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Angela Vincent: a pioneer of immune-mediated disease. 安吉拉-文森特:免疫介导疾病的先驱。
IF 48 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-01 Epub Date: 2024-03-20 DOI: 10.1016/S1474-4422(24)00125-X
Jules Morgan
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引用次数: 0
Multiple sclerosis diagnosis: a biologically driven perspective. 多发性硬化症的诊断:生物学驱动的视角。
IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-01 DOI: 10.1016/S1474-4422(24)00207-2
Massimo Filippi, Monica Margoni, Maria A Rocca
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引用次数: 0
Safety and efficacy of stent retrievers plus contact aspiration in patients with acute ischaemic anterior circulation stroke and positive susceptibility vessel sign in France (VECTOR): a randomised, single-blind trial. 法国对急性缺血性前循环脑卒中且易感血管征阳性患者使用支架取出器加接触式抽吸的安全性和有效性(VECTOR):随机单盲试验。
IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-01 DOI: 10.1016/S1474-4422(24)00165-0
Romain Bourcier, Gaultier Marnat, Cyril Dargazanli, François Zhu, Arturo Consoli, Eimad Shotar, Kevin Premat, François Eugene, Kevin Janot, Vincent L'Allinec, Julien Ognard, Jean-Philippe Desilles, Raphael Blanc, Jean-Christophe Gentric, Frédéric Bourdain, Julien Labreuche, Liang Liao, Frédéric Clarençon, Xavier Barreau, Héloïse Ifergan, Jean-François Hak, Basile Kerleroux, Raoul Pop, Sébastien Soize, Nicolas Bricout, Jildaz Caroff, Johann Sebastian Richter, Hubert Desal, Bertrand Lapergue, Aymeric Rouchaud
<p><strong>Background: </strong>Positive susceptibility vessel sign (SVS) in patients with acute ischaemic stroke has been associated with friable red blood cell-rich clots and more effective recanalisation using stent retrievers versus contact aspiration. We compared the safety and efficacy of stent retrievers plus contact aspiration (combined technique) versus contact aspiration alone as the first-line thrombectomy technique in patients with acute ischaemic anterior circulation stroke and SVS-positive occlusions.</p><p><strong>Methods: </strong>Adaptive Endovascular Strategy to the Clot MRI in Large Intracranial Vessel Occlusion (VECTOR) was a prospective, randomised, open-label study with blinded evaluation. Patients with SVS-positive anterior circulation occlusions on pretreatment MRI and arterial puncture within 24 h of symptom onset were enrolled from 22 centres in France. A centralised web-based method was used by interventional neuroradiologists for dynamic randomisation by minimisation. Patients were randomly assigned 1:1 to the combined technique or contact aspiration alone. The primary outcome was expanded Thrombolysis in Cerebral Infarction (eTICI) grade 2c or 3 reperfusion after three or fewer passes on post-treatment angiogram, adjudicated by a blinded independent central imaging core laboratory. The intention-to-treat population was used to assess the primary and secondary outcomes. This trial is registered with ClinicalTrials.gov (NCT04139486) and is complete.