Cerebellum最新文献

{"title":"Epidemiology of Autosomal Dominant Spinocerebellar Ataxias in Latin America: A Systematic Review and Meta-Analysis.","authors":"Milagros Galecio-Castillo, Jesus Gutierrez-Arratia, Alonso Abad-Murillo, Elison Sarapura-Castro, Ismael Araujo-Aliaga, Ana Saldarriaga-Mayo, Maryenela Illanes-Manrique, Mario Cornejo-Olivas","doi":"10.1007/s12311-025-01826-x","DOIUrl":"https://doi.org/10.1007/s12311-025-01826-x","url":null,"abstract":"<p><p>The Spinocerebellar Ataxias (SCAs) are a group of autosomal dominant neurodegenerative disorders characterized by progressive cerebellar ataxia, affecting motor coordination. SCAs are reported globally with large geographical and ethnic differences. This systematic review and meta-analysis aimed to update the frequency, and geographic distribution of SCAs in Latin America, including recently identified SCAs like SCA27B. We conducted a systematic search in PubMed, Scopus, LILACS, SciELO, and Web of Science databases, including studies published from inception to January 2025. We included 27 studies for the systematic review and 18 studies for the meta-analysis that met the inclusion criteria, representing a total of 5859 participants across eleven countries. Our meta-analysis revealed that about 50% (95% CI 26-74%) of hereditary ataxias in Latin America were confirmed to have a genetic diagnosis of SCA. The included participants with a known SCA have the following proportions: MJD/SCA3 (15%), SCA2 (11%), SCA7 (4%), SCA10 (3%), and SCA1 (3%). Geographic distributions were notable, MJD/SCA3 in Brazil, SCA2 in Cuba, Argentina and Mexico, SCA10 predominating in Peru, and SCA7 in Venezuela. Recently identified SCA types, like SCA27B and one case of SCA4, were identified in Brazil. In 22 countries there are no published studies on the epidemiology of SCAs. The distribution of SCAs in Latin America reflects the influence of historical migrations, founder effects, and ancestries, emphasizing regional heterogeneity. Our findings underscore the critical need for further epidemiological studies, particularly in understudied countries in the region.</p>","PeriodicalId":50706,"journal":{"name":"Cerebellum","volume":"24 3","pages":"75"},"PeriodicalIF":2.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143732850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pendular Nystagmus: a Novel Feature of ANO10-Related Disorders.","authors":"Thiago Yoshinaga Tonholo Silva, Vinícius Lopes Braga, Victor Rebelo Procaci, Luane Abdalla Gouvêa, Leonardo Furtado Freitas, Darine Christina Maia Villela, Michele Patricia Migliavacca, José Ricardo Magliocco Ceroni, André Macedo Serafim Silva, João Bosco Oliveira, Cláudia Ferreira da Rosa Sobreira, Orlando Graziani Povoas Barsottini, José Luiz Pedroso","doi":"10.1007/s12311-025-01828-9","DOIUrl":"https://doi.org/10.1007/s12311-025-01828-9","url":null,"abstract":"<p><p>ANO10-related ataxia is characterized by cerebellar and pyramidal signs, with prominent oculomotor abnormalities, including saccadic abnormalities, strabismus, and ptosis. While nystagmus is frequently observed, the specific subtype of horizontal pendular nystagmus has not been emphasized. This report describes two siblings with early-onset spastic-ataxia with horizontal pendular nystagmus, ultimately diagnosed with SCAR10. This report details the ocular abnormalities spectrum of ANO10-related ataxia by highlighting horizontal pendular nystagmus as a significant clinical feature in early-onset presentations. We also restate the importance of neurological examination, including detailed assessment of ocular movements, for accurate diagnosis and management of hereditary ataxias.</p>","PeriodicalId":50706,"journal":{"name":"Cerebellum","volume":"24 3","pages":"73"},"PeriodicalIF":2.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR-512-3p as a Potential Biomarker of Poor Outcome in Pediatric Medulloblastoma.","authors":"Carolina Alves Pereira Corrêa, Pablo Shimaoka Chagas, Mirella Baroni, Augusto Faria Andrade, Rosane Gomes de Paula Queiroz, Veridiana Kiill Suazo, Gustavo Alencastro Veiga Cruzeiro, Paola Fernanda Fedatto, David Santos Marco Antonio, Silvia Regina Brandalise, José Andres Yunes, Rodrigo Alexandre Panepucci, Carlos Gilberto Carlotti Junior, Ricardo Santos de Oliveira, Luciano Neder, Luiz Gonzaga Tone, Elvis Terci Valera, Carlos Alberto Scrideli","doi":"10.1007/s12311-025-01812-3","DOIUrl":"https://doi.org/10.1007/s12311-025-01812-3","url":null,"abstract":"<p><p>The tumorigenesis of medulloblastoma (MB), the most frequent malignant brain tumor in children, is not completely known. MicroRNA (miRNA) expression profiles have been associated with human cancers; however, the role played by miRNAs in pediatric MB has been poorly explored. Global miRNA expression in MB and non-neoplastic cerebellum samples was evaluated by microarray assay. Nine miRNAs (miR-31-5p, -329, -383, -433, -485-3p, -485-5p, -491, -512-3p, and 539-5p) in 51 pediatric MB and 7 pediatric non-neoplastic cerebellum samples were chosen for validation by qRT-PCR. The validated miRNAs were less expressed in the MB samples than in the non-neoplastic controls. In our cohort of patients, higher miR-512-3p expression was associated with incomplete degree of resection, classification as high risk, classification as group 4, and poor overall survival. In silico analysis in an independent cohort of MB patients identified that some of the miR-512-3p target genes were also correlated with prognostic features. Our results have shown that miR-512-3p could be associated with poor clinical outcomes in pediatric MB, suggesting that miR-512-3p is a potential biomarker of prognosis.</p>","PeriodicalId":50706,"journal":{"name":"Cerebellum","volume":"24 3","pages":"72"},"PeriodicalIF":2.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Smartphone Application for Spastic Ataxias Cross-Sectional Validation of a Newly Developed Smartphone App for Remote Monitoring in Spastic Ataxias.","authors":"Ilse H J Willemse, Sabato Mellone, Carlo Tacconi, Winfried Ilg, Rebecca Schüle, Matthis Synofzik, Jorik H Nonnekes, Bart P C van de Warrenburg","doi":"10.1007/s12311-025-01820-3","DOIUrl":"10.1007/s12311-025-01820-3","url":null,"abstract":"<p><p>Effective trial-planning in Spastic ataxias (SPAX) is impeded by the absence of validated outcome measures for detecting longitudinal changes. Digital outcome measures show promise, demonstrating sensitivity to disease severity changes in ataxia and strong correlations with clinical scales. The objective of this study was to develop a smartphone application for SPAX (SPAX-app) to obtain valid digital outcome measures for use in clinical trials. The app contains four tasks assessing gait, standing balance (stance), and finger and hand movements. We carried out a validation study in 22 SPAX patients and 10 controls. Subjects performed the tasks three times during one visit. In parallel, we performed Ambulatory Parkinson's Disease Monitoring (APDM) sensor recordings, Q-motor upper limb assessment, and the Scale for the Assessment and Rating of Ataxia (SARA). Significant correlations were found between the SPAX-app and APDM or Q-motor for step time (r = 0.91), all measures of stance (r = 0.51-0.87) and duration of hand alternation (r = 0.64). No significant correlations were found for variability measures (e.g. standard deviation of step time). All tasks of the SPAX-app, except for stance, can discriminate SPAX from controls and show moderate to high test-retest reliability (ICC 0.67-0.97). Significant correlations were found between SARA and step time (r = 0.70), inter-onset interval in finger tapping (r = 0.57), and duration of hand alternation (r = 0.65). The stance task did not show significant correlations with SARA. With the SPAX-app, we present a set of digital outcome measures for potential use in clinical trials. Longitudinal studies are needed to evaluate whether these measures can track disease progression.</p>","PeriodicalId":50706,"journal":{"name":"Cerebellum","volume":"24 3","pages":"71"},"PeriodicalIF":2.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11933166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduced Cerebellar Volumes Associate with P300 Amplitude Attenuation in Children with Clinical High Risk for Psychosis and Early Onset Psychosis.","authors":"Hanne van der Heijden, Hesham M Hamoda, Aliza Ray, Maria Goldman, Maya Golden, Kelsey Graber, Frank H Duffy, Eugene D'Angelo, Borjan Gagoski, Merve Koç Yekedüz, Carter R Petty, Jaymin Upadhyay, Joseph Gonzalez-Heydrich","doi":"10.1007/s12311-025-01822-1","DOIUrl":"https://doi.org/10.1007/s12311-025-01822-1","url":null,"abstract":"<p><p>Patients with psychotic illnesses, including early onset psychosis (EOP), often experience cognitive impairment. The cerebellum is critically involved in neurocognitive processes, yet possible regional alterations in the cerebellum and their associations with behavioral parameters remain largely unexplored in EOP. In this preliminary study, we aimed to investigate structural morphological properties of the cerebellum as well as the supratentorial brain, and how morphological changes in the central nervous system relate to neurocognitive performance in children with EOP and clinical high-risk for psychosis (CHR). We performed whole-brain structural magnetic resonance imaging (MRI) and voxel-based morphological analyses in children with EOP (N = 15), children with CHR (N = 11), and healthy controls (Con, N = 13). An auditory event-related potential (ERP) task to elicit a P300 response was also completed by a subset of children (N = 29) as a measure of neurocognitive functioning. Linear regression analyses were performed to explore relationships between cerebellar