Malignant Hyperthermia Susceptibility (MHS) is a pharmacogenetic disorder triggered by volatile anesthetics and muscle relaxants, leading to a hypermetabolic reaction in skeletal muscle that can be fatal if untreated. Diagnosis relies on an in vitro contracture test (IVCT) on muscle biopsy and/or genetic testing for pathogenic variants in the RYR1 gene, which accounts for most cases; less frequently, variants are found in CACNA1S and STAC3. However, unlike the IVCT, genetic testing is limited by the large number of RYR1 variants classified as of uncertain significance (VUS), preventing it from fully replacing the IVCT.
We report data from 250 MHS individuals followed over 20 years, in whom 100 RYR1 and 3 CACNA1S variants were identified. Among the RYR1 variants, 81 were previously reported and 19 were novel, all classified as VUS according to European Malignant Hyperthermia Group (EMHG) and Variant Curation Expert Panel (VCEP) criteria. Similarly, of the 3 CACNA1S variants, 1 was previously reported and 2 were classified as VUS.
The reporting of novel variants is crucial for improving the accuracy and consistency of variant classification, thereby supporting a more precise interpretation of their clinical significance.
{"title":"Identification of novel potentially causative RYR1 variants in individuals with malignant hyperthermia susceptibility","authors":"Daniela Rossi , Carlotta Pranzo , Sara Roccabianca , Lucia Galli , Alfredo Orrico , Giovanna Sorbello , Vincenzo Tegazzin , Pasquale D’Onofrio , Armando Fucci , Salvatore Quarta , Stefano Perni , Egidio Maria Rubino , Matteo Serano , Gianna Berti , Diego Lopergolo , Alessandro Malandrini , Filip Van Petegem , Vincenzo Sorrentino","doi":"10.1016/j.nmd.2025.106296","DOIUrl":"10.1016/j.nmd.2025.106296","url":null,"abstract":"<div><div>Malignant Hyperthermia Susceptibility (MHS) is a pharmacogenetic disorder triggered by volatile anesthetics and muscle relaxants, leading to a hypermetabolic reaction in skeletal muscle that can be fatal if untreated. Diagnosis relies on an <em>in vitro</em> contracture test (IVCT) on muscle biopsy and/or genetic testing for pathogenic variants in the <em>RYR1</em> gene, which accounts for most cases; less frequently, variants are found in <em>CACNA1S</em> and <em>STAC3</em>. However, unlike the IVCT, genetic testing is limited by the large number of <em>RYR1</em> variants classified as of uncertain significance (VUS), preventing it from fully replacing the IVCT.</div><div>We report data from 250 MHS individuals followed over 20 years, in whom 100 <em>RYR1</em> and 3 <em>CACNA1S</em> variants were identified. Among the <em>RYR1</em> variants, 81 were previously reported and 19 were novel, all classified as VUS according to European Malignant Hyperthermia Group (EMHG) and Variant Curation Expert Panel (VCEP) criteria. Similarly, of the 3 <em>CACNA1S</em> variants, 1 was previously reported and 2 were classified as VUS.</div><div>The reporting of novel variants is crucial for improving the accuracy and consistency of variant classification, thereby supporting a more precise interpretation of their clinical significance.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"58 ","pages":"Article 106296"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-10-24DOI: 10.1016/j.nmd.2025.106257
Leandre A. la Fontaine , Daniël van As , Guillaume Bassez , Nicholas E. Johnson , Catharina G. Faber , Peter A.C.’t Hoen , 287th ENMC workshop participants
The 287th ENMC International Workshop convened experts from ten countries to address the harmonization and federated analysis of Myotonic Dystrophy Type 1 (DM1) registries. With over 10,500 patients enrolled globally, registries remain fragmented, limiting their utility in modeling disease trajectories and supporting clinical trials. As new therapies enter advanced clinical testing, registries must evolve - not only to enable trial readiness but also to support downstream functions like pharmacovigilance. The workshop focused on four objectives: re-defining a core dataset, enabling FAIRification of registries, establishing federated analysis infrastructure, and developing longitudinal modeling strategies. Key outcomes included a revised core set of clinical and patient reported outcome measures that is feasible to collect in a routine care setting, strategies for FAIR data integration, and governance models for federated analysis. Pragmatic and interpretable statistical approaches such as latent variable modeling and unsupervised clustering were discussed, with key prediction targets identified across motor, cardiac, and pulmonary domains. The workshop emphasized the need for sustainable funding, patient-centered design, and international collaboration.