</p><p><strong>Findings: </strong>Between Nov 26, 2019, and Feb 14, 2022, 526 patients were enrolled, of whom 521 constituted the intention-to-treat population (combined technique, n=263; contact aspiration alone, n=258). The median age of participants was 74·9 years (IQR 64·4-83·3); 284 (55%) were female and 237 (45%) male. The primary outcome did not differ significantly between groups (152 [58%] of 263 patients for the combined technique vs 135 [52%] of 258 for contact aspiration; odds ratio [OR] 1·27; 95% CI 0·88-1·83; p=0·19). Procedure-related adverse events occurred in 32 (12%) of 263 patients in the combined technique group and 27 (11%) of 257 in the contact aspiration group (OR 1·14; 0·65-2·00; p=0·65). The most common adverse event was intracerebral haemorrhage (146 [56%] of 259 patients for the combined technique vs 123 [49%] of 251 for contact aspiration; OR 1·32; 0·91-1·90; p=0·13). All-cause mortality at 3 months occurred in 57 (23%) of 251 patients in the combined technique group and 48 (19%) of 247 in the contact aspiration group (OR 1·19; 0·76-1·86; p=0·45), none of which was treatment-related.</p><p><strong>Interpretation: </strong>The results of the VECTOR trial do not show superiority of the combined stent retriever plus contact aspiration technique over contact aspiration alone in patients with SVS-positive occlusion with respect to achieving eTICI 2c-3 within three passes. These findings support the use of either the combined technique or contact aspirat
背景:急性缺血性卒中患者的易感血管征(SVS)阳性与富含易碎红细胞的血栓有关,使用支架取栓器与接触式抽吸相比,支架取栓器能更有效地再通血栓。在急性缺血性前循环卒中和 SVS 阳性闭塞患者中,我们比较了支架取出器加接触式抽吸(联合技术)与单独接触式抽吸作为一线血栓切除技术的安全性和有效性:大颅内血管闭塞血栓磁共振成像适应性血管内治疗策略(VECTOR)是一项前瞻性、随机、开放标签研究,采用盲法评估。法国的22个中心共招募了在核磁共振成像检查中SVS阳性的前循环闭塞患者,并在症状出现后24小时内进行了动脉穿刺。介入神经放射学专家采用基于网络的集中方法,以最小化的方式进行动态随机分配。患者以 1:1 的比例被随机分配到联合技术或单独接触抽吸技术中。主要结果是治疗后血管造影通过三次或三次以下,脑梗塞溶栓(eTICI)2c级或3级再灌注,由独立的盲法中央成像核心实验室裁定。采用意向治疗人群评估主要和次要结果。该试验已在ClinicalTrials.gov(NCT04139486)上注册,并已完成:2019年11月26日至2022年2月14日期间,共有526名患者入组,其中521人构成意向治疗人群(联合技术,n=263;单独接触吸引,n=258)。参与者的中位年龄为 74-9 岁(IQR 64-4-83-3);女性 284 人(55%),男性 237 人(45%)。两组患者的主要结果差异不大(263 名患者中有 152 [58%] 采用联合技术,258 名患者中有 135 [52%] 采用接触式抽吸;几率比 [OR] 1-27;95% CI 0-88-1-83;P=0-19)。在联合技术组的 263 名患者中,有 32 人(12%)发生了与手术相关的不良事件;在接触式抽吸组的 257 名患者中,有 27 人(11%)发生了与手术相关的不良事件(OR 1-14; 0-65-2-00; p=0-65)。最常见的不良事件是脑内出血(联合技术组 259 名患者中有 146 人[56%],接触抽吸组 251 名患者中有 123 人[49%];OR 1-32;0-91-1-90;P=0-13)。联合技术组 251 名患者中有 57 人(23%)在 3 个月后全因死亡,接触式抽吸组 247 名患者中有 48 人(19%)全因死亡(OR 1-19;0-76-1-86;P=0-45),其中无一例外与治疗相关:VECTOR试验结果表明,在SVS阳性闭塞患者中,联合支架牵引器加接触式抽吸技术在三次抽吸中达到eTICI 2c-3方面并不优于单独的接触式抽吸技术。这些研究结果支持将联合技术或单独接触式抽吸技术作为急性前循环卒中患者的初始血栓切除策略,这些患者在治疗前的磁共振成像中出现 SVS:Cerenovus.
