi":"10.3881/j.issn.1000-503X.16110","DOIUrl":"https://doi.org/10.3881/j.issn.1000-503X.16110","url":null,"abstract":"<p><p>Objective To evaluate the effects of knee flexor and extensor strength on the subjective function and motor performance of knees after anterior cruciate ligament reconstruction. Methods A total of 53 patients who underwent anterior cruciate ligament reconstruction in the National Institute of Sports Medicine,General Administration of Sport of China from June 2015 to June 2021 and met the inclusion criteria were enrolled in this study.The patients were followed up time for at least 2 years.An isometric muscle strength test system was used to measure the strength of bilateral quadriceps and hamstring muscles.The patients were grouped according to whether the limb symmetry index (LSI) of peak torque of quadriceps and hamstring muscle reached 85% at an angular velocity of 60°/s.Specifically,26 patients were classified into group A (LSI≥85%) and 27 patients were classified into group B (LSI<85%).The subjective function and motor performance of knees were compared between the two groups. Results In terms of subjective function of knees,the international knee documentation committee (IKDC) score (88.76±9.93 <i>vs.</i> 81.08±12.57,<i>P</i>=0.017) and knee injury and osteoarthritis outcome score (KOOS) (86.27±8.96 <i>vs.</i> 80.22±11.31,<i>P</i>=0.036) were different between groups A and B.There was no significant difference in Lysholm score [95.0 (79.8,100.00) <i>vs.</i> 86.00 (66.00,100.00),<i>P</i>=0.238],ACL return to sports after injury scale score (66.08±22.25 <i>vs.</i> 61.12±23.53,<i>P</i>=0.434),Marx score [6.00 (4.75,7.00) <i>vs.</i> 6.00 (4.00,7.00),<i>P</i>=0.805] or Tegner activity score [8.00 (4.00,12.00) <i>vs.</i> 4.00 (2.00,12.00),<i>P</i>=0.566] between the two groups.In terms of motor performance,the single-leg triple hop LSI (0.92±0.13 <i>vs.</i> 0.81±0.18,<i>P</i>=0.016) and single-leg crossover hop LSI (0.96±0.12 <i>vs.</i> 0.84±0.22,<i>P</i>=0.021) showed significant differences between groups A and B,while there was no significant difference in single-leg hop LSI (0.90±0.18 <i>vs.</i> 0.79±0.25,<i>P</i>=0.116) between the two groups.In addition,there was no statistical significance in proprioception [30°:8.83±4.66 <i>vs.</i> 10.73±4.63,<i>P</i>=0.143;45°:6.94±3.82 <i>vs.</i> 7.66±3.93,<i>P</i>=0.504;60°:4.10 (3.20,4.72) <i>vs.</i> 3.90 (2.30,5.20),<i>P</i>=0.493] or Y-balance test results [anterior LSI:0.98 (0.84,1.02) <i>vs.</i> 0.94 (0.86,0.98),<i>P</i>=0.328;posterolateral LSI:1.00±0.08 <i>vs.</i> 0.97±0.07,<i>P</i>=0.249;posteromedial LSI:1.00 (0.97,1.03) <i>vs.</i> 0.96 (0.93,1.03),<i>P</i>=0.179] between groups A and B. Conclusion The patients with good symmetry of quadriceps and hamstring muscle strength after anterior cruciate ligament reconstruction had better subjective function and movement performance of knees than the patients with poor symmetry,which was mainly reflected in the IKDC score,KOOS,single-leg triple hop,and single-leg crossover hop.</p>","PeriodicalId":6919,"journal":{"name":"中国医学科学院学报","volume":"46 6","pages":"805-813"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knowledge Mapping of Osteoimmunology:A Bibliometric Study.","authors":"Ming-Zhou Chen, Sheng-Tao Wang, Dong-Xu Chen, Wei Peng, Zhao-Xu Li","doi":"10.3881/j.issn.1000-503X.16011","DOIUrl":"10.3881/j.issn.1000-503X.16011","url":null,"abstract":"<p><p>Objective To understand the research status of osteoimmunology by a bibliometric study and provide reference for potential research hotspots in the future. Methods The articles and reviews related to osteoimmunology were retrieved from the Web of Science Core Collection with the time interval from 2002 to 2022.VOSviewer,CiteSpace,and the Bibliometrix package in R were used to analyze the contributions and co-citation relationships of countries/regions,institutions,journals,authors,references,and keywords,and identify research hotspots. Results A total of 812 English-language articles published between 2002 and 2022 were collected,and the annual number of articles was increasing year by year.China had the most articles (<i>n</i>=233,28.69%),followed by the United States and Japan.Sichuan University had the highest number of articles (<i>n</i>=35,4.27%).Takayanagi H ranked first among both publishing authors and co-cited authors.