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Looking beyond the neurological diagnosis: considering frailty. 超越神经诊断:考虑虚弱。
IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-01 Epub Date: 2024-09-11 DOI: 10.1016/S1474-4422(24)00355-7
A Jon Stoessl
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引用次数: 0
On how a brain beholds beauty. 大脑如何看待美
IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-01 Epub Date: 2024-07-22 DOI: 10.1016/S1474-4422(24)00285-0
Rui Araújo
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引用次数: 0
Safety and efficacy of memantine and trazodone versus placebo for motor neuron disease (MND SMART): stage two interim analysis from the first cycle of a phase 3, multiarm, multistage, randomised, adaptive platform trial. 美金刚和曲唑酮与安慰剂治疗运动神经元疾病(MND SMART)的安全性和疗效:第三阶段、多臂、多阶段、随机、自适应平台试验第一周期的第二阶段中期分析。
IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-01 Epub Date: 2024-09-19 DOI: 10.1016/S1474-4422(24)00326-0
Suvankar Pal, Jeremy Chataway, Robert Swingler, Malcolm R Macleod, Neil O Carragher, Giles Hardingham, Bhuvaneish Thangaraj Selvaraj, Colin Smith, Charis Wong, Judith Newton, Dawn Lyle, Amy Stenson, Rachel S Dakin, Amarachi Ihenacho, Shuna Colville, Arpan R Mehta, Nigel Stallard, James R Carpenter, Richard A Parker, Catriona Keerie, Christopher J Weir, Bruce Virgo, Stevie Morris, Nicola Waters, Beverley Gray, Donald MacDonald, Euan MacDonald, Mahesh K B Parmar, Siddharthan Chandran
<p><strong>Background: </strong>Motor neuron disease represents a group of progressive and incurable diseases that are characterised by selective loss of motor neurons, resulting in an urgent need for rapid identification of effective disease-modifying therapies. The MND SMART trial aims to test the safety and efficacy of promising interventions efficiently and definitively against a single contemporaneous placebo control group. We now report results of the stage two interim analysis for memantine and trazodone.</p><p><strong>Methods: </strong>MND SMART is an investigator-led, phase 3, double-blind, placebo-controlled, multiarm, multistage, randomised, adaptive platform trial recruiting at 20 hospital centres in the UK. Individuals older than 18 years with a confirmed diagnosis of either amyotrophic lateral sclerosis classified by the revised El Escorial criteria, primary lateral sclerosis, progressive muscular atrophy, or progressive bulbar palsy, regardless of disease duration, were eligible for screening. Participants were randomised (1:1:1) to receive oral trazodone 200 mg once a day, oral memantine 20 mg once a day, or matched placebo using a computer-generated minimisation algorithm delivered via a secure web-based system. Co-primary outcome measures were clinical functioning, measured by rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R), and survival. Comparisons were conducted in four stages, with predefined criteria for stopping at the end of stages one and two. We report interim analysis from the stage two results, which was done when 100 participants per group (excluding long survivors, defined as >8 years since diagnosis at baseline) completed a minimum of 12 months of follow-up for the candidate investigational medicinal products. The trial is registered on the European Clinical Trials Registry, 2019-000099-41, and ClinicalTrials.gov, NCT04302870, and is ongoing.