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引用次数: 0
Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. 阿瑞莫司洛尔对早期肌萎缩侧索硬化症患者的安全性和疗效(ORARIALS-01):一项随机、双盲、安慰剂对照、多中心、三期试验。
IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-01 Epub Date: 2024-05-20 DOI: 10.1016/S1474-4422(24)00134-0
Michael Benatar, Thomas Hansen, Dror Rom, Marie A Geist, Thomas Blaettler, William Camu, Magdalena Kuzma-Kozakiewicz, Leonard H van den Berg, Raul Juntas Morales, Adriano Chio, Peter M Andersen, Pierre-Francois Pradat, Dale Lange, Philip Van Damme, Gabriele Mora, Mariusz Grudniak, Matthew Elliott, Susanne Petri, Nicholas Olney, Shafeeq Ladha, Namita A Goyal, Thomas Meyer, Michael G Hanna, Colin Quinn, Angela Genge, Lorne Zinman, Duaa Jabari, Christen Shoesmith, Albert C Ludolph, Christoph Neuwirth, Sharon Nations, Jeremy M Shefner, Martin R Turner, Joanne Wuu, Richard Bennett, Hoang Dang, Claus Sundgreen
<p><strong>Background: </strong>Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis.</p><p><strong>Methods: </strong>ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed.</p><p><strong>Findings: </strong>Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI -0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]).</p><p><strong>Interpretation: </strong>Arimoclomol did not improve efficacy ou
背景:肌萎缩侧索硬化症是一种进行性神经退行性疾病,会导致肌肉无力和呼吸衰竭。阿瑞莫司洛尔是一种热休克蛋白-70(HSP70)辅助诱导剂,在肌萎缩侧索硬化症动物模型中具有神经保护作用,其作用机制有多种,包括清除蛋白质聚集,这是散发性和家族性肌萎缩侧索硬化症的病理特征。我们旨在评估阿瑞莫司洛尔对肌萎缩侧索硬化症患者的安全性和有效性:ORARIALS-01 是一项跨国、随机、双盲、安慰剂对照、平行组试验,在欧洲和北美 12 个国家的 29 个中心进行。患者年龄在 18 岁或以上,符合埃尔埃斯科里亚尔临床可能、可能、实验室支持的可能、明确或家族性肌萎缩侧索硬化症标准;肌萎缩侧索硬化症功能评定量表-修订版得分在 35 分或以上;慢生命活动能力为根据患者年龄、身高和性别预测值的 70% 或以上。按照使用稳定剂量利鲁唑或未使用利鲁唑进行分层,患者被随机分配(2:1)至6个组块,接受枸橼酸阿瑞莫司唑口服液1200毫克/天(400毫克,每天三次)或安慰剂。随机序列由计算机集中生成。研究人员、研究人员和研究参与者均被蒙蔽,不知道治疗分配情况。主要结果是治疗76周后的功能和生存期综合评估(CAFS)排名得分。主要结果和安全性在修改后的意向治疗人群中进行分析。该试验已在 ClinicalTrials.gov 注册,编号为 NCT03491462,目前已完成:2018年7月31日至2019年7月17日期间,共筛选出287名患者,其中245人被纳入试验并随机分配。修改后的意向治疗人群包括 239 名患者(阿利莫司醇组 160 人,安慰剂组 79 人):其中男性 151 人(占 63%),女性 88 人(占 37%);平均年龄为 57-6 岁(SD 10-9)。76周的CAFS评分在组间无差异(阿利莫司莫尔组平均为0-51 [SD 0-29] ,安慰剂组为0-49 [0-28] ;P=0-62)。两组之间的克利夫三角洲比较值为 0-039 (95% CI -0-116 to 0-194)。两组患者的死亡比例相似:阿利莫司洛尔组 160 例患者中有 29 例(18%)死亡,安慰剂组 79 例患者中有 18 例(23%)死亡。大多数死亡原因是疾病进展。最常见的不良反应是胃肠道反应。与安慰剂组(41例[52%])相比,阿瑞莫司洛尔组(104例[65%])更常出现与治疗相关的不良事件,与安慰剂组(4例[5%])相比,阿瑞莫司洛尔组(26例[16%])更常导致治疗中断:与安慰剂相比,阿瑞莫司洛尔并未改善疗效。尽管现有的生物标志物数据不足以排除未来针对HSP反应的策略,但安全性数据表明,更高剂量的阿瑞莫司洛尔不会被耐受:Orphazyme.