<i>Froniters in Immunology</i> was the journal publishing the highest number of articles (<i>n</i>=45,impact factor of 7.3 in 2023) in this field.The clustering of key nodes and identification of keywords in co-cited references indicated that the research of osteoimmunology mainly focused on signal transduction mechanisms of bone immunity,bone immunity-mediated diseases,and drug treatment.In recent years,the research hotspots of osteoimmunology included macrophage polarization,bone biomaterials,bone regeneration,and therapy. Conclusion This study employed bibliometric methods to comprehensively analyze the countries,institutions,authors,keywords,and references of articles in osteoimmunology,providing guidance and reference for researchers engaged in this field.</p>","PeriodicalId":6919,"journal":{"name":"中国医学科学院学报","volume":"46 6","pages":"899-908"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progress in Prevention and Treatment of Dysplasia in Ulcerative Colitis Based on Cyclooxygenase-2/p53 Axis.","authors":"Yi-Lin Zhang, Shu-Sen Yang, Yu-Shan Liu, Shu-Guang Yan","doi":"10.3881/j.issn.1000-503X.15911","DOIUrl":"https://doi.org/10.3881/j.issn.1000-503X.15911","url":null,"abstract":"<p><p>Ulcerative colitis(UC)is a chronic inflammatory bowel disease characterized by non-specific,persistent inflammation in the intestines.This chronic inflammation often increases the risk of serious complications such as colorectal cancer.Dysplasia acts as a driver of cancer development and plays a connecting role in the occurrence and development of chronic intestinal inflammation and colorectal cancer.Cell proliferation/apoptosis imbalance is the driving factor for dysplasia development.The abnormal proliferation/apoptosis of intestinal mucosal epithelial cells may be affected by cyclooxygenase-2(COX-2),tumor suppressor gene p53,or both.Therefore,reasonable regulation of COX-2/p53 axis may be a key to achieving intestinal mucosal proliferation/apoptosis balance.This article discusses the effects and mechanism of COX-2 and p53 in regulating the occurrence and development of dysplasia in UC from the proliferation/apoptosis imbalance of intestinal mucosal epithelial cells,aiming to provide a reference for understanding the mechanism of dysplasia in UC and developing targeted therapeutic drugs.</p>","PeriodicalId":6919,"journal":{"name":"中国医学科学院学报","volume":"46 6","pages":"940-948"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Knee Joint Rotational Stability on Sport Performance After Anterior Cruciate Ligament Reconstruction.","authors":"Jing-Yi Sun, Feng Gao, Yi Qian, Ying-Qi Zhao, Chen He, Sen Guo, Jing-Bin Zhou","doi":"10.3881/j.issn.1000-503X.16141","DOIUrl":"https://doi.org/10.3881/j.issn.1000-503X.16141","url":null,"abstract":"<p><p>Objective To investigate the effects of rotation stability after anterior cruciate ligament reconstruction (ACLR) on subjective outcomes,sport performance,psychological readiness,and return to sport. Methods The patients who underwent ACLR in the Sports Hospital,National Institute of Sports Medicine,General Administration of Sport of China from January 2015 to January 2021 were followed up during the period from November 2022 to December 2023.The patients were grouped according to the results of the pivot shift test (PST) of the affected knee at the last follow-up visit.A total of 66 patients who participated in the follow-up and met the inclusion and exclusion criteria were finally enrolled in this study,including 32 patients showing a negative PST result (stable group) and 34 patients showing a positive PST result (unstable group).The basic information,subjective function score,and return-to-sport performance were compared between the two groups. Results In terms of sport performance,the two groups showed differences in the limb symmetry index in single-leg hops,triple hops,and crossover hops (<i>P</i>=0.028,<i>P</i>=0.024,and <i>P</i>=0.044,respectively).The anterior cruciate ligament-return to sport after injury scale score was higher in the stable group than in the unstable group [(70.44±22.82) scores <i>vs.</i> (53.44±21.74) scores,<i>P</i>=0.003].The mean of KT-2000 test results in the stable group was lower than that in the unstable group [(0.53±1.02) mm <i>vs.