{"title":"287th ENMC international workshop: Harmonization and federated analysis of myotonic dystrophy registries to model heterogeneous disease trajectories. Hoofddorp, the Netherlands, 28–30 March 2025","authors":"Leandre A. la Fontaine , Daniël van As , Guillaume Bassez , Nicholas E. Johnson , Catharina G. Faber , Peter A.C.’t Hoen , 287th ENMC workshop participants","doi":"10.1016/j.nmd.2025.106257","DOIUrl":"10.1016/j.nmd.2025.106257","url":null,"abstract":"<div><div>The 287th ENMC International Workshop convened experts from ten countries to address the harmonization and federated analysis of Myotonic Dystrophy Type 1 (DM1) registries. With over 10,500 patients enrolled globally, registries remain fragmented, limiting their utility in modeling disease trajectories and supporting clinical trials. As new therapies enter advanced clinical testing, registries must evolve - not only to enable trial readiness but also to support downstream functions like pharmacovigilance. The workshop focused on four objectives: re-defining a core dataset, enabling FAIRification of registries, establishing federated analysis infrastructure, and developing longitudinal modeling strategies. Key outcomes included a revised core set of clinical and patient reported outcome measures that is feasible to collect in a routine care setting, strategies for FAIR data integration, and governance models for federated analysis. Pragmatic and interpretable statistical approaches such as latent variable modeling and unsupervised clustering were discussed, with key prediction targets identified across motor, cardiac, and pulmonary domains. The workshop emphasized the need for sustainable funding, patient-centered design, and international collaboration.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"58 ","pages":"Article 106257"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145584382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-11-25DOI: 10.1016/j.nmd.2025.106297
Eleonora Torchia , Werner Stenzel , Raphael Raspe , Hans-Hilmar Goebel , Udo Schneider , Martin Nielsen
We report the case of a 54-year-old male patient with Behçet Disease (BD) complicated by aseptic pyomyositis with features of medium vessel vasculitis. His clinical course was characterized by severe myalgia, a palpable mass in the left quadriceps, blistering and ulcerative skin lesions, and systemic inflammation. Laboratory tests revealed neutrophilic leukocytosis, markedly elevated C-reactive protein, and approximately 13-fold increased creatine kinase levels. MRI demonstrated diffuse and asymmetric skeletal muscle oedema in the lower limbs, suggestive of multifocal abscess-like lesions. Muscle biopsy revealed sterile pyomyositis with granulocytic-necrotizing infiltrates and fibrinoid vascular necrosis with massive endomysial inflammatory infiltration. Muscle symptoms responded well to high-dose corticosteroid therapy, while cutaneous ulcers were initially refractory and improved only after multiple immunosuppressive treatments. This case highlights the complexity of diagnosing and managing severe muscular involvement and treatment-resistant skin manifestations in the context of BD.