</p><p><strong>Findings: </strong>Between Feb 27, 2020, and July 24, 2023 (database lock for interim analysis two), 554 people with a motor neuron disease were randomly allocated to memantine (183 [33%]), trazodone (185 [33%]), or placebo (186 [34%]). The primary interim analysis population comprised 530 participants, of whom 175 (33%) had been allocated memantine, 175 (33%) had been allocated trazodone, and 180 (34%) had been allocated placebo. Over 12 months of follow-up, the mean rate of change per month in ALSFRS-R was -0·650 for memantine, -0·625 for trazodone, and -0·655 for placebo (memantine versus placebo estimated mean difference 0·033, one-sided 90% CI lower level -0·085; one-sided p=0·36; trazodone vs placebo: 0·065, -0·051; one-sided p=0·24). The one-sided p values were both above the significance threshold of 10%, indicating that neither memantine nor trazodone groups met the criteria for continuation. There were 483 participants with at least one adverse event (145 [77%] on placebo, 170 [91%] on memantine, and 168 [9
背景:运动神经元病是一组以运动神经元选择性丧失为特征的渐进性不治之症,因此迫切需要快速确定有效的疾病改变疗法。MND SMART 试验的目的是对照一个同期安慰剂对照组,高效、明确地测试有前景的干预措施的安全性和有效性。我们现在报告美金刚和曲唑酮的第二阶段中期分析结果:MND SMART是一项由研究者领导的第3阶段、双盲、安慰剂对照、多臂、多阶段、随机、适应性平台试验,在英国的20家医院中心进行招募。18岁以上确诊为肌萎缩侧索硬化症(根据修订后的埃斯科里亚尔标准分类)、原发性侧索硬化症、进行性肌萎缩或进行性球麻痹的患者,无论病程长短,均有资格参加筛选。采用计算机生成的最小化算法,通过安全的网络系统将参与者随机分配(1:1:1)为每天一次口服曲唑酮 200 毫克、每天一次口服美金刚 20 毫克或匹配的安慰剂。共同主要结局指标为临床功能(以肌萎缩侧索硬化症功能评定量表修订版(ALSFRS-R)的变化率衡量)和存活率。比较分四个阶段进行,并预先确定了在第一和第二阶段结束时停止比较的标准。我们报告的是第二阶段结果的中期分析,即每组 100 名参与者(不包括长期存活者,定义为自基线确诊后超过 8 年)完成至少 12 个月的候选研究药物随访。该试验已在欧洲临床试验注册中心(2019-000099-41)和ClinicalTrials.gov(NCT04302870)上注册,目前正在进行中:2020年2月27日至2023年7月24日(中期分析二的数据库锁定期),554名运动神经元病患被随机分配到美金刚(183人[33%])、曲唑酮(185人[33%])或安慰剂(186人[34%])中。主要中期分析人群包括530名参与者,其中175人(33%)被分配了美金刚,175人(33%)被分配了曲唑酮,180人(34%)被分配了安慰剂。在12个月的随访中,美金刚每月ALSFRS-R的平均变化率为-0-650,曲唑酮为-0-625,安慰剂为-0-655(美金刚与安慰剂的估计平均差异为0-033,单侧90% CI较低水平为-0-085;单侧P=0-36;曲唑酮与安慰剂的估计平均差异为0-065,-0-051;单侧P=0-24)。单侧P值均高于10%的显著性阈值,表明美金刚组和曲唑酮组均不符合继续治疗的标准。有 483 名参与者至少出现过一次不良事件(安慰剂组 145 人 [77%],美金刚组 170 人 [91%],曲唑酮组 168 人 [90%])。88名参与者至少出现过一次严重不良事件(美金刚37例[20%]、曲唑酮27例[14%]、安慰剂24例[13%])。共有 11 例严重不良事件导致治疗中止。美金刚组有49例死亡,曲唑酮组52例死亡,安慰剂组48例死亡:与安慰剂相比,美金刚和曲唑酮均未改善疗效。这一结果足以证明,在本研究评估的剂量下,不再对运动神经元疾病患者进行曲唑酮或美金刚试验。多臂多阶段设计在缩短时间、降低成本、减少参与人数以得出最终结果方面具有重要优势:资助机构:尤安-麦克唐纳中心、苏格兰 MND、我的名字叫多迪基金会和 Baillie Gifford。
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引用次数: 0
Evobrutinib in multiple sclerosis: challenges and unmet goals. Evobrutinib 在多发性硬化症中的应用:挑战与未实现的目标。
IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-01 Epub Date: 2024-09-19 DOI: 10.1016/S1474-4422(24)00391-0
Anneke van der Walt
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引用次数: 0
Safety and efficacy of evobrutinib in relapsing multiple sclerosis (evolutionRMS1 and evolutionRMS2): two multicentre, randomised, double-blind, active-controlled, phase 3 trials. evobrutinib治疗复发性多发性硬化症的安全性和疗效(evolutionRMS1和evolutionRMS2):两项多中心、随机、双盲、主动对照、3期试验。
IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-01 Epub Date: 2024-09-19 DOI: 10.1016/S1474-4422(24)00328-4
Xavier Montalban, Patrick Vermersch, Douglas L Arnold, Amit Bar-Or, Bruce A C Cree, Anne H Cross, Eva Kubala Havrdova, Ludwig Kappos, Olaf Stuve, Heinz Wiendl, Jerry S Wolinsky, Frank Dahlke, Claire Le Bolay, Li Shen Loo, Sathej Gopalakrishnan, Yann Hyvert, Andrija Javor, Hans Guehring, Nadia Tenenbaum, Davorka Tomic