volume, cortical thickness, and P300 amplitudes. Volumetric reductions (Con > CHR > EOP) in bilateral Crus I, Crus II, lobule VI and VIIIa, left VIIIb, and right lobules V and IX of the cerebellum were observed (p < 0.05). This downward trend across study cohorts was also evident for rostral middle frontal cortical (RMFC) thickness, and for centroparietal P300 amplitudes. Significant positive correlations among P300 amplitudes and cerebellar volumes were observed (p < 0.05). Significant correlations between P300 amplitudes and RMFC thickness were not present. Robust morphological disruptions in cerebellar subdivisions and frontal subdivisions were quantified in children with EOP. Structural abnormalities in these regions, particularly in the cerebellum, may signify broader brain network disruptions, potentially contributing to neurocognitive dysfunction in EOP.</p>","PeriodicalId":50706,"journal":{"name":"Cerebellum","volume":"24 3","pages":"69"},"PeriodicalIF":2.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Review on Radiologic Hot Cross Bun Sign and Related Clinical Conditions.","authors":"Mehri Salari, Mohammad Golzarian, Kamran Rezaei, Masoud Etemadifar","doi":"10.1007/s12311-025-01830-1","DOIUrl":"https://doi.org/10.1007/s12311-025-01830-1","url":null,"abstract":"<p><p>The hot cross bun (HCB) sign is a cruciform-shaped hyperintensity on axial T2 weighted-image magnetic resonance imaging (MRI), mostly reported with multiple system atrophy (MSA). However, several other diagnoses were reported with this radiologic manifestation as well. This review investigates the wide spectrum of disorders in which the HCB sign has been reported as a positive radiologic manifestation. This narrative review was conducted using the PubMed database. Studies reporting the HCB sign in their manuscript are included in this manuscript. 83 studies with available full text met the inclusion criteria for this review. The total number of reported patients with HCB sign is addressed in the manuscript. In addition to MSA, the HCB sign has been reported in various other disorders, including spinocerebellar ataxia, malignancies, infections, autoimmune disorders, and some vascular and ischemic changes. Any disorder involving the pontocerebellar fibers can manifest the HCB sign following the gliosis changes or infarction-mediated damage to the region, whether due to gliosis changes. The range of diseases linked to the HCB sign is broader than previously recognized, as numerous disorders affect the transverse pontocerebellar fibers and cause radiologic HCB manifestation. MSA remains the most common condition; however, clinicians should consider alternate differential diagnoses in patients displaying the HCB sign in whom clinical presentation is not typical of MSA.</p>","PeriodicalId":50706,"journal":{"name":"Cerebellum","volume":"24 3","pages":"70"},"PeriodicalIF":2.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Rare Patient of SEZ6L2 Antibody-Associated Cerebellar Ataxia.","authors":"Chen-Hui Cao, Wen-Li Li, Yao Zhang, Ting Wei, Chun-Lin Yang, Xiao-Li Li, Bin Liu","doi":"10.1007/s12311-025-01824-z","DOIUrl":"https://doi.org/10.1007/s12311-025-01824-z","url":null,"abstract":"","PeriodicalId":50706,"journal":{"name":"Cerebellum","volume":"24 3","pages":"68"},"PeriodicalIF":2.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Spectrum of Peripheral-Vestibular Deficits and Their Change Over Time in CANVAS/RFC1-Related Ataxia Systematic Review and Meta-Analysis of Quantitative Head-Impulse Testing.","authors":"Maja Szymanska Heydel, Felix Heindl, Annette Hartmann, Max Borsche, Andreas Traschütz, Dominik Straumann, Michael Strupp, Alexander Andrea Tarnutzer","doi":"10.1007/s12311-025-01825-y","DOIUrl":"10.1007/s12311-025-01825-y","url":null,"abstract":"<p><p>Cerebellar ataxia, neuropathy, vestibular-areflexia syndrome (CANVAS) has been linked to biallelic intronic repeat-expansions in RFC1. Video-head-impulse testing (vHIT) offers a quantitative assessment of the angular vestibulo-ocular reflex (aVOR) of all three canals. We evaluated patterns of peripheral-vestibular impairment, its change over time and evaluated correlations with other parameters. PubMed/Embase were searched for articles reporting vHIT in patients with CANVAS/RFC1-related ataxia. A multiple linear-regression model was used to analyse relationships between vHIT-gains and clinical parameters (age, disease duration, sex, biallelic RFC1 expansion). A special focus was put on sequential vHIT in individual patients. 