</i> (2.06±2.31) mm,<i>P</i>=0.001].The Lysholm score,international knee documentation committee score,knee injury and osteoarthritis outcome score,Tegner score,and Marx score did not have significance between the two groups (all <i>P</i>>0.05).The return-to-sport rate was 43.8% (including 14.3% reaching safe return criteria,which accounted for 6.3% in all the patients) in the stable group and 35.3% (including 8.3% reaching safe return criteria,which accounted for 2.9% in all the patients) in the unstable group.There was no difference in the 60°/s isokinetic muscle strength,maximal muscle strength ratio of the affected extensor-flexor muscles,or Y-balance test result between the two groups (all <i>P</i>>0.05). Conclusions Knee joint rotational instability after ACLR results in poor performance in single-leg hops,triple hops,and crossover hops,low psychological readiness,and anterior-posterior knee laxity.In short- to medium-term follow-up for ACLR,the return-to-sport rate remained low regardless of knee joint rotational stability,with the majority of patients failing to meet safe return criteria.</p>","PeriodicalId":6919,"journal":{"name":"中国医学科学院学报","volume":"46 6","pages":"814-822"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Mutyh in Oxidative Stress Damage in Retinopathy of Prematurity.","authors":"Hui-Juan Li, Jie Tang, Rui Cheng","doi":"10.3881/j.issn.1000-503X.16032","DOIUrl":"https://doi.org/10.3881/j.issn.1000-503X.16032","url":null,"abstract":"<p><p>Objective To explore the role of the base mismatch repair gene Mutyh in retinopathy of prematurity(ROP). Methods Mutyh(-/-)and wild-type(WT)mice were used for the modeling of oxygen-induced retinopathy.The retinal oxidative stress was examined,and the ultrastructures of photoreceptors and mitochondria were observed.The biomarkers of photoreceptors and mitochondria were tested.Furthermore,the photoreceptor cell line 661W was treated with hydrogen peroxide for the modeling of oxidative stress.In the cell model,and the oxidative stress and photoreceptor functions in the cells were measured. Results In both the mouse and cell models,the expression of Mutyh was up-regulated.Mutyh knockout in mice and knockdown in cells exerted negative effects on photoreceptors and mitochondria.Mutyh overexpression showed protective functions in the cell model,indicating that Mutyh played a role in repairing photoreceptors and mitochondria. Conclusions Mutyh showed the potential to become a biomarker of ROP.Increasing Mutyh expression might have therapeutic effects on ROP,which needs further validation.</p>","PeriodicalId":6919,"journal":{"name":"中国医学科学院学报","volume":"46 6","pages":"862-871"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Remitting Seronegative Symmetrical Synovitis With Pitting Edema Syndrome With Fever as the First Clinical Manifestation:Report of One Case.","authors":"Tian-Chang Zhong, Zi-Hao Fang, Ying-Yan Wen, Kang-An Lai, Jia-Chun Li","doi":"10.3881/j.issn.1000-503X.15977","DOIUrl":"10.3881/j.issn.1000-503X.15977","url":null,"abstract":"<p><p>Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome is a rare seronegative synovial inflammatory disease in which fever is a rare symptom.There are few case reports of RS3PE syndrome with fever as the first clinical manifestation in China.In this paper,we report a case of RS3PE syndrome with fever as the first symptom and diagnosed by systematic fever investigation.</p>","PeriodicalId":6919,"journal":{"name":"中国医学科学院学报","volume":"46 6","pages":"970-973"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Features of Chinese Patients With Bullous Pemphigoid Induced by Immune Checkpoint Inhibitors.","authors":"Jing-Hui Li, Liu-Yi-Yi Yang, Yan Wang, Ya-Gang Zuo","doi":"10.3881/j.issn.1000-503X.16239","DOIUrl":"10.3881/j.issn.1000-503X.16239","url":null,"abstract":"<p><p>Objective To explore the clinical features and treatments of Chinese patients with bullous pemphigoid (BP) induced by immune checkpoint inhibitors (ICI). Methods A retrospective analysis was conducted on 18 Chinese patients with ICI-induced BP treated in the Peking Union Medical College Hospital and 14 Chinese patients with this disease reported in the literature.Furthermore,the research data of non-Chinese patients were used for comparison to outline the clinical features and treatment responses of the Chinese patients. Results A total of 32 patients (21 males and 11 females) were enrolled,and all of them presented BP induced by programmed death-1/programmed death ligand-1 inhibitors.Compared with non-Chinese patients,the Chinese patients with ICI-induced BP showed low average ages [(65.2±9.5) years <i>vs.