{"title":"Aseptic pyomyositis in Behçet’s disease: a case report and narrative review of muscle involvement phenotypes","authors":"Eleonora Torchia , Werner Stenzel , Raphael Raspe , Hans-Hilmar Goebel , Udo Schneider , Martin Nielsen","doi":"10.1016/j.nmd.2025.106297","DOIUrl":"10.1016/j.nmd.2025.106297","url":null,"abstract":"<div><div>We report the case of a 54-year-old male patient with Behçet Disease (BD) complicated by aseptic pyomyositis with features of medium vessel vasculitis. His clinical course was characterized by severe myalgia, a palpable mass in the left quadriceps, blistering and ulcerative skin lesions, and systemic inflammation. Laboratory tests revealed neutrophilic leukocytosis, markedly elevated C-reactive protein, and approximately 13-fold increased creatine kinase levels. MRI demonstrated diffuse and asymmetric skeletal muscle oedema in the lower limbs, suggestive of multifocal abscess-like lesions. Muscle biopsy revealed sterile pyomyositis with granulocytic-necrotizing infiltrates and fibrinoid vascular necrosis with massive endomysial inflammatory infiltration. Muscle symptoms responded well to high-dose corticosteroid therapy, while cutaneous ulcers were initially refractory and improved only after multiple immunosuppressive treatments. This case highlights the complexity of diagnosing and managing severe muscular involvement and treatment-resistant skin manifestations in the context of BD.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"58 ","pages":"Article 106297"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Primary desminopathies often present as myofibrillar myopathy with predominant dominant inheritance. There are only few reports of recessive desminopathies. Distinct muscle MRI features with predominant involvement of gluteus maximus, semitendinosus, sartorius, gracilis and peroneal muscles have been described in dominant desminopathies. We report five patients with recessive desminopathies carrying novel homozygous DES variants (c.1023+5G>A and c.958delG). All presented with features of congenital myasthenic syndrome since early childhood. Novel MRI features with fatty infiltration of gluteus medius/ minimus, adductor magnus, quadriceps femoris and hamstrings were noted. Gracilis and short head of biceps femoris were consistently spared. In the leg, in addition to peroneal muscle involvement, there was severe fatty atrophy of anterior leg muscles. There was also myoedema posterior leg compartment. Thus, this study expands the imaging features of desminopathies with myasthenic syndrome.
{"title":"Novel muscle MRI features in Desmin related myasthenic myopathy","authors":"Dipti Baskar , Seetam Kumar Tumulu , Kiran Polavarapu , Akshata Huddar , Gopikrishnan Unnikrishnan , Seena Vengalil , Saraswati Nashi , Vidya Nittur , Gautham Arunachal , Jitender Saini , Hanns Lochmuller , Atchayaram Nalini","doi":"10.1016/j.nmd.2025.106302","DOIUrl":"10.1016/j.nmd.2025.106302","url":null,"abstract":"<div><div>Primary desminopathies often present as myofibrillar myopathy with predominant dominant inheritance. There are only few reports of recessive desminopathies. Distinct muscle MRI features with predominant involvement of gluteus maximus, semitendinosus, sartorius, gracilis and peroneal muscles have been described in dominant desminopathies. We report five patients with recessive desminopathies carrying novel homozygous <em>DES</em> variants (c.1023+5G><em>A</em> and c.958delG). All presented with features of congenital myasthenic syndrome since early childhood. Novel MRI features with fatty infiltration of gluteus medius/ minimus, adductor magnus, quadriceps femoris and hamstrings were noted. Gracilis and short head of biceps femoris were consistently spared. In the leg, in addition to peroneal muscle involvement, there was severe fatty atrophy of anterior leg muscles. There was also myoedema posterior leg compartment. Thus, this study expands the imaging features of desminopathies with myasthenic syndrome.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"58 ","pages":"Article 106302"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-11-27DOI: 10.1016/j.nmd.2025.106300
Samna Haider , Ahmed Daud Siddiqui , Muhammad Asad , Marium Amjad , Nidal Bin Kamran , Hoor Ul Ain , Ayesha Khan , Hussain Haider Shah , Shahreena Athar Siddiqui , Amama Anis , Elsa Khan , Radeyah Waseem
Primary periodic paralysis (PPP) comprises inherited ion channelopathies, marked by episodic or sustained muscle weakness. Dichlorphenamide has been investigated as a treatment option, however existing studies report inconsistent and variable findings regarding its efficacy. To clarify these inconsistencies, we conducted a meta-analysis and systematic review evaluating its effectiveness in managing PPP. A comprehensive literature exploration was undertaken across multiple databases encompassing studies disseminated up to July 2025, assessing efficacy of dichlorphenamide in PPP. Primary outcomes encompassed mean changes in weekly attack frequency and severity-weighted scores. Meta-analysis was performed using RevMan, reporting mean differences (MD), statistical significance was ascribed to p-values < 0.05. Evidence certainty was evaluated using the GRADE framework. Clinically significant reductions in the frequency of weekly periodic paralytic attacks were observed in both the hyperkalemic and hypokalemic subgroups (MD -1.72, P-value: 0.01), as well as across the age subgroups, adolescents and adults (MD -0.95, P-value: <0.00001). Analysis of severity-weighted attack scores also revealed significant improvements across both etiological hyperkalemic and hypokalemic categories (MD -1.37, P-value: 0.002), and age-based subgroups (MD -1.28, P-value: <0.00001). Along with therapeutic benefits, some adverse effects were also associated with dichlorphenamide, such as paresthesias (p < 0.00001), cognitive disturbances (p: 0.008), dysgeusia (p: 0.01), and rash (p: 0.006). The GRADE analysis confirmed high-certainty evidence for primary outcomes, supporting dichlorphenamide’s consistent efficacy across etiologies and ages, though its side effects necessitate careful monitoring and counseling.