<p><strong>Background: </strong>Evobrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, has shown preliminary efficacy in people with relapsing multiple sclerosis in a phase 2 trial. Here, we aimed to compare the safety and efficacy of evobrutinib with the active comparator teriflunomide in people with relapsing multiple sclerosis.</p><p><strong>Methods: </strong>EvolutionRMS1 and evolutionRMS2 were two multicentre, randomised, double-blind, double-dummy, active-controlled, phase 3 trials conducted at 701 multiple sclerosis centres and neurology clinics in 52 countries. Adults aged 18-55 years with relapsing multiple sclerosis (Expanded Disability Status Scale [EDSS] score of 0·0-5·5) were included. Participants were randomly assigned (1:1) using a central interactive web response system to receive either evobrutinib (45 mg twice per day with placebo once per day) or teriflunomide (14 mg once per day with placebo twice per day), all taken orally and in an unfasted state, with randomisation stratified by geographical region and baseline EDSS. All study staff and participants were masked to the study interventions. The primary endpoint for each study was annualised relapse rate based on adjudicated qualified relapses up to 156 weeks, assessed in the full analysis set (defined as all randomly assigned participants) with a negative binomial model. These studies are registered with ClinicalTrials.gov (NCT04338022 for evolutionRMS1 and NCT04338061 for evolutionRMS2, both are terminated).</p><p><strong>Findings: </strong>The primary analysis was done using data for 2290 randomly assigned participants collected from June 12, 2020, to Oct 2, 2023. 1124 participants were included in the full analysis set in evolutionRMS1 (560 in the evobrutinib group and 564 in the teriflunomide group) and 1166 in evolutionRMS2 (583 in each group). 751 (66·8%) participants were female and 373 (33·1%) were male in evolutionRMS1, whereas 783 (67·2%) were female and 383 (32·8%) were male in evolutionRMS2. Annualised relapse rate was 0·15 (95% CI 0·12-0·18 with evobrutinib vs 0·14 [0·11-0·18] with teriflunomide (adjusted RR 1·02 [0·75-1·39]; p=0·55) in evolutionRMS1 and 0·11 (0·09-0·13 vs 0·11 [0·09-0·13]; adjusted RR 1·00 [0·74-1·35]; p=0·51) in evolutionRMS2. The pooled proportion of participants with any treatment-emergent adverse event (TEAE) was similar between treatment groups (976 [85·6%] of 1140 with evobrutinib vs 999 [87·2%] of 1146 with teriflunomide). The most frequently reported TEAEs were COVID-19 (223 [19·6%] with evobrutinib vs 223 [19·5%] with teriflunomide), alanine aminotransferase increased (173 [15·2%] vs 204 [17·8%]), aspartate aminotransferase increased (110 [9·6%] vs 131 [11·4%]), and headache (175 [15·4%] vs 176 [15·4%]). Serious TEAE incidence rates were higher with evobrutinib than teriflunomide (86 [7·5%] vs 64 [5·6%]). Liver enzyme elevations at least 5 × upper limit of normal were more common with evobrutinib than with teriflunomide, particularly
背景埃沃布替尼是一种布鲁顿酪氨酸激酶(BTK)抑制剂,在一项二期试验中显示出对复发性多发性硬化症患者的初步疗效。在此,我们旨在比较 evobrutinib 与特立氟胺(teriflunomide)在复发性多发性硬化症患者中的安全性和有效性:EvolutionRMS1和evolutionRMS2是两项多中心、随机、双盲、双假、活性对照的3期试验,在52个国家的701个多发性硬化症中心和神经病学诊所进行。研究对象包括 18-55 岁的复发性多发性硬化症成人患者(扩展残疾状态量表 [EDSS] 评分为 0-0-5-5)。参与者通过中央交互式网络响应系统被随机分配(1:1)到埃沃布鲁替尼(45 毫克,每天两次,安慰剂每天一次)或特利福罗米(14 毫克,每天一次,安慰剂每天两次)治疗方案中,所有药物均在非禁食状态下口服,并按地理区域和基线 EDSS 进行分层。所有研究人员和参与者都对研究干预措施进行了蒙蔽。每项研究的主要终点均为年化复发率,以156周内判定的合格复发为基础,采用负二项模型对全部分析集(定义为所有随机分配的参与者)进行评估。这些研究已在 ClinicalTrials.gov 注册(evolutionRMS1 为 NCT04338022,evolutionRMS2 为 NCT04338061,两项研究均已终止):主要分析使用了从 2020 年 6 月 12 日至 2023 年 10 月 2 日收集的 2290 名随机分配参与者的数据。1124名参与者被纳入evolutionRMS1的完整分析集(evobrutinib组560人,特立氟胺组564人),1166名参与者被纳入evolutionRMS2的完整分析集(每组583人)。evolutionRMS1组有751人(66-8%)为女性,373人(33-1%)为男性;evolutionRMS2组有783人(67-2%)为女性,383人(32-8%)为男性。evobrutinib的年复发率为0-15(95% CI 0-12-0-18 vs 0-14 [0-11-0-18] teriflunomide(调整后RR 1-02 [0-75-1-39]; p=0-55),evolutionRMS1的年复发率为0-11(0-09-0-13 vs 0-11 [0-09-0-13]; 调整后RR 1-00 [0-74-1-35]; p=0-51),evolutionRMS2的年复发率为0-11(0-09-0-13 vs 0-11 [0-09-0-13]; 调整后RR 1-00 [0-74-1-35]; p=0-51)。各治疗组中出现任何治疗突发不良事件(TEAE)的总人数比例相似(埃沃布替尼治疗组1140人中有976人[85-6%],特立氟胺治疗组1146人中有999人[87-2%])。最常报告的TEAE为COVID-19(埃沃布替尼223 [19-6%] vs 特立氟胺223 [19-5%])、丙氨酸氨基转移酶升高(173 [15-2%] vs 204 [17-8%])、天冬氨酸氨基转移酶升高(110 [9-6%] vs 131 [11-4%])和头痛(175 [15-4%] vs 176 [15-4%])。evobrutinib的严重TEAE发生率高于特立氟胺(86 [7-5%] vs 64 [5-6%])。evobrutinib的肝酶升高至少为正常值上限的5倍,比特立氟胺更常见,尤其是在前12周(55 [5-0%] vs 9 [解释:evobrutinib的疗效比特立氟胺好,但肝酶升高至少为正常值上限的5倍:evobrutinib的疗效并不优于特立氟胺。总之,疗效和肝脏相关安全性研究结果均不支持在复发性多发性硬化症患者中使用evobrutinib:默克公司。