</i> (69.9±10.3) years,<i>P</i>=0.020],increased proportion of BP induced by tislelizumab (28.1% <i>vs.</i> 0,<i>P</i><0.001),decreased proportions of BP induced by pembrolizumab (18.8% <i>vs.</i> 39.4%,<i>P</i>=0.029) and nivolumab (3.1% <i>vs.</i> 52.8%,<i>P</i><0.001),and decreased proportion of primary malignant melanoma (9.4% <i>vs.</i> 43.3%,<i>P</i><0.001).The incidence of pruritus (96.9% <i>vs.</i> 66.1%,<i>P</i><0.001) and mucosal involvement (59.4% <i>vs.</i> 15.7%,<i>P</i><0.001) in the Chinese patients were higher than those in the non-Chinese patients.The proportions of the Chinese patients treated with tripterygium glycosides (9.4% <i>vs.</i> 0,<i>P</i>=0.008),dupilumab (18.8% <i>vs.</i> 0.8%,<i>P</i><0.001),and topical corticosteroids (87.5% <i>vs.</i> 53.5%,<i>P</i><0.001) were higher than those of non-Chinese patients. Conclusions The Chinese patients with ICI-induced BP tend to have a younger age and a higher probability of BP induced by tislelizumab than the non-Chinese patients.Unlike that in the non-Chinese patients,the primary tumor in the Chinese patients with ICI-induced BP is predominantly lung cancer.Pruritus is more obvious,and mucosal involvement is more common in the Chinese patients.Systemic corticosteroid therapy is the international standard treatment for ICI-induced BP,while tripterygium glycosides and dupilumab are characteristic therapies in China.</p>","PeriodicalId":6919,"journal":{"name":"中国医学科学院学报","volume":"46 6","pages":"872-882"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research Progress of Drugs in Prevention and Treatment of Nephrolithiasis.","authors":"Sha-Sha Xia, Jun Shen, Kai-Wen Shen, Qiang Wang, Wei-Hu Cen","doi":"10.3881/j.issn.1000-503X.15987","DOIUrl":"10.3881/j.issn.1000-503X.15987","url":null,"abstract":"<p><p>With the improvement of people's living standards,the incidence of nephrolithiasis is increasing year by year.Nephrolithiasis poses a serious threat to the patients due to the unclear etiology,complicated composition of stones,and high recurrence rate after surgery.As the research on the pathogenesis and pathophysiology of nephrolithiasis keeps deepening in recent years,researchers have made achievements in the drug treatment,which has become a hot topic for urologists.This paper reviews the advances in the research on the possible formation mechanism and drug-induced litholysis and prevention for nephrolithiasis,aiming to provide theoretical references for subsequent clinical research.</p>","PeriodicalId":6919,"journal":{"name":"中国医学科学院学报","volume":" ","pages":"918-923"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in the Pathogenesis of Hereditary Angioedema.","authors":"Xiang-Yi Cui, Yu-Xiang Zhi","doi":"10.3881/j.issn.1000-503X.15915","DOIUrl":"https://doi.org/10.3881/j.issn.1000-503X.15915","url":null,"abstract":"<p><p>Hereditary angioedema (HAE) is a rare,unpredictable,autosomal dominant disorder characterized by recurrent swelling in subcutaneous and submucosal tissue.In recent years,the pathophysiology and pathogenesis of HAE have been continuously studied and elucidated.In addition to the genes encoding complement 1 esterase inhibitors,new pathogenic variants have been identified in the genes encoding coagulation factor Ⅻ,plasminogen,angiopoietin-1,kininogen,heparan sulfate 3-O-sulfotransferase 6,and myoferlin in HAE.Moreover,different pathogenic variants have different mechanisms in causing HAE.In addition,the pathogenic genes of some patients remain unknown.This review summarizes the recent progress in the classification,epidemiology,pathophysiology,and pathogenesis of HAE,aiming to provide ideas for further fundamental research,clinical diagnosis,and drug development of HAE.</p>","PeriodicalId":6919,"journal":{"name":"中国医学科学院学报","volume":"46 6","pages":"924-931"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}