{"title":"Safety and efficacy of dichlorphenamide in patients with periodic paralysis: A systematic review and meta-analysis","authors":"Samna Haider , Ahmed Daud Siddiqui , Muhammad Asad , Marium Amjad , Nidal Bin Kamran , Hoor Ul Ain , Ayesha Khan , Hussain Haider Shah , Shahreena Athar Siddiqui , Amama Anis , Elsa Khan , Radeyah Waseem","doi":"10.1016/j.nmd.2025.106300","DOIUrl":"10.1016/j.nmd.2025.106300","url":null,"abstract":"<div><div>Primary periodic paralysis (PPP) comprises inherited ion channelopathies, marked by episodic or sustained muscle weakness. Dichlorphenamide has been investigated as a treatment option, however existing studies report inconsistent and variable findings regarding its efficacy. To clarify these inconsistencies, we conducted a meta-analysis and systematic review evaluating its effectiveness in managing PPP. A comprehensive literature exploration was undertaken across multiple databases encompassing studies disseminated up to July 2025, assessing efficacy of dichlorphenamide in PPP. Primary outcomes encompassed mean changes in weekly attack frequency and severity-weighted scores. Meta-analysis was performed using RevMan, reporting mean differences (MD), statistical significance was ascribed to p-values < 0.05. Evidence certainty was evaluated using the GRADE framework. Clinically significant reductions in the frequency of weekly periodic paralytic attacks were observed in both the hyperkalemic and hypokalemic subgroups (MD -1.72, P-value: 0.01), as well as across the age subgroups, adolescents and adults (MD -0.95, P-value: <0.00001). Analysis of severity-weighted attack scores also revealed significant improvements across both etiological hyperkalemic and hypokalemic categories (MD -1.37, P-value: 0.002), and age-based subgroups (MD -1.28, P-value: <0.00001). Along with therapeutic benefits, some adverse effects were also associated with dichlorphenamide, such as paresthesias (<em>p</em> < 0.00001), cognitive disturbances (p: 0.008), dysgeusia (p: 0.01), and rash (p: 0.006). The GRADE analysis confirmed high-certainty evidence for primary outcomes, supporting dichlorphenamide’s consistent efficacy across etiologies and ages, though its side effects necessitate careful monitoring and counseling.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"58 ","pages":"Article 106300"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-12-15DOI: 10.1016/j.nmd.2025.106308
{"title":"A New Chapter for Neuromuscular Disorders by C. Weihl","authors":"","doi":"10.1016/j.nmd.2025.106308","DOIUrl":"10.1016/j.nmd.2025.106308","url":null,"abstract":"","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"58 ","pages":"Article 106308"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-10-24DOI: 10.1016/j.nmd.2025.106254
Pingping Fang , Jingzhe Han , Yuhao Wu , Di An , Yi Bu , Guang Ji , Mingjuan Liu , Jinliang Deng , Xu Han , Hongran Wu , Shaojuan Ma , Xueqin Song