{"title":"Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.","authors":"Michael Benatar, Thomas Hansen, Dror Rom, Marie A Geist, Thomas Blaettler, William Camu, Magdalena Kuzma-Kozakiewicz, Leonard H van den Berg, Raul Juntas Morales, Adriano Chio, Peter M Andersen, Pierre-Francois Pradat, Dale Lange, Philip Van Damme, Gabriele Mora, Mariusz Grudniak, Matthew Elliott, Susanne Petri, Nicholas Olney, Shafeeq Ladha, Namita A Goyal, Thomas Meyer, Michael G Hanna, Colin Quinn, Angela Genge, Lorne Zinman, Duaa Jabari, Christen Shoesmith, Albert C Ludolph, Christoph Neuwirth, Sharon Nations, Jeremy M Shefner, Martin R Turner, Joanne Wuu, Richard Bennett, Hoang Dang, Claus Sundgreen","doi":"10.1016/S1474-4422(24)00134-0","DOIUrl":"10.1016/S1474-4422(24)00134-0","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI -0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;Arimoclomol did not improve efficacy ou","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":" ","pages":"687-699"},"PeriodicalIF":46.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141088081","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}
引用次数: 0
Implementation research: an approach to overcoming the know-do gap. 实施研究:克服 "知与行 "差距的方法。
IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-01 DOI: 10.1016/S1474-4422(24)00219-9
Lesli E Skolarus, Linda S Williams
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引用次数: 0
Amyotrophic lateral sclerosis: a lesson in translation. 肌萎缩性脊髓侧索硬化症:一堂翻译课。
IF 48 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-01 Epub Date: 2024-05-20 DOI: 10.1016/S1474-4422(24)00223-0
Orla Hardiman
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引用次数: 0
Speculation on the transmissibility of Alzheimer's disease. 对阿尔茨海默病传播性的猜测。
IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-06-01 DOI: 10.1016/S1474-4422(24)00145-5
Alifiya Kapasi, Julie A Schneider
{"title":"Speculation on the transmissibility of Alzheimer's disease.","authors":"Alifiya Kapasi, Julie A Schneider","doi":"10.1016/S1474-4422(24)00145-5","DOIUrl":"10.1016/S1474-4422(24)00145-5","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":"23 6","pages":"555-556"},"PeriodicalIF":46.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140957995","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}
引用次数: 0
Elucidating a new path of CSF transport in the CNS. 阐明中枢神经系统 CSF 转运的新路径。
IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-06-01 DOI: 10.1016/S1474-4422(24)00164-9
Helene Benveniste, Jean-Leon Thomas
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引用次数: 0
RAB32 Ser71Arg in autosomal dominant Parkinson's disease: linkage, association, and functional analyses. 常染色体显性帕金森病中的 RAB32 Ser71Arg:联系、关联和功能分析。
IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-06-01 Epub Date: 2024-04-10 DOI: 10.1016/S1474-4422(24)00121-2
Emil K Gustavsson, Jordan Follett, Joanne Trinh, Sandeep K Barodia, Raquel Real, Zhiyong Liu, Melissa Grant-Peters, Jesse D Fox, Silke Appel-Cresswell, A Jon Stoessl, Alex Rajput, Ali H Rajput, Roland Auer, Russel Tilney, Marc Sturm, Tobias B Haack, Suzanne Lesage, Christelle Tesson, Alexis Brice, Carles Vilariño-Güell, Mina Ryten, Matthew S Goldberg, Andrew B West, Michele T Hu, Huw R Morris, Manu Sharma, Ziv Gan-Or, Bedia Samanci, Pawel Lis, Maria Teresa Periñan, Rim Amouri, Samia Ben Sassi, Faycel Hentati, Francesca Tonelli, Dario R Alessi, Matthew J Farrer