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引用次数: 0
Learning to be an adult with a disability. 学习成为一个有残疾的成年人。
IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-01 Epub Date: 2024-09-10 DOI: 10.1016/S1474-4422(24)00314-4
Jules Morgan
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引用次数: 0
Trial designs for motor neuron disease in the 21st century. 21 世纪运动神经元疾病的试验设计。
IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-01 Epub Date: 2024-09-19 DOI: 10.1016/S1474-4422(24)00353-3
Steve Vucic
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引用次数: 0
Equitable access to levetiracetam for people with epilepsy. 让癫痫患者公平获得左乙拉西坦。
IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-01 Epub Date: 2024-09-18 DOI: 10.1016/S1474-4422(24)00376-4
Arjune Sen, Neerja Chowdhary, Asma Hallab, Michele Romoli, J Helen Cross, Bernadette Cappello
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引用次数: 0
Frailty for neurologists: perspectives on how frailty influences care planning. 神经科医生的虚弱问题:关于虚弱如何影响护理规划的观点。
IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-01 Epub Date: 2024-09-11 DOI: 10.1016/S1474-4422(24)00291-6
Marco Canevelli, Caitlin Jackson-Tarlton, Kenneth Rockwood

The concept of frailty, now being adopted in most medical disciplines, is attracting growing interest in neurology. Every day, most neurologists care for patients with varying degrees of frailty, from very mild to very severe. Frailty exacerbates patients' health needs, complicates clinical decision making, and negatively affects their health outcomes. Increasing evidence suggests that frailty affects the risk, clinical presentation, and course of common age-related neurological disorders, including dementia, Parkinson's disease, stroke, and multiple sclerosis. Most neurologists should become familiar with assessing and measuring frailty. Doing so can provide information that is crucial for diagnosis, prognostication, and care planning. Consideration of frailty can help to elucidate the pathophysiological underpinnings of age-related neurological disorders, clarify the clinical validity and utility of candidate biomarkers, and identify novel therapeutic targets. Randomised controlled trials investigating late-life neurological diseases that address frailty have the potential to provide insight into these complex disorders.

虚弱(frailty)这一概念目前已被大多数医学学科所采用,在神经病学领域也引起了越来越多的关注。每天,大多数神经科医生都要照顾不同程度的虚弱患者,从非常轻微到非常严重不等。虚弱会加剧患者的健康需求,使临床决策复杂化,并对其健康结果产生负面影响。越来越多的证据表明,虚弱会影响常见的与年龄相关的神经系统疾病,包括痴呆症、帕金森病、中风和多发性硬化症的风险、临床表现和病程。大多数神经科医生都应熟悉评估和测量虚弱程度。这样做可以提供对诊断、预后和护理计划至关重要的信息。考虑虚弱问题有助于阐明与年龄相关的神经系统疾病的病理生理学基础,明确候选生物标志物的临床有效性和实用性,并确定新的治疗目标。针对虚弱状态的晚年神经系统疾病的随机对照试验有可能帮助人们深入了解这些复杂的疾病。
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引用次数: 0
RAB32 mutation in Parkinson's disease. 帕金森病中的 RAB32 基因突变。
IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1016/S1474-4422(24)00325-9
Pilar Gómez-Garre, Miguel Martín-Bórnez, Pablo Mir
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引用次数: 0
期刊
Lancet Neurology
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