This study aimed to investigate the effect of serine and arginine rich splicing factor 2 (SRSF2) on myoblast autophagy in Duchenne muscular dystrophy (DMD). Protein expressions of SRSF2 and HUWE1, and mRNA expressions of SRSF2, HUWE1 isoform 1/2/3 (HUWE1-S1/S2/S3) were detected in mdx mice (DMD model). SRSF2, HUWE1-S1 and HUWE1-S2 overexpression plasmids, and SRSF2, HUWE1-S1 and HUWE1-S2 siRNAs were transfected into mouse myoblast C2C12 cells alone or in combination. SRSF2, HUWE1-S1, and HUWE1-S2, but not HUWE1-S3, were upregulated in mdx mice compared with control mice. In myoblasts, SRSF2 positively regulated HUWE1-S1 and HUWE1-S2 but less affected HUWE1-S3. RNA immunoprecipitation confirmed that SRSF2 protein directly bound to HUWE1-S1 and HUWE1-S2, but not HUWE1-S3. SRSF2 overexpression reduced myoblast autophagy reflected by lower LC3B(II/I) expression and autophagic flux, while higher p62 expression; however, SRSF2 siRNA revealed opposite effects. Moreover, SRSF2 overexpression decreased while siRNA increased autophagy in dystrophin-deficient myoblasts. HUWE1-S1 overexpression or siRNA did not alter autophagy or attenuated SRSF2’s effect on autophagy in myoblasts. Notably, HUWE1-S2 siRNA improved autophagy in myoblasts, and attenuated SRSF2 overexpression-mediated myoblast autophagy impairment; meanwhile, HUWE1-S2 overexpression revealed opposite effects. Conclusively, SRSF2 is upregulated in DMD mouse model and impairs myoblast autophagy through alterative splicing HUWE1.
{"title":"SRSF2 is upregulated in Duchenne muscular dystrophy and impairs myoblast autophagy by alternatively splicing HUWE1","authors":"Pingping Fang , Jingzhe Han , Yuhao Wu , Di An , Yi Bu , Guang Ji , Mingjuan Liu , Jinliang Deng , Xu Han , Hongran Wu , Shaojuan Ma , Xueqin Song","doi":"10.1016/j.nmd.2025.106254","DOIUrl":"10.1016/j.nmd.2025.106254","url":null,"abstract":"<div><div>This study aimed to investigate the effect of serine and arginine rich splicing factor 2 (SRSF2) on myoblast autophagy in Duchenne muscular dystrophy (DMD). Protein expressions of SRSF2 and HUWE1, and mRNA expressions of SRSF2, HUWE1 isoform 1/2/3 (HUWE1-S1/S2/S3) were detected in mdx mice (DMD model). SRSF2, HUWE1-S1 and HUWE1-S2 overexpression plasmids, and SRSF2, HUWE1-S1 and HUWE1-S2 siRNAs were transfected into mouse myoblast C2C12 cells alone or in combination. SRSF2, HUWE1-S1, and HUWE1-S2, but not HUWE1-S3, were upregulated in mdx mice compared with control mice. In myoblasts, SRSF2 positively regulated HUWE1-S1 and HUWE1-S2 but less affected HUWE1-S3. RNA immunoprecipitation confirmed that SRSF2 protein directly bound to HUWE1-S1 and HUWE1-S2, but not HUWE1-S3. SRSF2 overexpression reduced myoblast autophagy reflected by lower LC3B(II/I) expression and autophagic flux, while higher p62 expression; however, SRSF2 siRNA revealed opposite effects. Moreover, SRSF2 overexpression decreased while siRNA increased autophagy in dystrophin-deficient myoblasts. HUWE1-S1 overexpression or siRNA did not alter autophagy or attenuated SRSF2’s effect on autophagy in myoblasts. Notably, HUWE1-S2 siRNA improved autophagy in myoblasts, and attenuated SRSF2 overexpression-mediated myoblast autophagy impairment; meanwhile, HUWE1-S2 overexpression revealed opposite effects. Conclusively, SRSF2 is upregulated in DMD mouse model and impairs myoblast autophagy through alterative splicing HUWE1.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"58 ","pages":"Article 106254"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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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