<p><strong>Background: </strong>Parkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play a part. The RAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. We aimed to explore genetic variability in RAB GTPases within cases of familial Parkinson's disease.</p><p><strong>Methods: </strong>We did whole-exome sequencing in probands from families in Canada and Tunisia with Parkinson's disease without a genetic cause, who were recruited from the Centre for Applied Neurogenetics (Vancouver, BC, Canada), an international consortium that includes people with Parkinson's disease from 36 sites in 24 countries. 61 RAB GTPases were genetically screened, and candidate variants were genotyped in relatives of the probands to assess disease segregation by linkage analysis. Genotyping was also done to assess variant frequencies in individuals with idiopathic Parkinson's disease and controls, matched for age and sex, who were also from the Centre for Applied Neurogenetics but unrelated to the probands or each other. All participants were aged 18 years or older. The sequencing and genotyping findings were validated by case-control association analyses using bioinformatic data obtained from publicly available clinicogenomic databases (AMP-PD, GP2, and 100 000 Genomes Project) and a private German clinical diagnostic database (University of Tübingen). Clinical and pathological findings were summarised and haplotypes were determined. In-vitro studies were done to investigate protein interactions and enzyme activities.</p><p><strong>Findings: </strong>Between June 1, 2010, and May 31, 2017, 130 probands from Canada and Tunisia (47 [36%] female and 83 [64%] male; mean age 72·7 years [SD 11·7; range 38-96]; 109 White European ancestry, 18 north African, two east Asian, and one Hispanic] underwent whole-exome sequencing. 15 variants in RAB GTPase genes were identified, of which the RAB32 variant c.213C>G (Ser71Arg) cosegregated with autosomal dominant Parkinson's disease in three families (nine affected individuals; non-parametric linkage Z score=1·95; p=0·03). 2604 unrelated individuals with Parkinson's disease and 344 matched controls were additionally genotyped, and five more people originating from five countries (Canada, Italy, Poland, Turkey, and Tunisia) were identified with the RAB32 variant. From the database searches, in which 6043 individuals with Parkinson's disease and 62 549 controls were included, another eight individuals were identified with the RAB32 variant from four countries (Canada, Germany, UK, and USA). Overall, the association of RAB32 c.213C>G (Ser71Arg) with Parkinson's disease was significant (odds ratio [OR] 13·17, 95% CI 2·15-87·23; p=0·0055; I<sup>2</sup>=99·96%). In the people who had the variant, Parkinson's disease presented at age 54·6 years (SD 12·75, range 31-81, n=16), and two-thirds
背景:帕金森病是一种进行性神经退行性疾病,其病因是多因素的,其中遗传风险因素起了一定作用。RAB GTPases 是 LRRK2 的调节因子和底物,而 LRRK2 基因的变异是帕金森病的重要风险因素。我们旨在探索家族性帕金森病病例中 RAB GTPases 的遗传变异:我们对来自加拿大和突尼斯无遗传病因的帕金森病家庭的原发性帕金森病患者进行了全外显子组测序,这些患者是从应用神经遗传学中心(加拿大不列颠哥伦比亚省温哥华市)招募的,该中心是一个国际联盟,包括来自 24 个国家 36 个地点的帕金森病患者。对 61 个 RAB GTP 酶进行了基因筛选,并对病例亲属中的候选变体进行了基因分型,以通过关联分析评估疾病的分离情况。此外,还对特发性帕金森病患者以及年龄和性别匹配的对照组进行了基因分型,以评估变体频率。所有参与者的年龄都在 18 岁或以上。利用从公开的临床基因组数据库(AMP-PD、GP2 和 100 000 基因组计划)和德国私人临床诊断数据库(图宾根大学)中获得的生物信息学数据,通过病例对照关联分析对测序和基因分型结果进行了验证。对临床和病理结果进行了总结,并确定了单倍型。还进行了体外研究,以调查蛋白质相互作用和酶活性:2010年6月1日至2017年5月31日期间,来自加拿大和突尼斯的130名受试者(47[36%]名女性和83[64%]名男性;平均年龄72-7岁[SD 11-7;范围38-96];109名白种欧洲血统、18名北非血统、2名东亚血统和1名西班牙血统)接受了全外显子组测序。发现了 15 个 RAB GTPase 基因变异,其中 RAB32 变异 c.213C>G(Ser71Arg)与 3 个家族中的常染色体显性帕金森病共患病(9 个患者;非参数连锁 Z score=1-95;p=0-03)。此外,还对 2604 名无血缘关系的帕金森病患者和 344 名匹配的对照者进行了基因分型,又发现了来自五个国家(加拿大、意大利、波兰、土耳其和突尼斯)的五名 RAB32 变异者。通过数据库搜索,共纳入了6043名帕金森病患者和62 549名对照者,又从4个国家(加拿大、德国、英国和美国)发现了8名RAB32变体患者。总体而言,RAB32 c.213C>G(Ser71Arg)与帕金森病的相关性显著(比值比 [OR] 13-17,95% CI 2-15-87-23;P=0-0055;I2=99-96%)。帕金森病患者的年龄为 54-6 岁(SD 12-75,范围 31-81,n=16),三分之二的患者有帕金森病家族史。RAB32 Ser71Arg 杂合子共享一个共同的单倍型,但渗透性不完全。一名患者的尸检结果显示,中脑和丘脑有稀疏的神经纤维缠结病变,但无路易体病变。在功能研究中,RAB32 Arg71 对 LRRK2 激酶的激活水平高于 RAB32 Ser71:RAB32 Ser71Arg是帕金森病的一种新型遗传风险因素,具有较低的渗透性。该变异在多个种族的帕金森病患者中发现,且具有相同的单倍型。体外检测显示,RAB32 Arg71 可激活 LRRK2 激酶,这表明家族性帕金森病的不同遗传原因具有相同的机制。RAB32 Ser71Arg 的发现还表明,帕金森病的几种遗传病因起源于控制细胞内免疫。在未来的转化研究中应考虑这种共同的病因,同时需要对RAB32 Ser71Arg的全球流行病学进行评估,以便为遗传咨询提供信息:美国国立卫生研究院、加拿大卓越研究教席计划、帕金森病科学联盟、迈克尔-J-福克斯帕金森病研究基金会和英国医学研究委员会。
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引用次数: 0