23/64 studies met inclusion criteria; additional 13 studies were identified through reference screening. Twenty-five studies reported individual vHIT-gains and demographic data, suitable for quantitative analysis. Substantial aVOR-gain reductions were found for horizontal (0.32 ± 0.02, n = 146 patients), anterior (0.39 ± 0.03, n = 27) and posterior (0.29 ± 0.03, n = 27) canals. Linear regression showed an association between horizontal vHIT-gains (n = 146 patients; range of gain: 0-1.3) and disease duration (range: 0-444 months, coef. =-0.0048, p = 0.031) and male sex (coef. =-0.1604, p < 0.001). A decline in horizontal-canal vHIT-gains at least one side over time was noted in 15/21 patients after a mean follow-up time of 33.4 ± 10.7 months. vHIT is a potential biomarker for monitoring progression of CANVAS/RFC1-related ataxia. The significant association between reduced vHIT-gains and disease duration, and their intra-individual decline over time emphasize that impairment of the aVOR reflects the underlying neurodegenerative disease process. Multi-centre prospective studies are needed for systematic early screening and longitudinal validation as outcome for future targeted therapy trials.</p>","PeriodicalId":50706,"journal":{"name":"Cerebellum","volume":"24 3","pages":"67"},"PeriodicalIF":2.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validation of the Italian Version of the Scale for the Assessment and Rating of Ataxia (SARA) in Multiple Sclerosis: A Cross-Sectional Study.","authors":"Giovanni Sellitto, Serena D'Aniello, Emanuele Amadio, Francescaroberta Panuccio, Andrea Marini Padovani, Rachele Simeon, Anna Berardi, Giovanni Galeoto, Ilaria Ruotolo","doi":"10.1007/s12311-025-01813-2","DOIUrl":"10.1007/s12311-025-01813-2","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is a chronic neurodegenerative disorder often associated with cerebellar ataxia. Accurate assessment of ataxia is crucial for monitoring disease progression and guiding rehabilitation. The Scale for the Assessment and Rating of Ataxia (SARA) is a clinician-reported outcome measure (ClinRO) designed to evaluate ataxia severity. This study aimed to translate, culturally adapt, and validate the Italian version of SARA in individuals with MS. This study follows a cross-sectional design and was conducted at the Neurorehabilitation Unit of Sapienza University of Rome. The translation followed ISPOR and ISOQOL guidelines to ensure linguistic and cultural equivalence. Psychometric properties evaluation included internal consistency (Cronbach's alpha), test-retest reliability (intraclass correlation coefficient [ICC]), construct validity (correlation with Berg Balance Scale [BBS], Mini-Balance Evaluation Systems Test [Mini-BESTest], and Timed Up and Go [TUG] test), and cross-cultural validity. Seventy-five MS patients (EDSS ≤ 6.5) were recruited. The Italian SARA version demonstrated excellent internal consistency (Cronbach's alpha = 0.855) and test-retest reliability (ICC = 0.993). Strong negative correlations were found with BBS (r = -0.838, p < 0.001) and Mini-BESTest (r = -0.767, p < 0.001), supporting construct validity. Significant differences emerged based on age, employment status, and EDSS scores. The Italian SARA is a valid and reliable tool for assessing ataxia severity in MS. Its strong psychometric properties support its use in clinical and research settings. Future studies should explore its responsiveness to rehabilitation interventions.</p>","PeriodicalId":50706,"journal":{"name":"Cerebellum","volume":"24 3","pages":"66"},"PeriodicalIF":2.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11922968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel C1A Domain Variant in Protein Kinase Cγ in Spinocerebellar Ataxia Type 14 Decreases Autoinhibition.","authors":"Gayatri Raj Ghosh, Tiffany H Kao, Connolly G Steigerwald, Nora L Chan, Alexandra C Newton, Nicolas J Abreu","doi":"10.1007/s12311-025-01818-x","DOIUrl":"10.1007/s12311-025-01818-x","url":null,"abstract":"<p><p>Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant neurodegenerative disorder characterized by adult-onset cerebellar ataxia, and occasionally pyramidal signs, cognitive changes, sensory changes, myoclonus, and tremor. SCA14 results from heterozygous gain-of-function pathogenic variants in PRKCG, which encodes protein kinase Cγ. The aim was to elucidate the molecular mechanism of disease in a 60-year-old man with SCA14 due to a novel heterozygous variant in PRKCG c.154T > C p.(C52R). Next-generation sequencing was completed in the proband, targeted variant analysis was conducted in his family, and biochemical functional assays were performed. The C52R variant segregated with disease. Like other C1A domain variants, it had increased basal activity yet was unresponsive to agonist stimulation and was relatively resistant to down-regulation. This expands the genetic landscape of SCA14 and supports the condition as a gain-of-function disease, with variants in the C1A domain having leaky activity yet unresponsiveness to agonist stimulation.</p>","PeriodicalId":50706,"journal":{"name":"Cerebellum","volume":"24 3","pages":"65"},"PeriodicalIF":2.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}