Safety and efficacy of inebilizumab for the treatment of neuromyelitis optica spectrum disorder: end-of-study results from the open-label period of the N-MOmentum trial. 伊维单抗治疗神经脊髓炎视谱系障碍的安全性和有效性:N-MOmentum试验开放标签期的研究结束结果。
IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-06-01 DOI: 10.1016/S1474-4422(24)00077-2
Bruce A C Cree, Ho Jin Kim, Brian G Weinshenker, Sean J Pittock, Dean M Wingerchuk, Kazuo Fujihara, Friedemann Paul, Gary R Cutter, Romain Marignier, Ari J Green, Orhan Aktas, Hans-Peter Hartung, Dewei She, William Rees, Michael Smith, Daniel Cimbora, Eliezer Katz, Jeffrey L Bennett
<p><strong>Background: </strong>Inebilizumab, an anti-CD19 B-cell-depleting antibody, demonstrated safety and efficacy in neuromyelitis optica spectrum disorder in the randomised controlled period of the N-MOmentum trial. Here, end-of-study data, including the randomised controlled period and open-label extension period, are reported.</p><p><strong>Methods: </strong>In the double-blind, randomised, placebo-controlled, phase 2/3 N-MOmentum trial, adults aged 18 years and older with an neuromyelitis optica spectrum disorder diagnosis, Expanded Disability Status Scale score of 8·0 or less, and history of either at least one acute inflammatory attack requiring rescue therapy in the past year or two attacks requiring rescue therapy in the past 2 years, were recruited from 81 outpatient specialty clinics or hospitals in 24 countries. Eligible participants were randomly assigned (3:1), using a central interactive voice system or interactive web response system, and a permuted block randomisation scheme (block size of 4), to receive intravenous inebilizumab (300 mg) or identical placebo on days 1 and 15 of the randomised period, which lasted up to 197 days. Participants and all study staff were masked to treatment assignment. The primary endpoint of the randomised period of the trial was time to onset of adjudicated neuromyelitis optica spectrum disorder attack on or before day 197. Participants in the randomised controlled period who had an adjudicated attack, completed 197 days in the study, or were in the randomised controlled period when enrolment stopped, could voluntarily enter the open-label period. In the open-label period, participants either initiated inebilizumab if assigned placebo (receiving 300 mg on days 1 and 15 of the open-label period) or continued treatment if assigned inebilizumab (receiving 300 mg on day 1 and placebo on day 15, to maintain B-cell depletion and masking of the randomised controlled period). All participants subsequently received inebilizumab 300 mg every 6 months for a minimum of 2 years. The end-of-study analysis endpoints were time to adjudicated attack and annualised attack rate (assessed in all participants who received inebilizumab at any point during the randomised controlled period or open-label period [any inebilizumab population] and the aquaporin-4 [AQP4]-IgG seropositive subgroup [any inebilizumab-AQP4-IgG seropositive population]) and safety outcomes (in all participants who were exposed to inebilizumab, analysed as-treated). This study is registered with ClinicalTrials.gov, NCT02200770, and is now complete.</p><p><strong>Findings: </strong>Between Jan 6, 2015, and Sept 24, 2018, 467 individuals were screened, 231 were randomly assigned, and 230 received at least one dose of inebilizumab (n=174) or placebo (n=56). Between May 19, 2015, and Nov 8, 2018, 165 (95%) of 174 participants in the inebilizumab group and 51 (91%) of 56 in the placebo group entered the open-label period (mean age 42·9 years [SD 12·4]
解读:N-MOmentum试验的研究末期分析数据显示,伊维单抗对神经脊髓炎视网膜频谱障碍患者的长期治疗具有持续的临床疗效,这支持了伊维单抗作为CD19+ B细胞耗竭疗法在神经脊髓炎视网膜频谱障碍中的作用:MedImmune 和 Viela Bio/Horizon Therapeutics(现为安进公司的一部分)。
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引用次数: 0
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Lancet Neurology
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